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PROGRESS TOWARD THE TOTAL SYNTHESIS OF THE HIGHLY
SELECTIVE CYTOTOXIC NATURAL PRODUCT, MAOECRYSTAL V
by
Tsuhen Michelle Chang
_________________________ Copyright © Tsuhen Michelle Chang
A Dissertation Submitted to the Faculty of
DEPARTMENT OF CHEMISTRY AND BIOCHEMISTRY
In Partial Fulfillment of the Requirements for the Degree of
DOCTOR OF PHILOSOPHY
WITH A MAJOR IN CHEMISTRY
In the Graduate College
THE UNIVERSITY OF ARIZONA
2012
2
THE UNIVERSITY OF ARIZONA
GRADUATE COLLEGE As members of the Dissertation Committee, we certify that we have read the dissertation prepared by Tsuhen Michelle Chang entitled Progress Toward the Total Synthesis of the Highly Selective Cytotoxic Natural Product, Maoecrystal V and recommend that it be accepted as fulfilling the dissertation requirement for the Degree of Doctor of Philosophy ___________________________________________________ Date: 04/11/12 Dr. Hamish Christie ___________________________________________________ Date: 04/11/12 Dr. Ann Walker ___________________________________________________ Date: 04/11/12 Dr. John Jewett ___________________________________________________ Date: 04/11/12 Dr. Dennis Lichtenberger Final approval and acceptance of this dissertation is contingent upon the candidate's submission of the final copies of the dissertation to the Graduate College. I hereby certify that I have read this dissertation prepared under my direction and recommend that it be accepted as fulfilling the dissertation requirement. ____________________________________________________Date: 04/11/12 Dissertation Director: Dr. Hamish Christie
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STATEMENT BY AUTHOR This dissertation has been submitted in partial fulfillment of requirements for an advanced degree at the University of Arizona and is deposited in the University Library to be made available to borrowers under rules of the Library. Brief quotations from this dissertation are allowable without special permission, provided that accurate acknowledgment of source is made. Requests for permission for extended quotation from or reproduction of this manuscript in whole or in part may be granted by the copyright holder. SIGNED: Tsuhen Michelle Chang
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TABLE OF CONTENTS
LIST OF FIGURES ............................................................................................... 8
LIST OF TABLES .................................................................................................. 9
LIST OF SCHEMES ............................................................................................ 10
ABSTRACT ......................................................................................................... 18
CHAPTER 1 – THE BACKGROUND .................................................................. 19
1.1 Total synthesis .......................................................................................... 19
1.2 Maoecrystal V – A natural product ............................................................ 21
1.2.1 Kauranes and ent-kauranes – a general class of molecules ........... 21
1.2.2 Isolation and structure determination of maoecrystal V ................... 24
1.2.3 Biological activity of maoecrystal V ................................................. 26
1.2.4 Proposed biosynthesis of maoecrystal V ......................................... 26
1.3 Reported synthetic strategies towards maoecrystal V .............................. 28
1.3.1 The Baran strategy .......................................................................... 29
1.3.2 The Yang strategy ........................................................................... 32
1.3.3 The Nicolaou strategy ..................................................................... 36
1.3.4 The Singh strategy .......................................................................... 40
1.3.5 The Thomson strategy .................................................................... 42
1.3.6 The Trauner strategy ....................................................................... 47
1.3.7 The Danishefsky strategy ................................................................ 51
1.3.8 The Zakarian strategy ..................................................................... 56
1.3.9 The Chen strategy ........................................................................... 60
5
TABLE OF CONTENTS – Continued
1.3.10 The Sorensen strategy .................................................................. 63
1.4 Summary and overview of the synthetic approaches to maoecrystal V .... 68
CHAPTER 2 – THE PLAN .................................................................................. 69
2.1 Planning a synthetic route to maoecrystal V ............................................. 69
2.1.1 Key transformations – The details ................................................... 71
2.1.2 The orthoester strategy ................................................................... 72
2.2 The proposed tandem Michael-Aldol ........................................................ 73
2.2.1 Control of diastereoselectivity ......................................................... 73
CHAPTER 3 – FORMATION OF THE CYCLOHEXENONE INTERMEDIATE ... 75
3.1 Initial attempts to form the orthoester intermediate 3.1 ............................. 75
3.2 Formation of the -unsaturated cyclohexenone ..................................... 78
3.3 Initial steps to form the nitrile intermediate ................................................ 79
3.4 Attempts to functionalize the nitrile ........................................................... 82
3.5 Completion of the cyclohexenone ............................................................. 85
3.6 Use of the Horner-Wadsworth-Emmons (HWE) reaction as alternative
strategy .................................................................................................... 88
CHAPTER 4 – EXPORING THE MICHAEL-ALDOL REACTION........................ 94
4.1 Attempts to achieve 1,4-addition ............................................................... 94
4.2 Initial studies using the pyruvate fragment ............................................... 95
4.2.1 Organolithium reagents ................................................................... 95
6
TABLE OF CONTENTS – Continued
4.2.2 Silyl enol ether reagents .................................................................. 96
4.2.3 Attempts using iminium and enamine chemistry ............................. 98
4.2.4 Organozinc, organocopper and organocuprate investigations ...... 100
4.2.5 The use of vinyl rather than allylic substrates ................................ 111
4.3 Testing the aldol reaction to form the bicyclo[2.2.2]octane ..................... 116
4.4 Model compound studies – Replacement of the ketoester ..................... 117
4.5 Exploring the aldol reaction using the modified substrate ....................... 124
4.6 Obtaining the bicyclo[2.2.2]octane intermediate ..................................... 130
CHAPTER 5 – A MODIFIED STRATEGY ......................................................... 133
5.1 A modified strategy toward maoecrystal V .............................................. 133
5.1.1 Modifications of the original synthetic route ................................... 138
5.1.2 Modified intramolecular tandem Michael-aldol reaction – the new key
transformation ................................................................................................... 143
5.2 Further functionalization – Addition to the ketone ................................... 147
5.3 Investigations into an appropriate protecting group ................................ 148
5.4 Investigations into an appropriate nucleophile ........................................ 149
5.5 Investigation of the oxidative cleavage of the alkynyl substitutent and
subsequent lactone formation ................................................................ 153
5.6 Concurrent investigation of the furanoid ring formation and reverse
prenylation .............................................................................................. 155
7
TABLE OF CONTENTS – Continued
5.7 Further elaboration of the advanced intermediates ............................. 167
CHAPTER 6 – FUTURE WORK ....................................................................... 173
6.1 Outline of route for completion of maoecrystal V .................................... 173
6.2 An Enantioselective Synthesis ................................................................ 175
6.2.1 Trials with an enantioselective Michael-aldol reaction ................... 175
6.2.2 Desymmetrization.......................................................................... 176
APPENDIX A .................................................................................................... 180
A.1 Experimental – Reactions in Chapter 3 .................................................. 181
A.1.1 Spectra of Compounds from Chapter 3 ........................................ 210
B.1 Experimental – Reactions in Chapter 4 .................................................. 247
B.1.1 Spectra of Compounds from Chapter 4 ........................................ 288
C.1 Experimental – Reactions in Chapter 5 .................................................. 336
C.1.1 Spectra of Compounds from Chapter 5 ........................................ 371
REFERENCES ................................................................................................. 412
8
LIST OF FIGURES
Figure 1.1 – The Core Structure of Kaurane/ent-Kaurane .................................. 21
Figure 1.2 – A Sampling of Compounds in the Kaurane Family ......................... 22
Figure 1.3 – Standard Numbering for ent-Kaurene Type Structures .................. 23
Figure 1.4 – Maoecrystal V with -Unsaturation Highlighted and Standard
Numbering of Carbon Framework ....................................................................... 23
Figure 1.5 – X-ray Crystal Structure of Maoecrystal V ....................................... 25
Figure 2.1 – The Bicyclo[2.2.2]octane Intermediate ............................................ 70
Figure 3.1 – The -Unsaturated Cyclohexenone, a Key Intermediate ............. 76
Figure 4.1 – Maoecrystal V and the Aldol Product ............................................ 118
Figure 4.2 – Model System Compared to Actual Orthoester Containing
System .............................................................................................................. 118
Figure 4.3 – Further Evidence of Configuration Assignment ............................. 122
Figure 5.1 – Stereochemical Outcome of the Michael-aldol Reaction Confirmed
by X-ray Crystal Structure ................................................................................. 146
Figure 5.2 – The Last Congested Carbon-Carbon Bond Formation Needed .... 156
Figure 5.3 – X-ray Crystal Structure of Furanoid Ring Intermediate 5.49 ......... 158
Figure 5.4 – X-ray Crystal Structure of Lactone Ring Intermediate 5.64 ........... 166
9
LIST OF TABLES
Table 1.1 – IC50 of Maoecrystal V and cis-Platin ................................................. 26
Table 4.1 – Investigation into Organocopper Reaction Conditions ................... 106
Table 4.2 – Investigations of Substrates for the Aldol Ring Closure Reaction .. 131
Table 5.1 – Investigation of Optimal Conditions for Double Cyclization ............ 145
10
LIST OF SCHEMES
Scheme 1.1 - Sun et al. Proposed Bio-synthetic Conversion of epi-Eriocalyxin A
to Maoecrystal V ................................................................................................. 27
Scheme 1.2 - Sun et al. Proposed Bio-synthetic Conversion of 7,20-epoxy-ent-
kaurane to the Maoecrystal V Carbon Framework .............................................. 28
Scheme 1.3 – Baran’s Model Study .................................................................... 29
Scheme 1.4 – Synthesis of the IMDA Intermediate ............................................. 30
Scheme 1.5 – Baran’s IMDA Reaction ................................................................ 31
Scheme 1.6 – Synthesis of Phenol Intermediate 1.33 ........................................ 33
Scheme 1.7 – The Key IMDA Reaction .............................................................. 34
Scheme 1.8 – Completion of the Total Synthesis of Maoecrystal V .................... 35
Scheme 1.9 – Nicolaou’s Syntheis of an IMDA Intermediate .............................. 37
Scheme 1.10 – Nicolaou’s IMDA Reaction ......................................................... 37
Scheme 1.11 – The Intramolecular Cyclopropanation/Fragmentation ................ 38
Scheme 1.12 – Construction of the Pentacyclic Lactone .................................... 39
Scheme 1.13 – Synthesis of the Aromatic Precursor .......................................... 41
Scheme 1.14 – Oxidative Dearomatization and IMDA ........................................ 41
Scheme 1.15 – Synthesis of Singh’s Tricyclic Intermediate ................................ 42
Scheme 1.16 – Synthesis of Thomson’s Tetracyclic Intermediate ...................... 43
Scheme 1.17 – An Attempt to Form the Furanoid Ring ...................................... 44
Scheme 1.18 – An Attempt to Form the Lactone Ring ........................................ 45
Scheme 1.19 – An Attempt to Form the Lactone Ring ........................................ 46
11
LIST OF SCHEMES – Continued
Scheme 1.20 – Trauner’s First-Generation Approach to Maoecrystal V ............. 48
Scheme 1.21 – Overcoming the Undesired Stereoselectivity ............................. 49
Scheme 1.22 – Stepwise Approach to Aldol Addition ......................................... 50
Scheme 1.23 – Trauner’s Investigation of the Reverse Prenylation ................... 51
Scheme 1.24 – Danishefsky’s Original IMDA Route ........................................... 52
Scheme 1.25 – Danishefsky’s Synthesis of a Precursor for IMDA ...................... 52
Scheme 1.26 – Danishefsky’s Modified IMDA .................................................... 53
Scheme 1.27 – Attempts toward Stereoselective Furanoid Ring Formation ....... 54
Scheme 1.28 – Methodology for Epimerization at C-5 ........................................ 55
Scheme 1.29 – Zakarian’s Formation of the Furanoid Ring ................................ 57
Scheme 1.30 – Formation of the IMDA Substrate (Zakarian) ............................. 58
Scheme 1.31 – The IMDA Reaction - Forming Zakarian’s Advanced Inter-
mediate ............................................................................................................... 59
Scheme 1.32 – Installation of the gem-Dimethyl Groups and Lactone Ring ....... 60
Scheme 1.33 – Lactone Ring Formation ............................................................. 61
Scheme 1.34 – Reversal of C-5 Stereochemistry ............................................... 62
Scheme 1.35 – Proposed Cascade Reaction ..................................................... 64
Scheme 1.36 – Proposed 1,5-Hydride Shift ........................................................ 65
Scheme 1.37 – Diels-Alder Reaction – Sorensen’s Version ............................... 65
Scheme 1.38 – Formation of the Allenone Intermediate ..................................... 67
Scheme 2.1 – The Proposed Synthetic Plan ...................................................... 69
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LIST OF SCHEMES – Continued
Scheme 2.2 – The Proposed Tandem Michael-aldol Reaction ........................... 71
Scheme 2.3 – The Key Transformation .............................................................. 71
Scheme 2.4 – Proposed Result of Opening the Orthoester ................................ 72
Scheme 2.5 – Chelation Control Model in the Tandem Michael-aldol Reaction . 73
Scheme 3.1 – Key Transformation Under Investigation ...................................... 75
Scheme 3.2 – First Attempt at Cyclohexenone Intermediate Synthesis .............. 76
Scheme 3.3 – Investigation of the Tollens Reaction for Triol Formation ............. 77
Scheme 3.4 – Formation of Pentaerythritol via a Tollens Condensation
Reaction .............................................................................................................. 77
Scheme 3.5 – Envisioned Routes to Intermediate 3.10 ..................................... 79
Scheme 3.6 – Formation of the Orthoester Alcohol ............................................ 80
Scheme 3.7 – Further Functionalization of the Orthoester Intermediate ............. 81
Scheme 3.8 – Plan for Organometallic Addition to the Nitrile ............................. 83
Scheme 3.9 – Orthoester Hydrolysis Investigations ............................................ 84
Scheme 3.10 – Incomplete Basic Hydrolysis ..................................................... 85
Scheme 3.11 – Completion of the Orthoester Cyclohexenone Intermediate ...... 86
Scheme 3.12 – Details of Vinyl Magnesium Bromide Addition ........................... 87
Scheme 3.13 – Allylmagnesium bromide Avoids Side-product Formation .......... 87
Scheme 3.14 – The HWE Approach to Cyclohexenone 3.10 ............................. 88
Scheme 3.15 – Initial Attempt to Synthesize the Substrate for the HWE
Reaction .............................................................................................................. 89
13
LIST OF SCHEMES – Continued
Scheme 3.16 – Methylation of Ester 3.28 Allowed for Nucleophilic Addition ...... 89
Scheme 3.17 – Initial HWE Reaction did not Yield the Desired Cyclo-
hexenone ............................................................................................................ 90
Scheme 3.18 – Use of the HWE Reaction in Exploring the Effect of the
Enolizable Proton ................................................................................................ 91
Scheme 3.19 – Completion of Orthoester Cyclohexenone by the HWE
Reaction .............................................................................................................. 92
Scheme 4.1 – Proposed Michael-Aldol Reaction ................................................ 94
Scheme 4.2 – Key Transformation Tested with a Lithium Enolate ...................... 96
Scheme 4.3 – Mukaiyama Aldol Trials ................................................................ 97
Scheme 4.4 – Results of Mukaiyama Aldol Reaction .......................................... 98
Scheme 4.5 – Envisioned Proline Promoted Condensation ................................ 99
Scheme 4.6 – Investigating an Enamine Nucleophile ....................................... 100
Scheme 4.7 – Modified Route Using an Organometallic Addition ..................... 101
Scheme 4.8 – Formation of Ethyl 2-(bromomethyl)acrylate .............................. 102
Scheme 4.9 – Model Studies of Organometallic Addition ................................. 102
Scheme 4.10 – An Example of Allylic Cuprate Addition .................................... 103
Scheme 4.11 – Use of TMSCl Facilitates Michael Addition .............................. 104
Scheme 4.12 – Studies of the Organocopper Addition on Cyclohexenone ....... 105
Scheme 4.13 – Product Obtained from Organocopper Conditions ................... 107
Scheme 4.14 – Further Investigations with the Model Compound .................... 108
14
LIST OF SCHEMES – Continued
Scheme 4.15 – Testing the 2,6-lutidine Modified Conditions ............................ 109
Scheme 4.16 – Organozinc Results .................................................................. 110
Scheme 4.17 – Organocuprate Results ............................................................ 110
Scheme 4.18 – Proposed Aldol Reaction ......................................................... 111
Scheme 4.19 – Modified Route to the Ketoester .............................................. 112
Scheme 4.20 – Investigating the Oxidative Cleavage ....................................... 113
Scheme 4.21 – Suggested Intermediate in Modified Ozonolysis ...................... 113
Scheme 4.22 – Route to the Ketoester ............................................................. 114
Scheme 4.23 – Synthesis of Phosphonate 4.47 ............................................... 115
Scheme 4.24 – Chelation Control in the Proposed Transition State of the Aldol
Reaction ............................................................................................................ 116
Scheme 4.25 – Test of Ring Closure with the Ketoester ................................... 117
Scheme 4.26 – Synthesis of the Ketoester Test Compound ............................. 119
Scheme 4.27 – Synthesis of the Aldehyde and Ketone Test Compounds ........ 119
Scheme 4.28 – Results of the Base Promoted Ring Closure on the Test
Compounds ...................................................................................................... 120
Scheme 4.29 – Oxidation to the Diketone Intermediate .................................... 121
Scheme 4.30 – Diastereoselectivity of the Ring Closure on the Model System 122
Scheme 4.31 – Chelation Control in the Proposed Transition of the Aldol
Reaction ............................................................................................................ 123
Scheme 4.32 – Synthesis Diketone 4.67 ......................................................... 124
15
LIST OF SCHEMES – Continued
Scheme 4.33 – Comparison of 1,2-addition Products ....................................... 125
Scheme 4.34 – Results of Ring Closure Investigations of Modified Orthoester
Intermediates .................................................................................................... 126
Scheme 4.35 – Synthesis of the MOM-protected Alcohol ................................. 127
Scheme 4.36 – Synthesis of the Benzyl Protected Alcohol ............................... 127
Scheme 4.37 – Reactivity of Differently Protected Alcohol Substrates ............. 128
Scheme 4.38 – Synthesis of Simple Diketone Substrate .................................. 129
Scheme 4.39 – Results of Ring Closure Investigations of Ketone 4.81 ........... 129
Scheme 4.40 – Results of Ring Closure Investigations of Aldehyde 4.83 ........ 130
Scheme 5.1 – Modified Strategy to Bicyclo[2.2.2]octane Substrate – the New
Strategy / Key Transformation .......................................................................... 133
Scheme 5.2 – Results of Ring Closure Investigations of Aldehyde 5.2 ............ 134
Scheme 5.3 – The Modified Synthetic Plan ...................................................... 135
Scheme 5.4 – The Model System for the Aldol Ring Closure Reaction ............ 136
Scheme 5.5 – Formation of 6-endo and 6-exo-hydroxybicyclo[2.2.2]-
octan-2-one ....................................................................................................... 137
Scheme 5.6 – Substituent on C-15 – a Useful Handle ...................................... 138
Scheme 5.7 – The Original Route to Aldehyde 5.2 ........................................... 138
Scheme 5.8 – Previous Functionalization Obstacle .......................................... 139
Scheme 5.9 – Shortened Synthetic Sequence Using a Methylcerium
Reagent ............................................................................................................ 140
16
LIST OF SCHEMES – Continued
Scheme 5.10 – Synthesis of Cyclohexene 5.31 from Methyl Ketone 5.10 ........ 141
Scheme 5.11 – Current Approach to the Bicyclo[2.2.2]octane Intermediate ..... 142
Scheme 5.12 – Exploring the Modified Tandem Michael-Aldol Reaction .......... 143
Scheme 5.13 – Optimized Double Cyclization Conditions ................................ 146
Scheme 5.14 – Potential Synthetic Route via Cyanide Addition ....................... 148
Scheme 5.15 – Protection of Alcohol 5.4 .......................................................... 149
Scheme 5.16 – Trying to Trap the Cyanohydrin (Boc-Version) ......................... 150
Scheme 5.17 – Trying to Trap the Cyanohydrin (CDI-Version) ......................... 150
Scheme 5.18 – Investigation of Nucleophilic Addition to Ketone 5.29
and 5.30 ............................................................................................................ 152
Scheme 5.19 – Investigations of Alkyne Functionalization ............................... 153
Scheme 5.20 – Further Functionalization of Alkyne 5.37 .................................. 154
Scheme 5.21 – Investigations into Lactone Ring Formation ............................. 155
Scheme 5.22 – Formation of the Furanoid Ring Containing Intermediate ........ 157
Scheme 5.23 – Plan for the Prenyl Fragment Addition ..................................... 159
Scheme 5.24 – Synthesis of Intermediate 5.54 ................................................ 159
Scheme 5.25 – Exploring the Reverse Prenylation ........................................... 160
Scheme 5.26 – Suggested Mechanism of Formation of Side Product 5.57 ...... 161
Scheme 5.27 – Synthesis of Benzyl Protected Substrate ................................. 162
Scheme 5.28 – Successful Reverse Prenylation .............................................. 163
Scheme 5.29 – Attempts to Elaborate the Furanoid Intermediate .................... 164
17
LIST OF SCHEMES – Continued
Scheme 5.30 – The Diol Substrate was Used in Studies for Both the Furanoid
and Lactone Ring Formation ............................................................................. 165
Scheme 5.31 – Successful Lactone Ring Formation ........................................ 165
Scheme 5.32 – Shortening the Route to the Lactone Ring Intermediate .......... 167
Scheme 5.33 – Oxidation of Diol 5.64 ............................................................... 167
Scheme 5.34 – Potential Routes for Cyclohexenone Formation ....................... 168
Scheme 5.35 – Attempts to Functionalize Intermediate 5.68 ............................ 169
Scheme 5.36 – Selective TBS-protection of the Diol Problematic .................... 170
Scheme 5.37 – TES-protection of the Diol 5.64 ............................................... 171
Scheme 5.38 – Silyl Migration Observed .......................................................... 171
Scheme 5.39 – Oxidation of TES-protected Substrates .................................... 172
Scheme 6.1 – Potential Route for Elaboration of Aldehyde 6.1 ........................ 173
Scheme 6.2 – Potential Route for Elaboration of Lactol 6.7 .............................. 174
Scheme 6.3 – Jørgensen’s Diastereoselective Michael-aldol Reaction ............ 175
Scheme 6.4 – Potential Pathway to an Enantioselective Michael-aldol
Reaction ............................................................................................................ 176
Scheme 6.5 – An Example of Asymmetric Acylation, Wirz et al. ...................... 177
Scheme 6.6 – An Example of Asymmetric Yeast Reduction ............................. 177
Scheme 6.7 – Potential Entry Point into an Enantioselective Synthesis ........... 178
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ABSTRACT
Strategies to synthesize the natural product maoecrystal V have been
investigated. The initial strategy involved a tandem Michael-aldol reaction to
form the [2.2.2] bicyclic core of maoecrystal V. This proposed route was not
successful. A modified route to maoecrystal V, inspired by studies on the aldol
ring closure reactions, enabled the synthesis of a complex intermediate that
allowed for the formation of the core structure. Further elaboration of this key
intermediate afforded the methodology to form four of the five rings in
maoecrystal V. Additionally, this key intermediate allowed for further
modifications that can potentially be an entry point toward an enantioselective
synthesis of maoecrystal V that intersects with the initial synthesis of the racemic
compound.
19
CHAPTER 1 – THE BACKGROUND
“The synthetic chemist is more than a logician and strategist; he is an explorer
strongly influenced to speculate, to imagine, and even to create. These added
elements provide the touch of artistry which can hardly be included in a
cataloguing of the basic principles of synthesis, but they are very real and
extremely important…”
- E.J. Corey1
“Chemists make molecules. They do other things as well, to be sure – they study
the properties of these molecules; they analyze, they form theories as to what
makes molecules stable, why they have the shapes or colors that they do; they
study mechanisms, trying to find out how molecules react. But at the heart of
their science is the molecule that is made, either by a natural process or by a
human being.
- R. Hoffmann2
1.1 Total synthesis
Complex molecules often inspire the work of synthetic chemists. Whether the
target molecule is a natural product, medicinally important active ingredient, or an
organic compound of theoretical interest in chemistry or biology – exploration of
new synthetic routes has inspired new methodology and educated the minds of
20
generations of chemists. Total synthesis is the science and art of designing a
method and route to a molecule from relatively simple molecular fragments.
One of the goals of natural product total synthesis is to prepare a compound in
greater quantity than available from natural sources. However, total synthesis
has also resulted in an ability to confirm the structure of a novel natural product.
A recent example of this is Scheidt’s synthesis of marine macrolide
Neopeltolide.3 In addition, total synthesis tests the limitations of our current
chemical methods. In his introduction the article, “The Art and Science of Total
Synthesis at the Dawn of the Twenty-First Century,” Nicolaou states that “Being
both a precise science and a fine art, this discipline has been driven by the
constant flow of beautiful molecular architectures from nature and serves as the
engine that drives the more general field of organic synthesis forward.”4 Lastly,
an additional, and often overlooked, purpose of total synthesis is to train the next
generation of synthetic chemists.
In 1828 Friedrich Wöhler synthesized urea and in doing so, demonstrated that
organic compounds could be made from inorganic precursors.4 The field has
obviously progressed from urea to many complex and beautiful molecular
architectures, some of which include cubane, brevetoxin B, and ginkolide B. In
particular, complex, polycyclic structures intrigue and inspire chemists to attempt
to design a total synthesis in a simple and efficient manner.
21
1.2 Maoecrystal V – A natural product
1.2.1 Kauranes and ent-kauranes – a general class of molecules
Kauranes and ent-kauranes are a subgroup of the tetracyclophytane diterpenes.
This sub-group contains C-20-non-oxygenated and C-20-oxygenated ent-
kauranes, where the latter group is further classified depending upon their
oxidation pattern. The nomenclature for these compounds is ambiguous as the
terms ent-kaurane and kaurane are often used interchangeably. Indeed, the term
kaurane and ent-kaurane often refer to the same tricyclic fused structure (see
Fig. 1.1).5
H
H
1.1
Figure 1.1 – The Core Structure of Kaurane/ent-Kaurane
Based upon the ent-kaurane carbon skeleton, a growing family of compounds
have been isolated (see Figure 1.2), some of which have been studied and
tested for biological activity.6
22
Figure 1.2 – A Sampling of Compounds in the Kaurane Family 7-9
Different target activity is related to the different functionality present in the
molecule.10 Many of these compounds exhibit interesting and useful biological
activities. Some include antitumor and antibacterial activity. Antibacterial activity
is thought to be related to the C-15, C-16, C-17 α-methylene cyclopentanone
(standard numbering of the kaurane family is used here), presumably as it
functions as a conjugate addition acceptor to a thiol containing enzyme (see
Figure 1.3).6,10,11 Hydrogen-bonding interactions between a C-6 hydroxyl and the
C-15 carbonyl has been proposed to enhance the antibiotic activity.
23
Figure 1.3 - Standard Numbering for ent-Kaurene Type Structures 6
The antitumor activity has also been attributed to the same α-methylene
cyclopentanone and the same hydrogen bonding sites as described above. In
addition, the hydroxyl groups at C-7 and C-14 were found to augment the
antitumor activity.10,11 These compounds have also been used as insect growth
inhibitors; likewise, this activity has been attributed to the α-methylene
cyclopentanone.6,10,11
O
OO
O
O
1.9
O
OO
O
O
1
2
3 4
5
7
89
1011
1213 14
1516
17
18 19
20
Figure 1.4 – Maoecrystal V with -Unsaturation Highlighted and Standard
Numbering of Carbon Framework
The ent-kaurane, maoecrystal V, is a highly congested molecule whose carbon
structure has been modified greatly from the basic ent-kaurane skeleton. Indeed,
24
the α-methylene functionality that was in the cyclopentanone is now seen as a
cyclohexenone (see Figure 1.4). Maoecrystal V exhibits biological activity.
However, the congestion due to the adjacent carbon C-4 containing geminal
methyl groups makes conjugate addition via a thiol-containing enzyme a
questionable route for biological activity. Additional intramolecular hydrogen-
bonding interactions are also not possible.
1.2.2 Isolation and structure determination of maoecrystal V
Maoecrystal V is a member of the ent-kaurane family of terpenes and is one of
over 600 novel diterpenoids isolated from the Isodon genus (formally Rabdisia)
found primarily in tropical and sub-tropical Asia.10,12 The crude plants or extracts
from various Isodon species are often used in traditional Chinese folk medicine to
treat respiratory and gastrointestinal bacterial infections, inflammation and
cancer. This has led numerous groups to focus on the isolation and identification
of the organic components present in the members of this genus. As of 2006,
over 50 diterpenes have been isolated and identified from this plant.12,13
Maoecrystal V was first isolated from Isodon eriocalyx in the 1990s by Sun and
co-workers.14 This effort identified 50 other ent-kauranoids, including 30 novel
compounds.14,15 The structure of maoecrystal V was preliminarily established
based on 1- and 2- dimensional nuclear magnetic resonance spectroscopy, mass
spectrometry and infrared spectroscopy. However, the proposed structure was
refined over several iterations and ultimately unequivocally established in 2004
25
by single crystal X-ray crystallography (see Figure 1.5 - Reprinted with
permission from Org. Lett., Vol. 6, No. 23, 2004. Copyright (2004) American
Chemical Society).12
Figure 1.5 – X-ray Crystal Structure of Maoecrystal V12
Maoecrystal V itself contains a unique bicyclo[2.2.2]octane system. It is of
particular interest because a [3.2.1]-bicycle is more characteristic of ent-
kauranoids as seen in previously mentioned examples (see Figure 1.2). The
structure has five highly congested rings. In addition to the bicyclo[2.2.2]octane
system, there is also a furanoid ring and a spirocyclic lactone in relation to a
cyclohexenone ring. Additionally, it contains six chiral centers, including three
contiguous quaternary chiral centers of which two are contiguous, fully carbon-
substituted centers. It has been said that this compound is “by far the most
modified naturally occurring ent-kauranoid known to date.”14,15 These structural
characteristics make maoecrystal V a unique and challenging target for studies in
synthesis.
26
1.2.3 Biological activity of maoecrystal V
Maoecrystal V was evaluated for its cytotoxicity towards five human tumor cell
lines.14 It displayed highly selective cytotoxicity towards the HeLa cell line. This
activity profile is intriguing because, as mentioned above, maoecrystal V lacks
the α-methylidene cyclopentanone (which is generally credited as the key
functionality to ent-kaurane cytotoxicity) but instead includes a highly congested
cyclohexenone ring system.16
Table 1.1 – IC50 of Maoecrystal V and cis-Platin14
IC50 (μg/mL)
Test substance K566 A549 BGC-823 CNE HeLa
Maoecrystal V 6.43 x 104 2.63 x 104 1.47 x 104 not
determined 0.02
cis-platin 0.38 1.61 0.25 2.31 0.99
1.2.4 Proposed biosynthesis of maoecrystal V
Two partial biosynthetic routes to the maoecrystal V framework have been
proposed by Sun et al.12,14 The conclusions drawn concerning the biosynthesis
are based on interconversions of other known ent-kauranoids to the maoecrystal
V framework. The first route proposed suggests that maoecrystal V is obtained
from epi-eriocalyxin A (see Scheme 1.1).
27
O O
O
O
HH
H
O
O
OO
O
OA complexset of biosynthetictransformations
15
15
16
16 99
13 13
8
8
epi-eriocalyxin A maoecrystal V1.91.10
Scheme 1.1 - Sun et al. Proposed Bio-synthetic Conversion of epi-Eriocalyxin A
to Maoecrystal V 17
The rearrangement of the carbon “bridge” of C-15 and C-16 on maoecrystal V
from being attached on C-8 to C-9 is similar to an acid-catalyzed rearrangement
on another compound in the kaurane family. However, this previously observed
acid-catalyzed rearrangement required key oxy-substituents that epi-eriocalyxin
A lacks. This observation thus leads to the conclusion that the transformation to
maoecrystal V “might be biochemically generated and enzyme-catalyzed.”15
The second route proposed starts from 7,20-epoxy-ent-kaurane 1.11 (see
Scheme 1.2). In studying another compound (isolated from the same medicinal
herb), namely maoecrystal Z, Sun et al. propose that both compounds could
originate from the same kaurane 1.11. The pathway proceeds through a
proposed series of transformations that are suggested to “be biochemically
generated and enzymatically catalyzed.”18
28
Scheme 1.2 - Sun et al. Proposed Bio-synthetic Conversion of 7,20-epoxy-ent-
kaurane to the Maoecrystal V Carbon Framework 17,18
It is important to note that these proposed biosyntheses are working hypotheses
and further investigation would be required to confirm their validity.
1.3 Reported synthetic strategies towards maoecrystal V
With such medicinal interest and synthetic challenges, numerous “progress
towards the total synthesis” papers have been published. Groups reporting
progress toward the total synthesis studies include Baran, Danishefsky,
Nicolaou, Sorensen, Trauner, Yang, Singh, Thomson, Zakarian and Chen.4,17,19-
22 Each of the known approaches will be discussed. Since the structure was
fully elucidated in 2004, only one group, Yang et al., has published a total
synthesis.
29
1.3.1 The Baran strategy19
In 2009 Baran et al. published the beginning of their approach to the synthesis of
the carbon skeleton of maoecrystal V. They began their work by doing some
model compound studies (see Scheme 1.3).
Scheme 1.3 – Baran’s Model Study
In exploring the coupling of a -keto aldehyde to a silyl enol ether, they realized
that the desilylation of a key ketone intermediate 1.17 gave the undesired
regioisomeric dienol ether which was problematic in the subsequent
intramolecular Diels-Alder reaction (IMDA).
30
Thus, they devised a route in which the diene was further dehydrogenated giving
the aromatic ring. Then the desired regioisomer was obtained by the Wessely
oxidation and this resulting diene 1.18 was useful in an IMDA reaction. The
major product 1.19 was the undesired diastereomer.
With the information gained from the model studies, work on the synthesis of the
actual carbon skeleton commenced. Knowing that the silylation of the ketone
would ultimately give the wrong regioisomer of the diene, a direct route to the
aromatic intermediate was used (see Scheme 1.4). This route began with the
coupling of the -unsaturated ketone intermediate 1.20 (prepared in three
steps from a commercially available diketone) with an aryl bismuth fragment.
Ar
O
OH
TBSO OMOM
Ar3BiCl2DBU
Ar=
1. Li(t-BuO)3AlH2. acryloyl chloride
OTBSO
Ar
OTBSO
O
1. TFA2. Pb(OAc)4
AcOH O
OTBSO
OAc
major isomer
1.20 1.21
1.22 1.23
O
O
O
O
Scheme 1.4 – Synthesis of the IMDA Intermediate
At this point, following the previously studied steps of reduction, esterification,
deprotection and Wessely dearomatization, the intermediate required for the
31
IMDA was obtained. This intermediate was subjected to IMDA conditions of
heating in a microwave reactor in o-DCB in the presence of BHT to obtain the
product in 79% yield (see Scheme 1.5).
At this juncture, the product of the IMDA reaction (1.25) was hydrogenated and
the acetate group was removed using SmI2 (see Scheme 1.5). The samarium
intermediate was protonated by methanol to give the methyl ketone as a mixture
of diastereomers (17:3) with the desired diastereomer as the major product.
Scheme 1.5 – Baran’s IMDA Reaction
Baran’s approach is elegant in that in the IMDA step, both the bicyclo[2.2.2]-
octane system as well as the lactone ring is formed. The use of the Wessely
oxidation is a creative solution to the diene being formed as the undesired
32
regioisomer. To finish the synthesis a functional handle to incorporate the
furanoid ring is needed. Additionally the TBS-protected alcohol needs to be
converted into the -unsaturated ketone required in the cyclohexenone ring
1.3.2 The Yang strategy23,24
After publishing a partial synthesis in 2009, very similar to Baran’s approach,
Yang et al. continued work on this compound. Their efforts and revisions to the
initial synthetic approach have resulted in the only total synthesis of maoecrystal
V. It is an efficient 16 step synthesis starting with 2,2-dimethylcyclohex-3-enone
and dimethyl carbonate (see Scheme 1.6).
The resulting -ketoester was subjected to oxidative arylation and the result of
this coupling is the formation of the first quaternary chiral center. This oxidative
coupling reaction and its use of the aryl-lead intermediate is reminiscent of
Baran’s use of the aryl-bismuth intermediate in the Barton arylation to form the
same type of intermediate in preparation for the upcoming Wessely oxidation and
subsequent intramolecular Diels-Alder (IMDA) reaction.
33
O O
CO2MeOMOM
Pb(OAc)3
O
MeO2C
OMOM
O
O
O , NaHpyr, CHCl3,
60 C
1. (Bu4N)BH4MeOH, 40 C
2. LAH, THF
OMOM
OH
HO
1. DMAP, EDCI, CH2Cl22-(diethoxyphosphoryl)-acetic acid
2. TsN3, DBU, 0 C
ROOH
O
O PO
OEt
OEt
N2
1. Rh2(OAc)4, PhH2. t-BuOK, (HCHO)n
THF, 0 C3. TFA, DCM
O
OOH
O
1.32 R = MOM
1.27 1.28 1.29
1.30 1.31
1.33
Scheme 1.6 – Synthesis of Phenol Intermediate 1.33
After some investigation, the two step treatment of the resulting aryl -ketoester
with (Bu4N)BH4 followed by LiAlH gave the diol with the desired configuration.
The observed diastereoselectivity was attributed to the “directing and
accelerating effect of the cationic-π interaction between the ammonium salt and
the phenyl ring in the substrate, which delivers the hydride to the ketone from the
top face.” The diol was then coupled with the diethyl phosphonate fragment
followed by treatment with TsN3 to give the diazo ester. With this phosphonate
intermediate, they are able to execute a Rh-catalyzed O-H bond insertion and
34
consecutive Horner-Wadworth-Emmons (HWE) reaction with paraformaldehyde
leading to the phenol 1.33 (after alcohol deprotection).
Phenol 1.33 was subjected to Wessely oxidative acetoxylation. This differs from
Baran’s synthesis and use of the “simpler” vinyl ester intermediate as the
dienophile in the IMDA. The result of the Wessely oxidative acetoxylation did
result in the diene required, but as a mixture of diastereomers 1.34. This
oxidation reaction oxidizes the phenol, giving an acetoxy ketone. The resulting
diene is set up for a Diels-Alder cycloaddition with the exocyclic methylene
group, and is similar to the strategy used by Baran. The mixture of
diastereomers (1.34) was subjected to IMDA conditions to give three products
(see Scheme 1.7).
Scheme 1.7 – The Key IMDA Reaction
35
Unfortunately, the stereoselectivity of this key step is not high, which results in
three isomers (totaling 76%). The team's desired compound was isolated in 36%
yield. Six more steps were required to complete the total synthesis (see Scheme
1.8).
Scheme 1.8 – Completion of the Total Synthesis of Maoecrystal V
Treatment of the IMDA product with NBS resulted in a bromide intermediate
which, upon reaction with Bu3SnH, gave an allylic radical, which was trapped with
TEMPO to give the hydroxyl amine. Reductive cleavage of the
tetramethylpiperidine and acetoxy groups followed by regioselective
hydrogenation and Dess-Martin periodinane (DMP) oxidation gave the C-16
epimer of maoecrystal V. Epimerization of the methyl bearing chiral center was
required and thus achieved under basic conditions using DBU to give a 1:1
mixture of the C-16 epimer and maoecrystal V.
36
Overall, this route published by Yang et al. is efficient in that only 16 steps are
required. The main drawback is that the IMDA reaction, while efficient in forming
the bicyclo[2.2.2]octane system as well as the lactone and hydrofuran ring,
resulted in a mixture of three isomers and the product that was desired was only
obtained in 36%. However, it is the only total synthesis to date and an elegant
synthetic route. In particular, the total synthesis is concise due to the use of a
bond insertion to form the seven-membered ring as well as the use of the
Wessely oxidation to form the substrate for the IMDA reaction.
1.3.3 The Nicolaou strategy25
In October of 2009, the Nicolaou group published their approach toward the
functionalized maoecrystal V core structure. Their approach was two-fold and
gave two advanced intermediates.
For the first approach, the beginning of their synthesis was the decarboxylative
Heck reaction with 2,6-dimethoxy benzoic acid and cyclohexenone (see Scheme
1.9). The resulting dimethyl intermediate was mono-demethylated with BBr3.
The desired alkenyl methyl ester was obtained through an O-alkylation with the
pyrrolidine fragment followed by elimination of its nitrogen moiety, thus
incorporating the dienophile. Formation of the silyl enol ether gave the requisite
diene for the IMDA.
37
OMe
CO2H
OMe
O1. Pd(TFA)2
Ag2CO32. BBr3
O
OH
OH
1. NaH
NCO2Me
Br
2. Na2CO3, MeI
O
OMe
O
MeO2C
TBSOTfNEt3
OTBS
OMe
O
MeO2C
OTBS
O
RMeO
1.39 1.40 1.41
1.42 1.43R = CO2Me
Scheme 1.9 – Nicolaou’s Syntheis of an IMDA Intermediate
At this point, the intramolecular [4 + 2] cycloadditon was performed without any
purification of the TBS enol ether to give the exo diastereomer as the major
product (see Scheme 1.10).
OTBSOMe
OMeO2C CO2Me
OTBS O
O
O
RMeO
MeO
1.43 R = CO2Me
K2CO3hydroquinonethen 1N HCl
1.43 1.44 .
Scheme 1.10 – Nicolaou’s IMDA Reaction
38
In this step, bicyclo[2.2.2]octane system is formed and thus, one of the all
carbon-substituted chiral centers is formed. The next hurdle was to form the
second of the contiguous all-carbon quaternary centers, and this was done
through an “intramolecular carbene-mediated cyclopropanation/fragmentation
process” (see Scheme 1.11).
CO2Me
O
O
MeO
1. NaOH2. (COCl)23. TMSCHN2
O
O
MeO O
N2
Rh2(OAc)4
O
O
MeO O
silicagel
O
O
O O
H2Pd/C
O
OO
O
H
5
1.44 1.45
1.46 1.47 1.48
Scheme 1.11 – The Intramolecular Cyclopropanation/Fragmentation
To this end, the methyl ester was saponified, functionalized to the acid chloride
and reacted with TMSCHN2 to give a diazo ketone. Treatment of this ketone with
a rhodium catalyst resulted in formation of the cyclopropane, which was then
fragmented to give the diene. The final step hydrogenation resulted in their first
39
advanced intermediate (1.48). It is important to note that the hydrogenation does
not give the desired epimer needed for maoecrystal V.
Their second approach gives a much more advanced intermediate, in that it also
incorporates the six-membered lactone ring. The beginning of the scheme is
very similar to the previous synthesis, in that it starts with the intramolecular Heck
reaction. The only difference being that, the demethylation step is complete and
both methyl groups are removed. This allows for incorporation of the MOM
protecting group prior to the incorporation of the methyl ester. As a result, the
product of the IMDA reaction contains a MOM protected phenol (see Scheme
1.12).
O
CO2MeH HCO2Me
O
O
MOMO CO2Me
O
O
O
OMeOMe
1. aq HCl2. PIFA, KHCO3
MeOHH2
Pd/C O
MeO
OMe
O
O
NaOH
CO2HH H
O
MeO
OMe
O
O
ClCH2IKOtBu
18-crown-6 O
MeO
OMe
O
O
O
O
O
O O
O
maoecrystal Vfor comparison
C15C16
5
1.49 1.50 1.51
1.52 1.53 1.9
Scheme 1.12 – Construction of the Pentacyclic Lactone
40
The dearomatization was done by first deprotecting the MOM-protected alcohol
and treatment with phenyliodine bis(trifluoroacetate) (PIFA) to give the dienone.
Subsequent hydrogenation gave the diketone compound containing the furanoid
ring, although it is again epimeric to maoecrystal V at C-5 (Scheme 1.12).
Saponification with NaOH gave carboxylic acid 1.52, which was followed by
alkylation with ClCH2I. Unfortunately, triple instead of double alkylation occurred.
Importantly, this second approach provided a creative method for incorporation of
the lactone ring. Although this is an advanced intermediate, further work is
needed in that the ketone on the [2.2.2] bicyclic system is on C-16 instead of C-
15. Additionally, they obtained the undesired diastereomer (in relation to C-5) in
the hydrogenation of the diketone. The cyclohexenone ring is not complete, and
the alkylation to form the lactone, although intriguing, gave an over-alkylated
product.
1.3.4 The Singh strategy26
The Singh group has also been studying a simple entrance to the main tricyclic
core of maeocrystal V. Their approach, similar to the previously mentioned
approaches, also uses a dearomatization followed by an IMDA reaction. To
begin, they synthesize an aromatic precursor from a readily available diol (see
Scheme 1.13).
41
Scheme 1.13 – Synthesis of the Aromatic Precursor
Protection of the diol followed by stepwise oxidative cleavage of the terminal
alkene followed by reduction of the aldehyde with NaBH4 gave alcohol 1.55.
Subsequent esterification and deprotection gave diol precursor 1.56. The
aromatic compound (1.56) underwent an oxidative dearomatization to give diene
1.57, required for entry into the IMDA reaction (see Scheme 1.14).
Scheme 1.14 – Oxidative Dearomatization and IMDA
42
The IMDA reaction to give tricyclic intermediate 1.58, occurs stereoselectively in
75% yield. At this point, their focus turned to converting the -keto-epoxide (see
Scheme 1.15).
Scheme 1.15 – Synthesis of Singh’s Tricyclic Intermediate
Epoxide opening followed by Jones oxidation gave the carboxylic acid
intermediate, which upon heating underwent decarboxylation. Finally,
hydrogenation gave Singh’s advanced tricyclic intermediate. Their approach is
simple and efficient in forming the bicyclo[2.2.2]octane system as well as the six-
membered ring lactone. However, their intermediate lacks functional handles for
further elaboration.
1.3.5 The Thomson strategy 27
In 2010, the Thomson group also published their approach to the carbocyclic
core of maoecrystal V. This approach is unique in that the bicyclo[2.2.2]octane
system is formed via a Diels-Alder reaction with nitroethylene. Their approach,
43
while fascinating, encountered unexpected, interesting chemistry which has thus
far prevented them from completing the total synthesis. Their synthesis began
with a regioselective Rubottom oxidation of 3,3-dimethycyclohexanone and
protection of the newly formed alcohol (see Scheme 1.16).
Scheme 1.16 – Synthesis of Thomson’s Tetracyclic Intermediate
The resulting ketone 1.62 underwent a HWE reaction with the Weinreb amide
phosphonate shown, which then reacted with an organolithium reagent to afford
the TBS protected dienone 1.63. Treatment with ferrous chloride effected the
Nazarov reaction, the transformation giving a spirocyclic ketone as a single
stereoisomer. Reduction of the ketone set up the diene to undergo a Diels-Alder
44
reaction with the reactive nitroethylene as the dienophile. The stereoselectivity
was predicted due to the TBS group controlling the facial selectivity of both the
Nazarov and Diels-Alder reactions. At this juncture, the synthetic plan was to
use the Nef reaction to convert the nitroalkane to the corresponding ketone, but
all attempts were met with minimal success.
They then turned their attention to forming the furanoid ring. Treatment of the
tetracyclic intermediate 1.65 with KOH resulted in complete epimerization of the
nitro group, which was an unexpected result (see Scheme 1.17).
Scheme 1.17 – An Attempt to Form the Furanoid Ring
Hydrogenation followed by Jones oxidation resulted in the ketone which
underwent a stereoselective Rubottom oxidation of the thermodynamically more
45
stable enol silane. Unfortunately, conditions to bring about the desired furanoid
ring formation to make the carbon-oxygen bond with C-5 could not be found.
Similar conditions used by Suárez and co-workers did not bring about the desired
ether formation, but rather a Grob fragmentation, which was hypothesized to be
due to “favorable alignment of the broken σC-C with σ*C-N of the leaving [nitro]
group.”
At this point, they turned their attention to formation of the lactone ring first,
before trying to form the bridging cyclic ether. However, attempts toward the
functionalization of the ketone via a Baeyer-Villiger reaction did not afford the
desired lactone. Instead, another lactone resulted from insertion at the other side
of the ketone. The undesired insertion, in conjunction with the TBS group being
removed in the acidic conditions, resulted in ketalization (see Scheme 1.18).
Scheme 1.18 – An Attempt to Form the Lactone Ring
To avoid the problems mentioned above, the epimerized Diels-Alder product was
subjected to a Rubottom oxidation (see Scheme 1.19).
46
Scheme 1.19 – An Attempt to Form the Lactone Ring
However attempts to oxidatively cleave the -hydroxy ketone led to complex
reaction mixtures. Another approach was to use an unsaturated ketone
intermediate 1.69 for the oxidative cleavage reaction. However, under various
hydrogenation conditions, a major product that was isolated was an unexpected
cyclopropane intermediate 1.70. The authors speculate that “the close proximity
and alignment of σ*C-N of the nitro group allows for an intramolecular alkylation of
the presumed palladium enolate intermediate.” The last transformation gave the
desired lactone ring. This was accomplished by treatment with periodic acid to
give the aldehyde intermediate, which was then reduced, and thus allowed
lactonization to occur.
Thomson’s approach was highly problematic as they encountered many
setbacks while trying to install both the lactone ring as well as the tetrahydrofuran
ring. The advanced tetracyclic intermediate contains an unwanted cyclopropane
ring, which one could foresee as being problematic, in particular to installation of
47
the cyclic ether. Additionally, due to the failure of the Nef reaction, the
conversion of the nitro functionality to a ketone has not been achieved. Lastly, a
total synthesis would still require the functionalization to the cyclohexenone ring.
1.3.6 The Trauner strategy 22
The Trauner group has also been working towards an efficient route to
maoecrystal V. Their approach is unique in that it does not approach forming the
bicyclo[2.2.2]octane system via a Diels-Alder type of reaction. Rather, the
incorporation is done through an aldol reaction. The synthesis of the
bicyclo[2.2.2]octane system starts with cyclohexenone 1.72 that is obtained by
alkylation with ethyl bromoacetate followed by Sakurai allylation. Ozonolysis
affords an aldehyde. The aldol reaction, under acidic conditions gave the desired
bicyclo[2.2.2]octane system as a 7:1 mixture of endo and exo isomers, which
could be separated after TBS protection to obtain the major diastereomer 1.73
(see Scheme 1.20). The authors mention that this synthetic approach via the
aldol reaction provides an intermediate that has the potential to be elaborated in
a symmetric fashion, as this has been developed by Kitahara et al. With the
successful aldol reaction complete, formation of the tertiary alcohol was explored,
in particular, reaction with Nagata’s reagent. Unfortunately, the cyanohydrin
formation gave the undesired diastereomer and transesterification to give a five-
48
membered ring lactone also occurred.
O
EtO
O
1. O3 then DMS2. HCl3. TBSCl, imid.
O
OTBS
EtOO
1. Et2AlCN2. LDA, CH2O
-40 C3. Me2CO, p-TsOH
OTBS
O
CN
OOO
1. DIBALH2. NaOH
OTBS
OO
OO
[M]
OTBS
OO
OOH
1.72 1.73 1.74
1.75 1.76
Scheme 1.20 – Trauner’s First-Generation Approach to Maoecrystal V
However, with this intermediate 1.74, the planned installation for the second all
carbon-substituted center via the addition of formaldehyde was explored. Under
LDA conditions, this was alkylation was successful as was the second Fráter-
Seeback alkylation. Protection of the diol, reduction of the lactone and treatment
with base led to the fragmentation of the lactol with the loss of cyanide. The keto
aldehyde 1.75 was used to explore a reverse prenylation reaction. However,
conditions to effect this transformation were not found.
Due to the addition of the cyanide giving the undesired diastereomer, other small
nucleophiles were studied in order to overcome the previously-observed
49
stereoselectivity. Ultimately, the anion of the TMS-acetylene (TMSA) added to
bicyclic ketone to give the desired stereoisomer (see Scheme 1.21).
O
OTBS
EtOO
1. TMSA, BuLi2. NaH, 40 C
OTBS
O
1. Pd/CaCO3H2, pyr
2. LDA, CH2O-40 C to rt
OTBS
O
O
OHO
HO
OTBS
O
OHO H
12% 54%
1.73 1.77
1.78 1.79
Scheme 1.21 – Overcoming the Undesired Stereoselectivity
NaH conditions resulted in both the formation of the five-membered ring lactone,
as well as the removal of the TMS group, to give the terminal alkyne, which was
reduced to give the alkene using Lindlar reduction. The double aldol addition
with formaldehyde with lactone 1.77 proved to be challenging, which was
presumed to be due to the more crowded steric environment. They reasoned
that the second alkylation was difficult “due to the considerable steric hindrance
that would be encountered in the formation of the requisite dianion through
double deprotonation” of intermediate 1.77. Ultimately, a route to successful
dialkylation was found. The alkylation was carefully controlled to give only mono-
alkyation (see Scheme 1.22). Oxidation with DMP and reduction of the enol
50
gave the hydroxymethyl lactone. With the -proton now more accessible, the
second aldol reaction proceeded give the diol in satisfactory yield. Ozonolysis
gave the lactone/lactol product 1.84.
OTBS
O
LDA, CH2O-40 C
O
OTBS
O
O
H
1. DMP2. NaBH4
OTBS
O
OH
LDACH2O-40 C
OTBS
O
OHO
HO
O3then DMS
OTBS
O
OHHOOO
1.80 1.81 1.82
1.83 1.84
HO
HO
O
O
O O
O
maoecrystal Vfor comparison
1.9
Scheme 1.22 – Stepwise Approach to Aldol Addition
Trauner’s approach was creative, in that the unexpected stereoselectivity of the
cyanide addition was reversed using an acetylene fragment. This ultimately
resulted in the formation of the six-membered ring hemiacetal intermediate 1.84.
The “undesired” diastereomer was used to explore future steps required for
futher elaboration to maoecrystal V. In particular, aldehyde intermediate 1.75
(see Scheme 1.23), albeit the undesired diastereomer, was used to explore the
reverse prenylation reaction to form the sterically crowded center and access the
-unsaturated six-membered ring.
51
Scheme 1.23 – Trauner’s Investigation of the Reverse Prenylation
Their paper ends with commentary that they plan to streamline their synthesis
and have expectations that an intramolecular approach may be required.
1.3.7 The Danishefsky strategy20,21
In 2009, Danishefsky’s group published a synthetic strategy for accessing the
bicyclo [2.2.2]-octane core of maoecrystal V, utilizing an IMDA reaction. Toward
this end, they designed a highly functionalized precursor and it did indeed
undergo an IMDA reaction but with the undesired facial selectivity (see Scheme
1.24).
52
O
O
OTBSMeO2C
R
OO
O
MeO2C
R
O
O
O O
O
maoecrystal Vfor comparison
1.9
180 Csealedtube
PhMe
1.78 1.79
Scheme 1.24 – Danishefsky’s Original IMDA Route
Due to this result, a modified sequence was designed in which the precursor was
less densely functionalized and symmetrical. The modified approach starts with
the Birch-type vinylogous acylation followed by a two step reduction re-oxidation
to give intermediate 1.82 (see Scheme 1.25).
CO2Me
Cl
O LDA, THF-78 C
O
CO2Me1. DIBALH
-78 C2. MnO2, CH2Cl2
O
OH Cl
O
SO2Ph
1. py, CH2Cl2, 0 C
2. TBSOTf, NEt3CH2Cl2, -78 C
OTBS
O
O
SO2Ph
1.80 1.81 1.82
1.83 1.84
Scheme 1.25 – Danishefsky’s Synthesis of a Precursor for an IMDA Reaction
53
This first step forms one of the two quaternary all-carbon chiral centers. This is
followed by esterification, which put into place the dienophile fragment.
Subsequent TBS enol ether formation forms the diene required for the IMDA
reaction.
IMDA cyclization gave the cycloadduct product, and upon in situ treatment with
TBAF, removed the TBS group and resulted in the spontaneous elimination of
the sulfone moiety, the bicyclo[2.2.2]octane intermediate 1.85 was obtained (see
Scheme 1.26).
Scheme 1.26 – Danishefsky’s Modified IMDA
Like the previous IMDA cycloaddition in the Danishefsky’s more complex system
(see Scheme 1.24), this reaction forms the second of the two quaternary carbon
centers required in maoecrystal V (see Scheme 1.26). With this simpler Diels-
Alder substrate, the correct facial selectivity was achieved. Attention turned
toward forming the tertiary alcohol on C-8, which is required for the formation of
the furanoid ring (see Scheme 1.27).
54
OO
O
HO
OO
O
1. H2O2, NaOHMeOH, 0 C
2. MgI2, DCM45 C
3. Bu3SnH, AIBNPhMe, reflux
OO
O
OH
1. m-CPBA, CH2Cl22. p-TsOH, H2O
CH2Cl2
1. Pd/C, H2EtOH
2. DMPNaOMe, O2
MeOH, 40 C
OO
O
O
OH
undesiredaldol
OO
O
O
undesiredisomer
H
O
H
5
88
1.85 1.86
1.87 1.88 1.89
OH
5 5
Scheme 1.27 – Attempts toward Stereoselective Furanoid Ring Formation
It was found that epoxide formation was stereoselective. Ring opening to form
the iodohydrin, followed by reduction, gave the desired tertiary alcohol
intermediate 1.86. In trying to form the furanoid ring, the alkene intermediate
was treated with m-CPBA to obtain a stereoselective epoxidation. Acidic
conditions resulted in epoxide opening by the tertiary alcohol and the formation of
the furanoid ring. Unfortunately, X-ray analysis of 1.87 showed the undesired
isomer at C-5 (see Scheme 1.27). In trying to reverse the stereocenter at C-5 to
obtain the desired epimer, the adjacent alcohol was oxidized to the ketone. This
diketone intermediate 1.88 was exposed to basic conditions. The result was an
unexpected intramolecular aldol reaction.
55
To avoid the unexpected intramolecular aldol pathway, the ketone at C-16 was
removed by dithioketal formation, followed by reduction with Raney-Ni (see
Scheme 1.28).
OO
O
O
incorrectisomer
1. CH3CH2SHBF3•OEt2, CH2Cl2
2. Raney-NiEtOH, 75 C
3. DMP, CH2Cl2
OH
1. NaBH4, MeOHCH2Cl2, -78 to -50 C
2. MsCl, DMAPCH2Cl2, 50 C
3. DBU, PhMe, 128 C
OO
O
DMDO, CH2Cl20 C then
Et2O, BF3•OEt2
O O
O
O LA
HO O
O
O
H
OO
O
HO
H
1616
1.87 1.90
1.91 1.92 1.93
15
5
Scheme 1.28 – Methodology for Epimerization at C-5
Oxidation of the alcohol at C-5 gave the ketone functionality. Further treatment
of the ketone intermediate 1.90 (which, unlike the diketone, could not undergo
the competing aldol pathway) surprisingly did not result in epimerization. They
hypothesize that the “intermolecular delivery of a proton to the ring junction
position” is too congested. Therefore, a pathway to allow for an intramolecular
transfer of a “strategically placed hydrogen atom” was used. To this end, ketone
intermediate 1.90 was reduced with NaBH4 followed by formation of the
56
methanesulfonate and elimination. This resulted in alkene intermediate 1.91.
This allowed for the epoxide formation, and rearrangement under Lewis acidic
conditions, an intramolecular hydride delivery gave the desired epimer at C-5.
This furanoid intermediate 1.93 showcases the success of using an IMDA
reaction to form the bicyclo[2.2.2]octane ring system. Additionally, creative
methodology was explored to enable the epimerization of C-5 of the furanoid ring
juncture. Similar to Nicolaou’s synthetic work on maoecrystal V, further work is
needed in that the C-16 ketone on the [2.2.2] bicyclic system needs to be
installed. Additionally, the geminal dimethyl substituents as well as the
cyclohexenone functionality need to be completed.
1.3.8 The Zakarian strategy28
As can be seen by the previously discussed work (especially that of Thomson
and Danishefsky) the installation of the furanoid ring is difficult because of the
ring strain as well as the congestion, due to its being flanked by the
bicyclo[2.2.2]octane system on one side and the cyclohexenone ring on the
other. With this analysis in mind, Zakarian’s group approached the synthetic
design by early installation of the furanoid ring followed by an IMDA reaction.
57
The synthesis starts with alkylation of sesamol under Mitsunobu conditions,
followed by coupling with methyl chloroxoacetate to give the ketoester
intermediate (see Scheme 1.29).
Scheme 1.29 – Zakarian’s Formation of the Furanoid Ring
Functional group transformation of the ketoester to the diazoester gave the
substrate that was used for formation of the benzofuran ring, creative in that it is
used an intramolecular C-H functionalization process with a rhodium catalyst.
At this point in their investigations, the C-10 carbon of the maoecrystal V model
was methylated to mimic the quaternary center in the natural product.
Methylation gave a 3:1 mixture of diastereomers, which upon reduction of the
ester, could be separated (see Scheme 1.30). In investigating the removal of the
58
methylidene group, it was found that treatment with MeMgBr at reflux afforded
the desired monoprotected ethyl ether. Upon oxidative dearomatization in
ethanol, the o-quinone intermediate, with a diethyl ketal functionality, was
obtained. Finally, reaction with acryloyl chloride gave the acrylate intermediate,
which was the substrate for the IMDA reaction.
O
OO
CO2MeH
H
1. LiN(SiMe3)2ZnEt2, MeIDMPU, THF
2. LAH, THF
O
OO
H
OH
1. MeMgBrPhH, 80 °C
2. PhI(OCOCF3)2NaHCO3, EtOH
O
O
H
OH
OEtEtO Cl
O
DIPEADMAP
O
O
H
O
OEtEtO
O
dr = 3:11.97 1.98
1.99 1.100
Scheme 1.30 – Formation of the IMDA Substrate (Zakarian)
With the IMDA substrate prepared, conditions were investigated and it was
observed that heating the acrylate in o-DCB in the presence of BHT resulted in
cycloaddition which gave the lactone/enol ether product (see Scheme 1.31), their
advanced intermediate, which they feel is suitable for eventual elaboration to
maoecrystal V.
59
Scheme 1.31 – The IMDA Reaction - Forming Zakarian’s Advanced Intermediate
Zakarian’s strategy of forming the furanoid ring prior to the formation of the
bicyclo[2.2.2]octane ring system avoids the problem encountered by previous
groups. Additionally, the advanced intermediate already incorporates the prenyl
fragment. Synthetic work still needs to be done to form both the cyclohexenone
the lactone rings (see Scheme 1.31), in particular, forming another carbon-
carbon bond at the C-8 position which is sterically congested and neopentyl.
Additionally, the extra carbon-carbon bond at C-11 needs to be cleaved in order
to form the lactone ring in maoecrystal V.
1.3.9 The Chen strategy29,30
Chen and coworkers have continued the work of Nicolaou in a second paper
published in 2011 in which methodology is developed to further the effort toward
completion of the total synthesis. They begin directly with the diene intermediate
60
1.50 described in their 2009 paper. The installation of the gem-dimethyl
substitutents was the first task that was investigated (see Scheme 1.32).
CO2Me
O
O
O
OMeOMe
1. NiCl2, NaBH4MeOH, 0 °C
2. Pd/C, H2EtOH
3. NaBH4, MeOH4. NaH, Ag2O
BnBr, DMF, 0 °C
CO2Me
OBn
OBnO
OMeOMe
1. TFA, CH2Cl2, 0 °C2. Tebbe reagent
PhMe/pyr (5:1)., 0 °C3. Et2Zn, CH2I2,
PhMe, 40 °C
1. Pd(OH)2H2, MeOH2. DMP, CH2Cl23. PtO2, H2AcOH, 40 °C
1.50 1.103
1.104 1.105
O
CO2Me
O
O
O
CO2Me
BnO
OBn
Scheme 1.32 – Installation of the gem-Dimethyl Groups and Lactone Ring
Starting with diene 1.50, a two step reduction of the diene gave an inseparable
mixture of four diastereomers, which was functionalized to the benzyl ether
derivatives 1.103 (see Scheme 1.32). The removal of the dimethyl ketal
functionality was done under acidic conditions to give the ketone.
Transformation of the ketone to the spirocyclic cyclopropane 1.104 was done via
a Tebbe reaction followed by Simmons-Smith reaction. Debenzylation of the
cyclopropane intermediate and oxidation of the resulting diol provided the
diketone intermediate. The cyclopropane was opened, to give the gem-dimethyl
61
groups at C-4 under acidic hydrogenolysis conditions, affording intermediate
1.105.
In the previously published work, use of the chloroiodomethane fragment to form
the lactone ring was effective but there was a problem of the undesired
installation of the exocyclic methylene moiety at C-2 (see Scheme 1.33).
Scheme 1.33 – Lactone Ring Formation
To avoid this extra alkylation, the olefin, in what would be the cyclohexenone ring
in maoecrystal V, was first introduced by the Saegusa oxidation. With the C-2
position safely “protected”, the saponificaition of the ester and subsequent
lactonization was successful.
62
At this juncture, there was a need for to establish methodology to obtain the
desired configuration at the C-5 position. To investigate this reversal, the diene
intermediate 1.108 (previous intermediate, see Scheme 1.32) was the starting
point (see Scheme 1.34). 1,2-reduction of the enone was stereoselective. Acidic
conditions transformed the dimethyl ketal to a ketone.
CO2Me
OH
O
O
OMeOMe
1. PPTSacetone/H2O (20:1)40 C
2. Pd/CH2, EtOH
CO2Me
OH
OHO
OH
H H
correctisomer
Ph3PMeBrLHMDS
THF, 0 C
CO2Me
OH
OHO
H
H H
1. Et2Zn, CH2I2PhMe, 40 C
2. DMP, CH2Cl23. PtO2, H2,
AcOH, 40 C
CO2Me
O
OH H
O
1 5
4
1.108 1.109
1.110 1.111
Scheme 1.34 – Reversal of C-5 Stereochemistry
This allowed for hydrogenation under normal Pd/C and H2 conditions to give the
desired isomer 1.109. The authors hypothesize that the “directing effect of a
stereochemically defined hydroxyl group”, formed at C-1 in the NaBH4 reduction
step, would “counter the intrinsic facial bias exhibited by the substrate.” A four-
step sequential procedure involving a Wittig olefination, a Simmons-Smith
63
cyclopropanation, a DMP oxidation and PtO2-mediated hydrogenolysis converted
the dihydroxy ketone at C-4 into the diketone (1.111).
This further work, a continuation of Nicolaou’s efforts, has provided methodology
for solving some of the challenges encountered by their approach with the IMDA
reaction. Methodology was developed to convert the dimethyl ketal at C-4 into
the gem-dimethyl groups. Additionally, a hydroxyl-directed hydrogenation was
employed to obtain the desired configuration at C-5.
1.3.10 The Sorensen strategy17
In 2010, McLeod’s thesis published the work done under Sorensen on the total
synthesis of maoecrystal V. Much of the work showed that many different
potential routes were explored. The bicyclo[2.2.2]octane system was formed by
a Diels-Alder reaction. Initially, they explored model systems to try to induce a
carbonyl-dependent cascade to form the lactone ring, cyclohexenone ring, and
the furanoid ring all in one step (see Scheme 1.35).
64
Scheme 1.35 – Proposed Cascade Reaction
However, when the model system was tested under conditions to initiate the
proposed cascade, it did not give the desired product and this route was
abandoned.
The new route that was explored would hinge on a 1,5-hydride shift as the key
step to forming the crowded carbon bond between C-4 and C-5 (see Scheme
1.36). Toward this end, they needed the allenone intermediate to test the 1,5-
hydride shift.
65
Scheme 1.36 – Proposed 1,5-Hydride Shift
Thus, the synthesis began with the preparation of this key intermediate (1.115).
To begin, dimethyl-2,2-bis(hydroxymethyl)malonate was protected to form the t-
butyl acetal (see Scheme 1.37), followed by Krapcho decarboxylation, which
gave cyclic mono-ester 1.117.
Scheme 1.37 – Diels-Alder Reaction – Sorensen’s Version
66
Aldol reaction with a commercially available vinylogous ester followed by
hydrolysis gave the -unsaturated ketone 1.118 as a single diastereomer.
Subsequent silyl enol ether formation and reduction of the ester gave the alcohol
intermediate1.119, which reacted with dimethylacetylene dicarboxylate (DMAD)
in a Diels-Alder reaction. The result of the Diels-Alder reaction was a mixture of
the hydroxyl ester as well as the lactone product. This mixture was taken directly
into the next step and subjected to mildly acidic fluoride conditions. Thus, the
TBS enol ether was deprotected to give the ketone as well as the cyclization of
the hydroxyl ester to the lactone ring.
With the successful Diels-Alder reaction, attention was turned to put in place the
allenone fragment. The ketone was first functionalized to trisubstituted olefin
1.121 by formation of the triflate followed by Negishi conditions (see Scheme
1.38). This was followed by deprotection of the acetal. Subsequently basic
conditions afforded a hetero-1,4-conjugate addition to give the required furanoid
ring. The unreacted primary alcohol was oxidized by DMP to give the
corresponding aldehyde intermediate 1.122. Finally, addition of the lithiated
allene fragment to the aldehyde and oxidation gave allenone 1.123, which was
used to test the 1,5-hydride shift. Many conditions were tested to afford this type
of 1,5-hydride shift. Various Lewis acids, solvents, temperatures were tried
unsuccessfully. Stronger Lewis acids and Brønsted acids were also investigated
as well as radical conditions all without success.
67
OO
OO
O
t-Bu
1. KHMDSTf2O, -78 C
2. Pd(PPh3)4THF, Et2Zn
OO
OO
t-Bu
CO2MeCO2Me
1. CSA, MeOH2. NaOMe
MeOH, 60 C3. DMP, Na2CO3
CH2Cl2, 0 C
OO
O
OCO2Me
•Li
1.
Et2O, -78 C2. DMP, Na2CO3
CH2Cl2O
OO
O
CO2Me
•
1,5-hydrideshift
1.120 1.121
1.122 1.123
Scheme 1.38 – Formation of the Allenone Intermediate
At this point in the synthesis, it was realized that if the 1,5-hydride shift could not
be utilized to form the cyclohexenone intermediate 1.114 , “activation” of the C-5
in the furanoid ring to form the C-4 to C-5 bond would be required.
Intermolecular approaches to install functionality at the C-5 of the furanoid ring,
such as radical chemistry, catalytic oxidations, dioxirane chemistry, and hydride
abstraction chemistry, all were not successful. Ultimately, it was concluded that
although the route that was attempted yielded interesting chemistry, the strategy
they investigated may be flawed.
68
1.4 Summary and overview of the synthetic approaches to maeocrystal V
In examining all the approaches of various groups, it becomes clear that the
dense, congested polycyclic structure has been a synthetic challenge. A majority
of groups have used various IMDA approaches. In fact, the one total synthesis
uses this approach. All groups have obtained a mixture of endo and exo
products. Some have been fortunate in having the desired diastereomer be the
major product. Thomson’s, Trauner’s and Sorensen’s group have approaches
that are vastly different from the IMDA routes. In all three cases, difficulties in
forming the cyclic ether and/or the lactone ring have been encountered.
Trauner’s aldol approach utilizes the well-used aldol reaction that has the
potential to be selective in that asymmetric studies of the aldol reaction have
been previously explored. Their approach has been very useful, in particular,
because our synthetic route has some similar functional handles, and their
studies have become useful to our studies and will be mentioned in this writing.
69
CHAPTER 2 – THE PLAN
2.1 Planning a synthetic route to maoecrystal V
The logic of our approach toward maoecrystal V (2.9) is outlined in Scheme 2.1.
Scheme 2.1 – The Proposed Synthetic Plan
70
The overall plan starts with the construction of orthoester cyclohexenone
intermediate 2.2 from commercially-available pentaerythritol (see Scheme 2.1).
Cyclohexenone intermediate 2.2 would be involved in the key step, a proposed
tandem Michael-aldol reaction. The tandem Michael-aldol reaction would result
in the formation of the the bicyclo[2.2.2]octane ring system in maoecrystal V.
From the orthoester intermediate 2.3, hydrolysis of the orthoester functional
group would result in lactone ring formation. Subsequent oxidation of the 1,3-diol
in intermediate 2.4 would give dialdehyde 2.5. An in situ ring closure to form the
furanoid ring is expected to give lactol intermediate 2.6. Reaction of aldehyde
2.6 with the organolithium nucleophile would give alkene 2.7. The formation of
the congested C-4 to C-5 bond is potentially possible via an intramolecular
reaction between the alkene and an in situ-formed oxocarbenium intermediate on
the furanoid ring. This ring closure, followed by an oxidation, would complete the
formation of the last ring, the cyclohexenone, to give maoecrystal V (2.9). Thus,
bicyclo[2.2.2]octane compound 2.3 was identified as a key intermediate.
Figure 2.1 – The Bicyclo[2.2.2]octane Intermediate
71
This key bicyclo[2.2.2]octane intermediate was expected to result from a tandem
Michael-aldol reaction between cyclohexenone 2.2 and a methyl pyruvate
fragment (see Scheme 2.2).
Scheme 2.2 – The Proposed Tandem Michael-aldol Reaction
2.1.1 Key transformations – The details
Therefore, the tandem Michael-aldol reaction to functionalize cyclohexenone 2.2
to bicyclo[2.2.2]octane 2.3 is key to the overall synthesis of maoecrystal V (see
Scheme 2.3). The initial synthetic efforts would be focused on the synthesis of
intermediate 2.2 in order to fully explore the key transformation.
Scheme 2.3 – The Key Transformation
72
2.1.2 The orthoester strategy
The orthoester functional group is also key in the strategy and design of the
synthesis. The orthoester has been used as a carboxylic acid protecting group.
Corey employs this methodology in various syntheses such as the total
syntheses of hybridalactone, (±)-retigeranic acid, and prostaglandin D2.31-33 A
key to approaching the congested polycyclic ring system of maoecrystal V was to
use this functional group in a two-fold manner.
First, the orthoester was expected to provide a good method to overcome the
steric demands of the two all-carbon-substituted chiral centers (C-9 and C-10)
embedded within the molecule (see Scheme 2.3). In “tying back” the three
carbons, neopentyl C-9 of intermediate 2.11 (see Scheme 2.2) would be made
accessible to alkylation. Secondly, serving simultaneously as a protecting group,
the orthoester upon hydrolysis, reveals three alcohol groups needed for further
functionalization (see Scheme 2.4).
OMe
CO2R
OH hydrolysis
OMe
OH
OO
HOHOOO
O
OMe
OH
OHHOHO CO2H
2.3 2.12 2.4
Scheme 2.4 – Proposed Result of Opening the Orthoester
73
Upon acid treatment, the revealed triol would be desymmetrized upon lactone
ring formation. Additionally, the functional handles required for further
elaboration are already incorporated into the molecule.
2.2 The Proposed tandem Michael-aldol
2.2.1 Control of diastereoselecivity
The tandem Michael/Aldol reaction could potentially provide diastereoselectivity
via a chelation controlled mechanism.
Scheme 2.5 – Chelation Control Model in the Tandem Michael-aldol Reaction
As demonstrated in Scheme 2.5, after the 1,4-addition, subsequent aldol reaction
was expected to proceed via a six-membered ring transition state due to a
chelation controlled transition state. In the bicyclo[2.2.2]octane intermediate 2.3,
the chiral center at C-8 would be formed diastereoselectively. A tandem
intramolecular Michael/aldol reaction would be key in developing a route in which
74
the diastereoselectivity at C-8 would be controlled by chelation in the ring closure
reaction by a metal ion. As a result, this would provide selectivity in the newly
formed quaternary chiral center at C-8 rather than a diastereomeric mixture.
75
CHAPTER 3 – FORMATION OF THE CYCLOHEXENONE INTERMEDIATE
3.1 Initial attempts to form the orthoester intermediate 3.1
The initial approach toward the synthesis of maoecrystal V required synthesizing
the Michael-aldol substrate, which under basic conditions would potentially result
in the formation of the desired bicyclo[2.2.2]octane intermediate 3.2 (see Scheme
3.1).
Scheme 3.1 – Key Transformation Under Investigation
Therefore, the first step in our synthesis was to explore how to synthesize the
-unsaturated cyclohexenone with the orthoester functional group (see
compound 3.1). This was identified as one of the key intermediates necessary in
the synthesis. With this intermediate in hand, the tandem Michael/Aldol reaction
could be fully explored (see Figure 3.1).
76
Figure 3.1 – The -Unsaturated Cyclohexenone, a Key Intermediate
Initially, the synthetic plan was to start with the methyl cyclohexenone and build
on the orthoester group via a Tollens reaction34 (see Scheme 3.2). 2-Methyl
cyclohexenone was alkylated with allyl bromide using LDA conditions.
Scheme 3.2 – First Attempt at Cyclohexenone Intermediate Synthesis
At this point, selective oxidative cleavage of the terminal alkene was desired.
Various oxidative cleavage methods were investigated and found to be
unsuccessful in revealing the aldehyde necessary for the Tollens condensation
reaction. Selectivity between the terminal alkene over the deactivated -
unsaturated alkene was expected but not observed. This led to a revised
approach, involving alkylation with methyl 2-bromoacetate followed by LiAlH4
reduction to produce the diol. Subsequent Swern oxidation35 gave the desired
dicarbonyl compound 3.4 (see Scheme 3.3).
77
Scheme 3.3 – Investigation of the Tollens Reaction for Triol Formation
This aldehyde intermediate was then used to explore various basic conditions for
the Tollens reaction. It was envisioned that the triol (from a Tollens condensation
with aldehyde 3.4) could be reacted with triethyl orthoacetate to give the
orthoester intermediate 3.1. The Tollens condensation reaction is usually done
under basic conditions and can be used to convert the aldehyde to the
corresponding triol. An example of this is the synthesis of pentaerythritol from
acetaldehyde (see Scheme 3.4).36
Scheme 3.4 – Formation of Pentaerythritol via a Tollens Condensation
Reaction36
78
However, reaction of aldehyde 3.4 under various basic conditions such as
Ba(OH)2, Ca(OH)2, and LiOH in the presence of formaldehyde did not result in
any of the triol but rather repeatedly gave a mixture of products, none of which
were isolable for structural determination.
The presence of multiple reactive sites in cyclohexenone substrate 3.4 may have
contributed to the mixture of products observed. This synthetic route was
attempted because it would have been quite straightforward to obtain the
cyclohexenone substrate required to investigate the Michael-aldol reaction.
However, this result led us to discard this methodology as a possible route to the
desired cyclohexenone intermediate.
3.2 Formation of the -unsaturated cyclohexenone
At this juncture, it was envisioned that a better route to the cyclohexenone
orthoester intermediate would be to first form the orthoester and then build the
cyclohexenone ring. With this in mind, two routes were investigated (see
Scheme 3.5). One approach was to form dialkene intermediate 3.12 after the
orthoester formation. Olefin methathesis37 of the dialkene would give the desired
cyclohexenone ring.
79
O
OO O
HO
HOHO O
O
OO O
O
POMe
OOMe
O
OO O
orthoesterformation
OR
HornerWadsworthEmmons
OlefinMetathesis
3.10
3.11
3.12
3.13
Scheme 3.5 – Envisioned Routes to Intermediate 3.10
The second approach was to make the orthoester and then form phosphonate
aldehyde intermediate 3.13 that would allow for a Horner-Wadsworth-Emmons38-
42 (HWE) type of reaction to give the cyclohexenone ring.
3.3 Initial steps to form the nitrile intermediate
The formation of the orthoester from pentaerythriol and triethyl orthoformate (see
Scheme 3.6) has been previously reported. The procedures by Hall et al.43
required the use of a high boiling solvent, dioctyl phthalate. This reaction has
also been done in toluene.44,45 Not having dioctyl phthalate readily available, the
80
reaction was initially tried with toluene. The result was an intractable reaction
mixture which appeared to be a thick, unmanageable oligomer with no products
identifiable by 1H NMR. Heating the reaction mixture under vacuum did not
sublime off any substantial amount of the orthoester alcohol product 3.15. Hall et
al. employed the use of dioctyl phthalate as the solvent in this type of reaction in
which they had to heat the reaction mixture to 195 ºC.43 They report that “Yields
were variable and the extreme conditions made these experiments somewhat
difficult.” In this study, it was found that the solvent was not necessary for this
reaction (see Scheme 3.6).
Scheme 3.6 – Formation of the Orthoester Alcohol
After distilling off most of the ethanol formed in the reaction, a thick, white slurry
was obtained. The orthoester alcohol 3.15 was sublimed (140 ºC, under 0.1 torr)
and collected as a white solid. This reaction was very reliable and could be
repeated on large scale to obtain hundreds of grams and whose product could be
recrystallized but can also be used directly in the next step after the sublimation.
81
With orthester alcohol 3.15 in hand, further functionalization to the
cyclohexenone was explored. Formation of the methanesulfonate of the alcohol
under normal conditions using triethylamine and methanesulfonyl chloride in
CH2Cl2 was high yielding (see Scheme 3.7) although the product is not stable to
column chromatography.
O
OO
OH
MsCl, NEt3CH2Cl2, 0 °C O
OO
OMsQuantitative
NaCN, DMSO110 C
O
OO
CN
72%
I
n-BuLi, THF-78 °C
O
OO
CN
67%
O
OO
CN
major minor
9 9
3.15 3.16
3.17
3.18
3.19 3.20
Scheme 3.7 – Further Functionalization of the Orthoester Intermediate
This is not a problem as the crude mesylate 3.16 can be reacted with NaCN in
DMSO to give nitrile 3.17 in good yield. Both these steps are very reliable and
the crude nitrile can be purified by recrystallization from ethanol. These first
three steps of the synthesis can reproducibly be done on hundreds of grams with
high yields and no purification is necessary until the nitrile is isolated and
recrystallized.
82
At this point, the nitrile was alkylated with homoallyl iodide using n-BuLi (see
Scheme 3.7). Alkene 3.19 was obtained although it was observed that there was
some side product, which turned out to be the dialkylated product 3.20. The ratio
of alkylated to dialkylated product was initially 7:1. This was surprising since the
neopentyl carbon is sterically hindered. Adding the nitrile anion mixture to a
cooled, stirring solution of homoallyl iodide resulted in obtaining a favorable ratio
of 20:1. Trials with HMPA did not improve the ratio significantly. Various bases
such as NaHMDS, KHMDS, n-BuLi, and LDA were tested. The best results
(conversion and product ratio) are obtained using 0.95 eq. of n-BuLi as the base
and adding the alkylating agent to the nitrile anion solution. Although the
dialkylation was unexpected, it demonstrated that this second alkylation was
possible as this is the C-9 carbon which would be involved with the aldol reaction
to form one of the quaternary all-carbon-substituted stereocenters in the
bicyclo[2.2.2]octane system. The C-9 carbon was accessible to alkylation,
despite being neopentyl at the carbon being alkylated and the orthoester strategy
of “tying back” the three carbons had excellent potential.
3.4 Attempts to functionalize the nitrile
On the outset, the most straightforward method to functionalize nitrile 3.19 was
expected to involve an organometallic addition,46-49 followed by hydrolysis of the
ketimine intermediate 3.21 to yield desired ketone 3.22 (see Scheme 3.8).
83
Scheme 3.8 – Plan for Organometallic Addition to the Nitrile
With this in mind, various organometallic agents were tested against nitrile 3.19
in anticipation of addition to the nitrile. This included vinyl lithium as well as vinyl
Grignard, which would have yielded the dialkene intermediate for the olefin
metathesis. However, none of these organometallic nucleophiles seemed to add
to the nitrile. In fact, any organometallic reagent, even the simple methyl
Grignard did not add. It was not clear at the outset the reason for the lack of
reactivity of the nitrile, as it is not particularly sterically hindered. Further
investigation, of this compound and more advanced compounds, revealed that
the protons are particularly acidic and the result was that rather than
organometallic addition, deprotonation was the major mechanistic trap. This
problem was solved at a later time but for the time being, it is noted here that
other methods for functionalization were utilized, as it was necessary to obtain
the cyclohexenone necessary to test our key transformation.
An alternative pathway was to hydrolyze the nitrile to the corresponding
carboxylic acid. As the orthoester functionality is very acid-sensitive, any acid-
promoted hydrolysis conditions are not amenable. In considering an alternative
84
route in the early stages of the investigation, the nitrile easily hydrolyzed under
acidic conditions (see Scheme 3.9), and as expected, the orthoester hydrolyzed
as well. Intramolecular ring closure gave lactone 3.23. Subsequent protection of
the diol resulted in benzylidene acetal 3.24. However, addition to the lactone to
form ketone 3.25, with various organometallic nucleophiles, was unsuccessful.
The route was not pursued further.
O
OO
CN
3.19
12 M HCl3:1 Dioxane:H2O
reflux O
O
HO
HO
cat. p-TsOHTHF
43%over two steps
Ph
OMe
OMe
O
O
OOPh
[M] R R
O
OOPh
OH
3.23
3.24 3.25
Scheme 3.9 – Orthoester Hydrolysis Investigations
Due to the incompatibility of the orthoester with acid hydrolysis conditions, base
hydrolysis was explored to give the carboxylic acid product. Investigations of
basic conditions showed that, in all cases, the hydrolysis was partial, leading only
to isolation of the amide rather than the carboxylic acid. Even heating with
sodium peroxide50,51 only yielded amide 3.26 (see Scheme 3.10).
85
Scheme 3.10 – Incomplete Basic Hydrolysis
3.5 Completion of the cyclohexenone
Due to the unsuccessful conversion of amide 3.26 to acid 3.27, amide 3.26 was
converted to methyl ester 3.28. Using the conditions reported by Visigalli et al.,52
the amide was functionalized to the methyl ester upon heating in sealed tube at
110 ºC in the presence of dimethylformamide dimethylacetal (DMF-DMA) in
methanol (see Scheme 3.11). The methyl ester was converted to Weinreb amide
3.2953,54 which was then reacted with vinylmagnesium bromide to give dialkene
3.12.
86
, THFO
OO O
NO
OO O
90%O
cat Grubbs2nd Gen.
DCMOO
O
O
80%
O
OO O
NH2O
OO O
OMe
HN(Me)(OMe)•HClMeMgCl, THF, -20 °C
95%88%
Me2N OMe
OMe
MgBr0 °C rt
3.26
MeOH, 110 °C
3.28
3.29 3.12 3.10
Scheme 3.11 – Completion of the Orthoester Cyclohexenone Intermediate
With the dialkene 3.12 in hand, a straightforward metathesis with Grubbs second
generation catalyst37 yielded cyclohexenone 3.10 in useful yields for a total of
nine steps from commercially available pentaeryritol. This route requires an
additional four steps in comparison to a direct organometallic addition (see
Scheme 3.8).
The reaction of the vinyl Grignard with the Weinreb amide, although initially
successful, became problematic on larger reaction scale. The workup required
slow addition of the reaction mixture to a large volume of NaHCO3. Otherwise, a
side-product (the result of the N,O-dimethylhydroxylamine adding to the formed
-unsaturated ketone in a 1,4-addition) would form in appreciable amounts
(see Scheme 3.12).
87
Scheme 3.12 – Details of Vinyl Magnesium Bromide Addition
However, with careful quenching, the by-product could be minimized and the
dialkene isolated in useful yields.
The N,O-dimethylhydroxylamine side-product 3.30 could be avoided by using
allyl allylmagnesium bromide instead of the vinylmagnesium bromide as the
nucleophile (see Scheme 3.13).
Scheme 3.13 – Allylmagnesium bromide Avoids Side-product Formation
88
However, this route required an extra step to isomerize the terminal alkene to
give the -unsaturated ketone 3.31 as a mixture of E/Z isomers. Dialkene 3.32
was also useful in the synthesis and gave cyclohexenone 3.10.
3.6 Use of the Horner-Wadsworth-Emmons (HWE) reaction as alternative
strategy
Athough it was gratifying that the orthoester cyclohexenone was made, the
previously mentioned problem encountered in the addition of the vinyl
magnesium bromide to the Weinreb amide prompted examination of the HWE
pathway toward the cyclohexenone (see Scheme 3.14).
Scheme 3.14 – The HWE Approach to Cyclohexenone 3.10
Dimethyl methylphosphonate was deprotonated with n-BuLi and, in the presence
of HMPA, was treated with the methyl ester (see Scheme 3.15)
.
89
POMe
O OMe
n-BuLi, THFHMPAO
O
OMe
OO
O
OO
O
POMe
OOMe
3.28 3.33
Scheme 3.15 – Initial Attempt to Synthesize the Substrate for the HWE Reaction
However, even upon warming, the methyl ester was unreactive toward the
phosphonate addition. Seeing this result and also considering the unreactive
nitrile that was previously observed, it was hypothesized that the problem here
was the acidic proton. Due to the ready enolization of the ester, the
dimethyoxyphosphoryl methyl lithium was behaving as a base and deprotonating
methyl ester 3.28 rather than nucleophilically adding. This was also
hypothesized to be the problem with the organometallic addition to the nitrile. To
test this hypothesis, the enolization pathway was blocked by installation of a
methyl group (see Scheme 3.16).
POMe
O OMe
n-BuLi, THFHMPA
O
O
OMe
OO
O
OO
O
POMe
OOMe
3.28 3.35
O
O
OMe
O OLDA, MeI
THF-78 °C to rt
98%
3.34
Me Me71%
Scheme 3.16 – Methylation of Ester 3.28 Allowed for Nucleophilic Addition
90
Thus, methyl ester 3.28 was deprotonated with LDA and MeI was added as the
methylating agent. With the methyl group in place, the reaction of the methyl
ester with the phosphonate anion took place, as deprotonation could no longer
occur at the neopentyl carbon, thus favoring nucleophilic addition (see Scheme
3.16).
Phosphonate 3.35 was subjected to oxidative cleavage conditions in order to
obtain aldehyde 3.36. However, ozonolysis conditions did not provide the
aldehyde. Oxidative cleavage conditions using OsO4 and NMO·H2O as the
reoxidant also did not provide the aldehyde. In both cases, cyclohexene 3.38
was obtained (see Scheme 3.17).
O3, NMO•H2OCH2Cl2, 0 C
orOsO4, NMO•H2O
then NaIO43:1 Me2CO/H2O
O
OO
O
O
POMe
OOMe
MeO
OO
O
POMe
OOMe
3.35
Me
not isolated
O
OO
O
OH
POMe
OOMe
MeO
OO
O
POMe
OOMe
Me
3.36
3.37 3.38
Scheme 3.17 – Initial HWE Reaction did not Yield the Desired Cyclohexenone
91
This result indicated that the oxidative cleavage reaction in both cases did
provide aldehyde 3.36. The resulting phosphonate anion reacted with the
proximal aldehyde. This is expected as the first step in the HWE reaction. But
rather than forming the oxaphosphetane intermediate, elimination occurred,
giving the undesired cyclohexenone 3.38.
Seeing this result, dimethyl methylphosphonate was replaced with diethyl
ethylphosphonate. With yet another extra methyl group installed, the undesired
elimination reaction could not occur. Thus, phosphonate 3.39 provided the
product of the HWE reaction, cyclohexenone 3.40 (see Scheme 3.18).
POEt
O OEt
O
OO
O
OMe
POEt
OOEt
DBU, LiClMeCN O
OO
O
Me
O
O
OMe
O O
Me
1. n-BuLiHMPA, THF
2. NMO H2OOsO4, NaIO4
36% over3 steps
LDA, MeITHF
-78 °C to rt
98%
O
O
OMe
OO
H
3.28 3.34
3.39 3.40
Scheme 3.18 – Use of the HWE Reaction in Exploring the Effect of the
Enolizable Proton
92
With the methyl group in place, the reaction of the methyl ester with the
phosphonate anion took place. The HWE reaction with DBU as the base gave
the cyclcohexenone orthoester, albeit with an “extra” methyl group. However,
this result provided insight into the previously mentioned failed attempts at
organometallic addition to the nitrile and would become useful in shortening the
synthesis.
Methyl ester 3.28 was also chlorinated in the position of the ketone
phosphonate. The plan to use this route by replacing the “blocking” methyl with
chloride was successful (see Scheme 3.19).
POMe
O OMe
1. OsO4, NMO•H2Othen NaIO4
2. DBU, LiClMeCN, 0 C
O
OO
O
Cl
O
O
OMe
O O
Cl
1. n-BuLi, THF2. K2CO3, MeI
acetone
40%
LDA, CCl4THF
-78 °C
62%
O
O
OMe
OO
H 50%
O
OO
O
Cl
POMe
OOMe
3.34 3.41
3.42 3.43
Scheme 3.19 – Completion of Orthoester Cyclohexenone by the HWE Reaction
The methyl ester was chlorinated with CCl4 and that product reacted with the
dimethyl methyl phosphonate anion. Surprisingly, the ethyl phosphonate did not
93
react with the ester and the dechlorinated methyl ester was recovered.
Therefore, an extra step of methylating the ketone phosphonate was required.
Oxidative cleavage followed by the intramolecular HWE reaction gave the
cyclohexenone product. Ultimately, this route was not used. Direct
organometallic addition to the nitrile 3.19 was found to be possible (see Scheme
3.8). Knowing that the neopentylic proton to the orthoester was particularly
acidic proved to be invaluable later in the synthetic studies.
After investigating the three routes to the cyclohexenone intermediate, it was
clear that the synthetic scheme of forming the orthoester first, followed by a ring
closure to form the cyclohexenone, would be the most straightforward.
Additionally, the olefin metathesis route was chosen as the shortest and most
efficient to make the desired cyclohexenone ring. With the cyclohexenone in
hand, the next step was the investigation of the intramolecular Michael-aldol
reaction.
94
CHAPTER 4 – EXPLORING THE MICHAEL-ALDOL REACTION
4.1 Attempts to achieve 1,4-addition
With the completion of cyclohexenone orthoester 4.1, focus shifted to exploring
the addition of the pyruvate fragment (1,4-addition) followed by a planned aldol
ring closure (see Scheme 4.1). This key transformation had been proposed for
forming the bicyclo[2.2.2]octane ring. It was initially envisioned that enolate 4.2,
formed from methyl pyruvate, could be the nucleophile in a Michael addition to
cyclohexenone 4.1, to give ketoester intermediate 4.3. Under the basic
conditions required for the Michael reaction, the ketoester could potentially
undergo an intramolecular aldol reaction to form alcohol 4.4.
OOO
OO
O
O
OH
O
OOO
O
O
O
O
Michael Aldol
4.1 4.2
4.3
4.4
OO
O
CO2Me
8
8
Scheme 4.1 – Proposed Michael-Aldol Reaction
95
The ketoester functional group was part of the synthetic design because the
congested C-8 chiral center would be set as a result of the aldol reaction.
Additionally, the ketone group of the ketoester is highly reactive and the ester on
C-8 would be useful to further elaborate to the lactone ring in maoecrystal V.
Conjugate addition to a cyclohexenone can be commonly acheived with the use
of an organocopper or organocuprate reagent but the goal was to examine the
optimal conditions for a tandem Michael-Aldol reaction. If indeed, optimal base
conditions could be found for the Michael addition with a methyl pyruvate
derivative, then the in situ aldol reaction could be expected. Many different
pyruvate derivatives and pyruvate equivalents as nucleophiles were investigated.
In the following section, various methods will be discussed. In many cases,
regioselectivity in the addition to the cyclohexenone was problematic.
4.2 Initial studies using the pyruvate fragment
4.2.1 Organolithium reagents
Investigation began with the simplest of the pyruvate nucleophiles.
Deprotonating methyl pyruvate with LDA resulted in the formation of the lithium
enolate (see Scheme 4.2). Normally, the lithium enolate would be expected to
add to the cyclohexenone in a 1,2-rather than a 1,4-sense.55,56 However, the
lithium enolate reagent was tested because the neighboring substituent, the
96
bulky orthoester group, could potentially hinder 1,2-addition and thus favor 1,4-
additon. The enolate, formed from methyl pyruvate, was reacted with
cyclohexenone intermediate 4.1. The 1,2-addition product did indeed result from
this reaction. This aldol addition product was not isolated. Rather, the resulting
oxyanion reacted with the ester in an intramolecular reaction forming the
spirocyclic dihydrofuran dione as a diastereomeric mixture. This intermediate,
4.6, could not be further elaborated toward maoecrystal V.
Scheme 4.2 – Key Transformation Tested with a Lithium Enolate
4.2.2 Silyl enol ether reagents
Another alternative was to use the silyl enol ether via a Mukaiyama-Michael
reaction.57 The Mukaiyama-Michael reaction is the condensation between a silyl
97
enol ether and an aldehyde or ketone. Thus, the silyl enol ether of methyl
pyruvate was formed (see Scheme 4.3).
OTMS
O
O
O
O
O
NEt3TMSClTHF
77%
TiCl4 or BF3•OEt2O
OO
O
O
O
O
O
OO
O
4.7 4.8
4.1
4.3
Scheme 4.3 – Mukaiyama Aldol Trials
These types of condensation reactions usually require a Lewis acid in either
stoichiometric or catalytic amounts (such as TiCl4 in Mukaiyama’s archetypical
example in 1973)57 to activate the ketone as an electrophile toward the addition
of the silyl enol ether. In this case, a strong Lewis acid is problematic in
conjunction with the presence of the orthoester functionality. Addition of Lewis
acids such as TiCl4 or BF3·OEt2, even in catalytic amounts, resulted in immediate
opening of the orthoester (see Scheme 4.4).
98
TiCl4 or BF3•OEt2CH2Cl2
OH
O
OOO
O
OTMS
O
O
Not isolated4.1
CO2MeOO
O
4.4
Scheme 4.4 – Results of Mukaiyama Aldol Reaction
Other Lewis acids as well as known activating reagents (such as SnCl4, DBU,
TBAF) were tested, but were found to be either too mild (and only the
cylcohexenone starting material was isolated) or too harsh and proved not
compatible to the orthoester functionality. For these reasons, this method was
abandoned.
4.2.3 Attempts using iminium and enamine chemistry
Another common method for 1,4-addition is the use of an in situ formed enamine
species as an active nucleophile (see Scheme 4.5). The enamine undergoes
condensation with aldehydes and ketones to give iminium intermediate 4.10
which upon hydrolysis gives the desired ketoester 4.3.58
99
Scheme 4.5 – Envisioned Proline Promoted Condensation
There are many examples using proline or proline derivatives as promoter
molecules to catalytically mediate aldol reactions.59,60 Efforts to effect
condensation between cyclohexenone 4.1 and methyl pyruvate, with proline and
known promoters such as tetra-butylammonium bromide (TBAB), were
unsuccessful. Recovery of the cyclohexenone starting material was often the
result and heating led to decomposition rather than nucleophilic addition.
To further investigate the possibility of an enamine type of addition, the reaction
was separated into two steps, the formation of the enamine and the addition to
cyclohexenone (see Scheme 4.6).
100
Scheme 4.6 – Investigating an Enamine Nucleophile
Thus, the enamine of the pyruvate fragment (4.11) was formed first (see Scheme
4.6) and then reacted with cyclohexenone 4.1. Various solvents such as toluene
and acetonitrile were tested, and even upon heating to reflux overnight, only
starting material was obtained. Mild Lewis acids can often be used in the
enamine reactions. Thus the reaction was also screened with these activating
reagents such as CuBr2 and SbCl3. The enamine was completely unreactive and
the starting material cyclohexenone was the re-isolated from these types of
reactions.
4.2.4 Organozinc, organocopper and organocuprate investigations
At this juncture, having no success with employing an enolate-type nucleophile,
attention turned to using the organocopper and organocuprate pyruvate
derivatives as nucleophiles for the Michael reaction. Conjugate additions are
often successful with “soft” nucleophiles.61 Thus, an appropriate organocuprate
101
reagent 4.12 would be chosen to investigate this route to the Michael product
(see Scheme 4.7).
Scheme 4.7 – Modified Route Using an Organometallic Addition
The 1,4-addition product 4.13 could potentially undergo subsequent oxidative
cleavage to give the substrate 4.15 (see Scheme 4.7). The -ketoester
intermediate 4.14 is the substrate necessary to investigate the intramolecular
aldol reaction to form the bicyclo[2.2.2]octane.
To gain access to the chosen organocopper reagent, an appropriate
bromoalkene was synthesized according to known procedures (see Scheme
4.8).62
102
Scheme 4.8 – Formation of Ethyl 2-(bromomethyl)acrylate62
A model compound, cyclohexenone, was used to test conditions that might yield
the addition product, which upon cleavage would afford ketoester 4.20 (see
Scheme 4.9). Thus, the design of an appropriate nucleophile had to incorporate
an unsaturated ester as the olefin would reveal the desired ketoester functionality
(following ozonolysis), which was crucial to the subsequent aldol reaction.
O
OEt[M]
O O
O
OEt
O
1.
2. Ozonolysis
4.19 4.20
Scheme 4.9 – Model Studies of Organometallic Addition
Lipshutz et al. reported on the temperamental behavior of allylic organocuprates
in the presence of -unsaturated ketones.63 As such, it is known that allylic
cuprates are ill-behaved and regioselectivity is often not observed. Lipshutz et
al. report that “they are overly reactive and in need of attenuation if discrimination
103
between the 1,4- and 1,2-modes of addition is to be achieved.”63 An example of
this is the addition of the allyl cuprate to the unsaturated ketone intermediate
4.21 (see Scheme 4.10).64 The result was a mixture of starting material, 1,2 and
1,4 products with no selectivity observed.
Scheme 4.10 – An Example of Allylic Cuprate Addition64
However, this type of addition has been studied and it has been shown that a
“neutral organocopper complex… together with TMSCl, provide an effective
means of delivering allylic ligands in a Michael sense.”65-67 Therefore, under
conditions of using TMSCl as an additive and a CuCN·LiCl complex to form the
organocopper reagent (RCuL vs. R2CuLi), a “deactivated” organocopper reagent
is formed. This “deactivated” organocopper reagent that would add exclusively in
the 1,4-sense to cyclohexenone (see Scheme 4.11).68 An example of this is the
addition of the allylic reagent 4.26 to cyclopentanone 4.25 which gave exclusively
the 1,4-addition product.
104
Scheme 4.11 – Use of TMSCl Facilitates Michael Addition68
Organocopper reagents have been synthesized from the reaction of copper salts
with various organometallic reagents. Organolithium reagents and Grignard
reagents are often used for this type of transmetallation to give the desired
organocopper reagent. However, because of the need to incorporate the
adjacent “ester” functionality as part of the nucleophilic fragment, an organozinc
reagent was more suitable. In constrast to organomagnesium and organolithium
reagents, the carbon-zinc bond in an organozinc nucleophile has been shown to
be highly covalent in nature and hence less reactive, allowing for preparation of
derivatives with a wider range of functionalities.69 In particular, it would allow for
direct incorporation of the ester group (part of the pyruvate fragment) which
would have been incompatible with either the organolithium or Grignard
reagents.
Thus, the synthetic plan was to react bromoalkene 4.18 with zinc powder to
obtain the organozinc species 4.29.70 In situ reaction of the organozinc with an
appropriate copper reagent leads to the organocopper reagent 4.30. After initial
screening of organocopper and organocurate reaction conditions with
105
cyclohexenone as the Michael acceptor, it was observed that a ratio of three
different products could be isolated (see Scheme 4.12).
Scheme 4.12 – Studies of the Organocopper Addition on Cyclohexenone
In addition to the formation of the desired 1,4-addition product, the two side
products that were isolated showed two competing reactions – the Wurtz
coupling of the organozinc reagent and 1,2-addition (see Scheme 4.12). Despite
using Lipshutz’s reported method of forming the deactivated organocopper
reagent,63 the regioselectivity was problematic.
Screening of various conditions to form the organocopper reagent was
investigated using cyclohexenone as the Michael acceptor. It was found that the
106
CuBr•Me2S reagent rather than the CuCN•2LiCl complex afforded a useful
organocopper reagent. Optimization of conditions thus led to acceptable yields
of the Michael product (See Table 4.1).
Table 4.1 – Investigation into Organocopper Reaction Conditions
O
EtO
O
OEt
O
Wurtz Product
O
O
1,2-addition product
OR OROEt
O
1,4-addition product
4.31 4.32 4.33
Entry Conditions Result
1 cat CuCN•2LiCl (-10 ºC) Cyclohexenone (-25 ºC)
4.32
2 cat CuCN•2LiCl (-78 ºC)
Cyclohexenone (78 ºC → RT) 4.32
3 cat CuCN•2LiCl (-20 ºC) Cyclohexenone (-78 ºC) 4.33
4 1.1 eq CuCN•2LiCl (-78 ºC → -20 ºC)
Cyclohexenone (-78 ºC) 4.33
5 2.1 eq CuCN•2LiCl (-78 ºC → -20 ºC)
Cyclohexenone added as ATPH71 complex (-78 ºC)
4.33
6 2.1 eq CuCN•2LiCl and TMSCl
(-10 ºC → 0 ºC) Cyclohexenone (-78 ºC)
No major product isolated
7 2.1 eq CuBr•Me2S (-78 ºC)
Cyclohexenone (-78 ºC) 4.33
8 2.1 eq CuBr•Me2S and TMSCl
(-78 ºC → -25 ºC) Cyclohexenone added at -78 ºC
4.31 48% yield
107
With satisfactory conditions found with the model compound, the same
conditions were used to react with orthoester cyclohexenone 4.1. The
application of the organocopper reaction with TMSCl as an additive did indeed
give the 1,4-addition product (see Scheme 4.13).
BrZn OEt
O
O b) CuBr•SMe2, thenTMSClc) Cyclohexenone
a)
O
OO
O OHO
O
OHOAcO
HOOEt
O
O
OEt
4.1 4.34
4.35
4.29
HO
H H
H
Scheme 4.13 – Product Obtained from Organocopper Conditions
Unfortunately, the TMSCl additive was not compatible with the orthoester
functionality. It was deduced that the orthoester had cleaved. Upon orthoester
cleavage, one of the resulting alcohol groups reacted with the ketone to give
hemiacetal product 4.35 (tentatively assigned). Interestingly, the 1,4-addition
was diastereoselective as only one isomer was isolated.
108
Because of this result, base “buffered” conditions were tested using the model
compound. Thus, the presence of a hindered base, such as 2,6-lutidine might
prevent the orthoester from being cleaved. The reaction conditions mentioned
above were again tested on the model compound with the addition of 2,6-lutidine.
Interestingly, the compound isolated was exclusively the 1,2-addition product
(see Scheme 4.14).
Scheme 4.14 – Further Investigations with the Model Compound
However, the 1,2-addition product 4.36, unlike the spirocyclic dihydrofuran 4.6
from the organolithium reaction, was seen as potentially useful in the synthetic
scheme because the resulting tertiary alchol was TMS-protected and did not
react with the existing ester to form a 5-membered ring. Upon reaction with tetra-
n-butylammonium fluoride (TBAF) to remove the TMS protecting group, an in situ
anionic oxy-Cope rearrangement occurred to give the same product as would
result from 1,4-addition (see Scheme 4.14). Again, the conditions that were
found effective for the model compound were tested against the orthoester
109
substituted cyclohexenone 4.1. However, it did not react and only the starting
material was recovered (see Scheme 4.15).
Scheme 4.15 – Testing the 2,6-lutidine Modified Conditions
The results of the organocopper trials revealed that the organocopper reagents
were not reactive enough and did not add to the cyclohexenone intermediate 4.1.
It was observed that the 1,2-addition product could be trapped and undergo a
oxy-Cope reaction to give the 1,4-addition product. In the previous reactions, the
organocopper reagents had their reactivity “tamed” due to the allylic cuprates
being ill-behaved toward -unsaturated ketones.63,65,66 However, if 1,2-addition
is useful via anionic oxy-Cope rearrangement, the allylic organocopper reagent
does not have the constraints that 1,4-addition requires and as a result, more
reactive nucleophiles could be used.
The more reactive organozinc reagent was investigated (see Scheme 4.16). The
organozinc reagent was not reactive at -78 ºC but upon warming, the organozinc
reacted to give the Wurtz product exclusively.
110
OO
OO
BrZn OEt
O
TMSCl, 2,6-lutidineTHF, -78 C
CyclohexenoneIntermediate 4.1
and WurtzCoupling Product 4.32
4.1
4.29
Scheme 4.16 – Organozinc Results
The organocuprate reagent did add to the cyclohexenone intermediate, albeit in
a 1,2-addition, as expected (see Scheme 4.17).
Scheme 4.17 – Organocuprate Results
However, without the addition of TMSCl, the resulting tertiary alcohol reacted
with the ester to give the spirocyclic dihydrofuran dione product 4.6. Addition of
111
the TMSCl (as an additive and to trap the tertiary alcohol and avoid the synthetic
trap of ring closure) gave no reaction.
4.2.5 The use of vinyl rather than allylic substrates
Due to the inability to add the pyruvate fragment or its allyl equivalent, a modified
synthetic route was devised to obtain ketoester 4.3 to test the second ring
closure (aldol reaction), of the key transformation, before more effort was
expended to make the 1,4-addition of the allyl fragment successful (see Scheme
4.18). The aim was to be able to move forward to test the synthetic plan to form
the bicyclo[2.2.2]octane.
Scheme 4.18 – Proposed Aldol Reaction
Rather than using the allylic nucleophile, vinyl cuprate was prepared via vinyl
magnesium bromide. The vinyl cuprate was reacted with cyclohexenone 4.1
(see Scheme 4.19). The vinyl cuprate, unlike the problematic and promiscuous
112
allylic nucleophile was successfully added and the resulting alkene was isolated
(5:1 dr).
Scheme 4.19 – Modified Route to the Ketoester
The mixture of diastereomers obtained from the vinyl cuprate addition was
subjected to ozonolysis conditions. Initially, the ozonolysis reaction was carried
out using addition of dimethyl sulfide (DMS) to decompose the ozonide.
However, even with the ozonolysis progress being monitored to avoid side
reactions, very low yields of around 15% were obtained. Due to this result other
oxidative cleavage conditions were investigated. One alternative was the
stepwise dihydroxylation and subsequent diol cleavage reaction sequence (see
Scheme 4.20). Using NMO/OsO4 conditions, the diol was obtained, however, in
low yields. Attempts to convert the diol to the aldehyde (via oxidative cleavage)
were unsuccessful. Subjecting the diol to NaIO4 conditions resulted in a product
in which the orthoester was hydrolyzed (confirmed by 1H NMR).
113
Scheme 4.20 – Investigating the Oxidative Cleavage
Ultimately, it was found that the alkene could be oxidized to the aldehyde using a
modified ozonolysis method utilizing addition of NMO●H2O (see Scheme 4.21).72
R3NO
R
OO
ONR3
RO
OO
R
primaryozonide
R
OO
O
CH2
carbonyloxide
O
O
O
R
1,2,4-trioxolane
DMS
amineoxide
O R
O R
4.41 4.42 4.43 4.44 4.45
4.46
4.47 4.45
O3NR3 orNMO
Scheme 4.21 – Suggested Intermediate in Modified Ozonolysis72,73
This method of ozonolysis avoids the formation of the 1,2,4-trioxolanes 4.44 by
intercepting the carbonyl oxide 4.43 with the nucleophilic amine oxide 4.46 (see
Scheme 4.21). The addition of the amine oxide to the carbonyl oxide generates
114
an unstable zwitterionic peroxyacetal 4.47. The peroxyacetal intermediate
undergoes decomposition to generate aldehyde 4.45.73
As stated by Dussault et al., “This reaction, which appears to involve an
unprecedented trapping and fragmentation of the short-lived carbonyl oxide
intermediates, avoids the hazards associated with generation and isolation of
ozonides or other peroxide products.”72 Additionally we found that Dussault’s
strategy was highly useful in our synthesis as these conditions do not require the
tradition DMS reduction step and the reaction mixture can then be worked up
with a Na2S2O3/NaHCO3 solution to remove the excess NMO. The product is
used directly in the next step without any purification, as the aldehyde was not
stable to chromotography (see Scheme 4.22).
O
OO O
H
H
OOO
O
O
NMO•H2O,O3, CH2Cl2
-78 C
P
O
OO
O
O
OTES
O
OO O
OTES
O
O
48%over 2 steps
LiNTMS2
NEt3, MeOHO
OO O
O
O
O
83%
4.37 4.40
4.48 4.3
4.47
Scheme 4.22 – Route to the Ketoester
115
After investigating the HWE reactions with a variety of known basic conditions
(such as Ba(OH)2 and DBU), it was found that the crude aldehyde could be
reacted with TES-protected phosphonate 4.47, with LiNTMS2 as the base, in
good yields.
The silyl enol ether type of phosphonates required for the HWE could be made in
a four step sequence from tartaric acid (see Scheme 4.23). Tartaric acid 4.49
was converted to the methyl ester under boric acid conditions74 followed by
oxidative cleavage with periodic acid.75 This resulted in the methyl glyoxylate
4.51 which was reacted with dimethyl phosphite in the presence of catalytic p-
TsOH to give methyl phosphonate 4.52.76 The methyl phosphonate could be
protected with TBSCl or TESCl.
Scheme 4.23 – Synthesis of Phosphonate 4.47
116
The TBS-protected version of the phosphonate intermediate was originally made
following a known procedure.76 However, it was found that deprotection of the
HWE product (the TBS-protected silyl enol ether) with TBAF and other fluoride
based reagents (as the orthoester is not compatible with the usual acidic
conditions) gave yields of about 15%. The TES-protected intermediate 4.48 was
thus synthesized and subsequent deprotection under mildly basic conditions
gave the desired ketoester (see Scheme 4.22) in much higher yields (83%).
4.3 Testing the aldol reaction to form the bicyclo[2.2.2]octane
With the desired ketoester synthesized, the key aldol reaction to form bicyclo
[2.2.2]-octane was investigated. It was initially envisioned that a lithium base
would be used to effect this key transformation (see Scheme 4.24).
Scheme 4.24 – Chelation Control in the Proposed Transition State of the Aldol
Reaction
117
However, testing of various lithium basic such as LDA and LHMDS all resulted in
decomposition. After further examination, it was concluded that the common
enolate forming base conditions (NaOMe, NaHMDS, KOtBu, NaOH) did not give
the ring closure product. Additionally, decomposition was a problem (see
Scheme 4.25).
Scheme 4.25 – Test of Ring Closure with the Ketoester 4.3
4.4 Model compound studies – replacement of the ketoester
The ketoester had been chosen initially for two main reasons. First, upon the
desired aldol ring closure, the sterically congested C-8 chiral center of
maoecrystal V (see Figure 4.1) would be made. Secondly, the ketoester would
provide a more reactive electrophilic carbonyl in the planned aldol ring closure
than many other carbonyl containing functional groups. However, due to
decomposition under the aldol conditions, further investigation into its suitability
was needed. Therefore model studies were used to determine possible
replacements for the ketoester functionality.
118
O
OO
O
O
8
O
CO2Me
OH8
maoecrystal V4.54 4.4
OO
O
Figure 4.1 – Maoecrystal V and the Aldol Product
Because all the base conditions tested for the aldol reaction had resulted in total
compound decomposition, three model systems were designed and tested for
determining if the ketoester functionality was not base compatible and if so, what
fragment would be suitable (see Figure 4.2).
Figure 4.2 – Model System Compared to Actual Orthoester Containing System
Three derivatives were made. First, cyclohexenone 4.56 was reacted with the
previously-used allylic organocuprate and the resulting alkene was subjected to
ozonolysis to give ketoester test compound 4.55 (see Scheme 4.26).
119
[Cu] OEt
O
O
O
OEt
O
1.
2. O3, CH2Cl2DMS
33%
O
4.56 4.55
Scheme 4.26 – Synthesis of the Ketoester Test Compound
Cyclohexenone 4.56 was also reacted with allyltrimethylsilane in the presence of
TiCl4 as the Lewis acid to give the Michael product with the terminal olefin 4.5777
(see Scheme 4.27).
Scheme 4.27 – Synthesis of the Aldehyde and Ketone Test Compounds
120
Alkene 4.57 was further functionalized with two separate routes. An oxidative
cleavage with OsO4/NaIO4 gave aldehyde 4.58. The same alkene starting
material could be dihydroxylated, mono-protected with TBSCl and oxidized
(using a final Ley oxidation)78,79 to give the protected keto-alcohol 4.60.
With these three model compounds synthesized, all were subjected to various
enolate forming basic conditions. Similar to the results of attempting base
promoted ring closure on the elaborated orthoester (containing the ketoester
4.3), decomposition was observed with the model ketoester compound 4.55 (see
Scheme 4.28).
O
O
OTBS
K2CO3MeOH
OH
OTBS
O
56%
O
O
O
O
O
O
OH
O
ProductDecomposition
87%
VariousConditions
K2CO3MeOH
4.55
4.58
4.60
4.62 a, 4.62b
4.61
Scheme 4.28 – Results of the Base Promoted Ring Closure on Test Compounds
121
This led to the conclusion that the ketoester functionality was unsuitable for the
aldol ring closure step. Aldehyde 4.58 as well as the TBS-protected ketoalcohol
compound cyclized under basic conditions, giving the bicyclo[2.2.2]octane
products in both cases.
Additional support for the bicyclic assignment was obtained by oxidation to
diketone 4.63 and confirmed by observed symmetry in 1H NMR (see Scheme
4.29)
OH
O
TPAPNMO H2O
CH2Cl24Å MS
97%
O
O4.87 4.63
Scheme 4.29 – Oxidation to the Diketone Intermediate
Ring closure of the TBS-protected alcohol 4.60 also gave two diastereomeric
products. Due to anisotropic shielding caused by the carbonyl group the
structures of both diastereomers could be assigned by 1H NMR (see Scheme
4.30). In particular, the protons residing in the shielded region of the carbonyl
group were shifted upfield at 1.3 ppm and 3.2-3.3 ppm in comparison to their
deshielded counterpart at 2.7 ppm and 3.4-3.7 ppm respectively.
122
Scheme 4.30 – Diastereoselectivity of the Ring Closure on the Model System
Further NMR studies were also done. HMBC provided further evidence for this
assignment of configuration (see Figure 4.3).
Figure 4.3 – Further Evidence of Configuration Assignment
In the undesired ring closure product, the 3-bond C-H coupling of the protons on
C-14 was highly informative. The carbon to which the TBS-protected alcohol is
attached is approximately eclipsed with the “top” proton (as drawn on C-14) and
123
thus has a small coupling constant of 3.3 Hz. However the geminal proton on C-
14 is not eclipsed and has a dihedral angle of approximately 109º (CVFF). This
gives a larger coupling constant of 10.9 Hz, confirming our previous structural
assignment.
It was also confirmed that the diastereoselectivity of the ring closure could be
controlled by using a lithium base. The diastereoselectivity was predicted to be
controlled by a chelating metal counter ion with a suggested six-membered ring
transition state (see Scheme 4.31).
Scheme 4.31 – Chelation Control in the Proposed Transition of the Aldol
Reaction
This selectivity was demonstrated in the model system. Under K2CO3/MeOH
conditions, with no chelating metal present, the undesired product 4.64 was
obtained as a major product (11:1). Switching to LDA/THF conditions, the
product obtained was predominantly the desired diastereomer 4.62a (35:1) (see
Scheme 4.30). This result may reflect a kinetic versus thermodynamic product
distribution.
124
4.5 Exploring the aldol reaction using a modified substrate
After obtaining these encouraging results, the orthoester starting material for the
aldol reaction was modified to have the protected alcohol motif rather than the
ketoester. This was done using a combination of methods that had been
established, from previous experience, to be compatible with the orthoester
functionality (see Scheme 4.32).
1. NMO•H2OOsO4
2.imid., TBSCl3. NMO•H2O
TPAP, 4Å MS
O
OO O
O
OTBS
O
OO O BrMg
O
OO O
O
OO HO
THF, -78 °C
H
H
H
H
H
KH, 18-crown-6THF, 0 °C rt
97% 66%
41%
4.1 4.65
4.66 4.67
Scheme 4.32 – Synthesis Diketone 4.67
Starting with cyclohexenone 4.1, Grignard addition to the ketone gave alcohol
4.65. Reaction of the alcohol with KH/18-crown-6 promoted the Cope
rearrangement and gave ketone 4.66. The Grignard addition resulted in 1,2-
addition but was remedied by the anionic oxy-Cope rearrangement to give
125
diketone 4.66 (see Scheme 4.33). Elaboration to the protected alcohol motif was
straightforward – dihydroxylation, mono-protection, and oxidation.
This route was possible since the allylmagnesium bromide nucleophile has no
ester component (as compared to the previous allyllic nucleophiles 4.12, 4.29),
the subsequent lactone formation cannot occur and thus the 1,2-addition is not a
dead-end (see Scheme 4.33). The TBS-protected alcohol 4.67 was subjected to
ring closure conditions (see Scheme 4.34).
Scheme 4.33 – Comparison of 1,2-addition Products
The TBS-protected alcohol 4.67 was subjected to ring-closure conditions (see
Scheme 4.34). Ring-closure investigation with the TBS-protected alcohol, using
LDA as the base, did not result in obtaining the desired bicyclo[2.2.2]octane
product 4.68. Unlike the previous ketoester trials, the starting matereial was
recovered and no decomposition was observed. Refluxing K2CO3/MeOH was
tried. Yet again, the starting material was the major product although 5% of the
ring closure product 4.69 (without the TBS group) was also isolated. This led to
the hypothesis that perhaps the TBS protecting group was too large and thus
126
prevented the desired ring closure. The TBS group was removed with TBAF and
the substrate resubjected to basic conditions. Aldol ring-closure product 4.69
obtained.
O
OO O
O
OTBS
OH
O
H
H
OTBS
K2CO3MeOHreflux
5%
OH
O
LDA, THF-78 °C to rt
StartingMaterial
1. TBAF, THF-78 C
2. K2CO3, MeOH
OH
O
4.67 4.68
4.69
4.69
OO
O
OO
O
OO
O
OH
OH
Scheme 4.34 – Results of Ring Closure Investigations of Modified Orthoester
Intermediates
This led to investigations into making the protected alcohol with other protecting
groups that would have differing steric effects. Thus another series of this type of
orthoester intermediate was synthesized (see Scheme 4.35 - 4.36).
127
Scheme 4.35 – Synthesis of the MOM-protected Alcohol
The MOM-protected alcohol was synthesized in the same manner as the TBS-
protected substrate. Starting with diol 4.70, the mono-protection with MOMCl
followed by Ley oxidation80 afforded the MOM-protected substrate (see Scheme
4.35).
O
OO O
ClMg OBn
THF, -78 C
87%
O
OO HO
BnO
KOtBu18-crown-6THF, 0 C
NMO•H2OOsO4 then
NaIO4
O
OO O
BnO
O
OO O
O
BnO
39%
23%
4.1
4.72
4.73
4.74 4.75
Scheme 4.36 – Synthesis of the Benzyl Protected Alcohol
128
The benzyl protected alcohol was synthesized via a route that incorporated the
Cope rearrangement methodology. Instead of using the simpler allylmagnesium
Grignard, the allylic nucleophile was functionalized to contain a benzyl protected
alcohol. After 1,2-addition and Cope rearrangement, oxidative cleavage afforded
the protected benzyl alcohol 4.75.
Both substrates (4.71 and 4.75) were treated with the previously established
basic conditions of K2CO3/MeOH as well LDA/THF (see Scheme 4.37).
Scheme 4.37 – Reactivity of Differently Protected Alcohol Substrates
Despite the smaller protecting group, neither of these substrates afforded the
desired ring closure/aldol product. Rather, in all cases, the starting material was
isolated from the reaction mixture.
Also synthesized was the diketone 4.81 which lacked the required alcohol
functionality for further elaboration to maoecrystal V (see Scheme 4.38). This
was envisioned as a “smaller” substituent (in comparison to -OTBS, -OMOM, -
129
OBn). The diketone 4.81 was synthesized from previously prepared Weinreb
amide 4.78. Addition of methylmagnesium chloride followed by Grubbs
metathesis afforded -unsaturated ketone 4.80. An intramolecular Michael
addition gave the desired diketone 4.81.
N
O
OO O
OMe
MeMgClTHF
0 C rt
89%
O
OO O
O
cat Grubbs2nd Gen.
O
OO O
O
K2CO3MeOH
O
OO O
O
57%
52%
4.78 4.79
4.80 4.81
Scheme 4.38 – Synthesis of Simple Diketone Substrate
Reacting the diketone under LDA or LHMDS conditions proved unsuccessful in
effecting ring closure (see Scheme 4.39).
Scheme 4.39 – Results of Ring Closure Investigations of Ketone 4.81
130
Prolonged heating under K2CO3/MeOH also proved unsuccessful (see Scheme
4.39). Failed cyclization via the aldol reaction was hypothesized to be a steric
issue (substituent size next to the C-8) and/or the reactivity issue of the carbonyl
at C-8. Varying the substituent size did not affect the desired ring closure.
4.6 Obtaining the bicyclo[2.2.2]octane intermediate
The route to ketone 4.81 could be modified to synthesize aldehyde 4.83 (see
Scheme 4.40). This was envisioned as the “smallest” carbonyl group possible (in
comparison to -OTBS, -OMOM, -OBn, -Me). Additionally, carbonyl (C-8) of the
aldehyde is more reactive than the previously investigated ketones.
Scheme 4.40 – Results of Ring Closure Investigations of Aldehyde 4.83
131
Aldehyde 4.83 successfully underwent the intramolecular Michael reaction to
give aldehyde 4.84. In the same reaction mixture, the double ring closure
product 4.85 was also isolated (see Scheme 4.40). Aldehyde 4.84 did produce
the bicyclo[2.2.2]octane product 4.85 (see Table 4.2)
Table 4.2 – Investigations of Substrates for the Aldol Ring Closure Reaction
Entry R Group Result
1 Decomposition
2
No Reaction
3
Aldol Product
4
No Reaction
5
No Reaction
6
No Reaction
7 H
O
Aldol Product
132
The ketoester did not give the aldol ring closure as it resulted in substrate
decomposition. The majority of ketone substituents were unreactive (see entries
2-6 in Table 4.2). The aldehyde substituent was the only successful substrate in
the aldol ring closure reaction. These results led to modification of the synthesic
route, to use aldol product 4.83 for further elaboration toward maoecrystal V.
133
CHAPTER 5 – A MODIFIED STRATEGY
5.1 A modified strategy toward maoecrystal V
Based on the results of the previous studies, the strategy was modified to use
aldehyde 5.2 to form the bicyclo[2.2.2]octane ring system (see Scheme 5.1).
O
OO O
O
O
OH
OO
O
O
Me
OO
O
O
O
OO
O
O
O
crossmetathesis
MichaelReaction
O
OO
H H
Nu
OH
OO
O
CO2R
OHAldol 8 8
5.1 5.2
5.3 5.4
5.5 5.6
Scheme 5.1 – Modified Strategy to Bicyclo[2.2.2]octane Substrate – the New
Strategy / Key Transformation
The aldehyde reacts in an intramolecular Michael reaction to give enolate 5.3.
Tautomerization to enolate 5.4 and subsequent aldol reaction provides the
desired bicyclo[2.2.2]octane product.
134
Thus, alkene 5.1 was reacted with crotonaldehyde to give aldehyde 5.2 and
subsequent aldol reaction under basic conditions provided the
bicyclo[2.2.2]octane product 5.4. The modified Michael-aldol reaction was
somewhat successful, although it did result in a mixture of single and double
cyclization products (see Scheme 5.2).
K2CO3MeOH
5.427%
O
OO O
O
OO O
H
O
5.1 5.2
OH
cat Grubbs2nd Gen.
65%
O
OO O
H
O
5.3
8
8
O
OH
OO
O
17%
Scheme 5.2 – Results of Ring Closure Investigations of Aldehyde 5.2
With aldehyde 5.1 chosen as the substrate in the modified strategy to obtain a
bicyclo[2.2.2]octane intermediate, the synthetic plan now needed to include a
nucleophilic addition to the ketone on C-8 (see Scheme 5.3).
135
OR
OO
O
OH
CNO
OR
OO
O
H+
OR
HO
HO
HO
OH
CN
OR
HO
HO
HO
OH
CO2H
OR
OHHO
HOO
O
CN8
8
OH
OO
R3Si
Me
Me
Li
Maoecrystal V
[O]
O
O
O O
O
O
O O
HO
OO
OR
O
OOO
OR
OR
O
OO
OR
OH
MO
R3Si
OR
5.7 5.8 5.9 5.10
5.11 5.12 5.13
5.14
5.15 5.16 5.17
Scheme 5.3 – The Modified Synthetic Plan
Cyanide addition to the ketone would provide nitrile 5.8. Simultaneous hydrolysis
of the orthoester group as well as the nitrile would give tetraol intermediate 5.10.
In situ ring closure would provide lactone intermediate 5.11. Oxidation of diol
5.11 would give dialdehyde 5.12. An intramolecular ring closure would give
furanoid intermediate 5.13. Reaction of aldehyde 5.13 with organolithium
nucleophile 5.14 would give alkene 5.15. An intramolecular reaction between the
alkene and an in situ-formed oxocarbenium ion intermediate on the furanoid ring,
followed by oxidation would result in the formation of the required cyclohexene
136
ring. Deprotection, oxidation, and methylation would result in a total synthesis of
maoecrystal V (5.17).
To use aldehyde 5.2 as the substrate for the modified synthetic plan, optimization
of the aldol ring closure reaction was required. An aldol reaction using aldehyde
5.18 was the method that provided a useful entry into the bicyclo[2.2.2]octane
ring system (see Scheme 5.4).
Scheme 5.4 – The Model System for the Aldol Ring Closure Reaction
This type of simplified ring closure had been studied in the synthesis of various
other natural products (see Scheme 5.5).81,82 In 1963, Ireland et al. studied this
type of intramolecular aldol reaction in synthetic studies toward the alkaloid
atisine.81 This is an important intramolecular process. It is useful for the
construction of bridged steroid derivatives since it leads to a bicyclo[2.2.2]octane
system. In 1966, Ireland et al. employed this type of intramolecular aldol in the
synthesis of kaurene.83
137
An important consideration in this type of ring closure is diastereoselectivity. In
the simplified case of compound 5.20, ring closure gives an epimeric mixture of
6-endo- and 6-exo-hydroxybicyclo[2.2.2]octan-2-ones which are in equilibrium
through the parent ketoaldehyde (Scheme 5.2).82
Scheme 5.5 – Formation of 6-endo and 6-exo-hydroxybicyclo[2.2.2]octan-2-one82
It has been shown that in this system, the endo product is the thermodynamic
and kinetic product. The endo epimer has 0.6 kcal/mol less strain energy than
the exo epimer.82,84,85
These results were encouraging for this synthesis in that there would potentially
be the necessary diastereoselectivity in the ring closure reaction. In particular,
the hydroxyl group on C-15 is potentially useful as a handle to control the
diastereoselective addition to the ketone on C-8 as well as the addition to the
proposed oxocarbenium intermediate 5.13 (see Scheme 5.6).
138
Scheme 5.6 – Substituent on C-15 – a Useful Handle
5.1.1 Modifications of the Original Synthetic Route
Initially, synthesis of enal 5.2 required a lengthy nine steps from penterythritol
(see Scheme 5.7). The synthesis of aldehyde 5.2 from pentaerythritol is
discussed in chapter four.
Scheme 5.7 – The Original Route to Aldehyde 5.2
However, a shorter sequence of steps is now employed for the large scale
synthesis of -unsaturated aldehyde 5.2, required for the tandem Michael-
aldol. Since the early stages of the synthetic work toward maoecrystal V, an
139
ongoing investigation into a shorter route to functionalize nitrile 5.25 (see
Scheme 5.8) had been continually on going.
Scheme 5.8 – Previous Functionalization Obstacle
Indeed, the lengthy route was primarily due to the inability to add nucleophiles
directly to nitrile 5.25. The original route required a lengthy procedure to
functionalize the nitrile to the diene 5.26. As previously discussed, the evidence
pointed toward the acidity of the neopentyl proton as being problematic. In
looking for a solution, organocerium reagents were considered.86 Imamoto et al.
has shown organocerium reagents to be less basic than Grignards and
organolithium reagents.87 Additionally, they react cleanly and are reliable
nucleophiles.88
Attempts to functionalize nitrile 5.25 were investigated using the organocerium
reagent. The nitrile could quickly be functionalized to the desired ketone 5.1 with
the use of a methylcerium reagent (see Scheme 5.9).
140
O
OO
CN
O
OO
O
I
n-BuLi, -78 °Cthen MeMgCl
CeCl3, THF0 °C
75%from the nitrile
AcOH, H2OTHF, rt
O
OO
CN
O
OO
NH
5.28 5.25
5.28 5.1
Scheme 5.9 – Shortened Synthetic Sequence using a Methylcerium Reagent
Therefore, starting from nitrile 5.28, addition of n-BuLi followed by addition of the
homoallyl iodide gave the alkylated nitrile 5.25 (the dialkylated species previously
discussed could be avoided with careful addition of less than one equivalent of n-
BuLi). In situ addition of the organocerium reagent (made from
methylmagnesium chloride) resulted in methyl addition to nitrile 5.25. Workup of
this reaction with non-acidic conditions to avoid hydrolysis of the orthoester
resulted in the isolation of imine 5.28, which could be hydrolyzed to the desired
ketone 5.1 using acetic acid. Thus, the methylcerium reagent allowed for direct
alkylation of the nitrile and this route avoids the lengthy hydrolysis sequence that
had been used previously.
141
The organocerium route was employed in making cyclohexenone 5.31 which was
used in investigating the previously proposed key transformation (see Scheme
5.10).
Scheme 5.10 – Synthesis of Cyclohexene 5.31 from Methyl Ketone 5.1
Application of the new strategy outlined in Scheme 5.4 required -unsaturated
aldehyde 5.2 as it was the substrate necessary for the modified tandem Michael-
aldol reaction. Using the organocerium reagent, synthesis of the -unsaturated
aldehyde 5.2 was a short six step sequence from commercially available
pentaerythritol 5.24 (see Scheme 5.11).
142
O
OO
O
O
OO
CNHO OH
OHHO
1. p-TsOH, MeC(OEt)3neat, 130 °C
2. MsCl, Et3NCH2Cl2, 0 °C
3. NaCN, DMSO95 °C, 12 h
1. i) n-BuLi, -78 °Cthen
I
Grubbs (II) catCH2Cl2, rt
75%
80%
71%
ii) MeMgClCeCl3, THF
0 °C2. AcOH, H2O
THF, rt
O
O
OO
O
O
5.24 5.28
5.1 5.2
Scheme 5.11 – Current Approach to the Bicyclo[2.2.2]octane Intermediate
From pentaerythritol 5.24, the steps of orthoester formation with
triethylorthoacetate, formation of the methanesulfonate and reaction with sodium
cyanide gives nitrile 5.28 with 71% yield over three steps. Then the modified
step of alkylating with homoallyl iodide and in situ addition of the methylcerium
reagent gave the imine product which can be hydrolyzed to ketone 5.1 in 75%
yield over two steps. Finally, olefin metathesis with crotonaldehyde gives the
-unsaturated aldehyde 5.2 in 80% yield. The synthesis to this new key
intermediate, aldehyde 5.2, is shortened from what would originally have been
nine steps to six high yielding steps, each of which can be carried out on
multigram scale.
143
5.1.2 Modified Intramolecular Tandem Michael Aldol Reaction – the New
Key Transformation
Aldehyde 5.2 was synthesized to be used as the substrate in testing our modified
strategy, which was a tandem intramolecular Michael-aldol reaction. The
conditions that were previously successful in the aldol reaction (K2CO3/MeOH)
were found to promote the desired ring closure to some extent (see Scheme
5.12).
O
OO O
O
HO
OO O
H
O
K2CO3MeOH
O
OH
OO
O
K2CO3MeOH
O
OH
OO
O
5.3 5.45.2
5.4
5 : 817% : 27%
O
OO O
H
O O
OH
OO
O5.3 5.4
5 : 8
Scheme 5.12 – Exploring the Modified Tandem Michael-Aldol Reaction
For an unoptimized reaction, the results were promising. Two products were
isolated in a ratio of 5:8. One product was the result of the first ring closure – the
Michael reaction giving aldehyde 5.3. The major product was the desired
144
product whereby the subsequent aldol reaction had occurred to give the
bicyclo[2.2.2]octane intermediate 5.4. Interestingly, the observed ratio of singly
versus doubly cyclized products represents the equilibrium ratio between these
two compounds under the K2CO3/MeOH conditions. If the doubly cyclized
product is isolated by chromatography and resubjected to the same
K2CO3/MeOH conditions, after a several hours, the equilibrium between the two
aforementioned products is reached. The same two products can be isolated in
the same ratio of 5:8.
The product ratio from the K2CO3/MeOH reaction conditions was not satisfactory.
Under the original conditions, 17% of Michael product 5.3 was isolated and only
27% of the desired bicyclo[2.2.2]octane product 5.4 was obtained from the
reaction. Thus, optimization was required.
Under some basic conditions, only product A (5.3), the result of the Michael
cyclization, was isolated. In other conditions, both product A and B (5.3 and 5.4)
were isolated as a mixture, much like the initial K2CO3/MeOH reaction conditions
used. Other reactions conditions gave primarily the desired product B (5.4) but
in low yields. After investigations into varying the base identity, reaction
temperature, and solvent systems, optimal reaction conditions were chosen (see
Table 5.1).
145
Table 5.1 – Investigation of Optimal Conditions for Double Cyclization
Base Conditions Result
1 LDA (0.9 eq) THF, -78 °C to RT A, major decomposed
2 KOtBu 1% THF, RT Mixture A and B and SM
3 KOtBu (0.8 eq) THF, -25 °C B with unknown impurity
4 KOtBu (0.1 eq) THF, -25 °C Product unknown impurity
5 K2CO3 CH2Cl2, RT No reaction
6 K2CO3 MeOH, reflux 2hrs Total decomposition
7 K2CO3 Acetone w/cat MeOH Mixture A and B and SM
8 K2CO3 DMF, RT No reaction
9 K2CO3 MeCN w/cat MeOH No reaction
10 K2CO3 DMF w/cat MeOH B – 52%
11 K2CO3 DMF/MeOH
cat BHT B – 45%
12 K2CO3 DMF w/cat MeOH
(no workup) B – 60%
13 Na2CO3 3:1 Dioxane/H2O B – 45%
14 Na2CO3 3:1 Dioxane/H2O
(no workup) B – 63%
15 DBU MeCN, RT(no workup) B - 12%
16 DBU MeCN (slow addition of SM,
no workup) B - 28%
17 DBU DMF, RT B - 40% (some product lost
in aqueous workup)
18 DBU DMF, 0 °C SM and B
19 DBU MeCN (dilute SM and DBU
soln – slow addition B – 22%
146
Using the 3:1 Dioxane/H2O solvent system as well as Na2CO3 as the base, the
desired bicyclo[2.2.2]octane intermediate can be obtained in 63% yield (see
Scheme 5.13). This reaction behaved well under scale up conditions and can
also be carried out on a multigram scale with slightly lower yields
Scheme 5.13 – Optimized Double Cyclization Conditions
The diastereoselectivity of the aldol cyclization was also of particular interest. As
previously discussed, the desired endo product was expected to be the major
diastereomer.
O
OH
OO
O 5.4
Figure 5.1 – Stereochemical Outcome of the Michael-aldol Reaction Confirmed
by X-ray Crystal Structure
147
The secondary ring closure is diastereoselective. Only one isomer of the
bicyclo[2.2.2]octane product was isolated. The crystal structure of the bicyclic
compound confirms the configuration of the alcohol chiral center (see Figure 5.1).
The exo product was not isolated from the reaction mixture.
The observed diastereoselectivity would play an important part in the further
functionalization toward maoecrystal V. The alcohol group allowed for
diastereoselective control of subsequent reactions in the elaboration of
bicyclo[2.2.2]octane 5.4.
5.2 Further functionalization – addition to the ketone
With the bicyclic framework completed, the next step was to investigate the
nucleophilic addition to ketone 5.7 (see Scheme 5.14). Thus, diastereoselective
addition to ketone 5.7 was crucial to the further functionalization toward
maoecrystal V.
Cyanide addition to ketone 5.7 would be ideal as it would potentially allow for
both the incorporation of one carbon as well as the formation of the lactone ring
upon hydrolysis (see Scheme 5.14).
148
OR
OO
O
OH
CNO
OR
OO
O
H+
OR
HO
HO
HO
OH
CN
OR
HO
HO
HO
OH
CO2H
OR
OHHO
HOO
O
CN
5.7 5.8 5.9
5.10 5.11
Scheme 5.14 – Potential Synthetic Route via Cyanide Addition
Another key aspect of this addition was that it was expected to be
diastereoselective. The alcohol becomes useful to control the formation of
subsequent chiral centers. In the nucleophilic addition to ketone 5.7, it was
expected that addition would favor approach from the bottom face (as drawn),
away from the alcohol group.
5.3 Investigations into an appropriate protecting group
The next step was to protect the alcohol group of ketone 5.4 which would allow
for nucleophilic addition to the ketone. At this stage, it was found that the alcohol
could be easily protected with either the –TES (triethylsilyl) or –Boc (tert-
butyloxycarbonyl) protecting groups (see Scheme 5.15). The alcohol on the
149
intermediate 5.4 was too hindered for (tert-butyldimethyl chloride) TBSCl to be
used.
Scheme 5.15 – Protection of Alcohol 5.4
Different protecting groups were necessary at a later stage, due to the
constraints of later reaction conditions. These will be discussed as they were
encountered. At this point, for the purposes of investigating the appropriate
nucleophile for addition to the ketone, the –TES and –Boc protected substrates
were used.
5.4 Investigations into an appropriate nucleophile
The usual nucleophilic cyanide reagents were investigated. NaCN, KCN,
TMSCN, and Nagata’s reagent (Et2AlCN)89 were tested as potential nucleophilic
reagents but in all cases, only starting material was recovered and cyanide
addition was not effected. Investigations were made into intramolecular trapping
of the cyanohydrin, one reason for the use of the Boc-protecting group (see
150
Scheme 5.16). However, despite testing the Boc-protected substrate against a
battery of hydrocyanation conditions, none yielded the desired transformation.
Scheme 5.16 – Trying to Trap the Cyanohydrin (Boc-Version)
Use of a more reactive trapping group was explored. Thus, the imidazole
carbamate intermediate 5.32 was made (see Scheme 5.17).
Scheme 5.17 – Trying to Trap the Cyanide Addition Product (CDI-Version)
151
Intermediate 5.32 was made with the consideration that the carbonyl group of
this derivative would be a more reactive electrophilic target than that of the Boc-
protecting group (the imidazole being a good leaving group). However, upon
reacting the imidazole intermediate 5.32 with various cyanide addition reagents,
the desired transformation did not occur. In fact, under some reaction conditions
(e.g. as in the KCN, 18-crown-6, ACN reaction), the product that was isolated
was the result of the imidazole carbamate fragment reacting with the cyanide
nucleophile to give the carbonocyanidate product 5.33. Heating this product at
reflux overnight under the same cyanide addition conditions still did not afford the
desired product of the cyanide addition to the ketone.
Unable to add cyanide to the ketone, even using trapping methods, other
nucleophiles were considered (see Scheme 5.18). In broadening the scope of
the search for a useful nucleophile, many “acyl” equivalents were examined. The
organolithium derivative (resulting from reaction of vinyl ethyl ether and t-BuLi) as
well as its organocerium derivative was unreactive toward the ketone group (see
Scheme 5.18). The “smaller” vinylmagnesium bromide and its organocerium
derivative were both examined as well, with no success. Only the TMS-
acetylide, termed a “slender” anion by Trauner,22 resulted in addition to the
ketone. It is hypothesized that the challenge here is a combination of 1) the
crowded environment around the neopentyl ketone as well as 2) an undesired
deprotonation reaction.
152
OPG
OO
O
OH
CNO
OPG
OO
O
CN
R
[M]
M= Mg or Li or CeR = H or OEt
OPG
OO
O
OH
R
OBoc
OO
O
OH
Me3Si [Ce]
-78 C -30 °C
TMS
73%PG = Boc
5.29, PG = TES5.30, PG = Boc
5.34 5.35
5.36
Scheme 5.18 – Investigation of Nucleophilic Addition to Ketone 5.29 and 5.30
As evidence of the undesired deprotonation, even the organomagnesium and
organolithium version of the “slender” TMS-acetylene did not add and only the
corresponding organocerium reagent was successful as a nucleophile. All other
reactions resulted in unreacted starting material.
The TMS-acetylene reaction was highly diastereoselective, the anion adding to
only one face of the ketone. This expected outcome was confirmed by X-ray
diffraction analysis.
153
5.5 Investigation of the oxidative cleavage of the alkynyl substitutent and
subsequent lactone formation
With the addition of the alkynyl nucleophile, further functionalization required
cleavage of the TMS group followed by oxidative cleavage of the terminal alkyne
to give either the carboxylic acid or ester intermediate (see Scheme 5.19).
Scheme 5.19 – Investigations of Alkyne Functionalization
The trimethysilyl (TMS) group can be cleaved using TBAF. However, oxidative
cleavage of the resulting terminal alkyne using RuO4 conditions90-92 gave
unsatisfactory results. Additionally, ozonolysis did not oxidatively cleave the
alkyne. Thus, the usual cleavage conditions of a terminal alkyne proved to be
ineffective, perhaps due to the crowded environment existing around the alkyne.
To further elaborate this intermediate, the alkyne was hydrogentated under
Lindlar conditions to give the alkene in good yield (see Scheme 5.20). The
154
alkene was also subjected to various oxidative cleavage conditions and it was
found that ozonolysis with added NMO·H2O resulted in effecting alkene cleavage,
forming aldehyde 5.41.
OBoc
OO
O
OH
OBoc
OO
O
OH
O
Pd on BaSO4pyr, PhMe
78%
OBoc
OO
O
OHO3, NMO•H2OCH2Cl2, 0 C
67%
OBoc
OO
O
OH
CO2H
[O]
5.37 5.40
5.41 5.38
Scheme 5.20 – Further Functionalization of Alkyne 5.37
However, further oxidation to the carboxylic acid could not be achieved.
Therefore, the aldehyde intermediate 5.41 was subjected to acidic conditions to
affect the hydrolysis of the orthoester (see Scheme 5.21). In situ hemiacetal
formation was expected and the mixture of four possible diastereomers was
further reacted, without purification, under basic conditions to cleave the acetate
group. Potentially, this series of steps would result in triol 5.43 as a mixture of
two diastereomers. However, these steps gave a crude material the identity of
which was inconclusive by 1H NMR. However, it could be determined that the
mixture of products was the result of the migration of the Boc protecting group
155
under the basic conditions due to the close proximity of numerous alcohol groups
on the molecule. Thus, it was concluded that a different protecting group was
needed.
OBoc
OO
O
OH
O
PPTS4:1
THF/H2O
K2CO3MeOH0 C
OBoc
HOAcO
OH
OHO
OBoc
AcOHO
OH
OHO
OBoc
HOHO
OH
OHO
Oxidation
OBoc
HOHO
OH
OO
1H NMR
inconclusive
5.41 5.42a 5.42b
5.43 5.44
Scheme 5.21 – Investigations into Lactone Ring Formation
5.6 Concurrent investigation of the furanoid ring formation and reverse
prenylation reaction
While work was on-going in the direction of the lactone ring formation, concurrent
investigations into the furanoid ring formation were also carried out. Of particular
interest was the methodology to form the congested carbon-carbon bond
between C-4 and C-5 on maoecrystal V (see Figure 5.2).
156
O
OO
O
O
4
5
Figure 5.2 – The Last Congested Carbon-Carbon Bond Formation Needed
Starting with the previously synthesized alcohol 5.4, it was found that addition of
the alkynyl cerium regeant could be effective without protection of the alcohol
functionality. Thus, TMS-acetylene addition was done on alcohol 5.4 to give diol
5.45 (see Scheme 5.22). Cleavage of the TMS group (to give the terminal
alkyne) was done using K2CO3/MeOH rather than TBAF as it gave much better
yields. Previously, with the synthetic route of first installing the Boc-protecting
group, basic TMS cleavage conditions would not have been suitable, especially
with the aforementioned evidence that the proximal hydroxyl group participates in
Boc migration. However, because the organocerium acetylene addition could be
done in the presence of the unprotected alcohol, this afforded us the opportunity
to remove the TMS group with high yields under the K2CO3/MeOH conditions.93
Due to the concurrent nature of the investigation into the lactone ring formation
and the furanoid ring formation, initially, the protecting group that was installed
was the Boc group. However, upon discovering evidence of the unsuitable
nature of the Boc group (in the lactone ring formation sequence), the p-
methoxybenzyl (PMB) protecting group was used instead.
157
OH
OO
O
OH
SiMe3
K2CO3, MeOH
91%
OH
OO
O
OH
1. cat PPTS, THF/H2O2. (MeO)2CMe2, PPTS3. K2CO3, MeOH
Bu2SnOPhMe
then PMBBr
81% (4 steps)
OPMB
OH
OO HO
OPMB
OO
O
OH
DMP, CH2Cl2
98%
OPMB
O
OO
HO
OH
OO
O
O
Li TMS
-78 Cthen CeCl3
76%
5.4 5.45
5.46 5.47
5.48 5.49
Scheme 5.22 – Formation of the Furanoid Ring Containing Intermediate
Therefore, diol 5.46 was mono-protected as a PMB derivative via an in situ tin
acetal formation94,95 (see Scheme 5.22). Hydrolysis of the orthoester,
subsequent protection of the resulting diol with 2,2-dimethoxypropane, and
acetate cleavage afforded diol 5.48 – all high yielding steps. Carefully monitored
Dess-Martin periodinane (DMP)96 oxidation gave lactol 5.49. The structure of the
compound was analyzed by X-ray diffraction and was confirmed to be that shown
(see Figure 5.3).
158
Figure 5.3 – X-ray Crystal Structure of Furanoid Ring Intermediate 5.49
The X-ray crystal structure that was obtained was informative in that it confirmed
the formation of the furanoid ring. Additionally, it also demonstrated the
stereoselective addition of the alkynyl group.
With successful furanoid ring formation, the next step in the synthesis was to
explore the reverse prenylation reaction to form the congested bond between C-4
and C-5 (see Scheme 5.23). The furanoid ring was the result of an
intramolecular ring closure, giving a hemiacetal. The hemiacetal presented an
opportunity to take advantage of oxocarbenium chemistry to form the congested
C-4 to C-5 bond. Trauner et al.22 found that on a related system, the reverse
prenylation to a neopentyl aldehyde was not successful. Because this necessary
carbon-carbon bond is so congested, the advantage of using an oxocarbenium
intermediate as a more reactive electrophile seemed a possible solution. This
next step – a nucleophilic additon of a prenyl fragment to an oxocarbenium ion –
would form the last crowded chiral center at C-5.
159
OPMB
O
OO
OPMB
O
OO
RO
LewisAcid
[M]OPMB
O
OO
OPMB
O
OO
HO
4
5
5
5.49 5.50
5.51
5.52
5.53
Scheme 5.23 – Plan for the Prenyl Fragment Addition
Lactol intermediate 5.49 was functionalized to acetate 5.54, a substrate suitable
for testing the viability of the planned reverse prenylation (see Scheme 5.24).
Scheme 5.24 – Synthesis of Intermediate 5.54
160
BF3·OEt2, TiCl4, MgBr2·OEt2, ZnCl2, and SnCl4 were tested as Lewis acids to
promote oxocarbenium ion formation and tributyl(3-methyl-2-butenyl)tin was
tested as the nucleophile. The reverse prenylation product was not one of the
products isolated in any of these reactions (see Scheme 5.25).
Scheme 5.25 – Exploring the Reverse Prenylation
A less bulky nucleophile, allyl trimethylsilane, was also tested with both BF3·OEt2
and SnCl4 as Lewis acids. No allyl addition was observed. The TMS ether of
isobutyraldehyde was made97 and also tested as a prenyl substitute. No addition
to the lactol was observed. However an interesting aldehyde side product was
isolated. This side product is the result of the silyl enol ether adding to the p-
methoxybenzyl cation (5.59). This provided evidence that the PMB protecting
group was too labile, perhaps due to its close proximity to the formed
oxocarbenium ion (see Scheme 5.25). It was hypothesized that the benzylic
161
oxygen of the –OPMB group could add to the proximal oxocarbenium ion forming
a 5-membered ring intermediate. This would allow for a subsequent
fragmentation of the PMB group (see Scheme 5.26). This p-methoxybenzyl
cation could then react with the silyl enol ether of isobutyraldehyde to give the
isolated side product.
O
O
OO
O
O
O
OO
O
oxocarbenium ion
O
H
OSiMe3
O
O
5.57 5.57
5.57 5.57 5.57
Scheme 5.26 – Suggested Mechanism of Formation of Side Product 5.57
Due to this result, the less labile benzyl (Bn) group was used. Thus the synthesis
from diol 5.46 consisted of six steps to the prenylation substrate 5.59 (see
Scheme 5.27).
162
1. cat. PPTS, THF/H2Othen NaOMe
2. (MeO)2CMe2, PPTS3. DMP, CH2Cl24. Ac2O, DMAP
CH2Cl2
BnBrNaH, THF
82%
64%
OH
OO
O
OH
OBn
OO
O
OH
OBn
O
OO
AcO
OH
OO
O
OH
Pd on BaSO4pyr., MeOH
98%
5.46 5.57
5.58 5.59
Scheme 5.27 – Synthesis of Benzyl Protected Substrate
The diol 5.46 was mono-protected with benzyl bromide. Hydrolysis of the
orthoester was simplified by adding base directly to the reaction mixture after
completion of the ring opening to effect an in situ acetate removal. Protection to
form the acetonide was followed by oxidation to the lactol with DMP. The lactol
alcohol was then functionalized as an acetate group, which was the substrate
necessary to test the reverse prenylation – in this case, with the less labile benzyl
group on the proximal alcohol (see Scheme 5.28).
Acetate 5.59 was then tested in the reverse prenylation conditions using SnCl4 as
the Lewis acid. Both allyltrimethylsilane and tributyl(3-methyl-2-butenyl)tin were
tested as potential nucleophiles (see Scheme 5.28).
163
Scheme 5.28 – Successful Reverse Prenylation
Isolation of the reverse prenylation product using the reaction conditions was
successful in the presence of the less labile benzyl protecting group. One of the
previously tested Lewis acids, SnCl4 served as a useful acid. This advanced
intermediate is of importance as it demonstrates the feasibility of our synthetic
plan to 1) use the orthoester to quickly functionalize both the furanoid ring as well
as 2) the use of reverse prenylation to form the congested C-4 to C-5 bond in
maoecrystal V. Only one diastereomer from this alkylation at C-5 was obtained
but diastereoselectivity of the addition needs to be confirmed.
Although the methodology used to form the furanoid ring and test the reverse
prenylation is highly informative, this advanced intermediate did not become
useful on the route to maoecrystal V. Investigations into further elaboration of
this furanoid intermediate were not successful (see Scheme 5.29).
164
OBn
O
OO
p-TsOHor
PPTS
OBn
O
HOHO
OBn
O
OO
O
O
Ozonolysis
5.62 5.61 5.63
Scheme 5.29 – Attempts to Elaborate the Furanoid Intermediate
Initially, attempts were made to cleave the acetonide but the usual mild acid
conditions only resulted in decomposition of the substrate. Additionally, attempts
to cleave either alkene (or both) were not successful. Reaction of meta-
chloroperoxybenzoic acid (m-CPBA) did not result in obtaining epoxide
formation. Rather, the starting material was obtained. Ozonolysis conditions
resulted in decomposition.
While work on the formation of the furanoid ring was being completed (to obtain
intermediate 5.61), simultaneously, the previously discussed diol alkyne
intermediate 5.45 was also being used to further explore lactone ring formation
(see Scheme 5.30). In particular, the use of the less labile benzyl protecting
group was also expected to address the previously encountered problem of
undesired Boc migration.
165
Scheme 5.30 – The Diol Substrate was Used in Studies for Both the Furanoid
and Lactone Ring Formation
Diol 5.45 was converted to the acetonide intermediate 5.65 in 5 steps as
described for the furanoid studies sequence. Ozonolysis of the alkene to the
aldehyde results in an in situ ring closure, forming a lactol. The lactol was
oxidized to the desired lactone under Swern conditions35 (see Scheme 5.31).
Scheme 5.31 – Successful Lactone Ring Formation
166
Synthesis of this advanced intermediate proves that the formation of the lactone
ring is possible. Additionally, the alkyne nucleophile is useful for installing a one
carbon unit necessary for formation of the lactone ring. The structure of the
lactone ring intermediate was also confirmed by X-ray crystal analysis (see
Figure 5.4).
Figure 5.4 – X-ray Crystal Structure of Lactone Ring Intermediate 5.64
On-going work to shorten the synthesis became useful and the route to the
lactone ring intermediate can be accomplished in three steps from alkene
intermediate 5.58. Hydrolysis of the orthoester group afforded tetraol 5.67.
Tetraol 5.67 was found to be a better substrate for ozonolysis so a shorter route
to lactone intermediate 5.64 was possible (see Scheme 5.32). Additionally, by
employing the mild oxidation conditions of iodine and calcium carbonate,98 the
lactol could be oxidized to the lactone, leaving the primarily alcohols unoxidized.
Thus, use of the acetonide could be avoided. Thus, the shortest route from the
alkene 5.58 to diol 5.64 became a three step procedure of hydrolysis, ozonolysis,
and oxidation (see Scheme 5.32)
167
Scheme 5.32 – Shortening the Route to the Lactone Ring Intermediate
5.7 Further elaboration of the advanced intermediates
With routes that establish the synthetic methodology to make the furanoid ring as
well as the lactone ring, focus turned toward merging the two routes toward the
synthesis of maoecrystal V. This effort began with further elaboration of
advanced lactone intermediate 5.64.
The diol substrate 5.64 was subjected to oxidizing conditions to try to
simultaneously effect formation of both the C-1 aldehyde and lactol ring (see
Scheme 5.33).
Scheme 5.33 – Oxidation of Diol 5.64
168
With the formation of the furanoid and lactone ring complete, attention turned
toward setting up to complete the cyclohexenone ring. Two potential routes to
effect the formation of the cyclohexenone ring were envisioned (see Scheme
5.34). From hemiacetal intermediate 5.68, the alcohol could potentially be
functionalized to the isobutyraldehyde fragment. Additonally, the aldehyde in
intermediate 5.68 could be functionalized to a methyl ketone. This would set up
for an intramolecular aldol reaction to give the cyclohexenone.
Scheme 5.34 – Potential Routes for Cyclohexenone Formation
The other route, also from intermediate 5.68, would form the cyclohexenone ring
via an olefin metathesis reaction (see Scheme 5.34). The alcohol in intermediate
5.68 could potentially be functionalized adding the prenyl fragment. Additonally,
169
the aldehyde in intermediate 5.68 could be functionalized to the -unsaturated
ketone. This would set up for the metathesis reaction to give the cyclohexenone.
With the purpose of forming the -unsaturated ketone (for the metathesis
route), vinylmagnesium bromide was reacted with intermediate 5.68 (see
Scheme 5.35). However, none of the alkene product was isolated from this
reaction. Other organometallic reagents such as methylmagnesium chloride
were also unsuccessful as nucleophiles to the aldehyde. Decomposition of the
substrate was often the result when trying to add to the aldehyde via an
organometaliic substrate.
Scheme 5.35 – Attempts to Functionalize Intermediate 5.68
170
Thus attempts were made to functionalize the lactol alcohol first. To prepare the
substrate for either a reverse prenylation or addition of the isobutyraldehyde
fragment via the silyl enol ether, acetate formation was attempted. Using the
previously established conditions of DMAP and acetic anhydride, surprisingly the
acetate was not formed. Rather, even under such mild conditions, it was
determined that substantial decomposition was occurring.
Because direct methods to functionalize the lactol aldehyde intermediate were
not successful, it was deemed that for further elaboration, triol 5.64 requires
mono-protection. This would allow for functionalization of the lactol alcohol on C-
5 and the alcohol on C-1 separately (see Scheme 5.36).
Scheme 5.36 – Selective TBS-protection of the Diol is Problematic
Mono-protection of diol 5.64 was challenging. Experimental results gave
evidence that selectivity between the two alcohols was not high. Use of the TBS
protecting group gave a mixture of three products – the two mono-protected
diastereomers as well as the doubly protected TBS product (see Scheme 5.36).
171
The TES protecting group fared better and some selectivity was observed at low
temperatures (see Scheme 5.37).
Scheme 5.37 – TES-protection of the Diol 5.64
However, migration of the silyl protecting groups was noticeable (see Scheme
5.38).
Scheme 5.38 – Silyl Migration Observed
Each of the mono-protected TES compounds could be isolated with good purity
by chromatography. If left overnight, silyl migration was evident. Thus
immediate oxidation of both products was necessary to maintain product purity.
172
The other synthetic option was to oxidize the mixture of TES-protected
diastereomers as separation of the two products could be affected to give both
aldehyde 5.79 and lactol 5.80 (see Scheme 5.39).
Scheme 5.39 – Oxidation of TES-protected Substrates
The synthesis of maoecrystal V is currently at this point. With the two TES-
protected substrates, it is now possible to explore the formation of the last ring,
the cyclohexenone ring.
173
CHAPTER 6 – FUTURE WORK
6.1 Outline of route for completion of maoecrystal V
The synthesis of the TES-protected compounds will allow for further elaboration
to maoecrystal V. With the two oxidation products that are TES-protected, both
have potential to be utilized toward the total synthesis.
OBn
OHO
OTESO
O
OBn
OHO
OTESO
O
OBn
OO
OO
OBn
OHO
OTESO
O
OBn
OO
OO
O
O
OO
O
O
Aldol
Metathesis
6.1 6.2 6.3
6.4 6.5 6.6maoecrystal V
Scheme 6.1 – Potential Route for Elaboration of Aldehyde 6.1
The planned routes from the protected intermediates are similar to the route
described in the previous chapter. Having one of the two alcohols protected
174
allows for independent elaboration. Both the planned aldol route, as well as the
metathesis route, is still viable. From the aldehyde, addition of the vinyl fragment
and eventual reverse prenylation prepares for the metathesis route to form the
cyclohexenone ring (see Scheme 6.1). On the other hand, elaboration of the
aldehyde to the methyl ketone and eventual addition of isobutyraldehyde sets up
for the aldol reaction to form the cyclohexenone.
From the hemiacetal intermediate 6.7, formation of the cyclohexenone ring would
require a reverse prenylation (see Scheme 6.2).
Scheme 6.2 – Potential Route for Elaboration of Lactol 6.7
175
The TES-protected alcohol would then be functionalized to the -unsaturated
ketone. Subsequent metathesis would give the cyclohexenone. On the other
hand, addition of the isobutyraldehyde fragment followed by functionalization of
the TES-protected alcohol to the methyl ketone would set up for an aldol reaction
to give the cyclohexenone ring.
6.2 An Enantioselective synthesis
6.2.1 Trials with an enantioselective Michael-aldol reaction
The key transformation, the intramolecular Michael-aldol reaction is a potential
entry point into an enantioselective synthesis of maoecrystal V. Jørgensen et al.
reported a strategy for enantioselective and diastereoselective Michael-aldol
reactions (see Scheme 6.3)99. Reactions of -ketoesters with -unsaturated
ketones were catalyzed with Jørgensen’s imiazolininone catalyst 6.12.
.
Ar1
O
R1
Ar2
O
CO2R
NH
N
CO2H
Ph(10 mol%)EtOH, rt
Ar2R1
O OAr1
CO2R
O
Ar1Ar2 CO2R
R1
HO
6.14
6.10
6.11
6.12
6.13
20-85% yielddr>97 : 3
ee 83-99%
Scheme 6.3 – Jørgensen’s Diastereoselective Michael-aldol Reaction99
176
In comparison, the key transformation in this synthesis is also a Michael-aldol
reaction. Reaction of a racemic mixture of -unsaturated aldehyde 6.10 and
use of a chiral catalyst (such as proline), the intramolecular Michael reaction
could potentially provide cyclohexanone intermediate 6.11 as a mixture of two
diastereomers. Upon, equilibration of the enolate to intermediate 6.12 and
subsequent aldol ring closure, this reaction could afford the ketone alcohol as
one enantiomer (see Scheme 6.4)
O
OO O
O
O
OH
OO
O
OO
O
O
O
OO
O
O
O
MichaelReaction
H
HAldol 8
6.10racemic 6.11
6.12 6.14aone enantiomer
H
H
H
NH
O
OHH
Scheme 6.4 – Potential Pathway to an Enantioselective Michael-aldol Reaction
6.2.2 Desymmetrization
Additionally, the racemic product of the tandem Michael-aldol reaction itself could
potentially be an entry point for an enantioselective synthesis. Asymmetric
acylation of meso-diol has been extensively studied by Wirz et al. involving
177
commercially available enzymes.100 An example of this is the use of Lipase QL
to furnish alcohol intermediate 6.16 as one enantiomer (see Scheme 6.5).
Scheme 6.5 – An Example of Asymmetric Acylation, Wirz et al.100
Oxidation to the diketone is another potential strategy to the enantioselective
total synthesis. Cyclohexane-1,3-diones can be asymmetrically reduced to
obtain one enantiomer. A common procedure is to use Baker’s yeast to reduce
cyclohexanone-1,3-diones.101 An example is bicylco[2.2.2]octane 6.17 (similar to
the product of the intramolecular Michael-aldol reaction), which is reduced to
ketone alcohol 6.18 (see Scheme 6.6).101-103
Scheme 6.6 – An Example of Asymmetric Yeast Reduction101-103
178
The racemic product of the ketone alcohol intermediate 6.14a and 6.14b could
potentially either be reduced to the meso diol product or oxidized to the achiral
compound (see Scheme 6.7). With either the meso-diol product 6.19 or the
achiral diketone product 6.20, desymmetrization of the substrates would result in
obtaining one enantiomer of the ketone alcohol. This one enantiomer would be
the entry point to the remainder of the synthesis and would therefore give
maoecrystal V as one enantiomer at the end of the synthesis.
Scheme 6.7 – Potential Entry Point into an Enantioselective Synthesis
Initial work has been done to both reduce and oxidize the racemic ketone
alcohol. Various conditions were not effective in obtaining the diketone
179
compound. However, in exploring the reduction of the ketone alcohol, sodium
borohydride (NaBH4) has been found to give the meso product 6.15 in good
yields. Thus, the product of the tandem Michael-aldol could potentially be an
entry point for an enantioselective synthesis.
180
APPENDIX A
General Procedures. All reactions were carried out under an argon atmosphere
with dry solvents using anhydrous conditions unless otherwise noted. RBF refers
to a round-bottom flask. Dry tetrahydrofuran (THF), diethyl ether (Et2O),
dichloromethane (CH2Cl2), and toluene were obtained by passing these solvents
through activated alumina columns. Dry triethylamine (Et3N), diisopropylamine,
pyridine, dimethyl sulfoxide (DMSO) and acetonitrile (MeCN) were obtained by
distilling over CaH2. Evaporation refers to removing solvents under reduced
pressure using a rotary evaporator. Reactions were monitored by thin layer
chromatography (TLC) carried out on silica gel plates and visualized using UV
light or stained with anisaldehyde, ceric ammonium molybdate (CAN), or basic
aqueous potassium permanganate (KMnO4).
1H NMR and 13C NMR spectra were recorded on Bruker DRX-600, Bruker DRX-
500, Bruker DRX-400, or Bruker DRX-250 and calibrated using residual
undeuterated solvent as an internal reference (CHCl3 @ 7.26 ppm 1H NMR, C6H6
@ 7.15 ppm 1H NMR, H2O @ 4.79 ppm 1H NMR, CHCl3 @ 77.0 ppm 13C NMR).
The following abbreviations (or combinations thereof) were used to explain the
multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, os =
overlapping signals, b = broad singlet. Intermediates that have not been
assigned numbers in the text are numbered sequentially in the experimental
section by chapter beginning with A1.
181
A.1 Experimental – Reactions in Chapter 3
Synthesis of Compound 3.3
Diisopropylamine (7.0 mL, 53 mmol) and THF (20 mL) were added to a RBF and
the mixture cooled with an ice-water bath followed by dropwise addition of n-BuLi
(2.30 M in hexanes, 17 mL, 59 mmol) using a syringe pump. The reaction
mixture was stirred at 0 °C for 10 min and then cooled with a dry ice/acetone
bath. 2-Methylcyclohex-2-enone (5.0 g, 53 mmol) as a THF solution (10 mL) was
added dropwise to the freshly prepared LDA solution at -78 °C and the resulting
mixture was allowed to stir for 30 min. Allyl bromide (19 mL, 0.26 mol) was
added dropwise and then the reaction mixture was warmed to rt. Reaction
progress was monitored by TLC. The reaction mixture was quenched by a
saturated NH4Cl solution. The mixture was extracted with EtOAc (3 x 50 mL) and
the combined extract washed with brine (50 mL) and dried with MgSO4 and
evaporated. The crude material was purified using flash chromatography
(hexanes/EtOAc = 95/5) to obtain alkene 3.3, 2.76 g (35%).
1H NMR (600 MHz, CDCl3) δ 6.68 (bs, 1H), 5.83 – 5.72 (m, 1H), 5.09 – 4.97
(os, 2H), 2.66 – 2.56 (m, 1H), 2.41 – 2.27 (os, 3H), 2.15 – 2.09 (m,
1H), 2.06 (dq, J = 13.4, 4.5 Hz, 1H), 1.76 (s, 3H), 1.74 – 1.67 (m,
1H).
182
TLC Rf = 0.25 (hexanes/EtOAc = 95/5) [Anisaldehyde]
Synthesis of Compound 3.5
Diisopropylamine (1.4 mL, 10 mmol) and THF (4.0 mL) were added to a RBF and
the mixture cooled with an ice-water bath followed by dropwise addition of n-BuLi
(2.30 M in hexanes, 3.5 mL, 9.1 mmol). The reaction mixture was stirred at 0 °C
for 10 min and then cooled with a dry ice/acetone bath. 2-methylcyclohex-2-
enone (1.0 g, 9.1 mmol) as a THF solution (1.0 mL) was added dropwise to the
freshly prepared LDA solution at -78 °C and the resulting mixture was allowed to
stir for 30 min. Methyl 2-bromoacetate (6.9 mL, 46 mmol) was added dropwise
and then the reaction was warmed to rt. Reaction progress was monitored by
TLC. The reaction was quenched by a saturated NH4Cl solution. The mixture
was extracted with CH2Cl2 (3 x 20 mL) and the combined extract washed with
brine (20 mL) and dried with Na2SO4 and evaporated. The crude material was
purified using flash chromatography (hexanes/EtOAc = 4/1) to obtain ester 3.5,
0.586 g (36%).
1H NMR (600 MHz, CDCl3) δ 6.69 (s, 1H), 3.68 (s, 3H), 2.89 – 2.79 (os, 2H),
2.48 – 2.38 (m, 1H), 2.33 (d, J = 18.8 Hz, 1H), 2.25 (dd, J = 8.5, 2.4
Hz, 1H), 2.10 – 2.02 (m, 1H), 1.83 – 1.76 (m, 1H), 1.75 (s, 3H).
TLC Rf = 0.43 (hexanes/EtOAc = 7/3) [Anisaldehyde]
183
Synthesis of Compound 3.6
O
90%
LiAlH4THF/
dioxaneMeO2C
OH
OH
3.5 3.6
LiAlH4 (63 mg, 1.7 mmol) was weighed into a RBF and Et2O (1.5 mL) was added.
The reaction flask was cooled with a dry ice/acetone bath followed by dropwise
addition ester 3.5 (0.10 g, 0.55 mmol) as a THF solution (1.5 mL). The reaction
mixture was stirred at -78 °C for 1 h and then warmed to rt. Reaction progress
was monitored by TLC. After 2 h, the reaction was complete and quenched by
sequential addition of water (0.15 mL), 15% NaOH (0.15 mL), and water (0.45
mL). The reaction mixture was filtered through Celite®. The Celite® pad was
washed with Et2O (6 x 3.0 mL). The crude material was purified using flash
chromatography (hexanes/EtOAc = 5/95) to obtain diol 3.6 as a mixture of
diastereomers, 0.078 g (90%).
1H NMR (600 MHz, CDCl3) δ 5.51 (s, 1H), 3.83 – 3.77 (os, 2H), 3.72 – 3.66
(m, 1H), 3.03 (bs, 2H), 2.05 – 2.00 (m, 1H), 1.98 – 1.93 (m, 1H),
1.75 (s, 3H), 1.70 – 1.58 (os, 4H), 1.45 – 1.35 (m, 1H).
TLC Rf = 0.32 (hexanes/EtOAc = 5/95) [Anisaldehyde]
184
Synthesis of Compound 3.4
OH
OH
DMSO, (COCl)2CH2Cl2, Et3N-78 0 ºC
O
O74%
3.6 3.4
CH2Cl2 (2.0 mL) was added to a RBF followed by DMSO (49 µL, 0.69 mmol).
The reaction flask was cooled with a dry ice/acetone bath followed by dropwise
addition of oxalyl chloride (51 µL, 0.59 mmol). The reaction mixture was stirred
at -78 °C for 30 min. A solution of diol 3.6 (35 mg, 0.22 mmol) in CH2Cl2 (2.0 mL)
was added dropwise and the reaction mixture was stirred for 1 h at -78 °C. NEt3
was added and the reaction mixture was stirred for an additional 5 min and then
gradually warmed to rt. Reaction progress was monitored by TLC. After 15 min
at rt, the reaction was complete. The reaction was quenched by water (5.0 mL).
The mixture was extracted with CH2Cl2 (3 x 5.0 mL) and the combined extract
washed with brine (10 mL) and dried with Na2SO4 and evaporated. The crude
material was purified using flash chromatography (hexanes/EtOAc = 70/30) to
obtain aldehyde 3.4, 0.021 g (74%).
1H NMR (250 MHz, CDCl3) δ 9.85 (s, 1H), 6.75 (m, 1H), 2.9 – 3.1 (os, 2H),
2.3 – 2.6 (os, 3H), 2.07 (m, 1H), 1.7 – 1.9 (m, 1H), 1.8 (s, 3H)
TLC Rf = 0.31 (hexanes/EtOAc = 70/30) [Anisaldehyde]
185
Synthesis of Compound 3.1543
Pentaerthritol (40 g, 0.29 mol) and triethylorthoacetate (54 mL, 0.29 mol) and p-
TsOH (0.15 g, 7.9 mmol) was placed in a RBF set up with a distillation apparatus
and heated to 140 °C gradually in 20 degree increments. Ethanol was collected
(54 mL) until no more distilled off. The reaction flask was cooled to rt and
transferred to a Kugelrohr apparatus. The orthoester alcohol 3.15 was sublimed
and deposited into an ice-cooled collecting flask as a white solid (47 g, 86%). No
purification was necessary and the compound was carried onto the mesylated
alcohol directly. An analytical sample was prepared by recrystallizing from
toluene. All data matched previously published literature data.
MP 118-120 °C
IR (Polyethylene Card) 3448, 1401, 1367, 1294, 1132, 1044 cm-1
1H NMR (600 MHz, CDCl3) δ 4.02 (s, 6H), 3.46 (d, J = 4.6 Hz, 2H), 1.50 (t, J
= 4.7 Hz, 1H), 1.46 (s, 3H)
13C NMR (125 MHz, CDCl3) δ 108.5, 69.3, 61.4, 35.6, 23.4
Synthesis of Compound 3.16
186
Alcohol 3.15 (41 g, 0.25 mol) and CH2Cl2 (830 mL) were added to a RBF and the
flask cooled with an ice-water bath followed by addition of NEt3 (39 mL, 0.28
mol), added in one portion to the reaction flask. MsCl (30 mL, 0.38 mol) was
added dropwise using a syringe pump. Upon completion of addition of MsCl, the
reaction mixture was gradually warmed to rt and allowed to stir for 1 h at rt.
Reaction progress was monitored by TLC. The reaction was quenched with a
0.1 M solution of K2CO3 (1.0 L). The mixture was extracted with CH2Cl2 (3 x 200
mL) and the extract washed with brine (100 mL) and dried with Na2SO4 and
evaporated. Methanesulfonate 3.16 was isolated as a yellow solid (60 g,
quantitative yield) and was again carried forward with no further purification.
TLC Rf = 0.15 (hexanes/EtOAc = 7/3) [KMnO4]
IR (Polyethylene Card) 3105, 2933, 2894, 1737, 1472, 1403, 1351,
1297, 1173, 1132, 1039 cm-1
1H NMR (500 MHz, CDCl3) δ 4.03 (s, 6H), 3.99 (s, 2H), 3.03 (s, 3H), 1.46 (s,
3H)
13C NMR (125 MHz, CDCl3) δ 108.9, 68.3, 66.1, 37.5, 34.3, 23.2
Synthesis of Compound 3.17
Methanesulfonate 3.16 (60 g, 0.25 mol) was dissolved in DMSO (500 mL) and
NaCN (25 g, 0.50 mol) was added in one portion. The reaction flask was fitted
with an air condenser and heated with an oil bath (at 110 °C) for ~4 h. The
187
reaction progress was monitored TLC. The reaction mixture was poured into a
5% Na2CO3 solution and extracted with CH2Cl2 (3 x 250 mL). The combined
extract was washed successively with 5% Na2CO3 (1 x 100 mL) and brine (1 x
100 mL) and dried with Na2SO4 and evaporated. The brown solid was purified by
recyrstallization from EtOH (9 mL/g) to obtain nitrile 3.16 as light brown crystals
(30 g, 72% after two crops).
MP 174-178 °C
TLC Rf = 0.5 (hexanes/EtOAc = 3/7) [KMnO4]
IR (Polyethylene Card) 2944, 2898, 2246, 1474, 1402, 1361, 1296,
1125, 1054, 1024 cm-1
1H NMR (500 MHz, CDCl3) δ 4.05 (s, 6H), 2.27 (s, 2H), 1.47 (s, 3H)
13C NMR (125 MHz, CDCl3) δ 114.3, 108.7, 70.0, 31.6, 23.1, 18.7
Synthesis of Compound 3.18104
Into a RBF, commercially available 3-Buten-1-ol A1 (45 g, 0.52 mol) was
dissolved in CH2Cl2 (1.3 L) and cooled with an ice-water bath and NEt3 (146 mL,
0.42 mol) was added in one portion to the reaction flask. MsCl (45 mL, 0.21 mol)
was added dropwise with a syringe pump. Upon completion of the addition, the
reaction mixture was gradually warmed to rt and allowed to stir for 30 min at rt.
The reaction mixture was poured into water (1.0 L) and extracted with CH2Cl2 (3
x 500 mL). The combined extract were washed successively with 1 N HCl (500
188
mL) and brine (1 x 500 mL) and dried with Na2SO4 and evaporated. Crude
methanesulfonate A2 (78 g, quantitative yield) was carried forward with no
further purification.
1H NMR (600 MHz, CDCl3) δ 5.71 (ddt, J = 17.0, 10.3, 6.7 Hz, 1H), 5.12 –
5.03 (m, 2H), 4.16 (t, J = 6.7 Hz, 2H), 2.91 (s, 3H), 2.41 (q, J = 6.6
Hz, 2H)
Into a RBF was added NaHCO3 (33 g, 0.39 mol) followed by sequential addition
of HPLC-grade acetone (1.3 L), methanesulfonate A2 (78 g, .52 mol), and NaI
(118 g, 0.78 mol). The reaction flask was fitted with a condenser, stirred
vigorously with a mechanical stirrer, and allowed to reflux overnight (the reaction
mixture turning from bright yellow to white). The reaction was cooled to rt and
quenched by water (1.5 L) and extracted with Et2O (3 x 500 mL). The combined
extract was washed with brine (500 mL), dried with MgSO4, and evaporated
using a 120 Torr pump (as the product is volatile) and to obtain crude homoallyl
iodide 3.18. Distillation of the crude product (85 °C, 120 Torr) gave homoallyl
iodide 3.18 (62 g, 66%) as a colorless liquid.
1H NMR (500 MHz, CDCl3) δ 1H NMR (500 MHz, CDCl3) δ 5.76 (ddt, J =
17.3, 10.9, 6.7 Hz, 1H), 5.16 – 5.09 (m, 2H), 3.18 (t, J = 7.2 Hz,
2H), 2.62 (q, J = 7.1 Hz, 2H)
13C NMR (125 MHz, CDCl3) δ 136.9, 117.0, 37.7, 4.7
189
Synthesis of Compound 3.19 (and side-product 3.20)
Nitrile 3.17 (12 g, 0.07 mol) and THF (200 mL) were added to a RBF and the
mixture cooled with a dry ice/acetone bath followed by dropwise addition of n-
BuLi (1.82 M in hexanes, 41 mL, 0.07 mol). The reaction mixture was stirred at -
78 °C for 30 min. Homoallyl iodide (17 g, 0.090 mol) as a THF solution (30 mL)
was added dropwise using a syringe pump and the resulting mixture was allowed
to stir for an additional 1 h at -78 °C. The reaction mixture was then warmed to
rt. Reaction progress was monitored by TLC. After 1h, the reaction was
quenched by a saturated NaHCO3 solution. The mixture was extracted with
CH2Cl2 (3 x 250 mL) and the combined extractwashed with brine (100 mL) and
dried with Na2SO4 and evaporated. The crude material was purified using flash
chromatography (hexanes/EtOAc = 75/25) to obtain alkene 3.19 as a yellow
liquid, 10.5 g (67%). The dialkylated product 3.20 was collected in earlier
fractions in to give 1.59 g (12 %).
Data corresponding to alkene 3.19
TLC Rf = 0.45 (hexanes/EtOAc = 1/1) [KMnO4]
IR (Polyethylene Card) 3077, 2946, 2886, 2241, 1641, 1403, 1298,
1129, 1057 cm-1
190
1H NMR (600 MHz, CDCl3) δ 5.76 – 5.64 (m, 1H), 5.18 – 5.05 (os, 2H), 4.04
(s, 6H), 2.42 (ddd, J = 12.5, 4.3 Hz, 2H), 2.20 – 2.10 (m, 1H), 1.60
(tdd, J = 12.6, 7.8, 4.8 Hz, 1H), 1.50 (tdd, J = 10.5, 7.3, 3.1 Hz, 1H)
13C NMR (125 MHz, C6D6) δ 135.7, 117.2, 116.8, 109.2, 68.6, 34.1, 31.9,
31.5, 25.17, 23.6
Data corresponding to dialkene 3.20
TLC Rf = 0.88 (hexanes/EtOAc = 1/1) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.75 (ddt, J = 16.8, 10.2, 6.5 Hz, 2H), 5.07 (dd,
J = 21.5, 13.7 Hz, 4H), 4.11 (s, 6H), 2.27 – 2.16 (os, 4H), 1.71 (ddd,
J = 13.8, 11.8, 5.4 Hz, 2H), 1.53 (ddd, J = 14.0, 11.8, 5.5 Hz, 2H),
1.44 (s, 3H)
Synthesis of Compound 3.23
Nitrile 3.19 (0.10 g, 0.45 mmol) and 3:1 dioxane:water (10 mL) were added to a
RBF. 1 M HCl (0.19 mL, 2.2 mmol) was added. The reaction mixture was stirred
and allowed to reflux overnight. Reaction completion was confirmed by TLC.
The mixture was evaporated to obtain diol 3.23 as a white solid. Diol 3.23 (0.72
g, 80%) was carried forward with no further purification.
191
TLC Rf = 0.52 (MeOH/EtOAc = 10/90) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.91 (td, J = 17.0, 6.7 Hz, 1H), 5.11 (dd, J =
32.8, 13.8 Hz, 2H), 4.37 (d, J = 9.4 Hz, 1H), 4.29 (d, J = 9.4 Hz,
1H), 3.68 (dq, J = 24.8, 11.7 Hz, 5H), 2.77 – 2.73 (m, 1H), 2.36 (dt,
J = 14.2, 7.0 Hz, 1H), 2.26 (td, J = 14.8, 7.4 Hz, 1H), 1.81 (td, J =
14.4, 8.2 Hz, 1H), 1.70 (td, J = 14.3, 6.7 Hz, 1H).
Synthesis of Compound 3.24
Diol 3.23 (0.19 g, 0.89 mmol), p-TsOH (0.011 g, 0.050 mmol), and THF (10 mL)
were added to a RBF. The reaction mixture was stirred overnight. Reaction
completion was confirmed by TLC. The reaction was quenched by a saturated
NaHCO3 solution. The mixture was extracted with EtOAc (3 x 20 mL) and the
combined extractwashed with brine (10 mL) and dried with MgSO4 and
evaporated. The crude material was purified using flash chromatography
(hexanes/EtOAc = 75/25) to obtain acetonide 3.24, 0.17 g (65%).
TLC Rf = 0.50 (hexane/EtOAc = 75/25) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 7.51 – 7.35 (m, 5H), 5.78 (ddt, J = 17.0, 10.3,
6.7 Hz, 1H), 5.48 (s, 1H), 5.10 (dd, J = 18.1, 13.7 Hz, 2H), 4.70 (d,
192
J = 9.5 Hz, 1H), 4.28 (d, J = 9.4 Hz, 1H), 4.09 – 4.01 (m, 3H), 3.97
(d, J = 11.6 Hz, 1H), 2.42 (td, J = 14.2, 7.0 Hz, 1H), 2.31 (td, J =
14.9, 7.2 Hz, 1H), 2.22 (dd, J = 8.7, 6.0 Hz, 1H), 1.79 (td, J = 14.5,
8.7 Hz, 1H), 1.53 (dt, J = 14.2, 6.7 Hz, 1H).
Synthesis of Compound 3.26
O
OO O
NH2Quantitative
Na2O2, H2O
O
OO
CN
3.19 3.26
Nitrile 3.19 (14 g, 0.060 mol) was brought up in water (500 mL) and stirred
vigorously (the nitrile does not dissolve but forms oily droplets in the water).
Sodium peroxide (9.6 g, 0.12 mol) was added, all in one portion. The reaction
mixture was heated with a water bath (at 50 °C) with vigorous stirring. After 2 h,
more sodium peroxide was added (4.8 g, 0.06 mol). Reaction progress was
monitored by TLC. A white precipitate had formed in the reaction vessel which
dissolved upon addition of EtOAc (200 mL). Na2SO3 (27 g, 0.21mol) was added
and the reaction mixture was vigorously stirred until all the solid had dissolved.
The mixture was extracted with EtOAc (4 x 100 mL) and the combined
extractdried with MgSO4 and evaporated. Amide 3.26 was obtained as a white
powder, 15 g (quantitative yield). The amide 3.26 can be carried forward without
further purification or can be recrystallized from EtOAc (10 mL/g).
TLC Rf = 0.85 (hexanes/EtOAc = 1/9) [KMnO4]
193
1H NMR (600 MHz, CDCl3) δ 5.71 (tdd, J = 15.1, 8.0, 5.7 Hz, 1H), 5.40 (bd,
J = 44.0 Hz, 2H), 5.08 – 4.98 (os, 2H), 4.10 (dd, J = 8.3, 3.3 Hz,
3H), 3.97 (dd, J = 8.3, 3.3 Hz, 3H), 2.23 – 2.14 (m, 1H), 1.96 – 1.86
(os, 2H), 1.78 (tdd, J = 12.7, 7.7, 4.9 Hz, 1H), 1.44 (s, 3H), 1.46 –
1.38 (os, 1H)
1H NMR (600 MHz, D2O) δ 5.81 (td, J = 16.9, 7.2 Hz, 1H), 5.06 (dd, J = 19.3,
13.8 Hz, 2H), 4.16 (dd, J = 8.6, 3.2 Hz, 3H), 4.06 (dd, J = 8.6, 3.2
Hz, 3H), 2.33 (dd, J = 12.3, 2.8 Hz, 1H), 2.14 – 2.07 (m, 1H), 1.92
(td, J = 15.5, 7.5 Hz, 1H), 1.63 (tdd, J = 12.9, 7.4, 5.4 Hz, 1H), 1.57
– 1.50 (m, 1H), 1.46 (s, 3H)
Synthesis of Compound 3.2852
Amide 3.26 (9.8 g, 0.040 mol) was dissolved in HPLC grade MeOH (160 mL) and
the solution was transferred into a thick-walled glass reaction flask (pressure
vessel). DMF-DMA (26 mL, 0.20 mol) was added and the pressure vessel was
sealed and heated with an oil bath (at 110 °C) for 48 h. The resulting dark brown
solution was cooled to rt and evaporated. The dark brown oily residue (which
contained the product as well as DMF-DMA) was purified by flash
194
chromatography (hexanes/EtOAc = 75/25) giving methyl ester 3.28 as a white
solid (9.2 g, 88%).
MP 34-36 °C
TLC Rf = 0.3 (hexanes/EtOAc = 75/25) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.70 (ddd, J = 16.8, 13.7, 6.9 Hz, 1H), 5.04 –
4.95 (os, 2H), 4.04 (dd, J = 8.4, 3.3 Hz, 3H), 3.89 (dd, J = 8.4, 3.3
Hz, 3H), 3.70 (s, 3H), 2.25 (dd, J = 12.4, 2.6 Hz, 1H), 2.07 – 1.99
(m, 1H), 1.88 (dq, J = 14.6, 7.4 Hz, 1H), 1.76 – 1.67 (m, 1H), 1.43
(s, 3H), 1.46 – 1.37 (os, 1H).
13C NMR (150 MHz, CDCl3) δ 172.3, 136.5, 116.2, 108.4, 77.2, 77.0, 76.8,
69.2, 51.8, 45.8, 34.5, 31.8, 25.6, 23.2
Synthesis of Compound 3.2954
Methyl ester 3.28 (9.1 g, 36 mmol) and dry THF (90 mL) were added to a RBF
and the mixture was stirred until all the methyl ester had dissolved. N,O-
Dimethylhydroxylamine hydrochloride (5.22 g, 0.053 mol) was added all in one
portion and the reaction flask was placed in a dry ice bath maintained at -20 °C
by adding dry ice chips. Methylmagnesium chloride (3.0 M in THF) was added
dropwise using a syringe pump, maintaining the dry ice bath at approximately -20
195
°C. The bath was allowed to warm to -10 °C and reaction progress was
monitored by TLC until complete. The reaction mixture was poured into a
vigorously stirring solution of saturated NaHCO3 (100 mL), extracted with CH2Cl2
(3 x 100 mL), dried with Na2SO4, and evaporated. Weinreb amide 3.29 was
obtained as a yellow oil and purified flash chromatography (hexanes/EtOAc =
3/2) to obtain Weinreb amide 3.29 (9.64 g, 95%) as a yellow solid.
MP 81-84 °C
TLC Rf = 0.6 (hexanes/EtOAc = 3/2) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.78 – 5.68 (m, 1H), 5.05 – 4.96 (os, 2H), 4.09
(dd, J = 8.4, 3.2 Hz, 3H), 3.92 (dd, J = 8.4, 3.2 Hz, 3H), 3.66 (s,
3H), 3.18 (s, 3H), 2.81 (d, J = 11.5 Hz, 1H), 2.05 – 1.95 (m, 1H),
1.90 – 1.76 (os, 2H), 1.42 (s, 3H), 1.46 – 1.37 (os, 1H).
13C NMR (125 MHz, C6D6) δ 173.1, 137.8, 115.4, 109.2, 69.7, 60.7, 40.5,
35.8, 3.18, 31.6, 26.2, 24.0
Synthesis of Compound 3.12 (and side-product 3.30)
Weinreb amide 3.29 (1.6 g, 5.4 mmol) in THF (5.5 mL) were added to a RBF and
cooled with an ice-water bath and vinylmagnesium bromide (0.97 M, 28 mL, 27
196
mmol) was added dropwise using a syringe pump. The reaction mixture was
maintained at 0 °C. Reaction progress was monitored by TLC until reaction was
complete. The reaction mixture was transferred into a flame-dried addition funnel
and added slowly (~5 mL/min) into saturated NaHCO3 (750 mL). The aqueous
layer was extracted with EtOAc (3 x 200 mL) and the combined extractions dried
with MgSO4 and evaporated. The dialkene 3.12 was purified by flash
chromatography (hexanes/EtOAc = 70/30) to obtain 1.27 g (90%).
Data corresponding to dialkene 3.12
TLC Rf = 0.31 (hexanes/EtOAc = 75/25) [KMnO4]
1H NMR (600 MHz, C6D6) δ 6.30 – 6.22 (m, 1H), 6.12 (d, J = 17.4 Hz, 1H),
5.78 (d, J = 10.5 Hz, 1H), 5.55 (td, J = 16.8, 6.5 Hz, 1H), 4.87 (dd, J
= 20.0, 13.8 Hz, 2H), 4.02 (dd, J = 8.4, 3.4 Hz, 3H), 3.90 (dd, J =
8.4, 3.4 Hz, 3H), 2.69 (d, J = 11.8 Hz, 1H), 1.91 – 1.83 (m, 1H),
1.76 – 1.63 (os, 2H), 1.34 (d, J = 11.7 Hz, 1H), 1.30 (s, 3H)
Data corresponding to methoxyamine side product 3.30
TLC Rf = 0.47 (hexanes/EtOAc = 4/1) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.68 (dt, J = 17.5, 6.6 Hz, 1H), 5.05 – 4.97 (os,
2H), 4.06 (dd, J = 8.2, 3.3 Hz, 3H), 3.92 (dd, J = 8.2, 3.3 Hz, 3H),
3.48 (s, 3H), 2.91 – 2.78 (os, 2H), 2.66 (t, J = 6.5 Hz, 2H), 2.57 (s,
3H), 2.48 (dd, J = 11.6, 2.6 Hz, 1H), 2.05 – 1.95 (m, 1H), 1.86 (td, J
= 15.0, 7.6 Hz, 1H), 1.78 – 1.66 (m, 1H), 1.42 (s, 3H), 1.47-1.34
(os, 1H).
197
Synthesis of Compound 3.10
Dialkene 3.12 (1.2 g, 4.8 mmol) and CH2Cl2 (15 mL) were added to a RBF.
Grubbs 2nd Generation catalyst (0.21 g, 0.24 mmol) was added in one portion
and the reaction mixture stirred for 2 h. Reaction progress was monitored by
TLC until the reaction was complete. Most of the CH2Cl2 was evaporated and the
crude material, a brown oil, was purified by flash chromatography.
Cyclohexenone 3.10 was obtained, 0.87 g (80%) as a tan solid.
TLC Rf = 0.30 (hexanes/EtOAc = 1/1) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 6.94 – 6.89 (m, 1H), 5.97 (d, J = 10.0 Hz, 1H),
4.20 (dd, J = 8.1, 3.2 Hz, 3H), 4.08 (dd, J = 8.1, 3.2 Hz, 3H), 2.44
(ddd, J = 19.2, 8.8, 4.3 Hz, 1H), 2.41 – 2.33 (m, 1H), 2.23 (dd, J =
12.4, 4.4 Hz, 1H), 2.00 (dq, J = 13.1, 4.3 Hz, 1H), 1.79 (ddd, J =
17.9, 13.3, 5.1 Hz, 1H), 1.45 (s, 3H)
13C NMR (125 MHz, C6D6) δ 196.8, 148.0, 130.5, 109.1, 69.0, 46.2, 35.3,
25.5, 24.1, 23.4
198
Synthesis of Compound 3.10 (via allylmagnesium bromide)
Weinreb amide 3.29 (0.25 g, 0.88 mmol) in THF (5.0 mL) were added to a RBF
and cooled with an ice-water bath and titrated allylmagnesium bromide (0.56 M,
5.5 mL, 3.1 mmol) was added dropwise using a syringe pump. The reaction
mixture was gradually warmed to rt. Reaction progress was monitored by TLC
until reaction was complete (3 h at rt). The reaction was quenched by a
saturated NaHCO3 solution. The mixture was extracted with EtOAc (3 x 10 mL)
and the combined extractwashed with brine (10 mL) and dried with MgSO4 and
evaporated. The crude material was purified using flash chromatography to
obtain a mixture of product 3.31 and 3.32. This mixture of products was not
separated and used as a mixture in the next step.
TLC Rf = 0.31 (hexanes/EtOAc = 80/20) [KMnO4]
O
OO O NEt3
THF
3.32
O
OO O
3.31major
O
OO O
3.32minor
The mixture of isomers 3.31 and 3.32 (0.23 g, 0.86 mmol), THF (5.0 mL), and
NEt3 (0.12 mL, 0.87 mmol) were added to a RBF. The reaction mixture was
stirred for 2 h. Most of the THF and NEt3 was evaporated and the crude material,
199
a mixture of E/Z isomers 3.32, was not further purified and compound was
carried onto the next step.
Dialkene 3.32 (0.23 g, 0.86 mmol) and CH2Cl2 (5.0 mL) were added to a RBF.
Grubbs 2nd Generation catalyst (37 mg, 0.04 mmol) was added in one portion
and the reaction mixture stirred for 3 h. Reaction progress was monitored by
TLC until the reaction was complete. Most of the CH2Cl2 was evaporated and the
crude material, a brown oil, was purified by flash chromatography.
Cyclohexenone 3.10 was obtained, 0.20 g (53% over three steps) as a tan solid.
1H NMR matched cyclohexenone 3.10 from previous olefin metathesis reaction.
TLC Rf = 0.30 (hexanes/EtOAc = 1/1) [KMnO4]
Synthesis of Compound 3.34
Diisopropylamine (0.37 mL, 2.6 mmol) and THF (10 mL) were added to a RBF
and the mixture cooled with an ice-water bath followed by dropwise addition of n-
BuLi (1.38 M in hexanes, 1.8 mL, 2.5 mmol). The reaction mixture was stirred at
0 °C for 10 min and then cooled with a dry ice/acetone bath. Methyl ester 3.28
200
(0.20 g, 0.78 mmol) as a THF solution (1.0 mL) was added dropwise to the
freshly prepared LDA solution at -78 °C and the resulting mixture was allowed to
stir for 30 min. Methyl iodide (97 µL, 1.6m mol) was added dropwise and then
the reaction was warmed to rt and allowed to stir overnight. The reaction was
quenched by a saturated NaHCO3 solution. The mixture was extracted with
CH2Cl2 (3 x 10 mL) and the combined extractwashed with brine (10 mL) and
dried with Na2SO4 and evaporated. The crude material was purified using flash
chromatography to obtain methyl ester 3.34, 2.1 g (98%).
TLC Rf = 0.25 (acetone/CH2Cl2 = 1/99) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.73 (ddt, J = 16.8, 10.1, 6.6 Hz, 1H), 4.98 (dd,
J = 19.6, 13.6 Hz, 2H), 4.06 (dd, J = 8.5, 3.2 Hz, 3H), 3.93 (dd, J =
8.5, 3.2 Hz, 3H), 3.70 (s, 3H), 2.07 – 1.98 (m, 1H), 1.86 (td, J =
12.2, 4.5 Hz, 1H), 1.79 – 1.70 (m, 1H), 1.42 (s, 3H), 1.34 – 1.28 (td,
J = 12.2, 4.5 Hz, 1H), 1.10 (s, 3H).
Synthesis of Compound 3.35
Dimethylmethyl phosphonate (67 µg, 0.62 mmol) and THF (1.0 mL) were added
to a scintillation vial and the mixture cooled with a dry ice/acetone bath followed
by dropwise addition of n-BuLi (1.82 M in hexanes, 0.32 mL, 0.59 mmol). The
201
reaction mixture was stirred at -78 °C for 30 min. Methyl ester 3.34 (42 mg, 0.16
mmol) as a THF solution (0.25 mL) was added dropwise followed by addition of
HMPA (0.20 mL) the resulting mixture was gradually warmed to rt and stirred for
4 h. Reaction progress was monitored by TLC. The reaction was quenched by a
saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 (3 x 1.0 mL)
and the combined extractwashed with brine (1.0 mL) and dried with Na2SO4 and
evaporated. The crude material was purified using flash chromatography to
obtain phosphonate 3.35, 0.40 g (71%).
TLC Rf = 0.21 (CH2Cl2/EtOAc = 10/90) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.70 (ddt, J = 16.8, 10.1, 6.3 Hz, 1H), 4.98 (dd,
J = 20.6, 13.7 Hz, 2H), 4.05 (dd, J = 8.4, 3.1 Hz, 3H), 3.94 (dd, J =
8.4, 3.1 Hz, 3H), 3.80 (d, J = 11.1 Hz, 6H), 3.17 (dd, J = 21.3, 15.2
Hz, 1H), 2.94 (dd, J = 22.8, 15.2 Hz, 1H), 2.01 – 1.88 (m, 2H), 1.76
(dd, J = 20.0, 12.2 Hz, 1H), 1.40 (s, 3H), 1.27 (s, 3H), 1.32 – 1.22
(m, 1H).
Synthesis of Compound 3.38
202
Ozonolysis Procedure
Phosphonate 3.35 (20 mg, 0.055 mmol), NMO·H2O (22 mg, 0.16 mmol), and
CH2Cl2 (2.0 mL) were added to a RBF and the mixture cooled with an ice-water
bath (at 0 °C). The reaction was sparged with ozone containing oxygen and
monitored by TLC until the starting material (phosphonate 3.35) was consumed.
The reaction was quenched by a solution of 1:1 saturated NaHCO3/Na2S2O3.
The mixture was extracted with CH2Cl2 (3 x 0.5 mL) and the combined
extractwashed with brine (0.5 mL), dried with Na2SO4, and evaporated. The
crude material was purified using flash chromatography to obtain cyclohexenone
3.38, 0.14 mg (73%).
OsO4 Procedure
Phosphonate 3.35 (25 mg, 0.07 mmol) and 3:1 acetone/water mixture (2.3 mL)
were added to a scintillation vial. Once the phosphonate dissolved, OsO4 (1 g/25
mL in water) (21 µL, 0.0034 mmol) and NMO·H2O (28 mg, 0.21 mmol) were
added and the reaction mixture was stirred overnight. TLC confirmed the alkene
starting material had been consumed. NaIO4 (74 mg, 0.35 mmol) was added to
the vigorously stirring reaction mixture. Reaction progress was monitored by
TLC and when the diol intermediate was consumed, the reaction was filtered
through a cotton plug. The filtrate extracted with CH2Cl2 (3 x 0.5 mL) and the
combined extractwashed with brine (0.5 mL), dried with Na2SO4, and evaporated.
The crude material was purified using flash chromatography to obtain
cyclohexenone 3.38.
TLC Rf = 0.18 (MeOH/EtOAc = 2.5/97.5) [KMnO4]
203
Synthesis of Compound 3.40
Diethylmethyl phosphonate (0.49 g, 3.0 mmol) and THF (5.0 mL) were added to
a RBF and the mixture cooled with a dry ice/acetone bath followed by dropwise
addition of n-BuLi (1.38 M in hexanes, 2.0 mL, 2.8 mmol). The reaction mixture
was stirred at -78 °C for 30 min. Methyl ester 3.34 (0.42 g, 1.5 mmol), as a THF
solution (0.25 mL), was added dropwise. HMPA (1.0 mL) was added to the
reaction mixture. The resulting reaction mixture was gradually warmed to rt and
then stirred for 1 h. Reaction progress was monitored by TLC . The reaction
was quenched by a saturated NaHCO3 solution. The mixture was extracted with
CH2Cl2 (3 x 5.0 mL) and the combined extractwashed with brine (1.0 mL), dried
with Na2SO4, and evaporated. The crude material was purified using flash
chromatography (CH2Cl2/EtOAc = 5/95) to obtain phosphonate A3, 0.152 g
(51%).
Data corresponding to phosphonate 3.39
TLC Rf = 0.51 (CH2Cl2/EtOAc = 5/95) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.72 (ddt, J = 12.4, 9.9, 6.3 Hz, 1H), 4.93 (dd,
J = 22.6, 13.6 Hz, 2H), 4.13 – 4.06 (os, 4H), 3.98 (dd, J = 8.4, 3.1
Hz, 3H), 3.89 (dd, J = 8.4, 3.1 Hz, 3H), 3.41 (dq, J = 21.0, 6.9 Hz,
1H), 2.00 – 1.92 (os, 2H), 1.87 – 1.81 (m, 1H), 1.43 (s, 3H), 1.38 (s,
204
3H), 1.37 (q, J = 6.7 Hz, 3H), 1.31 (dd, J = 15.5, 7.1 Hz, 6H), 1.17
(dd, J = 12.1, 8.5 Hz, 1H).
Phosphonate A3 (62 mg, 0.16 mmol) and an 3:1 acetone/water mixture (5 mL)
were added to a RBF. Once the phosphonate dissolved, OsO4 (1 g/25 mL in
water) (48 µL, 0.0076 mmol) and NMO·H2O (62 mg, 0.46 mmol) were added and
the reaction mixture was stirred overnight. TLC confirmed the alkene starting
material had been consumed. NaIO4 (0.16 g, 0.76 mmol) was added to the
vigorously stirring reaction mixture. Reaction progress was monitored by TLC
and when the diol intermediate was consumed, the reaction was filtered through
a cotton plug. The filtrate extracted with CH2Cl2 (3 x 5.0 mL) and the combined
extractwashed with brine (1.0 mL), dried with Na2SO4, and evaporated. The
crude aldehyde was used in the next step without purification.
TLC Rf = 0.63 (MeOH/EtOAc = 15/85) [KMnO4]
The crude aldehyde (4.1 mg, 10 µmol) from the previous reaction, acetonitrile
(0.5 mL), DBU (1.6 µL, 0.01 mmol), and LiCl (0.8 mg, 0.2 mmol) were added
successively and stirred vigorously. The reaction progress was monitored by
TLC. After 30 min, the reaction was complete. The reaction was quenched by a
saturated NaHCO3 solution. The mixture was extracted with CH2Cl2 (3 x 0.5 mL)
205
and the combined extractwashed with brine (0.25 mL), dried with Na2SO4, and
evaporated. The crude phosphonate 3.40 was purified by flash chromatography,
0.9 mg (36%).
TLC Rf = 0.51 (hexanes/EtOAc = 1/1) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 6.65 (s, 1H), 4.24 (dd, J = 8.3, 3.1 Hz, 3H),
4.03 (dd, J = 8.3, 3.2 Hz, 3H), 2.40 – 2.26 (os, 2H), 2.02 – 1.95 (m,
1H), 1.74 (s, 3H), 1.64 (dt, J = 13.4, 4.6 Hz, 1H), 1.43 (s, 3H), 1.08
(s, 3H).
Synthesis of Compound 3.42
Diisopropylamine (0.37 mL, 2.6 mmol) and THF (5 mL) were added to a RBF and
the mixture cooled with an ice-water bath followed by dropwise addition of n-BuLi
(1.37 M in hexanes, 1.8 mL, 2.5 mmol). The reaction mixture was stirred at 0 °C
for 10 min and then cooled with a dry ice/acetone bath. Methyl ester 3.28 (0.20
g, 0.78 mmol) as a THF solution (0.25 mL) was added dropwise to the freshly
prepared LDA solution at -78 °C and the resulting mixture was allowed to stir for
1 h. CCl4 (27 mL, 2.3 mmol) was added dropwise. Reaction progress was
monitored by TLC. The reaction was quenched by a saturated NaHCO3 solution.
The mixture was extracted with CH2Cl2 (3 x 0.25 mL) and the combined
extractwashed with brine (0.25 mL) and dried with Na2SO4 and evaporated. The
206
crude material was purified using flash chromatography to obtain methyl ester
3.41, 0.17 g (80%).
TLC Rf = 0.18 (hexanes/EtOAc = 90/10) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.74 (ddt, J = 16.9, 10.2, 6.6 Hz, 1H), 5.07 –
4.99 (os, 2H), 4.15 (dd, J = 8.5, 3.2 Hz, 3H), 4.06 (dd, J = 8.5, 3.2
Hz, 3H), 3.81 (s, 3H), 2.39 – 2.31 (m, 1H), 2.17 (ddd, J = 13.8,
10.8, 4.8 Hz, 1H), 1.95 – 1.86 (m, 1H), 1.75 (ddd, J = 13.7, 11.3,
4.4 Hz, 1H), 1.44 (s, 3H).
Synthesis of Compound 3.42
Dimethylmethyl phosphonate (0.65 mL, 6.0 mmol) and THF (5.0 mL) were added
to a scintillation vial and the mixture cooled with a dry ice/acetone bath followed
by dropwise addition of n-BuLi (2.27 M in hexanes, 2.5 mL, 5.7 mmol). The
reaction mixture was stirred at -78 °C for 30 min. Methyl ester 3.41 (0.42 g, 1.5
mmol), as a THF solution (0.25 mL), was added dropwise. The resulting reaction
mixture was stirred for 1 h. Reaction progress was monitored by TLC. The
reaction was quenched by a saturated NaHCO3 solution. The mixture was
extracted with CH2Cl2 (3 x 2.0 mL) and the combined extractwashed with brine
207
(1.0 mL), dried with Na2SO4, and evaporated. The crude material was purified
using flash chromatography to obtain phosphonate A4, 0.45 g (77%).
Data corresponding to phosphonate A4
TLC Rf = 0.21 (hexanes/EtOAc = 40/60) [KMnO4]
1H NMR (500 MHz, CDCl3) δ 5.67 (ddt, J = 12.8, 10.3, 6.4 Hz, 1H), 5.06 –
4.94 (os, 2H), 4.13 (dd, J = 8.3, 2.8 Hz, 3H), 4.05 (dd, J = 8.3, 2.9
Hz, 3H), 4.13 (dd, J = 8.3, 2.8 Hz, 3H), 4.05 (dd, J = 8.3, 2.9 Hz,
3H), 3.51 (dd, J = 20.2, 16.7 Hz, 1H), 3.34 (dd, J = 20.2, 16.7 Hz,
1H), 2.30 – 2.16 (os, 2H), 1.90 – 1.80 (m, 1H), 1.69 (t, J = 10.7 Hz,
1H), 1.41 (s, 1H).
Phosphonate A4 (0.10 g, 0.26 mmol) was dissolved in acetone (0.5 mL). To the
vigorously stirring mixture was added K2CO3 (46 mg, 0.33 mmol) and the
reaction mixture was cooled with an ice-water bath and allowed to stir for 5 min.
MeI was added dropwise and the reaction mixture was allowed to warm to rt and
stirred overnight. The reaction was quenched by a saturated NaHCO3 solution.
The mixture was extracted with CH2Cl2 (3 x 2.0 mL) and the combined
extractwashed with brine (1.0 mL), dried with Na2SO4, and evaporated. The
crude phosphonate 3.42 (35 mg, 34%) was used without further purification.
TLC Rf = 0.14 and 0.20 (CH2Cl2/EtOAc = 40/60) [Anisaldehyde]
208
Synthesis of Compound 3.43
Phosphonate 3.42 (34 mg, 0.09 mmol) and a 3:1 acetone/water mixture (2.0 mL)
were added to a scintillation vial. Once the phosphonate dissolved, OsO4 (1 g/25
mL in water) (27 µL, 0.0043 mmol) and NMO·H2O (35 mg, 0.26 mmol) were
added and the reaction mixture was stirred for 4 h. TLC confirmed the alkene
starting material had been consumed (CH2Cl2/hexanes = 70/30). NaIO4 (92 mg,
0.43 mmol) was added to the vigorously stirring reaction mixture. Reaction
progress was monitored by TLC (MeOH/EtOAc = 15/85) and when the diol
intermediate was consumed, the reaction mixture was filtered through a cotton
plug. The filtrate extracted with CH2Cl2 (3 x 0.5 mL) and the combined
extractwashed with brine (0.5 mL), dried with Na2SO4, and evaporated. The
crude phosphonate A5 (29 mg, 80%) was used without further purification.
TLC Rf = 0.15 (CH2Cl2/EtOAc = 15/85) [KMnO4]
Phosphonate A5 (29 mg, 0.07 mmol), acetonitrile (0.5 mL), DBU (12 µL, 0.08
mmol), and LiCl (6.3 mg, 0.15 mmol) were added successively and stirred
vigorously. The reaction progress was monitored by TLC. After 5 min, the
reaction was complete. The reaction mixture was quenched by a saturated
NaHCO3 solution. The mixture was extracted with CH2Cl2 (3 x 0.5 mL) and the
209
combined extractwashed with brine (0.25 mL), dried with Na2SO4, and
evaporated. The crude phosphonate 3.43 was purified by flash chromatography,
yielding 8 mg (40%).
TLC Rf = 0.26 (hexanes/EtOAc = 75/25) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 6.69 (d, J = 4.8 Hz, 1H), 4.37 (dd, J = 8.2, 2.8
Hz, 3H), 4.18 (dd, J = 8.2, 2.9 Hz, 3H), 2.72 – 2.63 (m, 1H), 2.33 (d,
J = 19.5 Hz, 1H), 2.20 – 2.14 (os, 2H), 1.80 (s, 3H), 1.46 (d, J = 6.4
Hz, 3H).
210
Spectra of Compounds from Chapter 3
Figure 3.1 – 1H NMR of Compound 3.3 (600 MHz, CDCl3)
211
Figure 3.2 – 1H NMR of Compound 3.5 (600 MHz, CDCl3)
212
Figure 3.3 – 1H NMR of Compound 3.6 (600 MHz, CDCl3)
213
Figure 3.4 – 1H NMR of Compound 3.15 (250 MHz, CDCl3)
214
Figure 3.5 – 1H NMR of Compound 3.15 (600 MHz, CDCl3)
215
Figure 3.6 – 13C NMR of Compound 3.15 (125 MHz, CDCl3)
216
Figure 3.7 – 1H NMR of Compound 3.16 (500 MHz, CDCl3)
217
Figure 3.8 – 13C NMR of Compound 3.16 (125 MHz, CDCl3)
218
Figure 3.9 – 1H NMR of Compound 3.17 (500 MHz, CDCl3)
219
Figure 3.10 – 13C NMR of Compound 3.17 (125 MHz, CDCl3)
220
Figure 3.11 – 1H NMR of Compound A2 (600 MHz, CDCl3)
221
Figure 3.12 – 1H NMR of Compound 3.18 (500 MHz, CDCl3)
222
Figure 3.13 – 13C NMR of Compound 3.18 (125 MHz, CDCl3)
223
Figure 3.14 – 1H NMR of Compound 3.19 (600 MHz, CDCl3)
224
Figure 3.15 – 13C NMR of Compound 3.19 (125 MHz, C6D6)
225
Figure 3.16 – 1H NMR of Compound 3.20 (600 MHz, CDCl3)
226
Figure 3.17 – 1H NMR of Compound 3.23 (600 MHz, CDCl3)
227
Figure 3.18 – 1H NMR of Compound 3.24 (600 MHz, CDCl3)
228
Figure 3.19 – 1H NMR of Compound 3.26 (600 MHz, CDCl3)
229
Figure 3.20 – 1H NMR of Compound 3.26 (600 MHz, D2O)
230
Figure 3.21 – 1H NMR of Compound 3.28 (600 MHz, CDCl3)
231
Figure 3.22 – 13C NMR of Compound 3.28 (150 MHz, CDCl3)
232
Figure 3.23 – 1H NMR of Compound 3.29 (600 MHz, CDCl3)
233
Figure 3.24 – 13C NMR of Compound 3.29 (125 MHz, C6D6)
234
Figure 3.25 – 1H NMR of Compound 3.12 (600 MHz, C6D6)
235
Figure 3.26 – 1H NMR of Compound 3.30 (600 MHz, CDCl3)
236
Figure 3.27 – 1H NMR of Compound 3.10 (600 MHz, CDCl3)
237
Figure 3.28 – 13C NMR of Compound 3.10 (125 MHz, C6D6)
238
Figure 3.29 – 1H NMR of Compound 3.31 and 3.32 (mixture) (600 MHz, CDCl3)
239
Figure 3.30 – 1H NMR of Compound 3.32 (600 MHz, CDCl3)
240
Figure 3.31 – 1H NMR of Compound 3.34 (600 MHz, CDCl3)
241
Figure 3.32 – 1H NMR of Compound 3.35 (600 MHz, CDCl3)
242
Figure 3.34 – 1H NMR of Compound 3.39 (600 MHz, CDCl3)
243
Figure 3.35 – 1H NMR of Compound 3.40 (600 MHz, CDCl3)
244
Figure 3.36 – 1H NMR of Compound 3.41 (600 MHz, CDCl3)
245
Figure 3.37 – 1H NMR of Compound A4 (500 MHz, CDCl3)
246
Figure 3.38 – 1H NMR of Compound 3.43 (600 MHz, CDCl3)
247
B.1 Experimental – Reactions in Chapter 4
Synthesis of Compound 4.6
• Using the organolithium
O
OO
O
O
O
O
LDA, THF-78 C
O
OO O
O O
4.1 4.6
Diisopropylamine (25 µL, 0.18 mmol) and THF (3.5 mL) were cooled with an ice-
water bath followed by dropwise addition of n-BuLi (1.94 M in hexanes, 0.10 mL,
0.19 mmol). The reaction mixture was stirred for 10 min and then cooled with a
dry ice/acetone bath. Methyl pyruvate (12 µL, 0.13 mmol) as a THF solution (0.5
mL) was added dropwise to the freshly prepared LDA solution at -78 °C and the
resulting mixture was allowed to stir for 30 min. Cyclohexenone 4.1 (20 mg,
0.089 mmol) as a THF solution (0.5 mL) was added dropwise and the reaction
mixture and was allowed to stir for 1 h. Reaction progress was monitored by
TLC. The reaction mixture was quenched with a saturated NaHCO3 solution.
The reaction mixture was extracted with EtOAc (3 x 5.0 mL) and the combined
extract washed with brine (5.0 mL), dried with MgSO4, and evaporated. The
crude material was purified using flash chromatography (hexanes/EtOAc = 25/75
until methyl pyruvate eluted, then hexanes/EtOAC = 1/1) to obtain compound 4.6,
14 mg (53%).
TLC Rf = 0.47 (hexanes/EtOAc = 1/1) [KMnO4]
248
1H NMR (500 MHz, CDCl3) δ 5.85 – 5.78 (m, 1H), 5.75 – 5.68 (m, 1H), 4.12
4.14 (dd, J = 8.1, 3.0 Hz, 3H), 4.09 (dd, J = 8.1, 3.0 Hz, 3H), 3.02
(dd, J = 20.8, 2.2 Hz, 1H), 2.79 (d, J = 20.9 Hz, 1H), 2.57 – 2.42
(os, 2H), 2.35 – 2.22 (m, 1H), 1.45 (s, 3H), 1.39 – 1.29 (os, 2H)
Synthesis of Compound 4.8105
To a RBF was added THF (6.5 mL) followed by sequential addition of NEt3 (0.96
mL, 6.9 mmol), methyl pyruvate (0.50 g, 4.7 mmol), and TMSCl (0.70 mL, 5.5
mmol). The reaction mixture was stirred at rt for 3.5 h. Reaction progress was
monitored by TLC. Once the reaction was complete, pentane (7.5 mL) was
added and the reaction mixture was filtered and the filtrate washed with water (2
x 5 mL) and brine (5 mL). The combined extract was dried with MgSO4 and
evaporated to obtain silyl enol ether 4.8 as a colorless liquid. 1H NMR matched
literature values.
1H NMR (600 MHz, CDCl3) δ 5.50 (s, 1H), 4.87 (s, 1H), 3.75 (d, J = 17.2 Hz,
3H), 0.23 (s, 9H).
249
Synthesis of Compound 4.11106
Et2O (50 mL) and piperidine (6.2 mL, 0.063 mol) were added to a RBF. The
reaction mixture was cooled with -25 °C with an acetone bath and dry ice chips.
AsCl3 (1.2 mL, 14 mol) was added as an Et2O solution (8.3 mL) over 30 min. The
reaction mixture was stirred for an additional 15 min at -20 °C. Methyl pyruvate
(2.0 g, 0.20 mol) was added as an Et2O solution (5.5 mL) and warmed gradually
to rt and left to stand overnight. The reaction mixture was filtered through a pad
of Celite® and the filtrate was evaporated. The crude enamine was purified using
a kugelrohr apparatus (100 °C, 8 torr) to obtain 4.11 as a pale yellow oil (1.1 g,
33%). 1H NMR matched literature values.
1H NMR (600 MHz, CDCl3) δ 5.12 (s, 1H), 4.55 (s, 1H), 3.80 (s, 3H), 2.85 –
2.75 (m, 7H), 1.6-1.9 (m, 5H)
Synthesis of Compound 4.33
250
Zinc powder (48 mg, 0.73 mmol) and THF (1.0 mL) were added to a scintillation
vial. The zinc was activated (by addition of cat 1,2-dibromoethane, heating to
reflux for 1 min with vigorous stirring, cooling to rt, addition of cat TMSCl, heating
to reflux for 1 min with vigorous stirring, and cooling to rt). The activated zinc
solution was cooled with an ice-water bath and ethyl-2-(bromomethyl)acrylate
(0.10 g, 0.52 mmol) was added dropwise to the reaction mixture. CuCN·2LiCl (1
M solution in THF, 0.57 mL, 0.57 mmol) was added to a separate scintillation vial
and cooled using a dry ice/acetone bath (at -78 °C). The organozinc solution
was syringed away from the residual zinc powder and added dropwise to the
CuCN·2LiCl solution. The reaction mixture was warmed gradually to -30 °C.
Cyclohexenone 4.1 (58 mg, 0.26 mmol) was added as a THF solution (0.5 mL)
and the reaction mixture was stirred for 1 h (at -30 °C). The reaction progress
was monitored by TLC. The reaction mixture was quenched with a saturated
NaHCO3 solution (5.0 mL), extracted with EtOAc (3 x 2.5 mL), the combined
extract washed with brine (1.0 mL), dried with MgSO4, and evaporated. The
crude material was purified using flash chromatography (hexanes/EtOAC = 1/1)
to obtain compound 4.33 and 4.1 (as a 1.3:1 mixture).
TLC Rf = 0.25 (hexanes/EtOAc = 1/1) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 6.29 (t, J = 2.7 Hz, 1H), 5.84 (dt, J = 10.0, 3.5
Hz, 1H), 5.65 (t, J = 2.4 Hz, 1H), 5.61 (d, J = 10.1 Hz, 1H), 4.11 (s,
6H), 2.94 – 2.81 (os, 2H), 2.25 – 2.14 (m, 1H), 1.80 – 1.77 (m, 1H),
1.65 (t, J = 4.5 Hz, 1H), 1.41 (s, 3H).
251
Synthesis of Compound 4.35
BrZn OEt
O
O b) CuBr•SMe2, thenTMSClc) Cyclohexenone
a)
O
OO
O OHO
O
O
OEt
4.1 4.35
4.29
HO
H
H
Zinc powder (72 mg, 1.1 mmol) and THF (1.0 mL) were added to a scintillation
vial. The zinc was activated (by addition of cat 1,2-dibromoethane, heating to
reflux for 1 min with vigorous stirring, cooling to rt, addition of cat TMSCl, heating
to reflux for 1 min with vigorous stirring, and cooling to rt). The activated zinc
solution was cooled with an ice-water bath and ethyl-2-(bromomethyl)acrylate
(0.15 g, 0.78 mmol) was added dropwise to the reaction mixture and stirred for 5
min. CuBr·SMe2 (0.18 g, 0.86 mmol) and THF (1.0 mL) were added to a
separate scintillation vial and cooled using a dry ice/acetone bath (at -78 °C).
The organozinc solution was syringed away from the residual zinc powder and
added dropwise to the CuBr·SMe2 solution followed by addition of TMSCl (0.11
mL, 0.86 mmol). The reaction mixture was warmed gradually to -30 °C. The
organocopper solution was then recooled with a dry ice/acetone bath (at -78 °C)
and cyclohexenone 4.1 (66 mg, 0.29 mmol) was added as a THF solution (0.5
mL) and the reaction mixture was stirred for 1 h (at -78 °C). The reaction
progress was monitored by TLC. The reaction mixture was quenched with a
saturated NaHCO3 solution (5.0 mL). The mixture was extracted with EtOAc (3 x
2.5 mL) and the combined extract washed with brine (1.0 mL), dried with MgSO4,
252
and evaporated. The crude material was purified using flash chromatography
(hexanes/EtOAC = 1/1) to obtain compound 4.35.
TLC Rf = 0.23 (hexanes/EtOAc = 1/1) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 6.17 (s, 1H), 5.50 (s, 1H), 4.23 – 4.21 (os, 2H),
4.18 (q, J = 14.3, 7.1 Hz, 2H), 3.90 (t, J = 5.6 Hz, 2H), 3.83 – 3.78
(os, 2H), 2.32 (dd, J = 13.9, 6.7 Hz, 1H), 2.23 (dd, J = 13.8, 7.0 Hz,
1H), 2.07 – 2.02 (os, 4H), 1.85 – 1.79 (os, 2H), 1.70 – 1.62 (os,
2H), 1.41 – 1.23 (os, 5H), 1.01 – 0.92 (m, 1H)
Synthesis of Compound 4.36
Zinc powder (72 mg, 1.1 mmol) and THF (1.0 mL) were added to a scintillation
vial. The zinc was activated (by addition of cat 1,2-dibromoethane, heating to
reflux for 1 min with vigorous stirring, cooling to rt, addition of cat TMSCl, heating
to reflux for 1 min with vigorous stirring, and cooling to rt). The activated zinc
solution was cooled with an ice-water bath and ethyl-2-(bromomethyl)acrylate
(0.15 g, 0.78 mmol) was added dropwise to the reaction mixture and stirred for 5
min. CuBr·SMe2 (0.18 g, 0.86 mmol) and THF (1.0 mL) were added to a
separate scintillation vial and cooled using a dry ice/acetone bath (at -78 °C).
The organozinc solution was syringed away from the residual zinc powder and
added dropwise to the CuBr·SMe2 solution followed by addition of TMSCl (0.11
253
mL, 0.86 mmol). The reaction mixture was warmed gradually to -30 °C. The
organocopper solution was then recooled with a dry ice/acetone bath (at -78 °C).
2,6-lutidine (0.10 mL, 0.86 mmol) and cyclohexenone (28 mg, 0.29 mmol) were
added and the reaction mixture was stirred for 30 min (at -78 °C). The reaction
progress was monitored by TLC. The reaction mixture was quenched with a
saturated NaHCO3 solution (5.0 mL). The mixture was extracted with CH2Cl2 (3 x
2.5 mL) and the combined extract washed with brine (1.0 mL), dried with
Na2SO4, and evaporated. The crude material was purified using flash
chromatography (hexanes/EtOAC = 1/1) to obtain compound 4.36.
TLC Rf = 0.59 (hexanes/EtOAc = 90/10) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 6.17 (s, 1H), 5.75 (dt, J = 9.4, 3.4 Hz, 1H), 5.65
(d, J = 10.1 Hz, 1H), 5.55 (s, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.58 (dd,
J = 33.3, 13.3 Hz, 2H), 2.05 – 1.86 (os, 2H), 1.75 – 1.63 (os, 2H),
1.63 – 1.53 (os, 2H), 1.30 (t, J = 7.1 Hz, 3H), 0.08 (s, 9H).
Synthesis of Compound 4.31
Methyl ester 4.36 (0.062 g, 0.29 mmol) and THF (1.0 mL) were added to a
scintillation vial which was then cooled with a dry-ice/acetone bath (at -78 °C).
TBAF (1.0 M solution in THF, 0.35 mL, 0.35 mmol) was added dropwise. After
15 min, the reaction mixture was quenched with a saturated NaHCO3 solution
254
(1.0 mL). The mixture was extracted with CH2Cl2 (3 x 1.0 mL) and the combined
extract washed with brine (1.0 mL), dried with Na2SO4, and evaporated to obtain
the crude methyl ester. The crude material was purified using flash
chromatography (hexanes/EtOAC = 1/1) to obtain compound 4.31 (10 mg, 15%
over two steps).
TLC Rf = 0.59 (hexanes/EtOAc = 90/10) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 6.21 (s, 1H), 5.52 (s, 1H), 4.20 (q, J = 7.1 Hz,
2H), 2.43 – 2.33 (os, 3H), 2.26 (ddd, J = 20.9, 14.1, 6.4 Hz, 2H),
2.07 – 1.97 (os, 3H), 1.91 (d, J = 13.2 Hz, 1H), 1.64 (q, J = 25.4,
12.6 Hz, 1H), 1.38 – 1.31 (os, 2H), 1.30 (t, J = 7.1 Hz, 3H).
Synthesis of Compound 4.37
CuBr•SMe2 (0.10g, 0.49 mmol) in 2:1 THF/DMS (5.5 mL) was added to a RBF
and cooled with a dry-ice/acetone bath (-78 °C ) and titrated vinylmagnesium
bromide (0.91 M, 4.3 mL, 3.9 mmol) was added dropwise. The reaction mixture
turned dark red. After stirring for 10 min, cyclohexenone 4.1 in THF (0.5 mL) was
added dropwise to the reaction mixture. After 1 h, the reaction was complete and
quenched by pouring the reaction mixture into a vigorously stirring solution of
10% NH4OH. The reaction mixture was filtered through Celite®. The Celite® pad
255
was washed with Et2O (3 x 5.0 mL). The aqueous layer was extracted with Et2O
(3 x 5.0 mL) and the combined extract dried with MgSO4 and evaporated. The
mixtures of diastereomers 4.37a and 4.37b was purified by flash chromatography
(hexanes/EtOAc = 75/25) to obtain 0.26 g and 0.051 g of 4.37a and 4.37b
respectively (70%).
TLC Rf = 0.44 and 0.35 (hexanes/EtOAc = 60/40) [KMnO4]
Data corresponding to maJor diastereomer 4.37a (Rf = 0.44)
1H NMR (600 MHz, C6D6) δ 5.37 (qd, J = 16.9, 10.3, 6.5 Hz, 1H), 4.81 (dd, J
= 10.2, 0.9 Hz, 1H), 4.73 (dd, J = 17.2, 1.1 Hz, 1H), 4.04 (dd, J =
7.8, 3.0 Hz, 3H), 4.00 (dd, J = 7.8, 3.1 Hz, 3H), 2.08 (d, J = 12.7
Hz, 1H), 1.76 (os, 4H)1.46 (t, J = 12.8 Hz, 1H), 1.29 – 1.21 (os,
2H), 1.07 (d, J = 12.8 Hz, 1H), 0.69 (qd, J = 12.7, 3.4 Hz, 1H), 0.58
(qd, J = 12.7, 3.4 Hz, 1H).
Data corresponding to minor diastereomer 4.37b (Rf = 0.35)
1H NMR (600 MHz, C6D6) δ 5.32 (qd, J = 16.5, 10.7, 5.6 Hz, 1H), 4.90 –
4.81 (os, 2H), 4.02 (dd, J = 7.7, 2.6 Hz, 3H), 3.99 (dd, J = 7.7, 2.6
Hz, 3H), 2.26 – 2.20 (m, 1H), 2.08 (d, J = 13.8 Hz, 1H), 1.78 – 1.72
(os, 4H), 1.30 (dd, J = 12.2, 5.8 Hz, 1H), 1.13 – 1.02 (os, 2H), 0.97
(ddd, J = 16.1, 12.2, 4.3 Hz, 1H), 0.93 – 0.87 (m, 1H).
256
Synthesis of Compound 4.39
O
OO O
H
H
NMO•H2OOsO4
Me2CO/H2O2:1
O
OO O
OH
35%
OH
4.37 4.39
H
H
Alkene 4.37 (6 mg, 0.02 mmol) and THF/water mixture (2:1) (1.0 mL) were added
to a scintillation vial. OsO4 (1 g/25 mL in water) (5 µL, 0.7 µmol) and NMO·H2O
(0.35 mg, 0.03 mmol) were added and the reaction mixture was stirred overnight.
TLC confirmed the alkene starting material had been consumed. Na2SO3 (8.5
mg, 0.06 mmol) was added to the vigorously stirring reaction mixture and the
reaction mixture stirred for 30 min. The mixture was extracted with EtOAc (3 x
1.0 mL) and the combined extract washed with brine (1.0 mL), dried with MgSO4,
and evaporated. The crude material was purified using flash chromatography to
obtain diol 4.39, 2.4 mg (35%).
TLC Rf = 0.48 (MeOH/EtOAc = 5/95) [KMnO4]
1H NMR (600 MHz, C6D6) δ 4.11 (d, J = 7.8 Hz, 3H), 4.09 (d, J = 7.8 Hz,
3H), 3.70 – 3.48 (os, 3H), 2.32 – 2.27 (os, 2H), 2.25 – 2.20 (m, 1H),
2.13 – 2.07 (m, 1H), 1.93 – 1.86 (m, 1H), 1.77 (s, 1H), 1.64 (dd, J =
29.1, 15.9 Hz, 1H), 1.57 (s, 1H), 1.56 – 1.50 (m, 1H), 1.49 – 1.33
(os, 4H)
257
Synthesis of Compound 4.48
Alkene 4.37b (0.23 g, 0.89 mmol), NMO·H2O (0.36 g, 2.7 mmol), and CH2Cl2 (10
mL) were added to a RBF and the mixture cooled with a dry ice/acetone bath.
The reaction was sparged with ozone containing oxygen and monitored by TLC
until the starting material (alkene 4.37b) was consumed. The reaction mixture
was warmed to rt and quenched with a solution of 1:1 saturated
NaHCO3/Na2S2O3. The mixture was extracted with CH2Cl2 (3 x 5.0 mL) and the
combined extract washed with brine (5.0 mL), dried with Na2SO4, and
evaporated. The crude aldehyde 4.40 was used in the next step without further
purification.
TLC Rf = 0.23 (hexanes/EtOAc = 75/25) [KMnO4]
1H NMR (600 MHz, C6D6) δ 8.90 (s, 1H), 3.92 (s, 6H), 2.16 (d, J = 14.6 Hz,
1H), 1.78 – 1.73 (m, 2H), 1.71 (s, 3H), 1.50 (dd, J = 14.5, 7.2 Hz,
1H), 1.35 (d, J = 13.0 Hz, 1H), 1.16 (dd, J = 12.4, 5.4 Hz, 1H), 0.84
– 0.80 (m, 1H), 0.79 – 0.64 (os, 2H)
LiNTMS2 (1.0 M in THF, 1.1 mL, 1.1 mmol) and THF (5.0 mL) were added to a
RBF and the reaction mixture was cooled with a dry-ice/bath (at -78 °C).
258
Phosphonate 4.47 (0.33 g, 1.1 mmol) in a THF solution (0.5 mL) was added to a
RBF and stirred for 15 min. Aldehyde 4.40 was added as a THF solution (0.5
mL) and the reaction mixture was stirred for 1 h. The reaction mixture was
quenched with a solution of 1:1 saturated NaHCO3/Na2S2O3 and extracted with
Et2O (3 x 5.0 mL) and the combined extract washed with brine (5.0 mL), dried
with MgSO4, and evaporated. The crude material was purified using flash
chromatography to obtain silyl enol ether 4.48 (0.19 g, 48% over two steps).
TLC Rf = 0.35 (hexanes/EtOAc = 1/1, 0.1% NEt3) [KMnO4]
1H NMR (600 MHz, C6D6) δ 5.13 (d, J = 9.6 Hz, 1H), 4.03 (dd, J = 7.9, 3.0,
Hz, 3H), 3.98 (dd, J = 7.9, 3.0 Hz, 3H), 3.39 – 3.25 (os, 1H), 2.28
(dd, J = 12.7, 2.2 Hz, 1H), 1.74 (s, 1H), 1.56 – 1.49 (m, 1H), 1.45 (t,
J = 12.7 Hz, 1H), 1.35 (dd, J = 12.5, 4.8 Hz, 1H), 1.15 – 1.08 (m,
1H), 1.02 (t, J = 7.9 Hz, 2H), 0.75 (dd, J = 20.8, 11.6 Hz, 1H), 0.69
(q, J = 7.9 Hz, 1H).
Synthesis of Compound 4.3
Silyl enol ether 4.48 (0.16 g, 0.36 mmol), NEt3 (0.05 mL, 0.36 mmol), and MeOH
(5.0 mL) were added to a RBF and stirred at rt for 6 h. Reaction progress was
monitored by TLC. The reaction mixture was quenched with a solution of
saturated NaHCO3 and extracted with CH2Cl2 (3 x 5.0 mL) and the combined
259
extract washed with brine (5.0 mL), dried with Na2SO4, and evaporated. The
crude material was purified using flash chromatography (hexanes/EtOAc = 45/55,
0.1% NEt3) to obtain compound 4.3 (0.10 g, 83%).
TLC Rf = 0.29 (hexanes/EtOAc = 40/60) [KMnO4]
1H NMR (600 MHz, C6D6) δ 4.00 (dd, J = 7.9, 3.0 Hz, 3H), 3.97 (dd, J = 7.9,
3.0 Hz, 3H), 3.24 (s, 3H), 2.24 (dd, J = 17.7, 7.3 Hz, 1H), 2.12 (dd,
J = 17.7, 5.7 Hz, 1H), 1.98 (ddd, J = 12.7, 3.8, 2.3 Hz, 1H), 1.74 (s,
3H), 1.31 – 1.20 (os, 4H), 1.03 (ddd, J = 12.8, 5.6, 3.2 Hz, 1H), 0.60
– 0.44 (os, 2H)
13C NMR (125 MHz, C6D6) δ 205.9, 191.6, 161.7, 109.2, 68.7, 68.7, 52.2,
49.8, 48.2, 45.3, 34.9, 34.8, 31.1, 26.7, 24.1
Synthesis of Compound 4.4774-76
Boric acid (82 mg, 1.3 mmol), L-tartaric acid (20 g, 0.13 mol), and HPLC grade
MeOH (300 mL) were added in a RBF and stirred overnight. Most of the MeOH
260
was evaporated off. Methyl ester 4.50 was recovered in quantitative yields and
used without further purification.
1H NMR (600 MHz, CDCl3) δ 3.66 (s, 2H), 3.87 (s, 6H), 4.56 (s, 2H)
Dimethyl tartrate 4.50 (7.5 g, 0.042 mol) and Et2O (60 mL) were added to a RBF
and the reaction mixture cooled with an ice-water bath (at °C). Periodic acid (11
g, 0.046 mol) was added in portions over 1h. The reaction mixture was gradually
warmed to rt and stirring was continued for 1h (at rt). The reaction mixture was
filtered through a pad of Celite®, and evaporated (with 45 torr pump). The crude
reaction mixture was purified using a kugelrohr apparatus (150 °C, 45 torr) to
obtain 4.51 as a clear liquid (3.6 g, 49% over two steps). Methyl glyoxalate 4.51
was used without further purification.
Methyl glyoxalate (0.78 g, 9.0 mmol), benzene (1.0 mL), dimethyl phosphite (0.82
mL, 9.0 mmol), and p-TsOH (2.5 mg, 0.013 mmol) were added in a RBF fitted
with a Dean-Stark trap and condenser. The reaction mixture was brought to
reflux. Reaction progress was monitored by TLC. After 2 h, heat was removed
and the benzene evaporated. The crude material was purified using flash
chromatography to yield phospohonate 4.52 (0.51 g, 29%).
TLC Rf = 0.38 (acetone/hexanes = 60/40) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 4.59 (d, J = 16.0 Hz, 1H), 3.90 (s, 3H), 3.87
(dd, J = 10.7, 7.6 Hz, 6H).
261
Phosphonate 4.52 (0.74 g, 3.8 mmol), CH2Cl2 (10 mL), TESCl (0.76 mL, 4.5
mmol), NEt3 (0.57 mL, 4.1 mmol), and DMAP (46 mg, 0.38 mmol) were added to
a RBF and the cloudy, white reaction mixture stirred. After a 1 h, the reaction
mixture became clear. Reaction progress was monitored by TLC. The reaction
mixture was quenched with a saturated solution of NaHCO3 and extracted with
CH2Cl2 (3 x 10 mL) and the combined extract washed with brine (10 mL), dried
with Na2SO4, and evaporated. The crude material was purified using flash
chromatography (hexanes/EtOAc = 25/75) to obtain phosphonate 4.47 (1.0 g,
86%).
TLC Rf = 0.63 (MeOH/ CH2Cl2 = 10/90)
1H NMR (600 MHz, C6D6) δ 4.66 (d, J = 18.1 Hz, 1H), 3.85 (dd, J = 10.5, 7.6
Hz, 6H), 3.82 (s, 3H), 0.98 (t, J = 7.9 Hz, 9H), 0.66 (q, J = 7.9 Hz,
6H).
Synthesis of Compound 4.55
Zinc powder (0.11 mg, 1.7 mmol) and THF (1.0 mL) were added to a scintillation
vial. The zinc was activated (by addition of cat 1,2-dibromoethane, heating to
reflux for 1 min with vigorous stirring, cooling to rt, addition of cat TMSCl, heating
to reflux for 1 min with vigorous stirring, and cooling to rt). The activated zinc
262
solution was cooled with an ice-water bath and ethyl-2-(bromomethyl)acrylate
(0.23 g, 1.2 mmol) was added dropwise to the reaction mixture and stirred for 5
min. CuBr·SMe2 (0.26 g, 1.2 mmol) and THF (1.0 mL) were added to a separate
scintillation vial and cooled using a dry ice/acetone bath (at -78 °C). The
organozinc solution was syringed away from the residual zinc powder and added
dropwise to the CuBr·SMe2 solution followed by addition of TMSCl (0.16 mL, 1.2
mmol). The reaction mixture was warmed gradually to -30 °C. The
organocopper solution was then recooled with a dry ice/acetone bath (at -78 °C).
Cyclohexenone 4.56 (50 mg, 0.45 mmol) was added and the reaction mixture
was stirred for 1 h (at -78 °C). The reaction progress was monitored by TLC.
The reaction mixture was quenched with a saturated NH4Cl solution (5.0 mL).
The mixture was extracted with CH2Cl2 (3 x 2.5 mL) and the combined extract
washed with brine (1.0 mL), dried with Na2SO4, and evaporated. The crude
material was purified using flash chromatography to obtain compound B1 (43
mg, 42%).
TLC Rf = 0.23 (hexanes/EtOAc = 90/10) [Anisaldehyde]
1H NMR (500 MHz, CDCl3) δ 6.21 (s, 1H), 5.53 (s, 1H), 4.20 (q, J = 13.8, 6.9
Hz, 2H), 2.49 – 2.36 (os, 2H), 2.36 – 2.16 (os, 3H), 2.00 – 1.80 (os,
2H), 1.68 – 1.58 (m, 1H), 1.43 – 1.21 (m, 1H), 1.30 (t, J = 7.1 Hz,
3H), 1.08 (d, J = 6.7 Hz, 2H), 1.02 (d, J = 6.4 Hz, 1H).
Alkene B1 (43 mg, 0.19 mmol), NMO·H2O (0.78 mg, 0.57 mmol), and CH2Cl2 (10
mL) were added to a RBF and the mixture cooled with an ice-water bath (at 0
263
°C). The reaction was sparged with ozone containing oxygen and monitored by
TLC until the starting material (alkene B1) was consumed. The reaction mixture
was quenched with a solution of 1:1 saturated NaHCO3/Na2S2O3. The mixture
was extracted with CH2Cl2 (3 x 5.0 mL) and the combined extract washed with
brine (5.0 mL), dried with Na2SO4, and evaporated. The crude material was
purified using flash chromatography (hexanes/EtOAC = 1/1) to obtain compound
4.55 as a mixture of diastereomers (48 mg, 78%).
TLC Rf = 0.23 (hexanes/EtOAc = 75/25) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 4.29 (q, J = 7.1 Hz, 2H), 2.91 – 2.77 (os, 1.5H),
2.71 (dt, J = 11.5, 5.7 Hz, 0.5H), 2.49 – 2.40 (os, 1.5H), 2.35 – 2.27
(m, 0.5H), 2.22 (dd, J = 14.0, 5.9 Hz, 0.5H), 2.11 – 2.03 (m, 0.5H),
2.01 – 1.85 (os, 1.5H), 1.66 – 1.53 (m, 1H), 1.45 (ddd, J = 24.4,
12.8, 2.9 Hz, 0.5H), 1.34 (t, J = 7.1 Hz, 3H), 1.07 – 0.97 (os, 3H).
Synthesis of Compound 4.57
O TiCl4,CH2Cl2
-78 to -40 °C
O
68%
TMS
4.56 4.57a
H HO
4.57b
H
HH
Cyclohexenone 4.56 (0.85 g, 7.7 mmol) and CH2Cl2 (20 mL) were added to a
RBF and cooled with a dry ice/acetone bath (at -78 °C). TiCl4 (1.7 mL, 0.015
mol) was added dropwise to the vigorously stirring reaction mixture. After
complete addition of the TiCl4, the reaction mixture was stirred for an additional
264
30 min (at -78 °C). Allyltrimethylsilane (1.5 mL, 9.4 mmol) was added as a
CH2Cl2 solution (5.0 mL) into the reaction mixture with a syringe pump. The
reaction mixture was stirred for 1 h at -78 °C and then warmed to -40 °C and
stirred for an additional 1 h. Reaction progress was monitored by TLC. The
reaction mixture was quenched with water and extracted with CH2Cl2 (3 x 20 mL)
and the combined extract washed with brine (20 mL), dried with Na2SO4, and
evaporated (with 120 torr pump). The crude material was purified using flash
chromatography (hexanes/EtOAc = 97/3) to obtain cyclohexenone 4.57a and
4.57b (0.80 g, 68%).
TLC Rf = 0.26 (4.57a) and 0.33 (4.57b) (hexanes/EtOAc = 95/5)
[KMnO4]
Data corresponding to compound 4.57a
1H NMR (600 MHz, CDCl3) δ 5.75 (dt, J = 16.2, 7.3 Hz, 1H), 5.04 (s, 1H),
5.02 (d, J = 5.2 Hz, 1H), 2.42 (d, J = 13.1 Hz, 1H), 2.33 (dp, J =
12.4, 6.2 Hz, 1H), 2.14 – 2.05 (os, 3H), 2.01 (t, J = 13.1 Hz, 1H),
1.90 (d, J = 13.0 Hz, 1H), 1.85 – 1.76 (m, 1H), 1.44 – 1.29 (os, 2H),
1.01 (d, J = 6.5 Hz, 3H).
Data corresponding to compound 4.57b
TLC Rf = 0.26 (4.57a) and 0.33 (4.57b) (hexanes/EtOAc = 95/5)
[KMnO4]
1H NMR (600 MHz, CDCl3) δ 5.72 (dt, J = 17.4, 7.1 Hz, 1H), 5.04 (s, 1H),
5.01 (d, J = 7.4 Hz, 1H), 2.47 – 2.38 (os, 2H), 2.25 (dd, J = 13.9,
6.4 Hz, 1H), 2.14 – 2.07 (m, 1H), 2.06 – 1.99 (os, 2H), 1.91 (dt, J =
265
19.0, 6.1 Hz, 1H), 1.83 (ddd, J = 13.6, 9.6, 4.3 Hz, 1H), 1.69 – 1.58
(os, 2H), 1.07 (d, J = 6.8 Hz, 3H).
Synthesis of Compound 4.58
Alkene 4.57 (0.50 g, 3.3 mmol) and 3:1 acetone/water mixture (11 mL) were
added to a scintillation vial. OsO4 (1 g/25 mL in water) (1.5 mL, 0.16 mol) and
NMO·H2O (1.3 mg, 9.9 mmol) were added and the reaction mixture was stirred
overnight. TLC confirmed the alkene starting material (4.57) had been
consumed. NaIO4 (0.35 g, 1.6 mol) was added and the reaction mixture was
stirred for 15 min. The reaction mixture was filtered through a cotton plug and
Na2SO3 was added to the filtrate and stirred for 5 min. The mixture was extracted
with CH2Cl2 (3 x 10 mL) and the combined extract washed with brine (10 mL),
dried with Na2SO4, and evaporated. The crude material was purified using flash
chromatography to obtain compound 4.58 (2.2 mg, 39%).
TLC Rf = 0.28 (hexanes/ EtOAc = 60/40) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 9.75 (s, 1H), 2.50 – 2.40 (os, 3H), 2.38 – 2.29
(os, 2H), 2.13 – 2.06 (os, 2H), 1.96 – 1.91 (m, 1H), 1.48 (ddd, J =
24.5, 12.9, 3.1 Hz, 1H), 1.40 (ddd, J = 26.1, 12.9, 3.1 Hz, 1H), 1.03
(d, J = 6.5 Hz, 3H)
266
Synthesis of Compound 4.60
Alkene 4.57 (0.50 g, 3.3 mmol) and 3:1 acetone/water mixture (80.0 mL) were
added to a scintillation vial. OsO4 (1 g/25 mL in water) (1.5 mL, 0.16 mol) and
NMO·H2O (1.3 mg, 9.9 mmol) were added and the reaction mixture was stirred
for 5 h. TLC confirmed the alkene starting material had been consumed. The
reaction mixture was quenched with a saturated solution of NaHSO3 and
extracted with Et2O (3 x 50 mL) and the combined extract washed with brine (50
mL), dried with MgSO4, and evaporated (with 120 torr pump). The crude diol
(4.59) was carried forward without further purification (0.57 g, 93%).
Diol 4.59 (0.57 g, 3.0 mmol) and CH2Cl2 (40 mL) were added into a RBF and
cooled with an ice-water bath. Imidazole (0.42 g, 6.1 mmol) and TBSCl (0.51 g,
3.4 mmol) were added to the reaction mixture. The reaction progress was
monitored by TLC and was complete after 3 h. The reaction mixture was
quenched with a saturated solution of NaHCO3 (50 mL) and extracted with
CH2Cl2 (3 x 50 mL) and the extract washed with brine (50 mL), dried with
Na2SO4, and evaporated. The crude material was purified using flash
chromatography (hexanes/EtOAc = 75/25) to obtain the TBS protected
compound as a mixture of diastereomers (0.11 g, 12%).
267
The TBS protected compound (33 mg, 0.11 mmol), CH2Cl2 (1.0 mL), NMO·H2O
(23 mg, 0.17 mmol), and 4Å MS were added into a RBF. After stirring for 5 min,
TPAP (2 mg, 6 µmol) was added and the reaction mixture was stirred overnight.
The reaction mixture was filtered through a pad of Celite®, evaporated, and
purified by column chromatography to obtain diketone 4.60 (16 mg, 49%).
TLC Rf = 0.36 (hexanes/EtOAc = 75/25) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 4.13 (s, 2H), 2.72 (hept, J = 5.9 Hz, 1H), 2.50
– 2.41 (os, 4H), 2.20 (dd, J = 13.9, 5.8 Hz, 1H), 1.97 (td, J = 10.5,
5.5 Hz, 1H), 1.93 – 1.86 (m, 1H), 1.65 – 1.59 (m, 1H), 1.59 – 1.52
(m, 1H), 1.06 (d, J = 6.7 Hz, 3H), 0.92 (s, 9H), 0.08 (s, 6H).
Synthesis of Compound 4.61
K2CO3MeOH
O
O OH
O
87%
4.58 4.61
Aldehyde 4.58 (0.10 g, 0.65 mmol), K2CO3 (81 mg, 0.58 mmol), and MeOH (13
mL) were added to a scintillation vial and stirred for 1 h. The reaction progress
was monitored by TLC. The reaction mixture was quenched with a saturated
NaHCO3 solution (10 mL). The mixture was extracted with EtOAc (3 x 10 mL)
and the combined extract washed with brine (10 mL), dried with MgSO4, and
evaporated. The crude material was purified using flash chromatography to
obtain compound 4.61 as a mixture of diastereomers (87 mg, 87%).
268
TLC Rf = 0.21 (hexanes/ EtOAc = 60/40) [KMnO4]
Data corresponding to maJor diastereomer
1H NMR (600 MHz, CDCl3) δ 3.90 (d, J = 8.6 Hz, 1H), 2.35 – 2.28 (m, 1H),
2.26 – 2.19 (os, 3H), 1.66 – 1.54 (os, 6H), 1.06 (s, 3H)
Synthesis of Compound 4.62a and 4.62b
Using K2CO3 as the base
Ketone 4.60 (16 mg, 0.05 mmol), K2CO3 (0.7 mg, 0.05 mmol) and MeOH (0.5
mL) were added into a scintillation vial and stirred overnight. The reaction
mixture was quenched with a saturated NH4Cl solution (0.5 mL). The mixture
was extracted with CH2Cl2 (3 x 0.5 mL) and the extract washed with brine (0.5
mL), dried with Na2SO4, and evaporated. The crude NMR show a ratio of 11:1 of
the two diastereomers 4.62a and 4.62b. The crude material was purified using
flash chromatography to obtain compound 4.62a and 4.62b (9 mg and 6 mg
respectively, 93%).
TLC Rf = 0.37 (4.62a) and 0.34 (4.62b) respectively (hexanes/EtOAc =
75/25) [Anisaldehyde]
Data corresponding to Compound 4.62a
1H NMR (600 MHz, C6D6) δ 3.19 (s, 2H), 2.14 – 2.08 (m, 2H), 1.99 (qt, J =
18.4, 2.8 Hz, 1H), 1.74 (dt, J = 5.9, 2.9 Hz, 1H), 1.69 (dt, J = 14.1,
269
2.6 Hz, 1H), 1.63 (s, 1H), 1.62 – 1.55 (m, 1H), 1.51 (dt, J = 14.1,
3.2 Hz, 1H), 1.29 – 1.23 (m, 3H), 1.07 (s, 1H), 1.06 – 1.02 (m, 9H),
0.88 (s, 1H), -0.03 (d, J = 11.2, 6H).
13C NMR (125 MHz, CDCl3) δ 215.0, 77.3, 77.0, 76.7, 73.2, 68.9, 50.5, 43.28,
41.0, 27.2, 26.8, 25.8, 24.5, 18.2, 13.7
Data corresponding to Compound 4.62b
1H NMR (600 MHz, CDCl3) δ 3.34 (d, J = 9.5 Hz, 1H), 3.25 (d, J = 9.6 Hz,
1H), 2.28 (s, 1H), 2.24 – 2.10 (os, 4H), 1.85 – 1.78 (os, 2H), 1.73
(dt, J = 14.4, 3.2 Hz, 1H), 1.63 (qd, J = 6.1, 3.1 Hz, 1H), 1.27 (ddd,
J = 13.8, 11.7, 5.9 Hz, 1H), 0.97 (s, 3H), 0.88 (s, 9H), 0.04 (d, J =
4.7 Hz, 6H).
Using LDA as the base
Diisopropylamine (1.4 mL, 10 mmol) and THF (4.0 mL) were added to a RBF and
the mixture cooled with an ice-water bath followed by dropwise addition of n-BuLi
(2.30 M in hexanes) (3.5 mL, 9.1 mmol). The reaction mixture was stirred at 0 °C
for 10 min and then cooled with a dry ice/acetone bath. Diketone 4.60 (1.0 g, 9.1
mmol) as a THF solution (1.0 mL) was added dropwise to the freshly prepared
LDA solution at -78 °C and the resulting mixture was allowed to stir for 30 min.
The reaction mixture was warmed gradually to rt. The reaction mixture was
quenched with a saturated NaHCO3 solution. The mixture was extracted with
270
CH2Cl2 (3 x 20 mL) and the combined extract washed with brine (20 mL), dried
with Na2SO4, and evaporated. The crude material was purified using flash
chromatography to obtain compound 4.62a and 4.62b as a mixture of
diastereomers 1:37 (19 mg combined, 95%).
TLC Rf = 0.37 (4.62a) and 0.34 (4.62b) respectively (hexanes/EtOAc =
75/25) [Anisaldehyde]
Data matched that from the K2CO3 experiments listed above.
Synthesis of Compound 4.63
Alcohol 4.61 (10 mg, 0.65 mmol), CH2Cl2 (1.0 mL), NMO·H2O (13 mg, 0.97
mmol), and 4Å MS were added into a RBF. After stirring for 5 min, TPAP (1 mg,
3 µg) was added and the reaction mixture was stirred overnight. The reaction
mixture was filtered through a pad of Celite®, evaporated, and purified by column
chromatography (hexanes/EtOAc = 60/40) to obtain diketone 4.60 (9.6 mg, 97%).
TLC Rf = 0.37 (hexanes/EtOAc = 60/40) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 2.65 – 2.61 (m, 1H), 2.55 (d, J = 21.0 Hz, 2H),
2.39 (d, J = 20.2 Hz, 2H), 1.91 (s, 4H), 1.11 (s, 3H).
13C NMR (125 MHz, CDCl3) δ 62.6, 43.9, 30.0, 27.5, 24.7, 12.1
271
Synthesis of Compound 4.65
O
OO O BrMg O
OO HO
THF, -78 °C
H97%
4.1 4.65
Cyclohexenone 4.1 (0.60 g, 2.7 mmol) and THF (5.0 mL) were added into a RBF
cooled with a dry ice/acetone bath. Allylmagnesium bromide (0.6 M in Et2O
solution, 8.9 mL, 5.4 mmol) was added dropwise with a syringe pump. TLC after
5 min showed reaction completion. The reaction mixture was quenched with a
saturated NaHCO3 solution (20 mL). The mixture was extracted with Et2O (3 x
20 mL) and the combined extract washed with brine (20 mL), dried with MgSO4,
and evaporated. The crude material was purified using flash chromatography to
obtain compound 4.65 as a white solid (0.63 mg, 97%).
TLC Rf = 0.18 (hexanes/EtOAc = 75/25) [KMnO4]
1H NMR (600 MHz, C6D6) δ 5.43 – 5.34 (m, 1H), 5.32 (ddd, J = 10.0, 4.3, 3.1
Hz, 1H), 4.98 (d, J = 10.0 Hz, 1H), 4.89 (d, J = 10.2 Hz, 1H), 4.80
(dd, J = 17.1, 1.2 Hz, 1H), 4.23 – 4.17 (os, 6H), 2.07 – 2.02 (m,
1H), 1.90 (dd, J = 14.1, 6.7 Hz, 1H), 1.77 (s, 3H), 1.54 – 1.47 (m,
1H), 1.33 – 1.26 (m, 1H), 1.12 – 1.03 (os, 2H), 0.92 – 0.85 (m, 2H).
272
Synthesis of Compound 4.66
KH (30% in mineral oil, 0.41 g, 0.010 mol) was weighed into a scintillation vial
and washed with THF (3 x 0.5 mL). KH was brought up in fresh THF (1.5 mL)
and the reaction mixture was cooled with an ice-water bath. 18-crown-6 (1.1 g,
4.4 mmol) was added and the reaction mixture was stirred for 5 min. Alkene 4.65
(0.55 g, 2.7 mmol) in a THF solution (0.5 mL) was added dropwise. Reaction
progress was monitored by TLC, completion was observed after 3 h. The
reaction mixture was quenched by slow, careful addition of the reaction mixture
to a vigorously stirring solution of saturated NaHCO3 solution (5.0 mL). The
mixture was extracted with CH2Cl2 (3 x 5.0 mL) and the combined extract
washed with brine (5.0 mL), dried with Na2SO4, and evaporated. The crude
material was purified using flash chromatography (hexanes/EtOAc = 75/25), to
obtain compound 4.66 as a white solid (0.63 mg, 97%).
TLC Rf = 0.65 (CH2Cl2/EtOAc = 90/10) [KMnO4]
1H NMR (600 MHz, C6D6) δ 5.43 (ddt, J = 17.2, 10.1, 7.2 Hz, 1H), 4.95 (dd,
J = 10.1, 0.7 Hz, 1H), 4.88 (dd, J = 17.0, 1.5 Hz, 1H), 4.06 (dd, J =
7.9, 3.1 Hz, 3H), 4.02 (dd, J = 7.9, 3.1 Hz, 3H), 2.02 (ddd, J = 12.6,
3.7, 2.2 Hz, 1H), 1.76 (s, 3H), 1.61 (tq, J = 13.8, 6.9 Hz, 2H), 1.30 –
1.25 (os, 2H), 1.24 – 1.19 (m, 1H), 1.15 – 1.06 (os, 2H), 0.62 – 0.47
(os, 2H)
273
Synthesis of Compound 4.67
• Synthesis of diol B2
Alkene 4.66 (0.10 g, 0.38 mmol), K2CO3 (16 mg, 0.11 mmol), and 3:1
acetone/water mixture (12 mL) were added into a RBF. OsO4 (1 g/25 mL in
water) (3.5 µL, 5.6 µmol) and NMO·H2O (46 mg, 0.34 mmol) were added and the
reaction mixture was stirred overnight. TLC confirmed the alkene starting
material had been consumed. Na2SO3 was added and the reaction mixture was
stirred for 30 min. The reaction mixture was extracted with EtOAc (3 x 50 mL)
and the combined extract washed with brine (20 mL), dried with MgSO4, and
evaporated. The crude diol B2 was obtained a mixture of diastereomers, 84 mg
(84%) and used without further purification.
Data corresponding to compound B2
TLC Rf = 0.15 (EtOAc = 100) [KMnO4]
1H NMR (600 MHz, C6D6) δ 4.06 (dd, J = 7.8, 2.9 Hz, 3H), 4.02 (dd, J = 7.8,
2.8 Hz, 3H), 3.32 – 3.27 (m, 0.36H), 3.23 – 3.18 (m, 0.43H), 3.12 –
3.07 (m, 0.75H), 2.99 – 2.92 (m, 0.62H), 2.17 (d, J = 13.4 Hz,
0.27H), 2.12 (d, J = 12.9 Hz, 0.33H), 1.76 (s, 3H), 1.56 – 1.45 (os,
274
1.23H), 1.40 – 1.23 (os, 6.35H), 1.15 – 1.08 (os, 1.83H), 1.00 –
0.86 (os, 1.58H), 0.84 – 0.79 (m, 0.49H), 0.76 – 0.71 (m, 0.40H),
0.65 – 0.59 (os, 1.30H), 0.57 – 0.48 (os, 0.94H)
• Synthesis of compound B3
Diol B1 (0.24 g, 0.80 mmol), imidazole (0.16 g, 2.4 mmol) and CH2Cl2 (16 mL)
were added into a RBF. TBSCl (0.18 g, 1.2 mmol) was added to the vigorously
stirring reaction mixture. Reaction progress was monitored by TLC (Rf = 0.80,
100% EtOAc). The reaction mixture was quenched with a saturated NaHCO3
solution (20 mL). The mixture was extracted with CH2Cl2 (3 x 10 mL) and the
combined extract washed with brine (10 mL), dried with Na2SO4, and evaporated.
The crude material was purified using flash chromatography to obtain compound
B3 as a white solid (0.21 mg, 63%).
Data corresponding to compound B3
TLC Rf = 0.26 (hexanes/EtOAc = 60/40) [Anisaldehyde]
1H NMR (600 MHz, C6D6) δ 4.07 (dd, J = 7.8, 3.0 Hz, 3H), 4.03 (dd, J = 7.8,
3.0 Hz, 3H), 3.50 (d, J = 44.6 Hz, 1H), 3.34 (td, J = 9.3, 3.9 Hz, 1H),
3.25 – 3.20 (m, 1H), 2.25 (dddd, J = 31.3, 12.6, 3.6, 2.1 Hz, 1H),
2.09 (d, J = 26.2 Hz, 1H), 1.75 (s, 3H), 1.72 – 1.63 (m, 1H), 1.51 –
275
1.34 (os, 3H), 1.29 – 0.95 (os, 3H), 0.92 (s, 9H), 0.76 – 0.58 (os,
2H), 0.01 (s, 6H).
• Synthesis of compound 4.67
O
OO O
OH
OTBS
H
H
NMO•H2OTPAP, 4Å MS
CH2Cl2
O
OO O
O
OTBS
H
H
78%
B2 4.67
TBS protected compound B2 (0.18 g, 0.11 mmol), CH2Cl2 (2.0 mL), NMO·H2O
(88 mg, 0.65 mmol), and 4Å MS (0.22 g) were added into a RBF. After stirring
for 5 min, TPAP (7.6 mg, 22 µmol) was added and the reaction mixture was
stirred overnight. The reaction mixture was filtered through a pad of Celite®,
evaporated, and purified by column chromatography to obtain diketone 4.67
(0.14 g, 78%).
Data corresponding to compound 4.67
TLC Rf = 0.24 (hexanes/EtOAc = 60/40) [Anisaldehyde]
1H NMR (600 MHz, C6D6) δ 4.03 (dd, J = 7.9, 3.0 Hz, 3H), 4.00 (dd, J = 7.8,
3.1 Hz, 3H), 3.83 (d, J = 2.0 Hz, 2H), 2.08 (ddd, J = 12.6, 3.8, 2.2
Hz, 1H), 1.96 (ddd, J = 22.5, 16.9, 6.4 Hz, 2H), 1.87 – 1.83 (m, 1H),
1.74 (s, 3H), 1.43 – 1.35 (os, 2H), 1.31 (dd, J = 12.8, 5.1 Hz, 1H),
1.14 – 1.07 (m, 1H), 0.94 (s, 9H), 0.69 – 0.55 (os, 2H), -0.01 (s,
6H).
276
Synthesis of Compound 4.69
Compound 4.67 (25 mg, 61 µmol) and THF (0.5 mL) were added into a
scintillation vial and the reaction mixture was cooled with a dry ice/acetone bath.
TBAF (1.0 M solution in THF, 67 µL, 67 µmol) was added dropwise. The
reaction mixture was held at -78 °C for 30 then warmed gradually to rt. Reaction
progress was monitored by TLC. After stirring at rt for 1.5 h, the reaction was
complete by TLC. The reaction mixture was quenched with a saturated NaHCO3
solution (1.0 mL). The mixture was extracted with EtOAc (3 x 10 mL) and the
combined extract washed with brine (1.0 mL), dried with MgSO4, and evaporated.
The crude material was purified using flash chromatography to obtain compound
B4 as a white solid (7.4 mg, 41%).
Data corresponding to compound B4
TLC Rf = 0.44 (MeOH/EtOAc = 5/95) [Anisaldehyde]
1H NMR (600 MHz, C6D6) δ 4.26 (s, 2H), 4.01 (dd, J = 7.9, 3.1 Hz, 3H), 3.97
(dd, J = 7.9, 3.1 Hz, 3H), 3.29 (s, 3H), 2.05 (ddd, J = 12.7, 3.7, 2.3
Hz, 1H), 1.83 – 1.72 (m, 4H), 1.54 (s, 3H), 1.33 (dd, J = 26.5, 13.3
Hz, 3H), 1.22 (dd, J = 12.6, 5.0 Hz, 1H), 1.08 – 1.00 (m, 1H), 0.61 –
0.49 (m, 2H)
Ketone alcohol B4 (1.6 mg, 5.4 µmol), K2CO3 (1.5 mg, 11 µmol), and MeOH (0.5
mL) were added into a RBF and stirred for 1 h. Reaction progress was
277
monitored by TLC. The reaction mixture was quenched with a saturated
NaHCO3 solution (1.0 mL). The mixture was extracted with CH2Cl2 (3 x 0.5 mL)
and the combined extract washed with brine (1.0 mL), dried with Na2SO4, and
evaporated. The crude material was purified using flash chromatography to
obtain compound 4.69 as a white solid (1.6 mg, quantitative yield).
Data corresponding to compound 4.69
TLC Rf = 0.39 (CH2Cl2 /EtOAc = 80/20) [Anisaldehyde]
1H NMR (600 MHz, C6D6) δ 3.99 (qd, J = 7.9, 3.1 Hz, 6H), 3.29 (s, 2H), 2.05
(ddd, J = 12.7, 3.7, 2.3 Hz, 1H), 1.83 – 1.72 (m, 1H), 1.75 (s, 3H),
1.71 – 1.65 (m, 1H), 1.54 (s, 2H), 1.33 (dd, J = 26.5, 13.3 Hz, 2H),
1.22 (dd, J = 12.6, 5.0 Hz, 1H), 1.08 – 1.00 (m, 1H), 0.55 (os, 2H).
Synthesis of Compound 4.71
Diol 4.70 (42 mg, 0.14 mmol) and CH2Cl2 (0.5 mL) were added into a RBF and
cooled with an ice-water bath. DIPEA (75 µL, 0.42 mmol) was added dropwise
and the reaction mixture was stirred for 5 min. MOMCl (13 µL, 0.78 mmol) was
added dropwise and the reaction progress was monitored by TLC. After 30 min
at 0 °C, the reaction mixture warmed gradually to rt and stirred for an additional 2
h. The reaction mixture was quenched with a saturated NaHCO3 solution (1.0
mL). The mixture was extracted with CH2Cl2 (3 x 0.5 mL) and the combined
278
extract washed with brine (1.0 mL), dried with Na2SO4, and evaporated. The
crude material was purified using flash chromatography to obtain the MOM-
protected alcohol intermediate as a mixture of diastereomers (28 mg, 58%).
TLC Rf = 0.31 (EtOAc) [Anisaldehyde]
The MOM-protected alcohol (6.4 mg, 19 µmol), CH2Cl2 (0.5 mL), NMO·H2O (3.8
mg, 2.8 µmol), and 4Å MS (25 mg) were added into a RBF. After stirring for 5
min, TPAP (0.3 mg, 0.97 µmol) was added and the reaction mixture was stirred
for 2 h. The reaction mixture was filtered through a pad of Celite®, evaporated
and purified by column chromatography to obtain diketone 4.71 (6.4 mg, 47%).
TLC Rf = 0.23 (MeOH/ CH2Cl2 = 5/95) [Anisaldehyde]
1H NMR (600 MHz, C6D6) δ 4.37 (s, 2H), 4.03 (dd, J = 7.9, 3.1 Hz, 3H), 4.00
(dd, J = 7.9, 3.1 Hz, 3H), 3.70 (d, J = 1.7 Hz, 2H), 3.08 (d, J = 3.8
Hz, 3H), 2.04 (ddd, J = 12.7, 3.5, 2.3 Hz, 1H), 1.90 – 1.77 (os, 3H),
1.76 (s, 3H), 1.40 – 1.30 (os, 2H), 1.27 (dd, J = 13.0, 5.1 Hz, 1H),
1.09 – 1.04 (m, 1H), 0.65 – 0.50 (os, 2H)
Synthesis of Compound 4.73
279
Magnesium (0.428 g, 18 mmol), one crystal of I2 and THF (5.0 mL) were added
into a RBF and the reaction flask was cooled with an ice-water bath. Allyl
chloride B5 (1.8 g, 8.8 mmol) was added dropwise as a THF solution (1.5 mL)
with a syringe pump. The reaction mixture progressed from cloudy to clear.
Cyclohexenone 4.1 (0.50 g, 2.2 mmol) and THF (2.0 mL) were added to a
separate RBF and cooled with a dry ice/acetone bath. The Grignard solution
was carefully syringed away from the unreacted magnesium and added dropwise
to the stirring, cooled cyclohexenone reaction mixture. The reaction mixture was
quenched with a saturated NaHCO3 solution (10 mL). The mixture was extracted
with EtOAc (3 x 20 mL) and the combined extract washed with brine (25 mL),
dried with MgSO4, and evaporated. The crude material was purified using flash
chromatography to obtain compound 4.73 (0.74 g, 85%) as a mixture of
diastereomers (ratio of 1:2)
TLC Rf = 0.23 and 0.39 (MeOH/ EtOAc = 10/90) [KMnO4]
1H NMR (600 MHz, C6D6) δ 7.31 – 7.19 (os, 2H), 7.11 – 6.98 (os, 3H), 5.44
– 5.21 (os, 3H), 5.05 (s, 0.5H), 4.95 (s, 1H), 4.78 (s, 0.5H), 4.71 (s,
1H), 4.32 – 4.07 (os, 12H), 3.73 – 3.58 (os, 3H), 3.54 (s, 1H), 3.41
(s, 0.5H), 2.39 (d, J = 12.9 Hz, 0.5H), 2.22 – 2.06 (os, 2.5H), 1.78
(s, 3H), 1.77 (s, 1.5H), 1.63 – 1.54 (os, 1.5H), 1.53 – 1.45 (m,
280
0.5H), 1.41 (d, J = 18.8 Hz, 1H), 1.32 (d, J = 11.8 Hz, 0.5H), 1.27 –
1.20 (os, 2H), 1.17 (dd, J = 13.5, 6.0 Hz, 0.5H), 1.14 – 1.07 (m,
1H), 0.81 (ddd, J = 24.9, 13.4, 5.8 Hz, 0.5H)
Synthesis of Compound 4.74
Allylic alcohol 4.73 (25 mg, 64 mmol), 18-crown-6 (0.10 g, 39 mmol), and THF
(6.5 mL) were added into a RBF and cooled with an ice-water bath. KOtBu (1.0
M in THF, 0.19 mL, 19 mmol) were added dropwise. The reaction mixture was
warmed gradually to rt and stirred for an additional 3 h. Reaction progress was
monitored by TLC. The reaction mixture was quenched with a saturated
NaHCO3 solution (10 mL). The mixture was extracted with Et2O (3 x 10 mL) and
the combined extract washed with brine (10 mL), dried with MgSO4, and
evaporated. The crude material was purified using flash chromatography to
obtain compound 4.74 (6 mg, 23%).
TLC Rf = 0.29 (hexanes/ EtOAc = 60/40) [KMnO4]
1H NMR (600 MHz, C6D6) δ 7.23 (dd, J = 56.3, 7.5 Hz, 4H), 7.08 (t, J = 7.4
Hz, 1H), 5.06 (s, 1H), 4.74 (s, 1H), 4.29 (s, 2H), 4.06 (dd, J = 7.9,
3.1 Hz, 3H), 4.02 (dd, J = 7.9, 3.1 Hz, 3H), 3.67 (d, J = 4.2 Hz, 2H),
2.11 (ddd, J = 12.6, 3.7, 2.2 Hz, 1H), 1.82 (dd, J = 13.8, 7.0 Hz,
281
1H), 1.76 (s, 3H), 1.78 – 1.67 (os, 2H), 1.43 (m, 1H), 1.34 – 1.23
(m, 3H), 1.13 – 1.08 (m, 1H), 0.54 (dddd, J = 28.1, 25.2, 13.1, 3.3
Hz, 2H).
Synthesis of Compound 4.75
Alkene 4.74 (5.7 mg, 15 µmol), NMO·H2O (6.0 mg, 44 µmol), and 3:1
acetone/water solution (0.5 mL) were added into a scintillation vial. OsO4 (1 g/25
mL in water) (5 µL, 0.7 µmol) was added to the stirring reaction mixture.
Reaction progress was monitored by TLC. After 3 h, NaIO4 (16 mg, 74 µmol)
was added to the reaction mixture and after 5 min, the diol intermediate was
completely consumed. The reaction mixture was filtered through a cotton plug
and Na2SO3 was added to the filtrate and stirred for 5 min. The mixture was
extracted with CH2Cl2 (3 x 0.5 mL) and the combined extract washed with brine
(0.5 mL), dried with Na2SO4, and evaporated. The crude material was purified
using flash chromatography to obtain compound 4.75 (2.2 mg, 39%).
TLC Rf = 0.16 (hexanes/ EtOAc = 50/50) [KMnO4]
1H NMR (600 MHz, C6D6) δ 7.34 – 7.28 (os, 4H), 7.19 (m, 1H), 4.30 (d, J =
1.8 Hz, 2H), 4.13 (dd, J = 7.8, 3.1 Hz, 3H), 4.09 (dd, J = 7.8, 3.1
Hz, 3H), 3.68 (d, J = 2.2 Hz, 2H), 2.17 – 2.13 (m, 1H), 2.05 (ddd, J
= 22.8, 17.0, 6.3 Hz, 3H), 1.94 (dd, J = 14.0, 7.1 Hz, 1H), 1.86 (s,
282
3H), 1.65 (s, 1H), 1.48 – 1.33 (m, 5H), 1.24 – 1.13 (m, 2H), 0.74 –
0.60 (os, 2H)
Synthesis of Compound 4.79
N
O
OO O
OMe
MeMgClTHF
0 C rt
89%
O
OO O
4.78 4.79
Amide 4.78 (1.0 g, 3.5 mmol) and THF (20 mL) were added into a RBF and
cooled with an ice-water bath. Methylmagnesium chloride (3.0 M in THF, 3.5 mL,
11 mmol) was added dropwise with a syringe pump. The reaction mixture
warmed gradually to rt and stirred overnight. The reaction mixture was quenched
with a saturated NaHCO3 solution (50 mL). The mixture was extracted with
EtOAc (3 x 25 mL) and the combined extract washed with brine (20 mL), dried
with MgSO4, and evaporated. The crude material was purified using flash
chromatography to obtain compound 4.79 as a white solid (0.75 g, 89%). An
analytical sample of ketone 4.79 could be prepared by recrystallization using
toluene/hexanes (5/1).
MP 48-52 °C
TLC Rf = 0.29 (hexanes/ EtOAc = 75/25) [KMnO4]
1H NMR (600 MHz, C6D6) δ 5.41 – 5.30 (m, 1H), 4.84 (d, J = 9.3 Hz, 1H),
4.78 (dd, J = 17.1, 1.5 Hz, 1H), 3.87 (dd, J = 8.2, 3.5 Hz, 3H), 3.71
(dd, J = 8.2, 3.5 Hz, 3H), 1.76 (dd, J = 11.7, 2.7 Hz, 1H), 1.68 (s,
283
3H), 1.62 – 1.55 (m, 1H), 1.45 (s, 3H), 1.44 – 1.31 (os, 2H), 0.84 –
0.77 (m, 1H)
13C NMR (125 MHz, C6D6) δ 208.5, 137.3, 115.8, 109.0, 69.2, 51.2, 35.2,
33.6, 31.99, 3.1, 23.9
Synthesis of Compound 4.80
O
OO O
O
cat Grubbs2nd Gen.
57%
4.79
O
OO O
O
4.80
To a RBF was added CH2Cl2 (10 mL). The CH2Cl2 was degassed by refluxing
under a constant stream of argon for 30 min. After the CH2Cl2 cooled to rt, the
methyl ketone 4.79 (0.1 g, 0.42 mmol) was added followed by the addition of the
methyl vinyl ketone (84 µL, 1.0 mmol). Grubbs 2nd Generation catalyst was
added to the reaction mixture and heated to reflux. The heating was maintained
for 1 h. The progress of the reaction was monitored by TLC. After 1 h, the
reaction mixture was cooled to rt and most of the CH2Cl2 was evaporated and the
crude material, a brown oil, was purified by flash chromatography to obtain
compound 4.80 as a tan solid (68 mg, 57%). The starting alkene (4.79) was also
recovered (26 mg, 26%).
TLC Rf = 0.35 (hexanes/ EtOAc = 25/75) [KMnO4]
1H NMR (600 MHz, C6D6) δ 6.10 (dt, J = 15.9, 6.6 Hz, 1H), 5.73 (d, J = 15.9
Hz, 1H), 3.84 (dd, J = 8.2, 3.5 Hz, 3H), 3.69 (dd, J = 8.2, 3.5 Hz,
284
3H), 1.85 (s, 3H), 1.67 (s, 3H), 1.63 (dd, J = 11.4, 2.7 Hz, 1H), 1.46
– 1.37 (m, 1H), 1.42 (s, 3H), 1.36 – 1.23 (os, 2H), 0.74 – 0.69 (m,
1H)
Synthesis of Compound 4.81
Diketone 4.80 (10 mg, 0.35 mmol), K2CO3 (25 mg, 0.18 mmol), and MeOH (0.5
mL) were added to a scintillation vial and stirred for 1 h. The reaction progress
was monitored by TLC. The reaction mixture was quenched with a saturated
NaHCO3 solution (10 mL). The mixture was extracted with EtOAc (3 x 0.5 mL)
and the combined extract washed with brine (0.5 mL), dried with MgSO4, and
evaporated. The crude material was purified using flash chromatography to
obtain compound 4.81 as a white solid (5.2 mg, 52%).
TLC Rf = 0.29 (hexanes/ EtOAc = 25/75) [KMnO4]
1H NMR (600 MHz, C6D6) δ 4.04 (dd, J = 7.9, 3.0 Hz, 1H), 4.00 (dd, J = 7.9,
3.0 Hz, 3H), 2.00 (ddd, J = 12.6, 3.9, 2.2 Hz, 1H), 1.76 – 1.66 (os,
5H), 1.65 – 1.59 (m, 1H), 1.58 – 1.52 (os, 4H), 1.37 – 1.27 (os, 3H),
1.13 – 1.06 (m, 1H), 0.67 – 0.58 (m, 1H), 0.56 – 0.47 (m, 1H).
13C NMR (125 MHz, C6D6) δ 206.6, 204.4, 109.3, 68.7, 49.9, 49.4, 48.5, 35.3,
34.91, 31.3, 29.8, 26.9, 24.2
285
Synthesis of Compound 4.83
In a RBF was added CH2Cl2 (10 mL). The CH2Cl2 was degassed by refluxing
under a constant stream of argon for 30 min. After the CH2Cl2 cooled to rt, the
methyl ketone 4.79 (0.1 g, 0.42 mmol) was added followed by the addition of the
crotonaldehyde (84 µL, 1.0 mmol). Grubbs 2nd Generation catalyst was added to
the reaction mixture. The progress of the reaction was monitored by TLC. After
1 h, most of the CH2Cl2 was evaporated and the crude material, brown oil was
purified by flash chromatography to obtain compound 4.83 as a tan solid (73 mg,
65%). The starting alkene (4.79) was also recovered (13 mg, 13%). An
analytical sample of aldehyde 4.83 could be prepared by recrystallization using
MTBE/EtOH (1/1).
MP 76-80 °C
TLC Rf = 0.42 (hexanes/EtOAc = 25/75) [KMnO4]
1H NMR (600 MHz, C6D6) δ 9.27 (s, 1H), 5.72 – 5.68 (os, 2H), 3.82 (dd, J =
8.1, 3.4 Hz, 3H), 3.67 (dd, J = 8.1, 3.4 Hz, 3H), 1.68 (s, 3H), 1.55
(d, J = 8.7 Hz, 1H), 1.37 (s, 3H), 1.41 – 1.31 (m, 1H), 1.25 – 1.16
(os, 2H), 0.66 – 0.59 (m, 1H)
13C NMR (125 MHz, C6D6) δ 207.7, 192.1, 154.2, 133.6, 109.1, 69.0, 51.2,
35.1, 33.6, 30.4, 24.9, 23.9
286
Synthesis of Compound 4.84 and 4.85
Compound 4.83 (10 mg, 0.35 mmol), K2CO3 (25 mg, 0.18 mmol), and MeOH (0.5
mL) were added to a scintillation vial and stirred overnight. The reaction
progress was monitored by TLC. The reaction mixture was quenched with a
saturated NaHCO3 solution (10 mL). The mixture was extracted with EtOAc (3 x
0.5 mL) and the combined extract washed with brine (0.5 mL), dried with MgSO4,
and evaporated. 1H NMR of the crude material showed no starting aldehyde
(4.83) and a 1:1.5 ratio of bicyclo[2.2.2]octane product 4.85 to the cyclohexenone
product 6.84. The desired product (4.85) could be obtained by being crystallized
from benzene obtain a white solid (2.7 mg, 27%).
Data corresponding to compound 4.85
TLC Rf = 0.29 (hexanes/ EtOAc = 25/75) [KMnO4]
1H NMR (600 MHz, CDCl3) δ 4.37 (dd, J = 8.2, 2.9 Hz, 3H), 4.23 (dd, J =
8.2, 2.9 Hz, 3H), 4.20 – 3.19 (m, 1H), 1.98 (d, J = 18.2 Hz, 1H),
1.77 (s, 3H), 1.69 (d, J = 18.2 Hz, 1H), 1.42 (s, 1H), 0.93 (t, J =
12.1 Hz, 1H), 0.81 (t, J = 10.2 Hz, 1H), 0.74 – 0.69 (m, 1H), 0.66 (d,
J = 14.1 Hz, 1H), 0.53 (ddd, J = 13.7, 11.0, 7.6 Hz, 1H), 0.44 (d, J =
3.4 Hz, 1H).
287
13C NMR (125 MHz, C6D6) δ 209.4, 109.5, 68.4, 67.8, 52.2, 44.6, 38.1, 37.5,
26.7, 25.0, 24.1, 21.1
288
Spectra of Compounds from Chapter 4 Figure 4.1 – 1H NMR of Compound 4.6 (500 MHz, CDCl3)
289
Figure 4.2 – 1H NMR of Compound 4.8 (600 MHz, CDCl3)
290
Figure 4.3 – 1H NMR of Compound 4.11 (600 MHz, CDCl3)
291
Figure 4.4 – 1H NMR of Compound 4.33 (600 MHz, CDCl3)
292
Figure 4.5 – 1H NMR of Compound 4.35 (600 MHz, CDCl3)
293
Figure 4.6 – 1H NMR of Compound 4.36 (600 MHz, CDCl3)
294
Figure 4.7 – 1H NMR of Compound 4.31 (600 MHz, CDCl3)
295
Figure 4.8 – 1H NMR of Compound 4.37a (600 MHz, C6D6)
296
Figure 4.9 – 1H NMR of Compound 4.37b (600 MHz, C6D6)
297
Figure 4.10 – 1H NMR of Compound 4.39 (600 MHz, C6D6)
298
Figure 4.11 – 1H NMR of Compound 4.40 (600 MHz, C6D6)
299
Figure 4.12 – 1H NMR of Compound 4.48 (600 MHz, C6D6)
300
Figure 4.13 – 1H NMR of Compound 4.3 (600 MHz, C6D6)
301
Figure 4.14 – 13C NMR of Compound 4.3 (125 MHz, C6D6)
302
Figure 4.15 – 1H NMR of Compound 4.52 (600 MHz, CDCl3)
303
Figure 4.16 – 1H NMR of Compound 4.47 (600 MHz, C6D6)
304
Figure 4.17 – 1H NMR of Compound B1 (500 MHz, CDCl3)
305
Figure 4.18 – 1H NMR of Compound 4.55 (600 MHz, CDCl3)
306
Figure 4.19 – 1H NMR of Compound 4.57a (600 MHz, CDCl3)
307
Figure 4.20 – 1H NMR of Compound 4.57b (600 MHz, CDCl3)
308
Figure 4.21 – 1H NMR of Compound 4.58 (600 MHz, CDCl3)
309
Figure 4.22 – 1H NMR of Compound 4.60 (600 MHz, CDCl3)
310
Figure 4.23 – 1H NMR of Compound 4.61 (600 MHz, CDCl3)
311
Figure 4.24 – 1H NMR of Compound 4.62a (600 MHz, C6D6)
312
Figure 4.25 – 13C NMR of Compound 4.62a (125 MHz, CDCl3)
313
Figure 4.26 – 1H NMR of Compound 4.62b (600 MHz, CDCl3)
314
Figure 4.27 – 1H NMR of Compound 4.63 (600 MHz, CDCl3)
315
Figure 4.28 – 13C NMR of Compound 4.63 (125 MHz, CDCl3)
316
Figure 4.29 – 1H NMR of Compound 4.65 (600 MHz, C6D6)
317
Figure 4.30 – 1H NMR of Compound 4.66 (600 MHz, C6D6)
318
Figure 4.31 – 1H NMR of Compound B2 (600 MHz, C6D6)
319
Figure 4.32 – 1H NMR of Compound B3 (600 MHz, C6D6)
320
Figure 4.33 – 1H NMR of Compound 4.67 (600 MHz, C6D6)
321
Figure 4.34 – 1H NMR of Compound B4 (600 MHz, C6D6)
322
Figure 4.35 – 1H NMR of Compound 4.69 (600 MHz, C6D6)
323
Figure 4.36 – 1H NMR of Compound 4.71 (600 MHz, C6D6)
324
Figure 4.37 – 1H NMR of Compound 4.73 (600 MHz, C6D6)
325
Figure 4.38 – 1H NMR of Compound 4.74 (600 MHz, C6D6)
326
Figure 4.39 – 1H NMR of Compound 4.75 (600 MHz, C6D6)
327
Figure 4.40 – 1H NMR of Compound 4.79 (600 MHz, C6D6)
328
Figure 4.41 – 13C NMR of Compound 4.79 (125 MHz, C6D6)
329
Figure 4.42 – 1H NMR of Compound 4.80 (600 MHz, C6D6)
330
Figure 4.43 – 1H NMR of Compound 4.81 (600 MHz, C6D6)
331
Figure 4.44 – 13C NMR of Compound 4.81 (125 MHz, C6D6)
332
Figure 4.45 – 1H NMR of Compound 4.83 (600 MHz, C6D6)
333
Figure 4.46 – 13C NMR of Compound 4.83 (125 MHz, C6D6)
334
Figure 4.47 – 1H NMR of Compound 4.85 (600 MHz, CDCl3)
335
Figure 4.48 – 1H NMR of Compound 4.85 (125 MHz, C6D6)
336
A.1 Experimental – Reactions in Chapter 5
Synthesis of Compound 5.1
THF (75 mL) and n-BuLi (3.35 M in THF, 12 mL, 40 mmol) were added into a
RBF. The reaction flask was cooled with a dry ice/acetone bath. Nitrile 5.28 (7.0
g, 41 mmol) in THF solution (100 mL) was added dropwise to the cooled n-BuLi
solution. The reaction mixture was stirred for 30 min and then warmed gradually
by moving the reaction flask to an ice-water bath. The reaction mixture was
stirred for an additional 10 min and then cooled again with a dry ice/acetone
bath. Homoallyl iodide (8.3 g, 46 mmol) in THF solution (10 mL) was added
dropwise to the reaction mixture. After stirring for 30 min at -78 °C, the reaction
mixture was allowed to warm gradually to 5 °C over 2.5 h. The reaction mixture
was moved to an ice-water bath and the CeCl3 mixture was added rapidly
through a cannula.
[To prepare the CeCl3 mixture: CeCl3 (15 g, 62 mmol) and THF (100 mL) were
added into a RBF and stirred for 2 h. The CeCl3 solution was cooled with an ice-
337
water bath and methylmagnesium chloride (2.78 M in THF, 21 mL, 58 mmol) was
added dropwise and stirred for 2.5 h.]
The reaction mixture was stirred for 1 h at 0 °C, and then quenched with a
saturated NaHCO3 solution and water. The mixture was extracted with EtOAc (3
x 200 mL) and the combined extract washed with brine (200 mL), dried with
MgSO4, and evaporated. The imine (5.29), THF (210 mL), water (11 mL), and
acetic acid (11 mL, 0.17 mol) were added into a RBF. The reaction progress was
monitored by TLC (hexanes/EtOAc = 10/90). After 2 h, the imide had completely
converted to the ketone. The reaction mixture was quenched with a saturated
NaHCO3 solution and water. The mixture was extracted with EtOAc (2 x 200 mL)
and the combined extract washed with brine (200 mL), dried with Na2SO4, and
evaporated to obtain a pale yellow/orange oil. The crude product was purified
using flash chromatography (hexanes/EtOAc = 75/25) to obtain compound 5.1,
6.5 g (65%).
TLC Rf = 0.24 (hexanes/EtOAc = 75/25) [KMnO4]
Analytical data matched the previous compound (4.70) isolated from the
Grignard reaction.
Synthesis of Compound 5.31
338
Alkene 5.1 (0.10 g, 0.42 mmol), NMO·H2O (0.17 g, 1.3 mmol), and CH2Cl2 (20
mL) were added to a RBF and the mixture cooled with an ice-water bath. The
reaction was sparged with ozone containing oxygen and monitored by TLC
(hexanes/EtOAc = 75/25) until the starting material (alkene 5.1) was consumed.
The reaction mixture was warmed to rt and quenched with a solution of 1:1
saturated NaHCO3/Na2S2O3. The mixture was extracted with CH2Cl2 (3 x 10 mL)
and the combined extract washed with brine (10 mL), dried with Na2SO4, and
evaporated. The crude aldehyde C1 was used in the next step without further
purification (81 mg, 80%).
Data corresponding to compound C1
TLC Rf = 0.23 (hexanes/EtOAc = 75/25) [KMnO4]
1H NMR (600 MHz, C6D6) δ 8.94 (s, 1H), 3.83 (dd, J = 8.2, 3.5 Hz, 3H), 3.69
(dd, J = 8.2, 3.5 Hz, 3H), 1.69 (dd, J = 11.5, 3.0 Hz, 1H), 1.67 (s,
3H), 1.44 – 1.38 (m, 1H), 1.37 (s, 3H), 1.33 – 1.21 (os, 2H), 1.05 –
0.96 (m, 1H).
Aldehyde C1 (81 mg, 0.34 mmol), CH2Cl2 (25 mL), and DBU (31 µL, 0.21 mmol),
were added into a RBF and stirred overnight. Reaction progress was monitored
by TLC (100% EtOAc). NEt3 (0.52 mL, 3.8 mmol) and MsCl (97 µL, 1.3 mmol)
were added to the reaction mixture. Reaction was complete after 5 min. The
reaction mixture was quenched with a saturated NaHCO3 solution. The mixture
was extracted with CH2Cl2 (3 x 25 mL) and the combined extract washed with
brine (25 mL), dried with Na2SO4, and evaporated. The crude product was
339
purified using flash chromatography (hexanes/EtOAc = 50/50) to obtain
compound 5.1 (55 mg, 59%).
TLC Rf = 0.32 (hexanes/EtOAc = 59/50) [KMnO4]
1H NMR matched the previous compound (3.10) isolated from the olefin
metathesis reaction.
Synthesis of Compound 5.4
Aldehyde 5.2 (0.50 g, 1.9 mmol) was dissolved in dioxane (30 mL). To the
aldehyde solution was added a Na2CO3 (0.30 g, 2.8 mmol) solution in water (10
mL). The reaction mixture was stirred at rt for 3 h. A Celite® pad was prepared
and the reaction mixture was filtered and the pad washed with dioxane (3 x 10
mL). The filtrate was evaporated to obtain a thick, brown oil. To the brown oil
was added benzene dropwise until crystallization began. The solid was filtered
and washed with benzene (3 x 0.25 mL) to obtain compound 5.4 as a white solid
(0.32 g, 63%).
1H NMR matched the previous compound (4.85) isolated from the K2CO3/MeOH
reaction conditions.
340
Synthesis of Compound 5.29
Imidazole (0.16 g, 2.3 mmol), DMAP (12 mg, 0.09 mmol), and DMF (1.0 mL)
were added into a RBF. TESCl was added dropwise to the vigorously stirring
reaction mixture. Alcohol 5.2 (25 mg, 0.09 mmol) was dissolved in DMF (0.25
mL) and added to the reaction mixture and stirred for 3 h. Reaction progress
was monitored by TLC (hexanes/EtOAc = 40/60). The reaction mixture was
quenched with a saturated NaHCO3 solution. The mixture was extracted with
EtOAc (3 x 10 mL) and the combined extract washed with brine (10 mL), dried
with MgSO4, and evaporated. The crude product was purified using flash
chromatography (hexanes/EtOAc = 75/25) to obtain compound 5.29 as a white
solid (33 mg, 93%).
TLC Rf = 0.32 (hexanes/EtOAc = 75/25) [CAM]
1H NMR (600 MHz, C6D6) δ 4.40 (dd, J = 8.2, 2.7 Hz, 3H), 4.29 (dd, J = 8.2,
2.7 Hz, 3H), 3.77 (d, J = 7.4 Hz, 1H), 2.12 (dt, J = 18.2, 2.4 Hz, 1H),
1.81 – 1.76 (dt, J = 18.2, 2.4 Hz, 1H), 1.76 (s, 3H), 1.53 (s, 1H),
1.32 (dd, J = 14.0, 7.6 Hz, 1H), 1.25 (d, J = 14.0 Hz, 1H), 1.04 –
0.97 (m, 1H), 0.94 – 0.87 (m, 1H), 0.84 (t, J = 8.0 Hz, 9H), 0.78 (dt,
J = 12.8, 9.4 Hz, 1H), 0.63 (ddd, J = 13.8, 11.0, 7.7 Hz, 1H), 0.44
(qd, J = 7.9, 2.2 Hz, 6H).
341
Synthesis of Compound 5.30
O
OH
OO
O
Boc2ODMAPCH2Cl2
O
OBoc
OO
O
88%
5.305.4
Boc2O (0.21 mL, 0.93 mmol) was dissolved in CH2Cl2 (5.0 mL). To the reaction
mixture were added NEt3 (0.13 mL, 0.93 mmol), DMAP (1.0 mg, 9.32 µmol), and
ketone 5.4 (50 mg, 0.19 mmol). The reaction mixture was stirred for 1 h and the
reaction progress monitored by TLC (hexanes/EtOAc = 40/60). The reaction
mixture was quenched with a saturated NaHCO3 solution. The mixture was
extracted with EtOAc (3 x 20 mL) and the combined extract washed with brine
(20 mL), dried with MgSO4, and evaporated. The crude product was purified
using flash chromatography (hexanes/EtOAc = 75/25) to obtain compound 5.30
as a white solid (63 mg, 88%).
TLC Rf = 0.32 (hexanes/EtOAc = 60/40) [Anisaldehyde]
1H NMR (500 MHz, C6D6) δ 4.84 (d, J = 8.1 Hz, 1H), 4.31 (dd, J = 8.3, 2.7
Hz, 3H), 4.26 (dd, J = 8.3, 2.7 Hz, 3H), 1.96 (dt, J = 18.5, 2.4 Hz,
1H), 1.72 (s, 3H), 1.67 (dt, J = 18.6, 3.2 Hz, 1H), 1.56 (dd, J = 14.8,
8.3 Hz, 1H), 1.36 (s, 1H), 1.30 (d, J = 14.8 Hz, 1H), 1.24 (s, 9H),
0.92 (ddd, J = 13.1, 10.6, 2.2 Hz, 1H), 0.76 (t, J = 10.4 Hz, 1H),
0.63 (dd, J = 20.5, 10.4 Hz, 1H), 0.54 (ddd, J = 13.6, 11.0, 7.5 Hz,
1H).
13C NMR (125 MHz, C6D6) δ 207.9, 152.5, 109.4, 82.3, 73.0, 67.2, 50.4, 44.3,
37.33, 34.8, 27.3, 26.2, 24.4, 23.7, 21.0
342
Synthesis of Compound 5.32
CDI (91 mg, 0.56 mmol) was weighed out into a RBF in a glove box. The CDI
was dissolved in CH2Cl2 (6.0 mL). NEt3 (0.13 mL, 0.93 mmol) was added to the
CDI solution. Alcohol 5.4 (50 mg, 0.19 mmol) was dissolved in CH2Cl2 (0.25 mL)
and added to the reaction mixture and stirred for 30 min. Reaction progress was
monitored by TLC. The reaction mixture was quenched with a saturated
NaHCO3 solution. The mixture was extracted with CH2Cl2 (3 x 10 mL) and the
combined extract washed with brine (10 mL), dried with Na2SO4, and evaporated.
The crude product was purified using flash chromatography (100% EtOAc) to
obtain compound 5.32 as a white solid (68 mg, 79%).
TLC Rf = 0.32 (100% EtOAc) [Anisaldehyde]
1H NMR (500 MHz, C6D6) δ 7.94 (s, 1H), 6.84 (d, J = 9.3 Hz, 2H), 4.79 (d, J
= 7.9 Hz, 1H), 4.08 (dd, J = 8.2, 2.7 Hz, 3H), 4.01 (dd, J = 8.2, 2.7
Hz, 3H), 1.67 (s, 3H), 1.61 (s, 2H), 1.33 (dd, J = 15.5, 8.9 Hz,1H),
1.26 (s, 1H), 0.91 (t, J = 7.2 Hz, 1H), 0.86 (d, J = 14.1 Hz, 1H), 0.73
(t, J = 13.5 Hz, 1H), 0.59 (ddd, J = 13.4, 9.6, 2.6 Hz, 1H), 0.45 –
0.41 (m, 1H).
343
Synthesis of Compound 5.33
Ketone 5.31 (10 mg, 0.027 mmol) and KCN·18-crown-6 complex (27 mg, 0.083
mmol) was dissolved in acetonitrile. The reaction mixture was stirred overnight
and reaction progress was monitored by TLC (100% EtOAc). The reaction
mixture was evaporated and purified by flash chromatography (MeOH/CH2Cl2 =
5/95) to obtain compound 5.33 as a white solid (4.5 mg, 45%)
TLC Rf = 0.51 (100% EtOAc) [Anisaldehyde]
Rf = 0.26 (MeOH/CH2Cl2 = 5/95) [Anisaldehyde]
1H NMR (500 MHz, C6D6) δ 4.98 (d, J = 8.0 Hz, 1H), 4.30 (d, J = 8.2 Hz,
3H), 4.27 (d, J = 8.2 Hz, 3H), 1.97 (d, J = 18.8 Hz, 1H), 1.78 (s,
3H), 1.72 (d, J = 18.6 Hz, 1H), 1.56 (dd, J = 14.8, 8.2 Hz, 1H), 1.38
(s, 2H), 1.31 (d, J = 15.0 Hz, 1H), 0.95 (t, J = 12.4 Hz, 1H), 0.80 (t,
J = 12.4 Hz, 1H), 0.73 – 0.64 (m, 1H), 0.55 (ddd, J = 13.7, 11.0, 7.5
Hz, 1H).
13C NMR (125 MHz, C6D6) δ 207.7, 109.6, 75.8, 75.1, 67.3, 50.5, 44.5, 37.56,
35.1, 26.4, 26.3, 24.3, 23.8, 21.2
344
Synthesis of Compound 5.36
O
OBoc
OO
O
OBoc
OO
O
OH
Me3Si [Ce]
-78 C -30 °C
TMS
73%
5.30 5.36
CeCl3 was brought up in THF (5.0 mL) and vigorously stirred for 1 h. In a
separate RBF were added THF (5.0 mL) and n-BuLi (3.33 M in THF, 0.32 mL,
1.1 mmol). The n-BuLi solution was cooled with a dry ice/acetone bath and
TMS-acetylene (0.15 mL, 1.1 mmol) was added dropwise and stirred for 1 h.
The CeCl3 was cannulated into the reaction mixture and stirred for an additional 1
h. Ketone 5.30 (0.20 g, 0.54 mmol) in a THF solution (0.5 ml) was cooled with a
dry ice/acetone bath and cannulated over to the organocerium reaction mixture.
The reaction mixture was allowed to stir for an additional 30 min and then
gradually warmed up to -30 °C and stirred for 2 h. Reaction progress was
monitored by TLC (hexanes/EtOAc = 40/60). The reaction mixture was
quenched with a saturated NaHCO3 solution and extracted with EtOAc (3 x 20
mL). The extract was washed with brine (20 mL), dried with MgSO4, and
evaporated. The crude product was purified using flash chromatography
(hexanes/EtOAc = 75/25) to obtain compound 5.36 as a white solid (0.20 g,
79%).
TLC Rf = 0.63 (hexanes/EtOAc = 40/60) [Anisaldehyde]
TLC Rf = 0.35 (hexanes/EtOAc = 75/25) [Anisaldehyde]
345
1H NMR (600 MHz, C6D6) δ 4.89 (d, J = 7.3 Hz, 1H), 4.61 (dd, J = 8.4, 3.1
Hz, 3H), 4.51 (dd, J = 8.4, 3.1 Hz, 3H), 2.69 (s, 1H), 2.28 – 2.19 (m,
1H), 1.73 (s, 3H), 1.64 – 1.54 (os, 3H), 1.51 – 1.43 (m, 1H), 1.35 –
1.27 (os, 2H), 1.22 (s, 9H), 0.83 (t, J = 10.0 Hz, 1H), 0.52 (ddd, J =
13.6, 10.6, 7.1 Hz, 1H), 0.09 (s, 9H)
13C NMR (125 MHz, C6D6) δ 152.3, 110.9, 109.0, 89.7, 82.8, 74.9, 72.4, 68.4,
48.6, 43.4, 39.8, 35.3, 27.5, 24.3, 23.9, 23.2, 22.5, -0.6
Synthesis of Compound 5.37
OBoc
OO
O
OH
TMS
TBAFTHF0 C
85%
OBoc
OO
O
OH
5.36 5.37
Compound 5.36 (32 mg, 69 µmol) was dissolved in THF (0.5 mL) and cooled with
an ice-water bath. TBAF (1.0 M in THF, 0.14 mL, 0.14 mmol) was added
dropwise to the reaction mixture and stirred for 15 min. Reaction progress was
monitored by TLC (hexanes/EtOAc = 60/40). The reaction mixture was
quenched with a saturated NaHCO3 solution and extracted with EtOAc (3 x 1.0
mL). The extract was washed with brine (2.0 mL), dried with MgSO4, and
evaporated. The crude product was purified using flash chromatography
(hexanes/EtOAc = 70/30) to obtain compound 5.37 as a white solid (0.20 g,
85%).
TLC Rf = 0.5 (hexanes/EtOAc = 60/40) [Anisaldehyde]
346
TLC Rf = 0.25 (hexanes/EtOAc = 70/30) [KMnO4]
1H NMR (600 MHz, C6D6) δ 4.84 (d, J = 7.9 Hz, 1H), 4.53 (dd, J = 8.4, 3.1
Hz, 3H), 4.43 (dd, J = 8.4, 3.1 Hz, 3H), 2.68 (s, 1H), 2.13 (dd, J =
13.7, 4.4 Hz, 1H), 1.90 (s, 1H), 1.72 (s, 3H), 1.57 (t, J = 14.6 Hz,
2H), 1.42 – 1.35 (m, 1H), 1.34 – 1.25 (os, 3H), 1.22 (s, 9H), 0.75 (t,
J = 10.9 Hz, 1H), 0.43 (ddd, J = 13.4, 10.6, 6.6 Hz, 1H)
Synthesis of Compound 5.40
Toluene (15 mL), quinoline (15 µL, 0.13 mmol), Pd on BaSO4 (5 mg), and alkyne
5.37 (10 mg, 25 µmol) were added into a RBF. The reaction mixture was put
under a hydrogen atmosphere and stirred vigorously. The reaction progress was
monitored by 1H NMR until all the alkyne was reacted. The hydrogen balloon
was removed and the reaction mixture was filtered through a pad of Celite® and
evaporated. The crude material was purified by flash chromatography to obtain
alkene 5.40 as a white solid (7.7 mg, 78%).
TLC Rf = 0.38 (CH2Cl2 /EtOAc = 90/10) [Anisaldehyde]
1H NMR (600 MHz, C6D6) δ 5.64 – 5.46 (os, 2H), 4.86 (dd, J = 10.2, 2.4 Hz,
1H), 4.69 (dd, J = 9.3, 3.2 Hz, 1H), 4.33 (dd, J = 8.4, 3.0 Hz, 3H),
4.27 (dd, J = 8.4, 3.0 Hz, 3H), 3.02 (d, J = 1.2 Hz, 1H), 1.82 (ddt, J
= 14.5, 9.3, 2.7 Hz, 1H), 1.69 (s, 3H), 1.50 (dt, J = 14.3, 3.1 Hz,
347
1H), 1.42 (dt, J = 14.3, 2.4 Hz, 1H), 1.31 (ddd, J = 14.1, 5.8, 3.0 Hz,
1H), 1.26 – 1.21 (os, 10H), 0.93 – 0.84 (m, 1H), 0.83 – 0.77 (m,
1H), 0.77 – 0.69 (m, 1H), 0.53 (ddd, J = 14.0, 10.7, 5.5 Hz, 1H).
Synthesis of Compound 5.41
Alkene 5.40 (1.5 mg, 3.8 µmol), NMO·H2O (1.5 mg, 11 µmol), and CH2Cl2 (13
mL) were added to a RBF and the mixture cooled with an ice-water bath. The
reaction was sparged with ozone containing oxygen and monitored by TLC
(CH2Cl2/EtOAc = 95/5) until the starting material (alkene 5.40) was consumed.
The reaction mixture was quenched with a solution of 1:1 saturated
NaHCO3/Na2S2O3. The mixture was extracted with CH2Cl2 (3 x 10 mL) and the
combined extract washed with brine (10 mL), dried with Na2SO4, and evaporated.
The crude material was purified by flash chromatography to obtain alkene 5.41
(1.0 mg, 67%).
TLC Rf = 0.32 (CH2Cl2 /EtOAc = 95/5) [Anisaldehyde]
1H NMR (600 MHz, C6D6) δ 9.17 (s, 1H), 4.57 (dd, J = 9.3, 4.0 Hz, 1H), 4.11
(dd, J = 8.4, 2.8 Hz, 3H), 4.08 (dd, J = 8.4, 2.8 Hz, 3H), 1.87 (ddt, J
= 12.5, 9.2, 2.9 Hz, 1H), 1.72 (s, 1H), 1.66 (s, 3H), 1.44 – 1.39 (os,
2H), 1.25 (s, 9H), 1.04 – 1.00 (os, 2H), 0.96 (d, J = 8.9 Hz, 2H),
0.72 (t, J = 9.8 Hz, 1H), 0.48 – 0.43 (m, 1H).
348
Synthesis of Compound 5.45
CeCl3 (1.5 g, 6.0 mmol) was brought up in THF (13 mL) and vigorously stirred for
2 h. In a separate RBF were added THF (2.5 mL) and n-BuLi (3.13 M in THF,
1.9 mL, 6.0 mmol). The n-BuLi solution was cooled with a dry ice/acetone bath
and TMS-acetylene (0.86 mL, 6.1 mmol) was added dropwise and stirred for 30
min. The CeCl3 was cannulated into the reaction mixture and stirred for an
additional 1 h. Ketone 5.4 (0.33 g, 1.2 mmol) in a THF solution (1.0 ml) was
cooled with a dry ice/acetone bath and cannulated over to the organocerium
reaction mixture. The reaction mixture was allowed to stir for an additional 30
min and then gradually warmed up to -30 °C and stirred for 2 h. Reaction
progress was monitored by TLC (hexanes/EtOAc = 40/60). The reaction mixture
was quenched with a saturated NaHCO3 solution and extracted with EtOAc (3 x
20 mL). The extract was washed with brine (20 mL), dried with MgSO4, and
evaporated. The crude product was purified using flash chromatography
(hexanes/EtOAc = 60/40) to obtain compound 5.45 as a white solid (0.34 g,
76%).
TLC Rf = 0.22 (hexanes/EtOAc = 40/60) [Anisaldehyde]
MP 158-162 °C
349
1H NMR (600 MHz, C6D6) δ 4.68 (dd, J = 8.2, 3.1 Hz, 3H), 4.60 (dd, J = 8.2,
3.1 Hz, 3H), 3.23 (td, J = 9.2, 5.0 Hz, 1H), 2.09 (s, 1H), 2.04 (d, J =
9.2 Hz, 1H), 1.94 (dt, J = 14.0, 2.6 Hz, 1H), 1.78 (s, 3H), 1.60 –
1.52 (m, 1H), 1.49 (d, J = 14.2 Hz, 1H), 1.29 – 1.22 (os, 2H), 1.12 –
1.04 (os, 1H), 1.01 (ddt, J = 13.5, 4.9, 2.5 Hz, 1H), 0.81 – 0.70 (os,
2H), 0.15 (s, 9H)
13C NMR (125 MHz, C6D6) δ 110.7, 109.1, 91.1, 72.8, 70.5, 68.6, 48.9, 43.7,
39.48, 38.4, 24.4, 24.1, 23.9, 22.1, -0.4
Synthesis of Compound 5.46
Compound 5.45 (0.28 g, 0.76 mmol), K2CO3 (0.11 g, 0.76 mmol), and MeOH (25
mL) were added into a RBF and stirred for 2 h. The reaction progress was
monitored by TLC. The reaction mixture was evaporated and brought up in
water (25 mL) and extracted with EtOAc (3 x 20 mL). The extract was washed
with brine (20 mL), dried with MgSO4, and evaporated. The crude product,
compound 5.46, was obtained as a white solid (0.34 g, 76%) and used without
further purification.
TLC Rf = 0.22 (hexanes/EtOAc = 40/60) [Anisaldehyde]
350
1H NMR (600 MHz, C6D6) δ 4.61 (dd, J = 8.3, 3.1 Hz, 3H), 4.54 (dd, J = 8.3,
3.1 Hz, 3H), 3.19 (td, J = 9.1, 4.9 Hz, 1H), 2.03 (s, 1H), 1.96 (d, J =
9.1 Hz, 1H), 1.93 (s, 1H), 1.84 – 1.78 (os, 4H), 1.56 – 1.49 (os, 2H),
1.42 (d, J = 13.1 Hz, 1H), 1.23 (s, 1H), 1.10 – 1.06 (m, 1H), 1.02 –
0.94 (m, 2H), 0.72 – 0.66 (os, 2H)
13C NMR (125 MHz, CDCl3) δ 108.2, 87.6, 75.9, 72.8, 70.7, 68.2, 49.1, 43.7,
39.0, 38.3, 24.2, 23.7, 23.5, 22.1
Synthesis of Compound 5.47
Diol 5.46 (0.19 g, 0.64 mmol) was suspended in toluene (15 mL) and
dibutyldimethoxytin (160 µL, 0.70 mmol) was added. The flask was fitted with a
Dean-Stark trap and the vigorously stirring reaction mixture was heated to reflux
and 12 mL of toluene was distilled off. TBAI (0.36 g, 0.98 mmol) and PMBBr
(110 µL, 0.75 mmol) were added to the reaction mixture. The reaction mixture
was heated with an oil bath (set at 80 °C) for 6 h. Reaction progress was
monitored by TLC. The reaction mixture was quenched with a saturated
NaHCO3 solution and filtered through a pad of Celite®. The filtrate was extracted
with CH2Cl2 (2 x 20 mL). The combined extract was dried with Na2SO4, and
evaporated. The crude product was purified using flash chromatography
351
(hexanes/EtOAc = 60/40) to obtain compound 5.47 as a white solid (0.21 g,
81%).
TLC Rf = 0.32 (hexanes/EtOAc = 40/60) [Anisaldehyde]
1H NMR (600 MHz, C6D6) δ 6.98 (d, J = 8.5 Hz, 2H), 6.65 (d, J = 8.6 Hz,
2H), 4.57 (dd, J = 8.4, 2.9 Hz, 3H), 4.54 (dd, J = 8.4, 2.9 Hz, 3H),
4.01 – 3.92 (os, 2H), 3.68 (d, J = 10.4 Hz, 1H), 3.25 (s, 3H), 3.22
(dd, J = 8.1, 1.9 Hz, 1H), 2.27 – 2.21 (m, 1H), 1.93 (s, 1H), 1.89 (d,
J = 13.7 Hz, 1H), 1.78 (s, 3H), 1.46 (ddd, J = 13.6, 10.8, 3.1 Hz,
1H), 1.37 (os, 2H), 1.27 (d, J = 12.4 Hz, 1H), 1.15 – 1.08 (m, 1H),
0.85 (t, J = 10.0 Hz, 1H), 0.58 (ddd, J = 13.4, 10.8, 6.2 Hz, 1H)
Synthesis of Compound 5.48
OPMB
OO
O
OH
5.47
cat PPTSTHF/H2O
(MeO)2CMe2PPTS
K2CO3MeOH
OPMB
HOHOOAc
OH
C2
OPMB
OH
OO AcO
C3
OPMB
OH
OO HO
5.48
92%overthreesteps
Compound 5.47 (42 mg, 0.10 mmol) and PPTS (2.0 mg, 7.9 µmol) and 1/1
THF/water (1 mL) were added to a RBF and stirred for 6 h. Reaction progress
was monitored by TLC (hexanes/EtOAc = 50/50). The reaction mixture was
quenched with a saturated NaHCO3 solution and extracted with EtOAc (3 x 1.0
352
mL). The combined extract was dried with MgSO4, and evaporated. The crude
product C2 was obtained and carried forward without further purification.
TLC Rf = 0.10 (hexanes/EtOAc = 50/50) [Anisaldehyde]
TLC Rf = 0.55 (100% EtOAc) [Anisaldehyde]
Compound C2, PPTS (5 mg, 20 µmol), and 2,2-dimethoxypropane (25 µL, 40
µmol) were dissolved in CH2Cl2 (500 µL) and stirred for 1 h. Reaction progress
was monitored by TLC (100% EtOAc). The reaction mixture was evaporated and
the crude compound (C3) was carried forward without further purification.
TLC Rf = 0.87 (100% EtOAc) [Anisaldehyde]
The crude residue (C3) was dissolved in MeOH (500 µL) and K2CO3 was added
(50 mg, 0.36 mmol) and the reaction mixture was stirred vigorously. Reaction
progress was monitored by TLC. The reaction mixture was quenched with water
and extracted with EtOAc (3 x 0.5 mL). The combined extract was dried with
MgSO4, and evaporated. The crude product 5.48 was obtained as a white solid
could be carried forward without further purification (40 mg, 92%).
TLC Rf = 0.17 (hexanes/EtOAc = 65/35) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 7.22 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz,
2H), 4.79 (s, 1H), 4.57 (d, J = 10.3 Hz, 1H), 4.47 (d, J = 12.4 Hz,
1H), 4.31 (d, J = 11.8 Hz, 1H), 4.24 (d, J = 10.3 Hz, 1H), 4.19 (dd, J
= 12.0, 4.6 Hz, 1H), 4.11 (dd, J = 11.9, 6.5 Hz, 1H), 4.01 (dd, J =
8.4, 3.6 Hz, 1H), 3.80 (s, 3H), 3.67 (d, J = 11.7 Hz, 1H), 3.63 (d, J =
12.4 Hz, 1H), 3.36 (s, 1H), 2.58 (s, 1H), 2.31 (dt, J = 13.7, 2.9 Hz,
1H), 2.13 (dt, J = 13.7, 2.5 Hz, 1H), 2.00 – 1.92 (os, 2H), 1.89 (ddd,
353
J = 15.7, 10.8, 4.8 Hz, 1H), 1.85 – 1.81 (m, 1H), 1.75 – 1.65 (os,
2H), 1.46 – 1.39 (os, 4H), 1.35 (s, 3H)
Synthesis of Compound 5.49
Compound 5.48 (40 mg, 0.093 mmol) was dissolved in CH2Cl2 (1.0 mL). DMP
(36 mg, 0.84 mmol) was added and the mixture stirred for 5 min. Reaction
progress was monitored by TLC. The reaction mixture was purified by flash
chromatography to obtain lactol 5.49 as a white solid as a 4:1 mixture of
diastereomers (40 mg, quantitative yield).
TLC Rf = 0.21 (hexanes/EtOAc = 70/30) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 7.20 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 8.3 Hz,
2H), 5.11 (d, J = 13.0 Hz, 2H), 4.37 (dd, J = 16.5, 11.7 Hz, 2H),
4.13 (d, J = 12.6 Hz, 1H), 3.99 (dd, J = 12.6, 2.8 Hz, 1H), 3.95 (d, J
= 8.3 Hz, 1H), 3.87 (dd, J = 11.4, 4.3 Hz, 2H), 3.32 (s, 3H), 2.72
(dd, J = 14.0, 10.2 Hz, 1H), 2.45 (dd, J = 12.9, 3.8 Hz, 1H), 2.30 (d,
J = 12.8 Hz, 1H), 2.20 – 2.15 (m, 1H), 2.14 (s, 1H), 1.76 (s, 1H),
1.65 (dt, J = 10.7, 8.0 Hz, 1H), 1.60 (d, J = 15.4 Hz, 1H), 1.56 (s,
3H), 1.50 (dd, J = 13.7, 8.4 Hz, 1H), 1.38 (s, 3H), 1.37 – 1.30 (m,
1H).
354
Synthesis of Compound 5.54
Compound 5.49 (18 mg, 0.042 mmol), as a mixture of diastereomers, acetic
anhydride (8.0 µL, 0.084 mmol), and DMAP (15 mg, 0.13 mmol) were dissolved
in CH2Cl2 (0.5 mL). Reaction progress was monitored by TLC. After 1.5 h, the
reaction mixture was purified by flash chromatography to obtain compound 5.54
as a mixture of diastereomers (20 mg, quantitative yield).
TLC Rf = 0.21 and 0.28 (hexanes/EtOAc = 70/30) [Anisaldehyde]
1H NMR (500 MHz, CDCl3) δ 7.26 – 7.22 (os, 2H), 6.87 (s,2H), 5.00 (d, J =
12.0 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 4.68 (dd, J = 15.4, 10.9 Hz,
2H), 4.52 (dd, J = 16.4, 11.0 Hz, 2H), 3.92 (dd, J = 12.0, 1.8 Hz,
1H), 3.90 – 3.83 (os, 2H), 3.80 (s, 3H), 3.08 (d, J = 11.3 Hz, 1H),
2.94 (s, 1H), 2.40 (d, J = 13.2 Hz, 1H), 2.15 (t, J = 10.9 Hz, 1H),
2.06 (s, 3H), 1.93 (d, J = 14.1 Hz, 1H), 1.89 – 1.82 (os, 2H), 1.65
(ddd, J = 13.7, 10.6, 7.1 Hz, 1H), 1.55 (s, 3H), 1.51 – 1.45 (os, 4H),
1.42 – 1.34 (os, 4H)
355
Synthesis of Compound 5.56
Compound 5.54 (5.0 mg, 1.1 µmol), silyl enol ether 5.55 (8.0 g, 5.5 µmol), and
CH2Cl2 (0.25 mL) were added into a scintillation vial. The reaction flask was
cooled with a dry ice/acetone bath. SnCl4 was added to the reaction mixture.
The reaction mixture was warmed gradually to rt. The reaction progress was
monitored by TLC. The reaction mixture was quenched with water and extracted
with EtOAc (3 x 0.25 mL). The combined extract was dried with MgSO4, and
evaporated. The crude mixture was purified by flash chromatography and
compound 5.56 was isolated.
1H NMR (500 MHz, CDCl3) δ 9.58 (s, 1H), 7.01 (d, J = 8.6 Hz, 2H), 6.81 (d, J
= 8.6 Hz, 2H), 3.79 (s, 3H), 2.72 (s, 2H), 1.04 (s, 6H).
Synthesis of Compound 5.57
MeOH (35 mL), pyridine (0.56 mL, 7.0 mmol), Pd on BaSO4 (15 mg, 7 µmol), and
alkyne 5.46 (0.21 g, 0.70 mmol) were added into a RBF. The reaction mixture
356
was placed under a hydrogen atmosphere and vigorously stirred. The reaction
progress was monitored by 1H NMR until all the alkyne was reacted (30 min).
The hydrogen balloon was removed and the reaction mixture was filtered through
a pad of Celite®, and evaporated. The filtrate was evaporated and redissolved in
EtOAc (25 mL) and washed with 10% CuSO4 solution (2 x 50 mL), to remove the
pyridine, and brine (25 mL). The extract was dried with MgSO4, and evaporated.
The crude product 5.57 was obtained as a white solid which could be carried
forward without further purification (0.20 g, 98%).
1H NMR (600 MHz, C6D6) δ 6.01 (dd, J = 17.2, 10.8 Hz, 1H), 5.19 (d, J =
17.1 Hz, 1H), 5.11 (t, J = 13.0 Hz, 1H), 4.26 (dd, J = 8.4, 3.1 Hz,
3H), 4.17 (dd, J = 8.3, 3.1 Hz, 3H), 3.63 – 3.55 (m, 1H), 2.88 (d, J =
9.8 Hz, 1H), 2.27 (s, 1H), 2.18 – 2.08 (m, 1H), 1.74 (s, 1H), 1.67
(dt, J = 14.4, 2.3 Hz, 1H), 1.41 – 1.24 (os, 9H).
Synthesis of Compound 5.58
Diol 5.57 (0.44 g, 1.5 mmol) was dissolved in THF (10 mL) and the solution was
cooled with an ice-water bath. NaH (60% dispersion, 0.18 g, 4.5 mmol) was
added to the vigorously stirring solution of diol. After 30 min, the reaction mixture
was warmed to rt and BnBr (0.35 mL, 3.0 mmol) was added dropwise and the
reaction mixture was stirred overnight. The reaction mixture was cooled with an
357
ice-water bath, carefully quenched with a saturated NaHCO3 solution, and
extracted with EtOAc (3 x 15 mL). The combined extract was dried with MgSO4,
evaporated, and purified using flash chromatography (hexanes/EtOAc = 67/33) to
obtain compound 5.58 as a white solid (0.52 g, 92%).
TLC Rf = 0.26 (hexanes/EtOAc = 50/50) [Anisaldehyde]
1H NMR (600 MHz, C6D6) δ 7.12 (d, J = 7.3 Hz, 2H), 7.07 (t, J = 7.3 Hz, 2H),
7.04 – 7.01 (m, 1H), 5.66 (dd, J = 16.8, 2.3 Hz, 1H), 5.57 (ddd, J =
16.8, 10.4, 1.5 Hz, 1H), 4.93 (dd, J = 10.4, 2.3 Hz, 1H), 4.40 – 4.36
(os, 4H), 4.29 (dd, J = 8.3, 3.0 Hz, 3H), 4.04 (d, J = 10.9 Hz, 1H),
3.76 (d, J = 10.9 Hz, 1H), 3.08 (dd, J = 9.0, 3.9 Hz, 1H), 1.73 (s,
3H), 1.67 – 1.63 (m, 1H), 1.53 (dt, J = 14.2, 2.8 Hz, 1H), 1.39 –
1.32 (os, 2H), 1.28 (d, J = 14.4 Hz, 1H), 0.99 – 0.89 (os, 2H), 0.82
(dd, J = 18.7, 10.7 Hz, 1H), 0.68 – 0.59 (m, 1H)
Synthesis of Compound 5.59
(MeO)2CH2PPTS
OBn
OH
OO HO
C4
DMPCH2Cl2
OBn
O
OO
HO
C5
cat PPTS,THF/H2Othen LiOH
OBn
OO
OMe
OH
OBn
OH
HOHO HO
5.58 5.67
Ac2O, DMAPCH2Cl2
OBn
O
OO
AcO
5.59
64%over 4steps
358
Compound 5.58 (0.45 g, 1.2 mmol) and PPTS (4.4 mg, 23 µmol) were dissolved
in a 4/1 solution of THF/water (40 mL). Reaction progress was monitored by
TLC. After 2 h, the reaction mixture was poured into a solution of LiOH (0.1 g,
2.3 mmol) in water (10 mL). Reaction progress was again monitored by TLC.
After 1 h, the reaction mixture was quenched with a saturated NaHCO3 solution,
and extracted with CH2Cl2 (3 x 30 mL). The combined extract was dried with
Na2SO4, and evaporated. Tetraol 5.67 was used without further purification.
Data corresponding to compound 5.67
TLC Rf = 0.21 (hexanes/EtOAc = 25/75) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 7.39 – 7.30 (os, 5H), 6.22 (dd, J = 16.9, 10.9
Hz, 1H), 5.38 (dd, J = 17.0, 1.3 Hz, 1H), 5.00 (dd, J = 10.9, 1.3 Hz,
1H), 4.76 (bs, 1H), 4.64 (d, J = 10.6 Hz, 1H), 4.34 (d, J = 10.6 Hz,
1H), 3.98 – 3.89 (os, 6H), 3.30 (bs, 3H), 1.94 – 1.83 (os, 5H), 1.69
– 1.63 (m, 1H), 1.61 – 1.53 (os, 2H), 1.48 (t, J = 7.1 Hz, 2H)
13C NMR (125 MHz, CDCl3) δ 143.5, 136.9, 128.7, 128.1, 128.0, 109.7, 78.9,
70.3, 64.0, 49.4, 48.1, 46.5, 33.7, 24.5, 24.3, 21.5
The tetraol (5.67) was redissolved in CH2Cl2 (5.0 mL). PPTS (5 mg, 20 µmol)
and 2,2-dimethoxypropane (0.14 mL, 1.2 mmol) were added. The reaction
mixture was stirred overnight. Reaction progress was monitored by TLC. The
reaction mixture was quenched with a saturated NaHCO3 solution, and extracted
with CH2Cl2 (3 x 30 mL). The combined extract was dried with Na2SO4,
evaporated, and purified by flash chromatography (CH2Cl2/EtOAc = 85/15) to
obtain compound C4 as a white solid (0.33 g, 70% over 2 steps).
359
Data corresponding to compound C4
TLC Rf = 0.28 (hexanes/EtOAc = 25/75) [Anisaldehyde]
1H NMR (500 MHz, CDCl3) δ 7.39 – 7.29 (os, 5H), 6.15 (dd, J = 16.9, 10.8
Hz, 1H), 5.41 (d, J = 17.0 Hz, 1H), 5.08 (d, J = 10.8 Hz, 1H), 4.68
(d, J = 10.7 Hz, 1H), 4.34 (d, J = 10.7 Hz, 1H), 4.22 (dd, J = 16.2,
12.7 Hz, 2H), 4.05 (d, J = 11.5 Hz, 1H), 4.00 – 3.95 (m, 1H), 3.90
(d, J = 11.9 Hz, 1H), 3.70 (d, J = 12.5 Hz, 1H), 3.45 (d, J = 11.4 Hz,
1H), 2.12 – 2.04 (m, 1H), 1.92 (s, 1H), 1.89 – 1.80 (os, 3H), 1.79 –
1.72 (os, 2H), 1.48 (bs, 2H), 1.33 (s, 3H), 1.31 (s, 3H)
13C NMR (125 MHz, CDCl3) δ 143.1, 136.6, 128.7, 128.2, 128.1, 110.8,
98.60, 78.4, 76.7, 70.3, 63.4, 63.2, 61.9, 47.4, 46.6, 45.9, 34.2,
26.8, 24.5, 24.3, 21.6, 21.6
Compound C4 (0.20 g, 0.50 mmol) was dissolved in CH2Cl2 (10 mL). DMP (0.23
g, 0.55 mmol) was added and stirred for 45 min. Reaction progress was
monitored by TLC. The reaction mixture was evaporated (removing a majority of
the CH2Cl2) and the slurry was purified by flash chromatography (hexanes/EtOAc
= 80/20) to obtain lactol C5 as a white solid (0.20 g, quantitative yield).
Data corresponding to compound C5
TLC Rf = 0.30 (hexanes/EtOAc = 35/65) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 4.4 Hz, 4H), 7.30 (dq, J = 8.7, 4.2
Hz, 1H), 6.21 (dd, J = 16.8, 10.6 Hz, 1H), 5.34 (dd, J = 16.8, 1.7
Hz, 1H), 4.98 (dd, J = 10.6, 1.7 Hz, 1H), 4.78 (d, J = 10.7 Hz, 1H),
4.67 (d, J = 12.6 Hz, 1H), 4.28 – 4.22 (os, 2H), 4.16 (d, J = 12.6 Hz,
360
1H), 3.95 – 3.90 (os, 2H), 3.76 (dd, J = 12.7, 2.8 Hz, 1H), 3.70 (d, J
= 12.3 Hz, 1H), 2.12 (dd, J = 28.5, 13.3 Hz, 2H), 2.02 (s, 1H), 1.94
(s, 2H), 1.79 (dd, J = 13.2, 5.3 Hz, 1H), 1.71 (d, J = 12.3 Hz, 1H),
1.61 – 1.55 (os, 2H), 1.41 (s, 3H), 1.35 (s, 3H)
13C NMR (125 MHz, CDCl3) δ 145.0, 136.7, 128.9, 128.3, 127.9, 111.8,
102.4, 97.5, 82.9, 78.9, 70.2, 66.2, 62.6, 48.8, 46.1, 40.4, 34.9,
28.1, 25.3, 24.93, 23.9, 19.2
Compound C5 (0.20 g, 0.50 mmol), acetic anhydride (57 µL, 0.60 mmol), and
DMAP (61 mg, 0.50 mmol) were dissolved in CH2Cl2 (10 mL). Reaction progress
was monitored by TLC. After 6 h, the reaction mixture was evaporated and
purified by flash chromatography to obtain compound 5.59 as a mixture of
diastereomers (20 g, 91% over 2 steps).
TLC Rf = 0.22 (hexanes/EtOAc = 80/20) [Anisaldehyde]
Data corresponding to compound 5.59
1H NMR (600 MHz, CDCl3) δ 7.37 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.6 Hz,
2H), 7.24 (t, J = 7.2 Hz, 1H), 6.31 (dd, J = 16.9, 10.9 Hz, 1H), 6.04
(s, 1H), 5.46 (dd, J = 16.9, 1.7 Hz, 1H), 5.06 (dd, J = 10.9, 1.8 Hz,
1H), 4.74 (d, J = 12.2 Hz, 1H), 4.33 – 4.26 (os, 2H), 3.94 – 3.87 (os,
4H), 2.23 – 2.14 (os, 2H), 2.05 (s, 3H), 1.97 (s, 1H), 1.88 – 1.82
(os, 2H), 1.82 – 1.77 (m, 1H), 1.76 – 1.71 (m, 1H), 1.64 – 1.58 (m,
1H), 1.56 (s, 1H), 1.38 (s, 3H), 1.34 (s, 3H)
361
Synthesis of Compound 5.60
Compound 5.59 (3.7 mg, 8.4 µmol) and trimethylsilane (6.7 µL, 42 µmol) were
dissolved in CH2Cl2 (0.5 mL). The reaction mixture was cooled with a dry
ice/acetone bath and SnCl4 was added dropwise. Reaction progress was
monitored by TLC (hexanes/EtOAc = 75/25). After 30 min, the reaction mixture
warmed to -40 °C and stirred for 15 min. The reaction mixture was quenched
with a saturated NaHCO3 solution, and extracted with CH2Cl2 (3 x 3 mL). The
combined extract was dried with Na2SO4, evaporated, and purified by flash
chromatography (hexanes/EtOAc = 90/10) to obtain compound 5.60 as a white
solid (1.5 mg, 37%).
TLC Rf = 0.54 (hexanes/EtOAc = 75/25) [Anisaldehyde]
TLC Rf = 0.27 (hexanes/EtOAc = 90/10) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 7.36 (d, J = 7.6 Hz, 2H), 7.32 (t, J = 7.6 Hz,
2H), 7.24 (t, J = 7.3 Hz, 1H), 6.42 (dd, J = 16.8, 10.7 Hz, 1H), 5.82
(ddt, J = 17.0, 10.0, 6.9 Hz, 1H), 5.52 (dd, J = 16.8, 2.1 Hz, 1H),
5.14 – 5.07 (os, 2H), 5.00 (dd, J = 10.7, 2.1 Hz, 1H), 4.73 (d, J =
12.2 Hz, 1H), 4.31 (d, J = 12.1 Hz, 1H), 4.23 (dd, J = 12.3, 2.5 Hz,
1H), 4.11 (dd, J = 9.4, 5.9 Hz, 1H), 3.96 (d, J = 12.2 Hz, 1H), 3.90
(t, J = 4.6 Hz, 1H), 3.82 (dd, J = 12.1, 2.4 Hz, 1H), 3.65 (d, J = 12.2
362
Hz, 1H), 2.40 – 2.33 (m, 1H), 2.23 – 2.16 (os, 2H), 2.13 (d, J = 12.9
Hz, 1H), 1.93 (s, 1H), 1.83 (s, 2H), 1.74 (dd, J = 13.5, 5.8 Hz, 1H),
1.72 – 1.67 (m, 1H), 1.60 – 1.55 (m, 1H), 1.54 (s, 3H), 1.52 – 1.47
(m, 1H), 1.36 (s, 3H), 1.34 (s, 3H).
Synthesis of Compound 5.61
OBn
O
OO
SnBu3
60%
OBn
O
OO
OAc
SnCl4, CH2Cl2-78 C rt
5.59 5.61
Compound 5.59 (52 mg, 0.12 mmol) and tributyl(3-methyl-2-butenyl)tin (0.10 mL,
3.0 mmol) were dissolved in CH2Cl2 (0.5 mL). The reaction mixture was cooled
with a dry ice/acetone bath and SnCl4 (21 µL, 0.18 mmol) was added dropwise.
Reaction progress was monitored by TLC (hexanes/EtOAc = 75/25). After 30
min, the reaction mixture was quenched with a saturated NaHCO3 solution, and
extracted with CH2Cl2 (3 x 5 mL). The combined extract was dried with Na2SO4,
evaporated, and purified by flash chromatography (hexanes/EtOAc = 90/10) to
obtain compound 5.61 as a white solid (53 mg, 60%).
TLC Rf = 0.65 (hexanes/EtOAc = 75/25) [Anisaldehyde]
TLC Rf = 0.29 (hexanes/EtOAc = 90/10) [Anisaldehyde]
1H NMR (500 MHz, CDCl3) δ 7.40 – 7.30 (os, 4H), 7.25 – 7.21 (m, 1H), 6.22
(dd, J = 16.8, 10.8 Hz, 1H), 5.87 (dd, J = 17.6, 10.8 Hz, 1H), 5.70
(dd, J = 16.8, 1.8 Hz, 1H), 5.25 (s, 1H), 5.13 (dt, J = 9.4, 4.7 Hz,
363
1H), 5.05 (td, J = 10.9, 1.3 Hz, 2H), 4.74 (d, J = 12.2 Hz, 1H), 4.28
(d, J = 12.2 Hz, 1H), 4.18 (d, J = 12.7 Hz, 1H), 3.94 (d, J = 12.7 Hz,
1H), 3.89 – 3.84 (os, 3H), 2.18 – 2.08 (os, 2H), 1.95 (s, 1H), 1.84
(s, 2H), 1.80 – 1.72 (os, 2H), 1.61 – 1.47 (os, 3H), 1.38 (s, 3H),
1.33 (s, 3H), 1.32 (s, 3H), 1.24 (s, 3H)
Synthesis of Compound 5.66
OBn
OH
OO
OO
1. O3, NMO•H2OCH2Cl2, -78 C
2. Swern
76%
OBn
OH
OO HO
5.65 5.66
Alkene 5.65 (50 mg, 0.12 mmol), NMO·H2O (50 mg, 0.37 µmol), and CH2Cl2 (20
mL) were added to a RBF and the mixture cooled with a dry ice/acetone bath.
The reaction was sparged with ozone containing oxygen and monitored by TLC
until the starting material (alkene 5.65) was consumed. The reaction mixture was
quenched with a solution of 1:1 saturated NaHCO3/Na2S2O3. The mixture was
extracted with CH2Cl2 (3 x 10 mL) and the combined extract washed with brine
(20 mL), dried with Na2SO4, and evaporated. The crude lactol was carried
forward without further purification
TLC Rf = 0.33 (hexanes/EtOAc = 65/35) [Anisaldehyde]
CH2Cl2 (1.0 mL) was added to the RBF followed by DMSO (0.18 mL, 2.5 mmol).
The reaction flask was cooled with a dry ice/acetone bath followed by dropwise
364
addition of oxalyl chloride (0.11 mL, 1.2 mmol). The reaction mixture was stirred
at -78 °C for 30 min. A solution of the crude lactol in CH2Cl2 (0.5 mL) was added
dropwise and the reaction mixture was stirred for 1 h at -78 °C. NEt3 (0.70 mL,
4.9 mmol) was added and the reaction mixture was stirred for an additional 30
min and then gradually warmed by moving the reaction flask to an ice-water bath.
After 30 min at 0 °C, the reaction was quenched with saturated NaHCO3. The
mixture was extracted with CH2Cl2 (3 x 2.0 mL) and the combined extract
washed with brine (2.0 mL), dried with Na2SO4, and evaporated. The crude
material was purified using flash chromatography to obtain lactone 5.66 (38 mg,
76%).
TLC Rf = 0.19 (hexanes/EtOAc = 75/5) [CAM]
1H NMR (600 MHz, CDCl3) δ 7.38 – 7.28 (os, 5H), 4.79 (d, J = 12.9 Hz, 1H),
4.66 (d, J = 10.8 Hz, 2H), 4.38 (d, J = 10.6 Hz, 1H), 4.15 – 3.99 (os,
4H), 3.95 (d, J = 11.6 Hz, 1H), 3.70 (d, J = 11.7 Hz, 1H), 3.08 –
3.01 (m, 1H), 1.97 (d, J = 8.7 Hz, 2H), 1.78 – 1.72 (m, 1H), 1.63 (d,
J = 14.1 Hz, 1H), 1.47 (d, J = 12.4 Hz, 1H), 1.38 (s, 3H), 1.36 (s,
3H), 1.33 – 1.24 (os, 3H)
13C NMR (125 MHz, CDCl3) δ 170.8, 136.3, 128.8, 128.4, 128.4, 97.6, 77.8,
76.3, 72.0, 70.2, 68.4, 63.9, 41.5, 37.9, 36.9, 32.7, 23.8, 23.1, 22.6
365
Synthesis of Compound 5.64 (from acetonide 5.66)
Compound 5.66 (4.0 mg, 9.9 µmol) and 1 small crystal of p-TsOH were dissolved
in a solution of 4:1 THF/water (0.5 mL). The reaction mixture was heated in an
oil bath set at 70 °C and heated for 4 h. Reaction progress was monitored by
TLC. The reaction was quenched with water. The mixture was extracted with
EtOAc (3 x 1.0 mL) and the combined extract washed with brine (2.0 mL), dried
with MgSO4, and evaporated. The crude material was purified using flash
chromatography to obtain diol 5.64 (2.5 mg, 69%).
TLC Rf = 0.19 (hexanes/EtOAc = 40/60) [Anisaldehyde]
1H NMR (600 MHz, CDCl3) δ 7.39 – 7.30 (os, 5H), 4.68 (d, J = 10.7 Hz, 1H),
4.57 (d, J = 11.9 Hz, 1H), 4.40 – 4.34 (os, 2H), 4.24 (d, J = 10.6 Hz,
1H), 4.15 (s, 1H), 4.00 (d, J = 10.9 Hz, 1H), 3.93 (d, J = 11.8 Hz,
2H), 3.85 (d, J = 10.9 Hz, 1H), 3.03 (ddd, J = 14.1, 4.2, 2.4 Hz, 1H),
2.49 (bs, 1H), 2.19 (bs, 1H), 1.97 (s, 1H), 1.95 – 1.90 (m, 1H), 1.80
– 1.72 (os, 2H), 1.68 (d, J = 14.1 Hz, 1H), 1.60 – 1.54 (m, 1H), 1.44
– 1.32 (os, 2H)
13C NMR (125 MHz, CDCl3) δ 171.1, 137.2, 128.8, 128.2, 127.9, 79.5, 76.5,
70.8, 70.5, 66.6, 65.4, 43.2, 41.9, 38.2, 32.8, 24.1, 23.4, 23.3
366
Synthesis of Compound 5.64 (from tetraol 5.67)
1. O3, NMO•H2OCH2Cl2, -78 C
2. I2, CaCO310:1 MeOH/H2O
OBn
OHHO
HOO
O
OBn
OH
HOHO HO
62%over 2 steps
5.67 5.64
Alkene 5.67 (0.10 g, 0.27 mmol), NMO·H2O (0.19 g, 1.4 mmol), and CH2Cl2 (10
mL) were added to a RBF and the mixture cooled with a dry ice/acetone bath.
The reaction was sparged with ozone containing oxygen and monitored by TLC
until the starting material (alkene 5.67) was consumed. The reaction mixture was
quenched with a solution of 1:1 saturated NaHCO3/Na2S2O3. The mixture was
extracted with CH2Cl2 (3 x 10 mL) and the combined extract washed with brine
(20 mL), dried with Na2SO4, and evaporated. The crude lactol was carried
forward without further purification.
The lactol intermediate was dissolved in MeOH (10 mL). CaCO3 (0.26 g, 2.6
mmol) was dissolved in water (1.0 mL) and added to the lactol solution. I2 (0.37
g, 1.6 mmol) was added and the reaction flask kept in the dark. The reaction
mixture was heated with an oil bath set at 80 °C for 5 h. Na2SO3 was added until
the reaction mixture turned from brown to colorless. Water was added until all
the solid had dissolved. The reaction mixture was quenched with saturated
NaHCO3, extracted with EtOAc (3 x 10 mL), the combined extract washed with
brine (10 mL), dried with MgSO4, and evaporated. The crude material was
purified using flash chromatography to obtain diol 5.64 (62 mg, 62% over 2
steps).
367
TLC Rf = 0.26 (hexanes/EtOAc = 25/75) [Anisaldehyde]
1H NMR matched compound 5.64 isolated from the deprotection of the acetonide
(see reaction above).
Synthesis of Compound 5.68
Compound 5.64 (15 mg, 0.041 mmol) was dissolved in CH2Cl2 (0.5 mL). DMP
(52 mg, 0.12 mmol) was added and the mixture stirred for 5 min. Reaction
progress was monitored by TLC. The reaction mixture was quenched with 10%
Na2S2O3 solution and extracted with CH2Cl2. The extract was washed with brine
(0.5 mL), and evaporated to obtain lactol aldehdye 5.68 (14 mg, 95%).
TLC Rf = 0.33 (hexanes/EtOAc = 60/40) [CAM]
1H NMR (500 MHz, CDCl3) δ 9.67 (s, 1H), 7.38 – 7.30 (os, 5H), 4.82 (d, J =
11.1 Hz, 1H), 4.68 (d, J = 11.2 Hz, 1H), 4.37 (d, J = 11.1 Hz, 1H),
4.22 (d, J = 11.2 Hz, 1H), 3.81 (d, J = 9.2 Hz, 1H), 3.08 (bs, 1H),
2.85 (d, J = 15.0 Hz, 1H), 2.07 – 2.03 (os, 2H), 1.86 – 1.79 (os, 2H),
1.76 (d, J = 14.4 Hz, 1H).
368
Synthesis of Compound 5.77 and 5.78
Imidazole (0.13 g, 1.9 mmol) and TESCl (34 µL, 0.20 mmol) were dissolved in
CH2Cl2 (1.0 mL). The reaction mixture was cooled with an ice-water bath. Triol
5.64 (67 mg, 0.19 mmol) was dissolved in CH2Cl2 (1.0 mL) and added to the
reaction mixture. Reaction progress was monitored by TLC. After 10 min, the
reaction mixture was quenched with NaHCO3 and extracted with CH2Cl2 (3 x 0.5
mL). The combined extract was dried with Na2SO4, evaporated, and purified by
flash chromatography to obtain 5.77 and 5.78 (26 mg and 15 mg respectively,
25% and 17%)
Data corresponding to compound 5.77
TLC Rf = 0.33 (CH2Cl2/EtOAc = 90/10) [Anisaldehdye]
1H NMR (500 MHz, CDCl3) δ 7.40 – 7.31 (os, 5H), 4.68 (d, J = 11.9 Hz, 1H),
4.63 (d, J = 10.4 Hz, 1H), 4.37 (d, J = 10.4 Hz, 1H), 4.32 (d, J = 7.4
Hz, 1H), 4.20 (s, 1H), 4.10 – 3.99 (os, 2H), 3.96 (d, J = 12.0 Hz,
1H), 3.92 (d, J = 10.0 Hz, 1H), 3.81 (d, J = 10.0 Hz, 1H), 3.05 (d, J
= 12.4 Hz, 1H), 2.22 (t, J = 6.3 Hz, 1H), 1.99 – 1.87 (os, 2H), 1.75 –
1.60 (os, 4H), 1.47 – 1.36 (os, 2H), 0.99 (t, J = 7.9 Hz, 9H), 0.90 –
0.88 (os, 3H), 0.65 (q, J = 7.9 Hz, 6H)
369
Data corresponding to compound 5.78
TLC Rf = 0.45 (CH2Cl2/EtOAc = 90/10) [Anisaldehdye]
1H NMR (600 MHz, CDCl3) δ 7.38 – 7.28 (os, 5H), 4.78 (d, J = 12.1 Hz, 1H),
4.68 (d, J = 10.8 Hz, 1H), 4.26 (d, J = 11.5 Hz, 2H), 4.22 (d, J = 7.4
Hz, 1H), 4.07 (d, J = 9.5 Hz, 1H), 4.03 – 3.98 (os, 2H), 3.96 – 3.86
(os, J = 10.3 Hz, 2H), 3.01 (d, J = 14.0 Hz, 1H), 2.17 (s, 3H), 2.12
(s, 1H), 1.98 (s, 1H), 1.88 (d, J = 14.5 Hz, 1H), 1.85 – 1.81 (m, 1H),
1.79 (dd, J = 13.3, 6.0 Hz, 1H), 1.69 (d, J = 14.0 Hz, 1H), 1.65 –
1.58 (m, 1H), 1.45 – 1.39 (m, 1H), 1.39 – 1.33 (m, 1H), 0.89 (t, J =
8.0 Hz, 9H), 0.52 (q, J = 8.0 Hz, 6H)
Synthesis of Compound 5.79 and 5.80
A mixture of compounds 5.77 and 5.78 (6.6 mg, 0.014 mmol) was dissolved in
CH2Cl2 (0.5 mL). DMP (6.5 mg, 0.015 mmol) was added and stirred for 30 min.
Reaction progress was monitored by TLC. The reaction mixture was purified by
chromatography to obtain compounds 5.79 and 5.80 (2.4 mg and 1.9 mg
respectively, 36% and 29%)
Data corresponding to compound 5.79
TLC Rf = 0.50 (CH2Cl2/EtOAc = 90/10) [Anisaldehdye]
370
1H NMR (600 MHz, CDCl3) δ 9.81 (s, 1H), 7.42 – 7.28 (os, 5H), 4.96 (d, J =
12.1 Hz, 1H), 4.85 (d, J = 12.1 Hz, 1H), 4.75 (d, J = 10.6 Hz, 1H),
4.30 (dd, J = 10.0, 4.9 Hz, 2H), 4.23 (dd, J = 15.8, 8.5 Hz, 2H), 3.95
(s, 1H), 3.10 (d, J = 14.1 Hz, 1H), 2.01 – 1.95 (os, 2H), 1.78 (dd, J
= 13.3, 8.1 Hz, 1H), 1.64 (d, J = 14.2 Hz, 1H), 1.42 – 1.28 (os, 4H),
0.86 (t, J = 8.0 Hz, 9H), 0.47 (q, J = 8.0 Hz, 6H)
Data corresponding to compound 5.80
TLC Rf = 0.30 (CH2Cl2/EtOAc = 90/10) [Anisaldehdye]
1H NMR (600 MHz, CDCl3) δ 7.39 – 7.28 (os, 5H), 5.72 (d, J = 5.9 Hz, 1H),
4.71 (dd, J = 14.8, 11.2 Hz, 2H), 4.48 (d, J = 10.8 Hz, 1H), 4.29 (d,
J = 11.6 Hz, 1H), 3.93 (d, J = 7.5 Hz, 1H), 3.86 (d, J = 10.4 Hz, 1H),
3.51 (d, J = 10.4 Hz, 1H), 2.84 (ddd, J = 13.7, 4.9, 2.4 Hz, 1H), 2.72
(d, J = 5.9 Hz, 1H), 2.02 (s, 1H), 1.98 – 1.92 (m, 1H), 1.82 (d, J =
10.0 Hz, 1H), 1.70 (d, J = 13.7 Hz, 1H), 1.51 – 1.40 (os, 3H), 0.94
(t, J = 8.0 Hz, 9H), 0.56 (q, J = 8.0 Hz, 6H)
371
Spectra of Compounds From Chapter 5 Figure 5.1 – 1H NMR of Compound C1 (600 MHz, C6D6)
372
Figure 5.2 – 1H NMR of Compound 5.29 (600 MHz, C6D6)
373
Figure 5.3 – 1H NMR of Compound 5.30 (500 MHz, C6D6)
374
Figure 5.4 – 13C NMR of Compound 5.30 (125 MHz, C6D6)
375
Figure 5.5 – 1H NMR of Compound 5.32 (500 MHz, C6D6)
376
Figure 5.6 – 1H NMR of Compound 5.33 (500 MHz, C6D6)
377
Figure 5.7 – 13C NMR of Compound 5.33 (125 MHz, C6D6)
378
Figure 5.8 – 1H NMR of Compound 5.36 (600 MHz, C6D6)
379
Figure 5.9 – 13C NMR of Compound 5.36 (125 MHz, C6D6)
380
Figure 5.10 – 1H NMR of Compound 5.37 (600 MHz, C6D6)
381
Figure 5.11 – 1H NMR of Compound 5.40 (600 MHz, C6D6)
382
Figure 5.12 – 1H NMR of Compound 5.41 (600 MHz, C6D6)
383
Figure 5.13 – 1H NMR of Compound 5.45 (600 MHz, C6D6)
384
Figure 5.14 – 13C NMR of Compound 5.45 (125 MHz, C6D6)
385
Figure 5.15 – 1H NMR of Compound 5.46 (600 MHz, C6D6)
386
Figure 5.16 – 13C NMR of Compound 5.46 (125 MHz, CDCl3)
387
Figure 5.17 – 1H NMR of Compound 5.47 (600 MHz, C6D6)
388
Figure 5.18 – 1H NMR of Compound 5.48 (600 MHz, CDCl3)
389
Figure 5.19 – 1H NMR of Compound 5.49 (600 MHz, CDCl3)
390
Figure 5.20 – 1H NMR of Compound 5.54 (500 MHz, CDCl3)
391
Figure 5.21 – 1H NMR of Compound 5.56 (500 MHz, CDCl3)
392
Figure 5.22 – 1H NMR of Compound 5.57 (600 MHz, C6D6)
393
Figure 5.23 – 1H NMR of Compound 5.58 (600 MHz, C6D6)
394
Figure 5.24 – 1H NMR of Compound 5.67 (600 MHz, CDCl3)
395
Figure 5.25 – 13C NMR of Compound 5.67 (125 MHz, CDCl3)
396
Figure 5.26 – 1H NMR of Compound C4 (500 MHz, CDCl3)
397
Figure 5.27 – 13C NMR of Compound C4 (125 MHz, CDCl3)
398
Figure 5.28 – 1H NMR of Compound C5 (600 MHz, CDCl3)
399
Figure 5.29 – 13C NMR of Compound C5 (125 MHz, CDCl3)
400
Figure 5.30 – 1H NMR of Compound 5.59 (600 MHz, CDCl3)
401
Figure 5.31 – 1H NMR of Compound 5.60 (600 MHz, CDCl3)
402
Figure 5.32 – 1H NMR of Compound 5.61 (500 MHz, CDCl3)
403
Figure 5.33 – 1H NMR of Compound 5.66 (600 MHz, CDCl3)
404
Figure 5.34 – 13C NMR of Compound 5.66 (125 MHz, CDCl3)
405
Figure 5.35 – 1H NMR of Compound 5.64 (600 MHz, CDCl3)
406
Figure 5.36 – 13C NMR of Compound 5.64 (125 MHz, CDCl3)
407
Figure 5.37 – 1H NMR of Compound 5.68 (500 MHz, CDCl3)
408
Figure 5.38 – 1H NMR of Compound 5.77 (500 MHz, CDCl3)
409
Figure 5.39 – 1H NMR of Compound 5.78 (600 MHz, CDCl3)
410
Figure 5.40 – 1H NMR of Compound 5.79 (600 MHz, CDCl3)
411
Figure 5.41 – 1H NMR of Compound 5.80 (600 MHz, CDCl3)
412
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(4) Nicolaou, K.; Vourloumis, D.; Winssinger, N.; Baran, P. S. Angewandte Chemie International Edition 2000, 39, 44.
(5) Fujita, E.; Node, M. Progress in the Chemistry of Organic Natural Products 1984, 46, 77.
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