comparative strategies in natural products synthesis
TRANSCRIPT
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
1
Comparative Strategies in Natural Products Synthesis
Université Bordeaux 1Master de Chimie (CO-3)
Stéphane Quideau, Ph.D.Institut Européen de Chimie et Biologie
&Laboratoire de Chimie des Substances Végétales
Centre de Recherche en Chimie MoléculaireUniversité Bordeaux 1
[email protected] : 05-40-00-30-10Cel : 06-62-91-65-51
The objective of this course is to provide graduate students majoring in chemistry with a strengthenedknowledge of organic synthesis. The student will utilize his/her knowledge of organic reactions,mechanisms, and controls to critically and comparatively study the challenges of natural productssynthesis. Toward this objective, total syntheses of various targets accomplished by different researchgroups over the years will be discussed. The different synthetic strategies will be compared via aretrosynthetic analysis approach (i.e., topological disconnection path to starting materials). The differenttactics (i.e., choice of reactions and combinations thereof) will be discussed by highlighting the key steps ofthe actual syntheses.
Targets: Camptothecin, Biotin, Denticulatins, Dynemycin A , Dysidiolide, Epothilones, FK-506,Quadrone, Strychnine, Zaragozic Acids, Taxol.
Suggested Readings and Reference Sources:• E. J. Corey and Xue-Min Cheng, The Logic of Chemical Synthesis, Wiley.• K. C. Nicolaou and E. J. Sorensen, Classics in Total Synthesis, VCH.• Tse-Lok Ho, Tactics of Organic Synthesis, Wiley.• A. Koskinen, Asymmetric Synthesis of Natural Products, Wiley.• S. Warren, Designing Organic Synthesis, Wiley.• S. Warren, Organic Synthesis, The Disconnection Approach, Wiley
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
2
• Strategies and Tactics in Organic Synthesis (volume series).
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
3
General Guidelines
A. Convergent / linear synthesis
9
92 20vs.
better not so good
The overall yield is a function of the yield of every steps !
eg, 10 steps95% each 0.9510 = 60%90% each 0.9010 = 34%70% each 0.7010 = 3%
B. Timing of bad risky steps early middle late1 3 2
C. sp2 centers vs. sp3 centers available less available, but stereogenic centers ⇒ Diels-Alder
ClaisenCarbonyl addition
D. Intra/intermolecular reactions
Intramolecular bond forming reaction have entropic and stereochemical/conformational advantages!
E. Double diastereodifferentiation
RO
HMe
OMR'
OH+
Si/Re5/1 (inherent preference)
Si/Re1/5
R
Me
OHR'
Me OH
O
R
Me
R'
OH
O
reflects both inherent preferences
+ 25/1
OH
Me
NB: This estimate does not take into account kinetic resolution
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
4
F. Enantiomeric excess
definition = (d% - l% / d% + l%) x 100
Coupling chiral, scalemic (not racemic) fragments
A + B → C ee?
90% ee
90% ee
95/5 d/l
dd 0.95 x 0.95 = 0.90dl 0.95 x 0.05 = 0.05 (separable diast.)ld 0.05 x 0.95 = 0.05 (separable diast.)ll 0.05 x 0.05 = 0.0025
⇒ ee = 90/025 ⇒ 360/1 ⇒ 99.4%
NB: This estimate does not take into accountkinetic resolution
G. Natural and unnatural polarization of functional groups
Synthetic target may be viewed in terms of their ionic components
R
O
α
β
γ
Nu
R
Oα α carbon is negative!
R
O β
E
β carbon is positive!
Nu
R
O
γ
δ
δ
δ
δ
δδ
δ
Michael 1,4-addition
γ carbon is negative!
BaseR
O
γ
E
Arrays of alternate negative/positive centers are easier to construct!
O
O
δ
δ
δ
δ not so trivial to put together!
Umpolung chemistry, i.e., polarity reversal ⇒ synthetic equivalent with unnatural polarity
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
5
R
O
acyl anion(not accessible!)
S S
R
S S
R HR
O
HE
H. Topological disconnections to simplify structures ⇒ Retrosynthetic analysis
• E. J. Corey, JACS 1975, 97, 6116 (strategic bond disconnections).• E. J. Corey and Xue-Min Cheng, The Logic of Chemical Synthesis, Wiley.
Perception of strategic bondsThe most desirable bond disconnections in the antithetic manipulation of structure are those in which thefollowing structural features are minimized:
(i) appendages(ii) appendages carrying chiral centers(iii) rings of medium or large size(iv) bridged ringsStrategic bonds (to break in the retrosynthetic manipulation) vs. core bonds (not to break!)
Analysis of Bridged Polycyclic Molecular Networks
Me OH
a b
c d
a b
cd
Me OH Me OH
Me OH Me OH
*
**
*
*
*
**
Rule #1A strategic bond must be in a four-, five-, six- or seven-membered “primary” ring (relatively easy to form)
a secondary six-membered ringenvelope of two fused four membered-ring
A primary ring is one which cannot be expressed as the envelope of two or more smaller rings bridged orfused to one another.
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
6
Rule #2
A strategic bond must be directly attached to another ring (exo to another ring, except three-membered rings)because a ring disconnection which produces two functionalized appendages leads to a more complex systemthan a ring disconnection that lead to one or no functionalized appendages.
⇒ mimimize appendages on rings!
A1
2
Out of six bonds in ring A, only bonds 1 and 2 can be strategic
Rule #3
To achieve maximal simplification of the cyclic system, strategic bonds should be in the ring (or rings) whichexhibits the greatest degree of bridging.
central four-membered ringof maximum bridging
Disconnection of any bond in that central four-membered ring produces a major network simplification to adecalin system.
The maximum bridging ring is selected from the set of “synthetically significant rings” (all primary rings— Rule #1— plus all secondary rings less than eight membered, ie, those that can be formed from a pair ofsmaller primary rings)
Maximum bridging rings of a molecule are those rings which are bridged at the greatest number of sites.
** *
*How many sitesbridged at?
Rule #4
To avoid the formation of rings having greater than seven members, any bond common to a pair of bridged orfused rings whose envelop is > eight-membered cannot be considered strategic.
The bonds that are eliminated from further consideration by this rule are termed core bonds
a core bondDO NOT BREAK!
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
7
Exception : when the two fused or bridged rings being examined are directly joined elsewhere by anotherbond.
core bond?No, breaking does not lead to a ten-membered ring, butto two fused six-membered rings!
Rule #5
Bonds within aromatic rings are not considered to have potential strategic character.
Rule #6
If a cyclic arc linking a pair of common atoms (fusion atoms, bridgeheads, or spiro ring junction atoms)contains a chiral carbon atom, then none of the bonds in the cyclic arc may be considered strategic.
⇒ mimimize appendages with chiral centers!
Don’t!
This situation is undesirable because it is difficult to control stereochemistry efficiently at centers onappendages as opposed to centers in rings.
Exception : A bond directly attached to a chiral center can be broken if that center is the only chiral one onthe arc linking the two common atoms
OK!(but again don’t if center 3 is chiral!
Rule #7 : The C-Heterobond Procedure
To the set of strategic bonds determined by rules 1-6, C-X bonds (X = O, N, S) are added!
OHH
1 23
4OHH
* *
12
34
O2NHO
12
34
O2NO
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
8
“One-Group Transforms”
“Two-Group Transforms”
NB: This analysis is limited to one-bond disconnections. Keep in mind the possibility of bond-pairdisconnecting transforms ⇒ applications of powerful ring transforms [4+2], [2+2], [2+1]
Ref: EJ Corey, JACS, 1974, 96, 7724
O
OH
O
OH
eliminated by rule 2 (not exocyclic)kept by the C-Heterobond procedure
O
FGA 1-GRP
OLG
alkylation
FGA
O
FGI
O OH
2-GRP
aldolO CHO
FGI
O
FGI
O
O
2-GRP
Michael
O
O
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
9
0Quadrone - “The Taxol of its time”
A. General
• Sesquiterpene (i.e., 15 carbon skeleton) isolated from Aspergillus terreus in 1978• This quadicyclic ketone was viewed as “a popular test of design and execution” for synthetic organic chemists • Four rings, 5 contiguous steregenic centers:
one cis-fused bicyclo[3.3.0]octane subunitone bicyclo[3.2.1]octane subunit4 neopentyl and 1 quaternary (C-1) asymmetric carbonC-1 is common to each four rings!
• Shows cell-growth inhibitory activity:somewhat surprising, since quadrone is devoid of the electrophilicfunctionality common in sesquiterpene antitumor agents
quadrone is actually the progenitor of the α-methyleneketone, terrecyclic acid A
• Antitumor activity against:human epidermoid carcinoma; ED50 = 1.3 µg/mLlymphocytic leukemia in mice; LD50 > 340 mg/kg
NB: quadrone and terrecyclic acid A are the only twonatural products known to possess such a carbon skeleton
B. References
Burke, JACS 1984, 106, 4558See also: Strategies and Tactics in Organic Synthesis , Volume 2, Chapters 2 (Burke) and 5 (Helquist)Kende, JACS 1982, 104, 5808 Danishefsky, JACS 1981, 103, 4136Magnus, JOC 1987, 52, 1483 Wender, JOC 1985, 50, 4418Yoshii, JACS 1983, 105, 563 Wender, Org. Photochem. 1989, 10, 439Schlessinger, JOC1983, 48, 1147 Smith,JACS 1991, 113, 3533
O
O
O
H
13 28
45
6
9
7
10
1211
1314 15
(+)-quadrone
CO2H
O
H
terrecyclic acid Agreater acute toxicity than quadrone itself!
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
10
C. Retrosynthetic Analysis and Synthesis
Topological disconnection in bridged polycyclic framework (E.J. Corey, JACS 1975, 97, 6116):
1) Identify rings with maximum bridging:look for bridgehead carbons to identify the ring of maximum bridging
2) Identify strategic bonds vs. core bonds:• A strategic bond (i.e., most desirable to break in retrosynthetic analysis) must be within a ring of
maximum bridging• A core bond (i.e., not to be broken in retrosynthetic analysis)
O
O
core bondDo Not Break !
O
• Breaking this core bond would lead to a nine-membered ring ⇒ need for a medium-size ringformation synthetic step (difficult!)
• Any non-core bonds in maximally-bridged ring can be a strategic bond!
O
O
Burke
O
O
CHO
O
O
Kende
O
O
Magnus
CO2Et
TMSO
R
acyclic!
O O O
core bond broken!
O
O
bridging
bridge head bridge head
O
O
O
H
O
O
ring with maximum bridging!
O O
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
11
The Burke routeJACS 1984, 106, 4558
All new carbon-carbon bonds are formed via intramolecular deliveryRetrosynthetic analysis
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
12
This is actually (ent)-quadrone
O
O
CHO
O
OO
OO
1
O
CHO
O
key starting materialwith correct stereo. at spiro center!
spiro[4,5]decadienoneBurke, JOC 1981, 46, 2400
Aldol
CHO
O
O
O
O
CHO
O
OH
O
OHC
H
axial! ⇒ contrathermodynamic ⇒ kinetic control
E Nu
retro-Aldol
thermoneutral+ 5 Kcal/mol
E Nu
1
core bond
convexe
concave
retro-Michael
downhill- 20 Kcal/mol
i.e.,
This plan involves a bond formation through the convexe face ⇒ difficult!This was in the first Burke's grant proposal; a referee claimed that such a bond was impossible to make!Burkeet al. found a way (more than 50 sets of conditions were tried...
O
O
CHOMichael
Nu centers = -E centers = +
+
+
+ + We shall see how Burke et al. controlled this reaction!
exo-orientation of CHO, as exo-face slightlyless hindered (not obvious! Burke was concerned about the possibility of having formed the endo-product, for Aldol was difficult to achieve
convexe/exo-face is less hindered!
Synthesis
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
13
O O
O
CHO
O
O
O
CHO
O
CHO
O
OO
O
electron-rich alkenecould use electrophilic ozone,but degradation problems!
HO
1. OsO4 cat., N-methyl morpholine N-oxide2. NaIO4
TsOH, PhH
O
TiCl4, R4N OCOCF3
H
A
CO2MeH
A
B
B
C
KOH, PhH, refluxdibenzo-18-crown-6
95%
92%
96%remains to build lactone!
not so trivial due to difficulties in forming C-5 enolate regioselectively
HO
TsOH, morpholinePhH, reflux
OO
50 trials withdifferent condition sets
JACS 1984, 106, 4558
O
Danishefsky's intermediateJACS 1981, 103, 4136
axial ⇒ contrathermodynamic: this is not so easy, but Burke provided a solution to complete his formal total synthesis
add 1C
Wharton fragmentationJOC 1961, 26, 3615
H
OO
1. HOCH2CH2OH, TsOH2. t-BuOOH, NaOH, aq. MeOH (epoxidation at α-face because β-face is blocked by the ethano bridge)
H2NNH2.xH2OMeOH–AcOH
OH
5
92%
O
i.e. allylic transposition from enone
Hg(OAc)2, i-Pr2NEt, xylene, Δ
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
14
O
12
3
1 2
3
allyl vinyl ether ⇒ [3,3] Claisen with sterecontrol!
α-face
[3,3]
CHO
α-faceH2, Pd/C
CHO
axialO
O OO O
O
Danishefsky'sintermediate
56
contains all the target carbons!
formal total Σ total Σ
need to:1. form C5–C6 bond
2. reduce C-6, oxidize C-73. disconnect C-6 and C-7,
then reattach through oxygen togive lactone
7
total synthesis completion
1. aq. HCl2. HOAc–H2SO4 (Aldol)
CHOOO O
AcO 79% (4:1)
400 °Csealed tube
O
O
+
61%
33%
TBSO OHOH
Ag2CO3 – CeliteFetizon's reagent
O
XO
YA: X = O, Y = H, HB: X = H, H, Y = O
92% (1:1)
Jones
(+)-quadrone
19 steps and 6.2% overall yield from spiro [4,5]decadienone
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
15
The Kende routeJACS 1982, 104, 5808
Pd(II)-mediated cycloalkenylation
Retrosynthetic analysis
CO2MeO
H
Danishefsky'sintermediate
O
O
O
CO2Et
TMSO
Synthesis
O O
CO2Me
CO2Et TMSO CO2Et
CO2Et
TMSO HOMe3Si
EtO2C
Pd
OEtO
O
O
O O
1. LiOH (selective ester hydrolysis + decarboxylation)
Pd(OAc)2, CH3CN, rt"Pd"
2. 0.95 equiv. LDA, THF, - 78 °C → - 0 °C(thermo enolate), TMSCl
β-hydrideelimination
oxidationNaH, PhCH3 hydroboration
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
16
CO2HO
H
O
H
O O
3:1O
CO2H
H
terrecyclic acid A
H melting point!!! quadrone
isoquadrone
O
CO2H
H
HO
mp was for isoquadrone, not quadrone!!!mp changed on second measure ⇒ quadrone!!! (ouf!!!)
14 steps, 2.4% overall
Danishefsky
LDA (3 equiv.), CH2O gas62%
H2, Pd-C
O
CO2H
H
HO
100%
190 -195°C5 min
The Sclessinger routeJOC1983, 48, 1147
Intramolecular Diels-AlderRetrosynthetic analysis
O
CO2HH
O
OO
OH
O
OH
O
O
(+)-quadrone Danishefsky'sintermediate
1 23
4
5
23
45
1 remove 1C
cyclohexene⇒ D.A.
core bond
core bond
Synthesis
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
17
O
MeO2CI
O
MeO2C
O
OH
NHN
O
OHOO
CO2HO
O
CO2H
H
OH
NN
Cr
OO
OH
O
N
HN
Cr
OOH
ON
NCr
OHOH
O
regioselectivity of allylic oxidation?more stable trisubstituted olefin product !? (thermo control !)Also complex attacks less hinderedface (hydrogen) of molecule!
O
[2,3]
Salmond et al., JOC 1978, 43, 2057-2059
1. LDA (2 equiv.), TMSCl (2 equiv.)2. O3, then NaIO4, CrO3
Hase and McCoySynth. Commun. 1979, 9, 63
"remove 1C"
Danishefsky'sintermediate
13 steps, 6% overall
Base (2 equiv.) 1,3-diCO dianion alkylation
1. LiCl, DMSO/H2O (decarboxylation)2. [(CH3)2N]2CHOt-Bu (Brederick's reagent)3. Dibal-H
Diels-Alderprecursor
NaH, xylene, Δ
NN
Cr
OHO
OO
Chem. Ber. 1968, 101, 41
OH
PhCH3, CH3CN120 °C
48%
trans-decalin system!⇒ need to epimerize
to cis-decalin
CrO3
O
"Cr(VI)""Cr(IV)"
"Cr(VI)"
CrOH
OH
"Cr(VI)" O
allylic oxidation via 3,5-dimethylpyrazole•CrO3 complex
NN
break 2 πC=C ⇒ 2x70 Kcal/molgain 2 σC–C⇒ 2x90 Kcal/mol⇒ downhill by 40 Kcal/mol
"Cr(IV)"
HO
cannot collapse to ketone, since no hydrogen to remove!
or "Cr(V)" O
O
[3,3]
nice 1,3-diaxial dispostion for [3,3]i.e., 6-membered TS
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
18
The Wender routesJOC 1985, 50, 4418
Intramolecular Diels-Alder / Ring Expansion SequenceRetrosynthetic analysis
terrecyclic acidi A
CO2t-BuOCO2H
H
Oring
expansion
CO2t-Bu
OMeCl
LG
cycloaddition
OMe
MeO2C
t-BuO2C
core bond broken!
form core bond!
Synthesis of (+)-desdimethylquadroneOrg. Photochem. 1989, 10, 439
Alkene-Arene Photochemical Coupling - “The Home Run Approach”NB: Only novel development of carbon-carbon bond forming reaction (with Stille coupling)
in the past 25-30 years!Background Analysis
Possibilities of photocycloadditions
ortho para
weird, but so clever!meta
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
19
mechanism?
hν*
exciplexSynthesis
MeO2C MeO2C MeO2C MeO2CH
H
HMeO2C
H
H
H
HMeO2C
MeO2C
H
H
H
MeO2C HHH
intramolecular meta photocycloaddition
HH
21
H
CO2Me
hν via exciplex3
45
2,66
slightly favored!gives rise to CO2Me in less sterically
favored axial orientation in cycloadduct
1,3
1,5
+ epimer
poor regio- and diastereoselectivity,but highly expeditous synthesis!
versus
exciplex 1
MeO2C
NB: regio- and diastereoselectivity improves when ester group is replaced by more bulky alcohol group (via reduction)
H
H
exciplex 2
2
H3
[1,5]
CO2H
H
5
O
4
OO1
Δ
(+)-desdimethylquadrone
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
20
Strychnine
A. General
Strychnos alkaloid (poison / rain forest)first isolated from Strychnos ignatii by Pelletier and Caventou (1818)
complex heptacyclic structure (24 skeletal atoms):6 contiguous assymetric carbon centers5 of those are included within one saturated six-membered ring1 is quaternary!7-membered oxygen heterocyclic motif
“For its molecular size it is the most complex substance known”(Sir Robert Robinson, 1952)
B. References
Robinson, Chem. Ind. 1953, 245. Overman, JACS 1993, 115, 9293Woodward, JACS 1954, 76, 4749. Kuehne, JOC 1993, 58, 7490.Wooddward, Tetrahedron 1963, 19, 247. Beifuss, Angew Chem. IEE 1994, 22, 1144.Magnus, JACS 1992, 114, 4403. Rawal, JOC 1994, 61, 7873.Overman, Acc. Chem. Res. 1992, 25, 352 Martin, JACS 1996, 118, 9804.
C. Retrosynthetic Analysis and Synthesis
N
O
N
HO
H
N
O
N
HHO
N
O
N
HO
H
NH
N
HO
H
HO
no obvious disconnection!
Woodward(1954)
First
N
O
N
HO
H
isostrychnine I
"Best"
NNH
corynantheoid alkaloid skeleton
conjugate addition
Biomimetic
OH
Overman(1993)
MeO2C
Wieland-Gumlich aldehyde
H
H
2C introductionlactamization
Martin(1996)
N
O
N
HO
H
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
21
The Woodward RouteTetrahedron 1963, 19, 247
JACS 1954, 76, 4749.
7-membered ether ring last!Retrosynthetic Analysis
N
O
N
HO
HN
O
N
HHO
isostrychnine I
conjugate addition
N
O
N
HO
H
N
O
N
HO
allylic rearrangement
N
O
N O
O
diastereoselectiveorganometallic
addition
H attack at ketonefrom convex face
amide C=O
ketone C=O
dehydrostrychninone
lactamization
N
O
NH
CHO
Oglyoxal
H
N
O
NH
OH
oxidationneeds epimerization!
N
O
NP
OMe
O
OH Dieckmann
N
CO2R
O
NP
OMe
O1,3-diC=O(enol form)
H H
needs epimerization!
NP
CO2R
NP
CO2Me
Hlactamization
CO2Me
trans
cis
NP
CO2R
NP
OMe
OMe
veratryloxidative cleavage
C–C spiral bondformation
N OMe
OMe
NCO2R
X–P
B
H N OMe
OMeH
OMe
OMeNHNH2
O
+Fischer indolesynthesis
2C/N + 2Cintroduction
phenylhydrazine
acetoveratrone
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
22
Synthesis
OMe
OMe
NHNH2O
+ Fischer indolesynthesis
phenylhydrazine acetoveratrone
PPA
N OMe
OMeH2
3blocked!
2-veratrylindole
CH2O, Me2NH
Schiff base
aq. AcOHNH
N OMe
OMeH
NMe2
N OMe
OMeH
N
1. MeI2. NaCN, DMF (97% over 2 steps)3. LAH, THF, Δ (85%)4. Ethyl glyoxylate, PhH (92%)
92%
CO2Etp-TsCl, pyr.
Nu E
N
CO2Et
NSO2Ar
OMe
OMe
N
CO2Et
NSO2Ar
OMe
OMe
vs.
not formed!only product (64%)close spatial relationshipbetween two sites of
complementary reactivity! 1. NaBH4, EtOH2. Ac2O (84% over 2 steps)3. O3, aq. AcOH (regioselective but only 29% )
NAc
CO2Et
NSO2Ar
CO2Me
H
MeO2C
MeOH, HCl, Δ
3 transforms in one steps:acetate cleavage
lactamizationepimerization
cannot lactamize here!
N
CO2Et
O
NSO2Ar
OMe
O
H
aromatic!
H
hydride attack at sp2 center from less hindered α face (not critical
since stereogenic center subsequently destroyed!
need epimerization to allow Dieckmann cyclization!
N
CO2Me
O
NAc
OMe
O
H
Tosyl group incompatibility ⇒ 3 extra steps!
75%
NaOMe, MeOH, ΔDieckmann
N
O
NAc
OMe
O
OHH
88%
N
O
NH
OH
several steps
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
23
N
O
NH
OHN
O
NH
CHO
OH N
O
NH
CHO
OH
N
O
N O
ONa, THF (53%)
N
O
N
HHO
N
O
N O
OH
N
O
N O
OH
SeO2, EtOH
H
trans-glyoxal cis-glyoxal
can cyclize!
dehydrostrychninone
1. cyclize2. oxidise
1. HBr, AcOH (allylic bromide formation)2. aq. H2SO4, Δ (allylic isomerization, 13%)
isostrychnine I
21
concavetop face
convexbottom face
attack at less hindered face
N
O
N
HO
1. H2, Lindlar catalyst, i.e., Pd-CaCO3-PbO (86%)2. LAH, Et2O (30%)
intramolecular hydride deliveryfrom C21 aluminum alkoxide
to C8 β face!
8
218
N
O
N
HO
HKOH, EtOH strychnine
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
24
The Overman RouteJACS 1993, 115, 9293
“Domino aza-Cope/Mannich transform”
NR
HO [3,3]
aza-Cope NR
HOMannich
NR
OHC
3-formylpyrrolidine
1 2 3
321
1
23
32
1
N
O
N
HO
H
Wieland-Gumlich aldehyde
one step to strychnine !Robinson (1953)
NH
N
HO
H
HO
lactonization
NH
N
MeO2C OH
CarboxymethylationImine formationtautomerization
N
Ot-Bu
ONP2
NR2
N
tBuO
HO
look for the3-formylpyrrolidine
motif!
NR2
N
tBuO
HO
aza-Cope Mannich
NR2
HN
tBuO
HO
epoxide opening
R2N
O
PHN
OtBu
olefinationepoxidationcarbonylative Stille
R2NI
TIPSO
OtBu
Bu3Sn+
AcOOAc
prochiral meso1,4-diacetoxycyclopent-2-ene
1
2
34
567
8910
11
12
3
4 5
6
7
89
10
11
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
25
Synthesis
Overman, JACS 1993, 115, 9293See also: Classics, 646-653
AcO
OAcAcO
OH
AcOO
OOMe
EtO2CO
Ot-Bu
AcOO
CO2EtH
AcOOH
CO2EtH
O TiLn
CO2Et
R
H
H OH
CH2Ot-Bu
R H
CO2Et
O
Ot-Bu Ot-Bu
Ot-Bu
TIPSO
Me3SnOt-Bu
TIPSO
97%MeOCOCl, pyr.
electric eelacetylcholinesterase
Ph
O
Ph
NaH, Pd2(dba)3 (1%)PPh3 (15%), THF, rt 1:1 (91%)
displacement of allylic carbonatevia π-allyl Pd species
NaCNBH3, TiCl4 anti:syn >20:1
CH2Ot-Bu
NI
H
Felkin-Ahn
NN
O
4 steps 1. L-Selectride, PhNTf2, THF-78 °C → 0 °C
L-Selectride =
dba =
N-phenyltriflimide
2. Me6Sn2, Pd(Ph3P)4 (10%)LiCl, THF, 60 °C
conjugate reduction
lithium tri-sec-butylborohydrideLiB[CH(CH3)CH2CH3]3H
NO
vinylstannane
triazone-protectedortho-iodoanilinePd-catalyzed
carbonylative Stille
Overman, JACS 1993,115, 3966NMP =
N-methyl-2-pyrrolidinone
R2N
O
TIPSO
OtBu
Pd2(dba)3 (2.5%), Ph3As (22%)CO, LiCl, NMP, 70 °C
Triton B = N-benzyltrimethylammonium hydroxide
80%
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
26
NR2
HN
tBuO
HOR2N
O
TIPSO
OtBu
1. t-BuOOH, Triton B2. Ph3P=CH2, THF3. TBAF
Key aza-Cope/Mannich
rearrangement substrate
4. MsCl, i-Pr2NEt5. LiCl, DMF6. NH2COCF3, NaH, DMF7. NaH, PhH, 100 °C8. KOH, EtOH-H2O
43% over these 8 steps!!!
(CH2O)n, Na2SO4MeCN, 80 °C
N
Ot-Bu
ONR2
98% (crystalline !)
N
O
N
HO
H
strychninevia Wieland-Gumlich
aldehyde
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
27
The Martin RouteJACS 1996, 118, 9804
“biomimetic base-mediated rearrangement of corynantheoid skeletoninto strychnoid skeleton”
N
O
N
HO
HNH
N
MeO2C OR
NNH
OBnMeO2CH
H
NNH
OHMeO2CH
H
Cl
NN
OBnH
H
MeO2C
NNH
OH
HO
OBn
NNH H
O
OOBn
H
NNH
R = H (Overman's intermediate)R = Bn (Martin's intermediate, cannot deprotect!!!)
corinantheoidskeleton
OTMS
Hetero DA
+OBn
COCl+
vinilogous Mannich
6-membered ring from acyclic prec.with regio and stereocontrol!
H
SynthesisJACS 1996, 118, 9804
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
28
Epothilones
A. General
• Macrolides isolated from myxobacteria of the genus sorangium 16-membered macrocyclic polyketides featuring: methyl/hydroxyl triads (polyketide trademark) an aromatic thiazole ring (⇒ cysteine) an oxirane ring a gem-dimethyl group 7 stereogenic centers Multigram-scale supply from single batch fermentation! • Antitumor agents with antimitotic activity via stabilization of microtubules (Taxol-like activity!): broad activity against eukaryotic cells; epothilone B is twice as active as epothilone A epothilone B ⇒ apoptosis of mouse fibroblasts (L929) within three days at an IC50 dose of 2 ng/ml in vitro activity against breast and colon tumor cell epothilones and taxol probably occupy different but possibly overlapping binding sites on microtubules 1000 to 5000 times more active against multiple drug-resistant tumor cell lines 30 times more soluble in water
NB: the microtubule-stabilizing activity of the epothilones and taxol is shared by only one other naturalproduct ⇒ discodermolide
B. References
Höfle et al., Angew. Chem. IEE 1996, 35, 1567 (isolation, manuscript received on March 26)Danishefsky et al., Angew. Chem. IEE 1996, 35, 2801 (epothilone A, manuscript received on October 17)Danishefsky et al., Angew. Chem. IEE 1997, 36, 757 (epothilone B)Danishefsky et al., JACS 1997, 119, 10073 (the full story!)Nicolaou et al., Angew. Chem. IEE 1997, 36, 166 (epothilone A, manuscript received on November 25, 1996)Nicolaou et al., JACS 1997, 119, 7960 and 7974 (epothilones A and B, the full story!)Schinzer et al., Angew. Chem. IEE 1997, 36, 523 (epothilone A)Schinzer et al., Chem. Eur. J 1996, 2, 1477Wessjohann, Angew. Chem. IEE 1997, 36, 715 (highlights)
O
S
N
O
O
OH
R
OH O
epothilone A ⇒ R = Hepothilone B ⇒ R = Me
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
29
C. Analysis
O
S
N
O
O
OH
R
OH O
O
S
N
O
OH
OH O
R
Aldol
esterification
Wittig
Three major fragments:one thiazole unittwo aldol components
disconnectionorder vary
Epoxidation is the last step in all syntheses
Variations ⇒ disconnection strategies and tactics to synthesis each fragment, especially in the northern half!
Northern half
Southern half
Possible macrocyclization strategies:macrolactonizationmacroaldolizationring-closing olefin metathesis
NB: Danishefsky implemented them all!
The Danishefsky’s routeJACS 1997, 119, 10073
First Syntheses of Epothilones A and Bvia Suzuki Coupling and Macroaldolization
Retrosynthetic analysis
O
S
N
O
OH
OH O
R
OH
S
N
R
X
X
O
OP
OP
B-alkyl Suzuki
Xmacroaldolization
+
esterificationA
B
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
30
SynthesisA
+
OP
OPX
TBSO OTPSOMeOMe
BnO
OMe
OTMS
O
H
1. TiCl4, CH2Cl2, -78°C2. CSA, PhH, rt
O
O
OBn* ***
chelation-controlled facially selectivediene-aldehyde cyclocondensation
triad
JACS 1985, 107, 1256JACS 1987, 109, 862Aldrichimica Acta 1986, 19, 59
"dihydropyrone"
8 possible triads!
87%
L.a.
O
H
BnO
reactive conformer
Z ⇒ syn
attack at C=O from less hindered α-face
chelated Cram control of diastereofacial selectivity ⇒ anti Cram–Felkin product
ideal for the synthesis of polypropionate-based natural products, such as polyketides
O
O
OBn O
OH
OBn
H I
1. NIS, MeOH2. n-BU3SnH, AIBN cat.PhH, reflux3. Ph3SiCl, imidazole
O
OTPS
OBn
OMe
cyclopropane solvolysis
TBSO OTPSOMeOMe A
2 steps
6 steps
OH
S
N
R
X
B
OAc
S
N
R
I
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
31
O
S
N
O
OTBS
OTPS3. p-TsOH, aq. dioxane
R
O
O
S
N
O
OTBS
OTPS
R
OH
71%, R = H77%, R = Me
KHMDS, THF, -78°C
R = H ⇒ 6:1 (51%)R = Me ⇒ 2:1 (60%)
A2. "Pd(II)",
1. 9-BBN, THF, rt
O
oxidation-reduction sequence to epimerize undesired isomer
S
N
O
OTBS
R
OH
B
deprotection + Dess–Martin O
Suzuki
DMD
epothilone A ⇒ >16:1 (49%)epothilone B ⇒ >20:1 (97%)
non-enolizable aldehyde!
Suzuki Coupling and MacrolactonizationRetrosynthetic Analysis
O
S
N
O
OH
OH O
R
OH
S
N
R
X
OP
O
B-alkyl Suzuki
OP
+C
B
macrolactonization O
HO
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
32
Synthesis
TBSO OTPSOMeOMe
ATBSO O O
OTBS
OR
R = TBS
a more advanced intermediate already containing the C1–C2 acetyl moiety of epothilones
6 steps1 2
S
N OTBS
TBSO
B C+
R = H
OHO2C
1. Suzuki2. K2CO3, aq. MeOH
OHYamaguchi's conditions
2,4,6-trichlorobenzoyl chloride,TEA, DMAP, CH2Cl2, rt
O
S
N
O
OTBS
OR OR = TBS
macrolactonization
epothilone A88%
intermediate in macroaldolization route!
NB: Danishefsky and his co-workers also developped a route to epothilones based on ring-closing olefinmetathesis to achive macrocyclization (JACS 1997, 119, 10073).
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
33
The Nicolaou’s routeJACS 1997, 119, 7960 and 7974
Macrolactonization-Based Strategy
Retrosynthetic Analysis
O
S
N
O
OH
OH O
R
OH
S
N
O
OP
OP O
R
HO
OP
S
NO OP O
R
HOO
Aldol
macrolactonization
OP
S
N
asymmetric allylboration
R
OP
+
PPh3IEnders alkylation
Wittig
O
a phosphonium salt(ylide)
+OP
S
N
O
asymmetric allylboration
Synthesis
Thiazole unit:
1. (+)-Ipc2B(allyl)
2. TBSCl, imidazole OTBS
S
N
S
N O Et2O, -100°C
asymmetric allylboration 1. OsO42. Pb(OAc)43. NaBH4
OTBS
S
N
OH 1. I2, Ph3P2. Ph3P
OTBS
S
N
PPh3I
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
34
(+)-Diisopinocampheyallylborane
OH
S
N
S
N O
B
O
BH
R
BO
H
R
Et2O, -100°C2
JACS 1957, 79, 1920
favored complex
H. C. Brown's Chemistrye.g., JACS 1986, 108, 5919
1.
2. TBSCl, imidazole
allyl transfer
asymmetric allylboration
Zimmerman–Traxler TS
OR
96%, ee > 97%
Aldehyde/ketone Unit:
Enders alkylation
H
NN OMe
Enders' chiral hydrazoneform SAMP = (S)-1-amino-2-(methoxymethyl)pyrrolidine
LDA, I(CH2)4OBN
H
NN
OMe
OBn
Tetrahedron 1995, 51, 10699
TBSOO
For epothilone A
1. MeMgBr2. TPAP, NMO TBSO O
For epothilone B
NMO = 4-methylmorpholine N-oxideO
NO
TPAP = tetrapropylammonium perruthenate (CH3CH2CH2CH2)4NRuO4
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
35
HO2CTBSO O
OTBS
S
N R
OTBS
PPh3I
O
NaHMDS
OTBS
S
N
R
OTBS
R = H : THF, 0°C, 15 min ⇒ 77% (Z:E = 9:1)R = Me : THF, - 20°C, 12h ⇒ 73% (Z:E = 1:1)
1. CSA (selective desilylation of primary hydroxyl group2. SO3•Pyr (oxidation)
OTBS
S
N
R
O
LDA (3 equiv), THF, -78°CTBSO
S
N
R
OH
OTBSOHO2C
+ diastereomer (1:1)
sodium hexamethyldisilazaneTMS
NTMS
Na
HO
S
N
R
OTBS
OTBSOHO2C
1. Yamaguchi macrolactonization2. desilylation
CF3
O O3.epothilone A (α:β epoxide = 2:1)epothilone B (α:β epoxide = 1:1)
The Olefin Metathesis Approach to Epothilone A
Retrosynthetic Analysis
O
S
N
O
OH
OP O
O
S
N
O
OH
OP O
olefin metathesis
esterification
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
36
OH
S
N
O
OH
OP O
HO
O OP O
HOO
OP O O O
+
Wittig
+
Aldolasymmetric allylboration
asymmetric allylboration
Synthesis
S NO O
O
S NO O
OO
HO2CTBSO O
HO2CTBSO O
HO2C
OH
TBSO O
OHOH
S
N
1. LAH2. TPAP, NMONaHMDS, C5H9I
Oppolzer's acylated sultam chiral auxiliaryTetrahedron Lett. 1989, 30, 5603
O
LDA
S
N +
O
OH
OP OEDC, DMAP
3:2
+ diastereomer(31%)
EDC = 1-ethyl-3-((dimethylamino)propyl)carbodiimide HCl52% from keto acid
A
A
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
37
O
S
N
O
OH
OP O
CHPhClCl
PCy3
PCy3
O
S
N
O
OH
OP O
CHPh RuPh
RuRu
Ph
O
S
N
O
OH
OP O
Ru
ring-closing olefin metathesis
AAIEE 1995, 34, 2039JACS 1996, 118, 6634JACS 1996, 118, 100ACR 1995, 28, 446
Grubbs' chemistry
[2 + 2]Ru
Z (46%)
+ E isomer (39%)
remove
P = TBSP = TBS
P = TBS
1. TFA2. methyl(trifluoromethyl)dioxirane epothilone A
[2 + 2]
The Schinzer’s routeAngew. Chem. Int. Ed. Engl. 1997, 36, 523
Double Diastereodifferentiating Aldol and Ring-closing Metathesis
Retrosynthetic Analysis
O
S
N
O
OH
OH O
OH
S
N
O O O
Oolefin metathesis
esterification
Aldol
A
B
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
38
Synthesis
POS
N
OH OH O OTBS BIpc2 OTBS
OH
MgBr
TBSO OH
TBSOO
OTBS
OEtOEt S
N OH
OTBS
1.2. Sharpless resolution
B
1. NaH, TBSCl2. Swern
1. Me2CO, H+, CuSO42. NaIO4, OsO4 cat.3. EtMgBr4. TPAP, NMO
1. TBSCl, imidazole2. ozonolysis
BuLi, THF
1.
1. Dess–Martin2. Wittig3. TBAF
A
2. HF, MeCN, a few splinters of glass(catalysis by H2SiF6)
O O O OO O O OH
TBSO O OTBSHO2C
O
NO
OO
HO
+B
Anti–Cram Aldol
LDA, THF, -78°C
oxazolidinone-based Evans' chiral auxiliary
How would you make this chiral aldehyde?
This a case of double diasteredifferentitionoverruling Cram selectivity (mismatched chiral pair)
+ NaHMDS, MeI
hept-6-enoic acid
asymmetric alkylation
70%
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
39
TBSO O OTBSHO2C
OH
S
N
A
+DCC, DMAP
O
S
N
O
OTBS
OP O
P = TBS
80% via ring-closing metathesisepothilone A
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
40
Dynemicin A
A. General
• Enediyne isolated from fermentation broth ofMicromonospora chersina(Konishi, 1989)
• Antitumor antibiotichigh levels of invitro antitumor activity comparable to those of two other enediyne natural products, calicheamicin andesperamicin (show overhead!)
• Only members of the natural enediynes to possess an anthraquinone, astructural feature also common to the anthracycline antibiotics.
No carbohydrate moiety (affect DNA binding properties)Strained epoxy (Z)-enediyne bridge across bicyclic ring system
• Bergman cycloaromatization of enediynes:H
H
H
H
ΔBergman cyclization
H
H
H
H
highly unstable1,4-dehydrobenzene
a biradical species!
Natural enediynes are thought to display their antitumor activity via Bergman cycloaromatization of theirenediyne unit; the resulting biradical species being capable of inducing double-stranded DNA cleavage! Thiswas a novel biomechanism of action for antitumor agents!
• Biomechanism of action of dynemicin A:1) the anthraquinone unit functions as a DNA intercalating agent (i.e., delivery system), and as the initial site of reduction in the activation of dynemicin A.2) base-mediated epoxide opening to a quinone methide followed by trapping with a bionucleophile (i.e., triggering device: sp2 → sp3) causes the two triple bonds of the otherwise inactive enediyne unit (i.e., warhead) to come close enough together to undergo Bergman cyclization.3) Bergman cyclization: biradical product abstracts DNA hydrogen ⇒ DNA cleavage!
HNOH
OH
O
O OH
OOMe
CO2H bioreduction
3.54 Å
HNOH
OH
O
OH OH
OOMe
CO2HHB
HNOH
OH
O
OH OH
HOOMe
CO2H
a quinone methide!
BioNu
HNOH
OH
OH
OH OH
HOOMe
CO2H
Nu
3.17 Å
Bergman!
HNOH
OH
O
O OH
OOMe
CO2H
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
41
B. References
Hoffmann, American Scientist 1993, 81, 324 (of what use enediynes)Bergman, Acc. Chem. Res. 1973, 6, 25 (Bergman cyclization)Konishi et al., J. Antibiot. 1989, 42, 1449 (isolation)Schreiber et al., JACS 1993, 115, 10378Myers, A. G.et al., JACS 1997, 119, 6072, and Chem. & Biol. 1995, 2, 33Danishefsky, JACS 1996, 118, 9509
NB: For a non radical but polar cycloaromatization alternative pathway to biological activity, see:Magnus et al., JACS 1993, 115, 12627.
C. Retrosynthetic Analysis and Synthesis
The Myers’s routeJACS 1997, 119, 6072
Chem. & Biol. 1995, 2, 33
Highly Convergent Route Allowing for the Synthesis of Dynemicin Analogs
Retrosynthetic Analysis
isobenzofuran 4π component
F
F
+
+
" "
a stable quinone imineas 2π component
HNOH
OH
O
O OH
OOMe
CO2HN
O
OOMe
CO2ROH
OH
O
OH
OH
HNA
D
O
O OH
O
N
O
OA
D
O
X
Y
B
C
analogs
loci of chirality!
B
CE
[4π + 2π]
angucycline chemistry
E
NB: reactive anthraquinone unit is introduced at the later stage of the synthesis! Synthetic problem is reducedto the preparation of the quinone imine Diels-Alder component ⇒ easy access to various analogs!
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
42
N
O
OOMe
CO2RN
OTBS
H
O
O
OH
OMeOMe
oxidation to quinone imineFGI within A ring
A
HN
OMe
O
OMe
a quinolone
down to one stereogenic center !need syn addition of (Z)-enediyne unit!
B(OH)2NH
OMe
O
O
+
Suzuki
TfO
O
OMe
O
Synthesis
O
O OO
OEtO
O
O O500 g scale (94 %)2. recrystallization
(benzene)
1.
O
O
O OMeMeO
NHBOC
B(OH)2
36 %
KO-t-Bu, t-BuOH, reflux
Enantioselective Synthesis of Quinone Imine
Michael-Dieckman
A. G. Myers, M. E. Fraley, N. J. TomJACS, 1994, 116, 11556-11557
1. NaH, (TfO)2O, - 78 °C, Et2O2. Pd(PPh3)4, Na2CO3dioxane, reflux
dry MeOH, CSA
regioselectively in 71 %
rt, 12 h
Suzuki
O
O
OMeMeO
NHBOC86 %
HN
O
OMe
OMe
180 °C30 min
84 %4-chlorophenol(weakly acidic solvent)
desired quinolone!
removal BOC groupwithout cleaving methyl enol ether,and lactamization
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
43
N
OMe
OMe
OMe
OH
N
OMe
OTBS
OMe
OH
N
OMe
OTBS
OMe
OH
1. (TfO)2, 2,6-di-t-BuPyr, CH2Cl2 (triflate in 86 %)2. m-CPBA, MeOH, reflux (α alcohol in 67 %) 3. formic acid, Et3N, Pd(PPh3)4, dioxane, reflux(reductive cleavage of triflate to quinoline in 97 %)
TBS
Me-TMS exchange
O
O
EtMgBr, 0°C → reflux, THF
9 g scale89 %
> 25:1
1. m-CPBA (88 %)2. TBAF (100 %)3. TBSCl, imidazole (93 %)4. Swern secondary alcohol (92 %)5. KHMDS (deprotonate acetylide),CeCl3
HN
O
OMe
OMe TL 1986, 27, 5541
will control syn adition of acetylide
3 steps
would require harshconditions for removal
65 %
NTBSO
H
O
H
OMe
OMe
Me
H
MgX
half-chair
H
magnesium chelation with methoxyl oxygenscauses the alkoxide to adopt a half-chair conformation in which the methyl group is placedin a pseudoequatorial position!
axial mode of entry for the acetylide!
cis
TBS
H
EtMgBr, -78°C → 0°C, THFO
O Cl
Yamaguchi reaction
TL 1983, 24, 1801
N
OTBS
O
OHOMeOMe
O
O
94 %
1. p-TsOH.H2O, acetone (hydrolyse ketal in 83 %)2. 1,1'-thiocarbonyl-diimidazole, DMAP (85 %) N
OTBS
O
O
O
OO
S
a thionocarbonate
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
44
1. 3HF.Et3N (91%)2. TfOSi(i-Pr)3, imidazole (69 %)
89 %
Bu3SnH, cat. Pd(PPh3)2Cl2, wet CH2Cl2
49 %
60 %
2. KOtBu, Et2O, then MeOTf, toluene
3. iodosobenzene, MeOH(oxidize phenol, MeOH trapping)
cleave Alloc, eliminate MeOH!
N
OTBS
O
O
O
OO
S
N
OTBS
O
O
O
OH
N
OTBS
O
O
O
OMeH
CO2HN
O
O
O
O
OMeH
CO2Si(i-Pr)3
MeO
N
O
OOMe
H
CO2R
Bu3SnH, AIBN
97 %
1. CO2, MgBr2, Et3N, acetonitrile(α-keto acid formation as per Rathke))
O
OHN(TMS)2, cat, H2SO4
N
O
O
quinone imine
isobenzofuran
OH
OH
O
OTMSO
OTMS H
O
OTMSTMSO
OTMS
CO2R
OMe
THF, reflux, 30 min
oxygenated phthalide(all oxygens required to access
desired anthraquinone are in place !)
100 %
N
O
OOMe
OTMS
TMSO
O
KN(TMS)2, THF
Base
+
TMSO
TMSCl trappingof enolate
R = Si(i-Pr)3
55 °C
exo
CO2R
dienophile
diene
Diels-Alder
70-80%
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
45
3HF•Et3N
(+)-dynemicin A53 %
F
N
O
OCO2Si(i-Pr)3
OMe
OTMS
TMSO
O
HNOH
OH
O
O OH
OOMe
CO2H
OSiMe3
MnO2
THF, rt, 9 min
The Schreiber’s routeJACS 1993, 115, 10378
Regioselective Friedel–Crafts CouplingRetrosynthetic Analysis
HNOMe
OMe
O
O OMe
OOMe
CO2Me
OMe
OMe
O
O
Br
N
OMe
OH
CO2MeO
OMeO2C
N
OMe
O
MeO
CO2H
N
OMe
O
MeO
H
O
H
O+
retro
N
OMe
many steps!
1
2 OP
OH
Friedel–Crafts
FGI retro
N Br
OMe
Diels-Alder
weaknessof tactic
Stille
3-alkenylquinoline 3-alkenyl-6-methoxyquinoline
H
N
OMe
OMe
CO2Me
MeO OMe
OO
O
OMeO2C
Synthesis
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
46
1.
N
OMe
O
MeO
H
O
Yamaguchi reaction
early!
H
H O
N
OMe
OTBS SiMe2thexyl
MgBrCl
O
OMe
N
OMe
OH
O
MeO
H
Br
O
OH
2. TBAF
first stereogenic
center(axial)
60%
!?
JACS 1990, 112, 7410
50%
DBUepimerization
N
OMe
OH
O
MeO
Johnson, Chem. Rev. 1968, 375Allylic A1,3 strain!
CO2H
Pd(PPh3)4, CuI
Cl Cl
Cl O
Cl
ideal for subsequentcyclization!
1.
2. LiOH DMAP, toluene, rt
Yamaguchi macrolactonization conditions
N
OMe
O
O
MeO
O
N
OMe
O
MeO
H
O
H
H O
or PyBroP, Et3N
involve benzylic oxidation with CAN to oxygenate at C-11
N
OMe
O
O
OH
O
H
H O
OBzbase-labile
via β-elimination
113
4
need to reposition C3–C4 olefin,while controlling stereo at C4
JACS 1992, 114, 5898
direct hydride introdution at C4 withconcommitant deoxygenation at C11 of the allylic alcohol moiety to repositionthe olefin with desired stereochemistry at C4did not work ⇒ allylic diazene rearrangement!
1. MeAlCl2, CH2Cl22. MesNHNH2
N
OMe
O
RO
N
O
H
H ON H
stereoselectivesigmatropic [1,5] shift
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
47
N
OMe
O
RO O
H
H O
11 steps N
OMe
O
O
butyrolactone vinylogous carbonate
CO2Me
OH
OMe
OMe
O
O
Br
Friedel–Crafts
1. anhydrous AgOTf, 1 min 2. Me2SO4, K2CO3
N
OMe
OMe
CO2Me
MeO OMe
OO
O
OMeO2C
MeO2C
H 57% (1:1)
CO2HNOMe
OMe OMe
OMe
CO2Me
MeAlCl2, Et3SiHO
OR
NOMe
OMe OMe
OMe
CO2MeO
OR
1. SOCl22. TMSOTf3. DDQ
51%OH
O1. m-CPBA (epoxidation)2. DBU (removal of carbamate via β-elimination)3. CAN (oxidation to target)
HNOMe
OMe
O
O OMe
OOMe
CO2Me
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
48
The Danishefsky’s routeJACS 1996, 118, 9509
Stille-mediated Ethylene Interpolation
Retrosynthetic Analysis
HNOH
OH
O
O OH
OOMe
CO2H
ZZHN
OP
X
Y
W W
V
U
TT
ZZN
OP
X
Y
V
U
ZZN
OP
V
U WintramolecularReissert coupling
intermolecularethylene interpolation
2 4
7
stereochemically more demandingsince need to control cis relationships between C2, C4 and C7!
need to control cis stereochemistryat C4 and C7, cis stereochemistry at C2 would be fixed by cyclization
unsuccessful?
successful!
Popp, Chem. Heterocycl. Comp. 1982, 32, 353
Yamaguchi reaction-like
Synthesis
OCHO
OMe
ZnCl2, CH2Cl2, rt
endo-selectiveDiels–Alder O
OMe
H
H CHO60%
hemiacetal formationpossible since reactive centersare both on the α-face ⇒ would not be possible with exo-cycloadduct!
racemate!
CAN
O
O
H
O
HO
47
control of C4–C7 cis relatioship!
4
7
1. NH4OAc, AcOH, 100 °C2. TBSCl, imidazole
90%
N
OTBSOTBS
desired quinoline!
87%
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
49
N
OTBSOTBS
N
OTBSOTBS
OH
OH
N
TBSO
OTBSH
HO
O
W
W
N
OTBSOTBS
O
O
PhPh BrMg TIPS
O
O
Cl
N
OTBSOTBS
O
O
PhPh
O
O
TIPS
N
OTBS
O
O
PhPh
O
O
TIPS
Danishefsky's solution fi render the α-face even more hindered than the β-face:
TMS O
O
N
2
OTBS
undesired attack sterically prevented
OH
OH
80% (9:1)
TEOC
I
1. Ph2C(OMe)2, H2SO4, CH2Cl22. TBSCl, imidazole
83%
I
THF, -20°C
difficult task of the ethylene interpolation route: an ethynyl group must be introduced at C2 cis to both C4 and C7, that is onto the already sterically hindered β-face
Me3Sn SnMe3
OsO4, NMO
90%
47
N
OTBS
TEOC
DMF, 75 oC
O
O
2
5% Pd(PPh3)4
OH
OH
1. conc. HCl, THF2. Swern oxidation3. Corey–Fuchs (TL 1972, 13, 3769)
81%
TEOC =
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
50
N
O
OCO2MOM
OMe
OMOM
MOMO
O
O
O
LHMDSN
O
OCO2MOM
OMe
OMOM
MOMO O
3 steps
(rac)-dynemicin A
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
51
Dysidiolide
A. General
• sesterterpene (i.e., C25) γ-hydroxybutenolide isolated from the marine sponge Dysidea etheria de Laubenfels • Antimitotic activity; it is the only known natural inhibitor of cdc25A, a signaling
protein phosphatase known to activate the G2/M transition of the cell cycle:
inhibition of cdc25A ⇒ cell cycle arrestation ⇒ cell division prevention⇒ applications for cancer treatment
micromolar activity against A-549 human lung carcinoma and P388murine leukemia cancer cells
Is this cancer cell growth inhibition due to the inhibition of cdc25A by dysidiolide?
• Unusual rearranged carbon skeleton with two fused six-membered rings possessing four stereogeniccenters, plus two functionalized appendages.
B. References
Isolation: Gunasekera, Clardy et al., JACS, 1996, 118, 8759First synthesis: E.J. Corey and Roberts, JACS, 1997, 119, 12425 (December 24) (-)-dysidiolideSecond synthesis: Boukouvalas et al., JOC, 1998, 63, 228 (January 8) ent-dysidiolideThird synthesis: Danishefsky et al., JACS, 1998, 120, 1615 (February 5) rac-dysidiolide
C. Retrosynthetic Analysis and Synthesis
H
OOHO
HO (-)-dysidiolide
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
52
H
OH
O
OO
O
O
O
Corey Boukouvalas
O
Hagiwara, JOC, 1988, 53, 2308
H
Danishefsky
+
asymmetric Robinson-like cyclization
OBn
+CHO
EtO2C
TIPSO
OH
+O
O
OTBDPS
different strategy same strategy, different tactics
The Corey’s routeJACS, 1997, 119, 12425
Biomimetic cationic rearrangementSynthesis
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
53
O
OO
O
OO
O
OOTMS
HO
O
O
Li-NH3, isopreneallyl bromide
82%single diastereomer (more stable trans-decalin)Hagiwara, Perkin 1 1995, 757
1. LDA (2 equiv.), HMPA-THF2. PhSSPh3. m-CPBA
TMS
4. (MeO)3P, PhH, reflux5. TMSLi, HMPA-Et2O
H
HTBDPSO
O
TMS
7 steps
M
did not work!
1. allylMgBr, Et2O, -78°C → rt (stereospecific, equatorial attack!)2. Hydroboration–oxidation (→ primary-tertiary diol)3. TBSCl, DMAP
HTBDPSO
TMS91 %
OH
OTBS
BF3 gas, CH2Cl2, -78°C
Key cationic rearrangement step
HTBDPSO
TMS
OTBS
(σ → p)π
β−hyperconjudation effect stabilizing CHOBF3 HOBF2 + F
[1,2]
PPTS (1 equiv.), EtOHselective removal of TBS
H
TBDPSO
H
HO
1. I2, Ph3P, imidazole2. Br
, t-BuLi, CuI
iodine displaced by in situ generated vinyl cuprate
H
TBDPSO
H
1. TBAF2. Dess–Martin
OI
O
AcO
OAcOAc
periodinane
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
54
H
OH
1.O
Li, THF
2. O2, hν, rose bengali-Pr2NEt, CH2Cl2, -78°C
(–)-dysidiolide
Photochemical oxidation of the furan moiety
O+ O O
singlet (excited state)
[4 + 2]O
O OH
Base
O OO OOO H
Kerman and Faulkner, JOC 1988, 53, 2773
O
ClClCl
Cl CO2NaI
O
I
NaOII
The Boukouvalas’s routeJOC, 1998, 63, 228
Diels-Alder cycloadditionSynthesis
OH
OBn
CHO
EtO2C
TIPSO
+
OBn
OCO2Me
both enantiomers are commercially availabled'Angelo et al., Tetrahedron Asym. 1992, 3, 459
1. LAH, THF2. NaH, BnBr, THF3. TPAP, NMO, 4 Å sieves
O
OBn1. CH2=CHMgBr, CeCl32. CuSO4, PhH, reflux (dehydration)
diene
BA
A
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
55
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
56
OTIPS
CHO
TIPSO
EtO2C
BnO
CO2EtO
H
OTIPS
H
BnO
CO2EtO
H
OTIPS
H
H
OBn
CHO
OTIPS
EtO2C
H
OBn
EtO2CCHO
H
TIPSO
OBn
EtO2CCHO
TIPSO
H
CO2EtO
OTIPS
H
OBn
dienophile
1. EtMgBr, THF, ClCO2Et2. CH2=CHLi, CuI, THF
H
CO2EtO
A
OTIPS
+ B
B
H
3 variable stereogenic centers⇒ 8 possible stereoadducts! only 2 observed!
OBn
3. O3, MeOH, CH2Cl2, then Me2S
BnO
+
H
1:2.3
TIPSO
Diels-Alder
EtO2C CHO
EtAlCl2CH2Cl2, -94°C
diastereofacial selectivitydieneophile approach fromless hindered diene face!
role of EtAlCl2 ⇒ only activation!?
endo
endo
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
57
OBn
TIPSO
LiEt3BH
OH
HO
1. MeLi, (Me2N)2PCl (Ireland et al., JACS 1972, 94, 5098 2. Li, EtNH2 (Benkeser reduction with debenzylation)
O OH
TIPSO
via diphosphoramidate
CHO
4 steps
85%OTIPSO
Ti(Oi-Pr)3
, Et2O, -78°C
OHO
TIPSO+ epimer (14%)
58%
1. DMD, acetone2. Amberlyst-15/H2O(+)-dysidiolide
longest linear sequence = 15 steps5.26% overall yield
The Danishefsky’s routeJACS, 1998, 120, 1615
Dioxolenium-mediated Diels-Alder Reaction
NB: most concise route !Synthesis
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
58
+
OH
O
O
OTBDPSA B
an allylic acetal as activated dienophilevia dioxolenium ion !
Gassman's chemistry:see refs in JACS, 1998, 120, 1615
diene
LiO I
DME, HMPA
O
a racemate!49%
1. Tf2O, base2. CH2=CHSnBu3, Pd(PPh3)4, LiCl
StilleA
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
59
dienophile
O
O
OTBDPS
BO
O 1. Me2CuLi, ICH2CO2Et2. reduction, silylation
TBDPSO
O
O
Diels-Alder
Lewis acid mediation
TBDPSO
O OTMS
TMSOTf Lewis acid-activateddienophile ⇒ vinyl oxolenium ion
secondary orbital interactions between oxolenium LUMO and diene HOMO ⇒ endo
dienophile approaches from lesshindered diene α-face ⇒ diastereofacialcontrol !
β-face is more hindered ⇒ clever usage of the differing steric demand of fully appended precursor
CH2Cl2, -90°C
TBDPSO OO
1. Montmorillonite K102. Wolff-Kishner reduction3. TPAP, NMO (Aldehyde!)4. 3-lithiofuran
OHO
+ epimerHow to epimerize ?1. oxidation, reduction2. Mitsunobu, reduction
singlet O2
OHO
O
HO
Bordeaux I University Stéphane Quideau, Ph.D.Centre de Recherche en Chimie Moléculaire Laboratoire de Chimie des Substances végétales
60