j. h.-j. k. organic synthesis highlights€¦ · library of congress card no.: 90-13003 british...

J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig

Organic Synthesis Highlights

VCH Weinheim - New York - Base1 - Cambridge

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OVCH Verlagsgesellschaft mbH, D-6940 Weinheim (Federal Republic of Germany), 1991

Distribution: VCH, P. 0. Box 101161, D-6940 Weinheim (Federal Republic of Germany) Switzerland: VCH, P. 0. Box, CH-4020 Basel (Switzerland) United Kingdom and Ireland: VCH (UK) Ltd., 8 Wellington Court, Cambridge CB1 1HZ (England) USA and Canada: VCH, Suite 909,220 East 23rd Street, New York, NY 10010-4606 (USA)

ISBN 3-527-27955-5 (VCH, Weinheim) ISBN 0-89573-918-6 (VCH, New York)



VCH Weinheim - New York - Base1 - Cambridge

Prof. Dr. Johann Mulzer Institut fiir Organ. Chemie Fachbereich Chemie Institut fiir Organ. Chemie der Freien Universitat der Universitlt/Gesamthochschule UniversitatsstraBe 1 TakustraBe 3 Warburger StraBe 100 D-4000 Diisseldorf 1 D-1000 Berlin 33 D-4790 Paderborn

Prof. Dr. Hans-Josef Altenbach Prof. Dr. Manfred Braun

Prof. Dr. Karsten Krohn Institut fur Organ. Chemie der TU Braunschweig PetersenstraBe 22 Hagenring 30 D-6100 Darmstadt D-3300 Braunschweig

Prof. Dr. Hans-Ulrich Reissig Institut fur Organ. Chemie

This book was carefully produced. Nevertheless, authors and publisher do not warrant the information contained therein to be free oferrors. Readersare advised to keep in mind that statements, data, illustrations, proceduraldetailsor other items may inadvertently be inaccurate.

Published jointly by VCH Verlagsgesellschaft mhH, Weinheim (Federal Republic of Germanv)

_ I

VCH Publishers, Inc., New York, NY (USA)

Editorial Management: Karin von der Saal Production Manager: Elke Littmann

Cover illustration: A starburst dendrimer

Library of Congress Card No.: 90-13003

British Library Cataloguing-in-Publication Data: Organic synthesis highlights. 1. Organic compounds. Synthesis I. Mulzer, J. 547.2 ISBN 3-527-27955-5

Deutsche Bihliothek Cataloguing-in-Publication Data: Organic synthesis highlights I J. Mulzer ... - Weinheim ; New York ; Basel ; Cambridge : VCH, 1990 ISBN 3-527-27955-5 (Weinheim . . .) ISBN 0-89573-918-6 (New York) NE: Mulzer, Johann

OVCH Verlagsgesellschaft mbH, D-6940 Weinheim (Federal Republic of Germany), 1991 Printed on acid-free paper. All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form - by photoprinting, microfilm, or any other means - nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law. Composition and printing: Krebs-Gehlen Druckerei, D-6944 Hemsbach. Bookbinding: J. Schlffer GmbH & Co. KG, D-6718 Grunstadt. Printed in the Federal Republic of Germany

Preface

Organic synthesis is as highly developed, ver- satile, and interdisciplinary branch of natural science. It allows the preparation of complex molecules and new materials with unexpected properties. Based on the accomplishments of modern analytical techniques (spectroscopy, X- ray analysis, chromatography) and on the knowledge of quantum chemistry, the mecha- nistic understanding of organic reactions has been immensely enlarged and may now be used in the planning of more efficient synthetic routes. Novel, highly selective reagents appear every month. New reactions or modifications of old reactions have been devised to meet the ever-increasing demands of selectivity in modern synthesis.

“Organic Synthesis Highlights” provides an overview of the rapid progress, the trends, and the accomplishments of synthetic organic chemistry over the past five years. It was written by five young authors, who are all active re- searchers in different fields of organic chemistry. “Organic Synthesis Highlights” in not another textbook on organic chemistry. It addresses university teachers, research chemists in indus- try, and advanced students. Instead of attempt- ing to cover the entire subject in full-blown de- tail, its essay-like approach gives the reader an impression of the competitive atmosphere, the creativity, and resourcefulness which is so char- acteristic of organic synthesis today.

The book contains 49 articles on almost every aspect of modern organic synthesis. In the first part, methodology, reagents, and reactions are described, especially with respect to their chemo-, regio-, and stereoselectivity potential. Particular emphasis has been laid on the rap- idly developing organometallic and biooriented procedures. Wherever necessary, mechanisms are discussed for a better understanding of the reaction. In the second part, this knowledge is applied to the synthesis of target compounds, mostly natural products with remarkable phys- iological properties such as pheromones, alka- loids, prostaglandins, and steroids. Frequent use is made of retrosynthetic analysis to show how a multi-step synthesis may be planned to avoid inefficient bond connections and isomeric mixtures. The syntheses are discussed with the aid of concise flowcharts aiming at the principal understanding of the sequence and leaving the details to the more than 1000 references which consider even the most recent literature.

It is the hope of the authors that this volume might be helpful in many respects: for getting a quick introduction to a new research area, for preparing seminars, lectures, or examinations, for getting a hint of how to solve a specific problem in synthesis, or just for having fun with good new chemistry.

Berlin, September 1990 J. Mulzer

Contents

Part I. Methods, Reagents and Mechanisms

A. Various Aspects of Stereodifferentiating Addition Reactions

Cram’s Rule: Theme and Variations ................................................... 3

Stereoselective Reactions of Cyclic Enolates ............................................

Chiral Sulfoxides in the Synthesis of Enantiomerically Pure Compounds . . . . . . . . . . . . . . . .

Chiral Cyclic Acetals in Synthesis ......................................................

Syntheses with Aliphatic Nitro Compounds ............................................

Boron: Reagents for Stereoselective Syntheses ..........................................

a-Hydroxylation of Carbonyl Compounds .............................................

Electrophilic Aminations .............................................................. 45

Asymmetric Induction in Diels-Alder Reactions ..................................

Chiral Lewis Acids .................................................................... 66

C-C Bond-Forming Reactions in Aqueous Medium ...................................

Natural Product Synthesis via 1,3;Dipolar Cycloadditions ..............................

J. Mulzer

9 K. Krohn

14 K, Krohn

19 H.-J. Altenbach

25 M. Braun

33 M. Braun

40 H.- U. Reissig

K. Krohn

K. Krohn

H.-J. Altenbach

71 H.- U. Reissig

77 J. Mulzer

VIII Contents

[4 + 11 and [3 + 21 Cycloadditions in the Synthesis of Cyclopentanoids . . . . . . . . . . . . . . . . .

Recent Applications of the Paterno-Buchi Reaction .....................................

Diastereoselective Claisen Rearrangements .............................................

Ester Enolate Claisen Rearrangements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

96 K. Krohn

105 M . Braun

11 1 H.-J. Altenbach

116 H.-J. Altenbach

B. Cyclization Reactions

The Weiss Reaction . . . . . . . . . . . . . . . . . . . .................... . . . . . . . . . . . . . . . I21

Radical Reactions for Carbon-Carbon Bond Formation . . . . . . . . . .................... 126

Cyclization of Allyl- and Vinylsilanes ....................................... . . . . . 131

Nazarov and Pauson-Khand Reactions ............................... . . . . . . . . . . . . . 137

Polyepoxide Cyclizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145

Syntheses of Macrocyclic Ethers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H.-J. Altenbach Halolactonization: The Career of a Reaction . . . . . ......................... J. Mulzer

H.- U. Reissig

M . Braun

K. Krohn

K. Krohn

H.-J. Altenbach

151

C. Organotransition Metals in Synthesis

New Aromatic Substitution Methods .................................................. M. Braun

Palladium-Catalyzed Arylation and Vinylation of Olefins ...............................

Regio- and Stereoselective Aryl Coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Benzannulation Reactions Employing Fischer Carbene Complexes ......................

Methylenations with Tebbe-Grubbs Reagents ..........................................

167

174 H.- U. Reissig

181 H.-J. Altenbach

186 H.- U. Reissig

192 H.-U. Reissig

Contents IX

D. Electrochemistry in Selective Synthesis

Anodic Oxidation and Amidoalkylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 H.- U. Reissig

E. Bio-oriented Methodology

Enzymes in Organic Synthesis, I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Enzymes in Organic Synthesis, I1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Enzyme Chemistry - Valuable New Applications ......................................

Biomimetic Natural Product Syntheses ................................................

207 J. Mulzer

216 J. Mulzer

224 H.-J. Altenbach

232 M. Braun

F. Synthesis with Ex-Chiral-Pool Starting Materials

(R)- and (S)-2,3-Isopropylidene Glyceraldehyde -

J. Mulzer “Unbiased” Chiral Starting Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chiral Building Blocks from Carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

243

251 K. Krohn

Part 11. Applications in Total Synthesis

A. Synthesis of Classes of Natural Products

Some Recent Highlights From Alkaloid Synthesis . . . ........................... 263 K. Krohn

Synthesis of 0-Glycosides . . ............................. ........................ 277 K. Krohn

Cembranoid Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 H.-J. Altenbach

Optically Active Glycerol Derivatives ................................. 292 H.-J. Altenbach

300 Asymmetric Syntheses of a-Amino Acids ............................................... H.-J. Altenbach

X Contents

B. Synthesis of Individual Natural Products

Compactin and Mevinolin . . . . . . . ......... ................................ 309 M. Braun

The Coriolin Story, or The Thirteen-Fold Way . . . . . . . . . . . . . . . 323 J. Mulzer

Fr ontalin ................................. ..................................... 335

Milbemycin /j3 ......................... ......................................... 344 M. Braun

H.- U. Reissig

Daunosamine . . . . . . . . . . . . . . . . . . . . . . . . . . ........................................... 351 M. Braun

Two Strategies, One Target: Swainsonine .................................. 359

Syntheses of Statine ....................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365 H.- U. Reissig

H.-J. Altenbach

C. Syntheses of Non-Natural Target Compounds

Fenestranes - A Look at “Structural Pathologies” 371

“Starburst Dendrimers” and “Arborols” ............................................... 378

.................................... K. Krohn

K. Krohn

Author Index .......................................................................... 385

Subject Index.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391

Abbreviations

9-BBN Bn = Bzl Bz DEAD DIBAH = DIBAL DHP DME DMF DMAP DMSO DBN DBU BOC BuLi LAH LDA MEM MOM MsCl MCPBA = mCPBA HMPA = HMPT NBS PCC PDC Phth PPA PPTS TBDMS TBDPS TMEDA TMM TMS Ts THP

9-Bora-bicyclo[3.3.1]nonane Benzyl Benzoyl Diethyl-azo-dicarboxylate Diisobutyl-aluminium-hydride Dihydropyrane Dimethoxy-ethane Dimethylformamide 4-N,N-Dimethylaminopyridine Dimethylsulfoxide 1,5-Diaza-bicyclo[4.3.O]nonene-5 1,5-Diaza-bicyclo[5.4.O]undecylene-5 tert-Butyloxy-carbonyl n-Butyllithium Lithiumaluminiumhydride Lithiumdiisopropylamide 2-Methoxyethoxymethyl Methoxy-methyl Methanesulfonylchloride m-Chloroperbenzoic acid Hexamethylphosphoric acid triamide N-Bromosuccinimide Pyridiniumchlorochromate Pyridinium-dichromate Phthaloyl Polyphosphoric acid Pyridinium-p-tosylate ter-Butyldimethylsilyl tert-Butyldiphenylsilyl Tetramethyl-ethylene-diamine Trimethylene methane Trimethylsilyl Tosyl Tetrahydropyranyl

I. Methods, Reagents and Mechanisms

A. Various Aspects of Stereo- differentiating Add it ion React ions

This chapter deals with various aspects of addition to sp2-carbons. Addition reactions per- mit C,C- and C-heteroatom bonds to be formed in such a way as to create new stereocenters, and hence enantiomers or diastereomers. The process is called “stereodifferentiation” and it must be performed with as much selectivity as possible; a stereoisomer ratio of 9:l- or better is desirable. Cycloadditions like the Diels-Alder reaction produce two bonds in one step with the potential for up to of 16 stereoisomers! It is one of the great achievements of modern synthetic methodology that such additions may be controlled to yield only one isomer by use of appropriate auxiliaries and conditions. Sigma- tropic rearrangements like the Claisen rear-

rangement proceed with self-immolative stereochemistry, which means that a new stereocenter is generated at the cost of a previous one. In the Claisen case, a C - 0 bond is transformed into a C-C bond with a quantitative chirality transfer.

Literature: Asymmetric Synthesis (J. D. Morrison, Editor), Academic Press, 1983/84, Vol. 2 + 3. Natural Products Synthesis Through Pericyclic Re- actions, G. Desimoni, G. Tucconi, A. Barco, G. P. Pol- lini, ACS Monograph 180, American Chemical So- ciety, Washington, D. C., 1983. Stereodifferentiating Reactions, Y. Zzumi, A. Tui, Ko- dansha, 1911.

Organic Synthesis Highlights Edited by J. Mulzer, H.-J. Altenbach, M. Braun, K. Krohn, H.-U. Reissig

OVCH Verlagsgesellschaft mbH, 1991

Cram’s Rule: Theme and Variations

Cram’s rule was formulated in the early fifties and has been an evergreen in organic stereochemistry ever since. In their original paper [l] Cram and Abd Elhafez studied the addition of various organometals and complex hydrides to prochiral carbonyl functions, summarizing their findings in the following postulate: “In non-catalytic reactions of this type that dia- stereomer will predominante which could be formed by the approach of the entering group from the least hindered side of the double bond when the rotational conformation of the C - C- bond is such that the double bond is flanked by the two least bulky groups attached to the adjacent center”.

Despite its verbose formulation this so-called “Cram’s rule” soon became an indispensable in- gredient of organic textbooks; the simple substituent classification according to effective size (L = large, M = medium, S = small) and the seductively clear influence of steric shielding on the direction of nucleophilic attack were re- sponsible for this popularity. In today’s view, Cram’s rule - similar to Prelog’s rule [2] - attempts a heuristic treatment of the problem of diastereoface selectivity. Owing to the vicinal chiral center, both faces of the carbonyl group are diastereotopic, which means that re- and si- attack differ in energy [3] and unequal amounts of the adducts (2) and (3) are produced. Re- cently, general descriptions of these phenomena have been developed, resulting in the Seebach- Prelog topicity concept [4]. In principle,

Cram’s rule has been applied to both 1,2- and 1,3-inductions; this article, however, will be re- stricted to the 1,2-case, following Cram’s original definition [l].

Ironically, concepts based on questionable premises frequently turn out particularly fruit- ful. In fact, Cram’s rule appears highly oversim- plified in several respects: (a) No distinction is made between ground state and reactive conformation. The postulate that (I) is the ground state conformation of the metal carbonyl complex, is incorrect, as shown by Cornforth [S] and Karabatsos [6]. True, however, is that complexation is indispensable for the activation of the carbonyl group. An uncomplexed car- bony1 group is unreactive towards organometallic attack. (b) In view of the low rotational barriers around C(0) - C-bond axes more than one reactive conformation may be involved, according to the Curtin-Hammett principle [7]. Among these, ( I ) is highly unfavorable, as it leads to the fully eclipsed arrangements (2) and (3) in the course of nucleophilic addition! (c) The substituents are classified as S , M, and L only with respect to their bulk. Any dipolar interactions with the nucleophile are neglected. This deficiency was partly remedied by Corn- forth [S]; he suggested a “dipolar model” for electronegative ct-substituents (Cl, etc.), which he assumed would adopt the L-position in (1). A more general improvement was made by Felkin [S] who realized the importance of the transition state. To avoid eclipsing interactions



4 Stereodgferentiating Addition Reactions

Cram-Modell

Ooolt Met

Felkin model*)

R'-Met I

Met L

(4) major

Felkin-Anh modello)

R'-Met /

:V2R -+ (2) Met L

(6) major

Houk model") - I I Y X

L

(8) minor

R'- Met - (Met = Mg. Li. Zn, etc.)

Met *,, M

o%+ + I L

R (2) (3)

(major) (minor)

R'-Met I

M & S

O ~ ~ i l M e t 4 (3) RF- L (5) minor

R'-M Burgi-Dunitz trajectory of R'-Met: interaction R'-Met - S is smaller than interaction R'-Met ++ M

0 * r3) L Met

(7) minor

n X Y I I

L

(9) major

Felkin preferred the semi-staggered geometries (4)/(5) and postulated nucleophilic attack from an antiperiplanar position with respect to substituent L. Thus, instead of considering one conformation and two modes of attack, as Cram and Cornforth had done, Felkin suggested two

reactive conformations (4)/(5) and only one mode of attack. L is generally the substituent with the highest repulsive effect, which may be of steric or dipolar (e.g. OR, NRJ origin. For electronegative substituents like OR or NR2 the transition states (4)/(5) gain an extra stabiliza-

5

tion by electron transfer from the nucleophile into the low-lying o*-orbital of the C- L bond (“antiperiplanar effect” [9].

However, Felkin’s interpretation failed to ex- plain why (4) is favored over (5). The answer to this problem was given by Biirgi/Dunitz and Anh [lo] who developed the concept of “non- perpendicular attack”. Due to repulsion from the carbonyl-oxygen, the nucleophile ap- proaches the carbonyl-carbon at an angle of ca. 100” with respect to the carbonyl axis. Thus, (4) changes to (6) and (5) to (3, with (6) (R’M interacts with S ) clearly better than (7) (R’M interacts with M). This co-called Felkin-Anh model has been reconsidered by Heathcock in a series of papers [lOa]. He found that steric and electronic effects are sometimes compara- ble for two substituents (e.g. OMe and Ph), so that altogether four reactive conformations have to be considered: two for OMe and two for Ph in the role of L. Such considerations have also been the subject of ab-initio calculations by Houk [lob].

Some time ago, Houk extended the Felkin- Anh concept to the stereochemistry of C=C- additions (“Houk’s model” [ll]). In this case, the reactive conformations are (8) (= (6)) and (9) (= (7)). In contrast to the carbonyl addition, no repulsive interactions need here be considered. Hence, orthogonal quasicyclic transition states are postulated, and the reactive conformation must be so chosen that a minimum of steric interactions arises inside the cyclic frame- work. This means that (9) is a better geometry than (8).

Despite this fascinating theoretical evolution, reported cases of high Cram-Felkin-Anh selectivity have been rare for some years. Only quite recently have new solutions to this problem emerged. One possibility is replacement of the traditional Grignard or organolithium compound by novel organometallics. For example, the trialkoxy titanates ( i f b ) / ( i f c ) show a far superior Felkin-Anh selectivity in many cases [12,13]. High selectivity is also found for the

(11) M = Cram : anti-Cram

kj2L 2. HCI HzC’ BnO

I OH Bn = Benzyl

OH

2 -Desoxy- L -1yxo-

hexose”)

6 Stereodifferentiating Addition Reactions

addition of tin(I1) or zinc diallyl to alkoxy aldehydes like (12) and (13).

Fuganti [14] and Mukaiyama [lS] utilized this observation in certain monosaccharide syntheses. High Felkin-Anh selection was also found for 2-metallated furane [15a], thiazole [lsb] and chromium(I1) ally1 reagents [lSc]. Similarly, the Cram-Felkin-Anh selectivity of ester enolates may be dramatically enhanced by using the 0-silyl-derivatives (1 4b) under BF3- catalysis instead of the lithium compounds (14a) [16].

H2C

Cram's Rule: Theme and Variations 7

OAc

4 '& R iMea \ / OMe

Bu + AcO 'f&Q - iMe,tBu

\ / OMe ( 23) (241

4 : l

is thus opposite to the Felkin-Anh model. It turns out that the chelate model is far more reliable and efficient than the non-chelate model. In particular, ketones like (29) exhibit an extraordinary degree of stereoselection [23]. Applications in synthesis are manifold, one example being the conversion of diol (30) into racemic muscarine [24]. However, no reliable

(2-5)

> 97% (26) H A H - - (30)

OMe

transition state II CH2

the case of a-alkoxy, a-hydroxy-, and a-amino- carbonyl compounds. Prior to organometallic addition the cation M forms a chelate (28) which is attack from the least hindered face, i.e. from the side of S. The corresponding induction

Chelate Cram Model

8'

B n e O B n

BnO -0Bn

e ,. CHaNMe3 cle muscarine

HO chloride

> 100 : 1 XJ : 1 anti-Cram seiectivip)


criteria have yet been found for making a clear prediction whether a given substrate-reagent combination will follow the chelate or the non- chelate pathway. For example, Grignard additions to the dialkoxy aldehydes (12)/(13) are non-chelated, whereas aldehyde (31) shows high chelate-induced selectivity [25]. Important factors apparently are the Lewis acidity of the cation and the nature of the 0- or N-protecting group [26,27,28].

Its numerous deficiencies notwithstanding, Cram’s rule has triumphed as one of the central ideas in acyclic 1,2-~tereoinduction. It is quite likely that the weaknesses of the original formulation inspired many of the fascinating experiments reported in recent years.

References [I] D. J. Cram and F. A. Abd Elhafez, J . Am. Chem.

SOC. 74, 5828 (1952). For a discussion see: E. L. Eliel, in Asymmetric Synthesis (J. D. Morrison, Editor). Vol. 2A, p. 125, Academic Press, 1983.

[2] V. Prelog, Helv. Chim. Acta 36, 308 (1953). [3] V. Prelog and G. Helmchen, ibid 55, 2581 (1972). [4] D. Seebach and V. Prelog, Angew. Chem. 94,696

(1982), Angew. Chem. Int. Ed. Engl. 21, 654 (1982).

[5] J. W. Cornforth R. H. Cornfort, and K. K. Ma- thews, J . Chem. SOC. 1959, 112.

[6] G. J.. Karabatsons, J . Am. Chem. SOC. 89, 1367 (1967).

[7] cited in E. L. Eliel, Stereochemie der Kohlenstoff- Verbindungen, Verlag Chemie, Weinheim, 1966, p. 290.

[8] M. Cherest, H. Felkin, N. Prudent, Tetrahedron Lett. 1968, 2199.

[9] P. Caramella, N. G. Ronda, M. N. Paddon-Row, K. N. Houk, J . Am. Chem. SOC. 103, 2438 (1981).

[lo] N. T. Anh, Top. Curr. Chem. 88, 145 (1980); H. B. Biirgi, J . D. Dunitz, J. M . Lehn, and G. Wipff; Tetrahedron 30, 1563 (1974).

[IOa] E. P. Lodge and C. H. Heathcock, J . Am. Chem. SOC. 109, 2819, 3353 (1987).

[lob] Y. D. W u and K. N. Houk, J . Am. Chem. SOC. 109, 906, 908 (1987).

[ I l l M . N. Paddon-Row, N. G. Rondan, and K. N. Houk, J . Am. Chem. SOC. 104, 7162 (1982).

121 M. T. Reetz, Top. Curr. Chem. Res. 106,l (1982). Monography: Organotitanium Reagents in Or- ganic Synthesis, Springer, Berlin, 1986.

131 B. Weidmann and D. Seebach, Angew. Chem. 95, 12 (1983), Angew. Chem. Int. Ed. Engl. 22, 31 (1983).

[14] G. Fronza, C. Fuganti, P. Grasselli, G. Petrocchi- Fanton, and C. Zirotti, Tetrahedron Lett. 23, 4143 (1982).

[IS] T. Mukaiyama, T. Yamada, and K. Suzuki, Chem. Lett. 1983, 5.

[l5a] S. Pikul, J. Raczko, K. Anker, and J. Jurczak, J. Am. Chem. SOC. 109,3981 (1987) and ref. cited.

[ISblA. Dondoni, G. Fantin, M. Fagangnolo, A. Med- ici, and P. Pedrini, J . Org. Chem. 54, 693 (1989).

[l 5c] J. Mulzer, Th. Schulze, A. Strecker, and W. Den- zer, J . Org. Chem. 53, 4098 (1988).

[16] C. H. Heathcock and L. A. Flippin, J . Am. Chem. SOC. 105, 1667 (1983).

[17] S. Masamune, W. Choy, J. S. Petersen, L. R. Sita, Angew. Chem. 97, 1 (1985); Angew. Chem. Int. Ed. Engl. 24, 1 (1985).

[17a] S. Masamune, Sk. A. Ali, D. L. Snitman, and D. S. Garuey, Angew. Chem. 92, 573 (1980); Angew. Chem. Int. Ed. Engl. 19, 557 (1980).

[18] D. A. Evans, J. V. Nelson, and T. R. Taber, Top. Stereochem. 13, l(1983).

[19] Y. Kishi et al., J . Am. Chem. SOC. 101,259 (1979), 102, 7962 (1980), Tetrahedron Lett. 1979, 4343.

[2O]J. K. Cha, W. J. Christ, and Y. Kishi, Tetrahedron Lett. 24, 3943 (1983).

[21] R. W. Franck, T. V. John, K. Olejniczak, and J. F. Blount, J . Am. Chem. SOC. 104, 1106 (1982), cf. D. Horton, T. Machinami, Y. Takagi, C. W. Berg- mann, and G. C. Chirstoph, J . Chem. SOC., Chem. Commun. 1983, 1164. J . Mulzer, M. Kappert, G. Huttner, and I. Jibril, Tetrahedron Lett. 26, 1631 (1 985).

[22] W. R. Roush, B. Lesur, Tetrahedron Lett. 24, 2231 (1983).

[23] W. C. Still and J. H. McDonald ZZZ, Tetrahedron Lett. 21, 1031 (1980).

[24] W. C. Still and J. Schneider, J. Org. Chem. 45, 3375 (1980).

[25] M. Asami and T. Mukaiyama, Chem. Lett. 1983, 93.

[26] M. T. Reetz, Angew. Chem. 96, 542 (1984), An- gew. Chem. Int. Ed. Engl. 23, 556 (1984).

[27] G. E. Keck, S. Castellino, S. D. Kahn, and W. J. Hehre, Tetrahedron Lett. 28, 279, 281 (1987).

[28] M. T. Reetz, M. W. Drewes, and A. Schmitz, Angew. Chem. 99, 1186 (1987), Angew. Chem. Int. Ed. Engl. 26, 1141 (1987).

Stereoselective Reactions of Cyclic Enolates

The search for stereoselective reactions, especially in noncyclic systems, is one of the more active areas of current research. There is hardly a single recent report of a natural‘product synthesis in which stereoselectivity is not claimed in the title. Often it is not enantioselectivity, but rather diastereoselectivity that poses the more difficult problems [l]! The quest for generally applicable principles to the understanding of stereoselectivity has almost certainly not ended despite the wealth of information to be found in a number of very useful reviews and books [2-41. According to McGarvey [ S ] the problem of stereoselectivity in kinetically controlled reactions of chiral enolates can be analyzed in terms of three models: chelate control (I), covalent control (2), and stereoelectronic control (3). Electronic influences can certainly not be excluded in cyclic models. However, steric effects - which are in a delicate balance with electronic interactions [6] in a case such as (3)

MO

- are more clearly defined in cyclic than in open chain models.

Stereochemical results can be relatively easily predicted if the reaction conditions allow a choice between chelate control and non-chelate control [7, 81. This contribution presents examples that illustrate the possibility of stereo- control with cyclic enolates on the basis of the covalent model (3). In all the cases described it is possible to transform cyclic compounds into open chain molecules by simple chemical op- erations (e. g. hydrolysis).

We examine first the 0-lactones investigated by Mulzer et al., representing the smallest ring system meeting above requirements. Alkyl hal- ides, and aldehydes [9] or Michael acceptors [lo] may be used as electrophiles. In both cases the electrophile - an aldehyde is shown in (4) - enters opposite the bulky substituent R’ (R’ = tert-butyl), which effectively shields one side of the rigid planar ring system. In addition, the third chiral center of the chiral alcohol (5) is generated with high selectivity due to steric interactions between R2 and R3, which favor transition state (4). Mulzer has called this phe- nomenon “Dreierdiastereoselectivitat”.



10 Stereodgferentiating Addition Reactions

Five-membered ring systems with various heteroatoms in the P-position relative to the chiral center have also been intensively investigated. Alkylation of the 0-amido butyrolac- tone (6), which can be converted into the dianon (7) by treatment with 2.2 equivalents of lithium diisopropylamide, was studied by McGarvey in the context of his synthesis of amphotericin B [S]. Addition of methyl iodide also occurs in this case preferentially from the top of the molecule, and the mono-alkylation products (8) and (9) are formed in a ratio of 11 : 1.

H\

(6)

11 1 (8) (9)

The center that transfers the chirality is situated y to the enolate. The investigations of Seebach et al. [I1 -141 have shown that effective stereoselectivity is also possible with chiral center in the P-position. The 1,3-dioxolanes ( I O U ) [ I l l , 1,3-oxazolidines (fob) [12], and 1,3- imidazolidinones (1Oc) [I 31 prepared from chiral a-amino or a-hydroxy acids have the structural features of both lactones or amides and acetals or aminals.

The substituent R is derived from the substrate and may vary widely depending upon the chiral natural products available. In any case, the reaction is essentially the same, as illus-

3’ :vxo R (roa): X = Y = 0 ( lob) : X = 0; Y = NBz (IOc): X = NCH,, Y = NBz

trated by the example of L-lactic acid (11) [ll]. Benzaldehyde and pivalaldehyde have been shown to be best suited for acetal formation with (11) due to the pronounced steric effect of the bulky tert-butyl or phenyl groups. Interest- ingly, the cis-acetal is the major product in kinetically controlled acetal formation. Dia- stereomeric purity of the acetal is a prerequisite to enantiomeric purity of the subsequent products. Fortunately, this is no problem since (12) is crystalline and can easily be purified. Al- though the original chiral center of (12) is de- stroyed by treatment with LDA in the subsequent enolization step, a base-stable chiral center is created in the position opposite, and here the introduction of an incoming electrophile can be directed from the Re side with high selectivity (typically > 97% ds). This process has been called “self-reproduction of chirality” by Seebach [14]. Acetal cleavage leads to enantiomerically pure tert-alcohols that are otherwise

“CH,

Reactions of Cyclic Enolates 11

r

E

not easily accessible. An elegant example appears in the frontalin synthesis described else- where in this book [lS].

In all the endocyclic enolates considered so far the ring system is flattened by at least two sp2-centers, and the electrophile adds from the rear of the molecule irrespective of the position of the shielding substituent. But what about exocyclic enolates such as (16) or (19), derived from the esters (IS) and (18)? Here the bicyclic chelate structure (16), in which the tert-butyl substituent is pushed more or less into an equa- torial position, favors addition of the electrophile from the same side, afford the cis-adduct (17) [16]. Similar conditions prevail in enolate (19) of the acetonide (18). Nevertheless, reaction of (18) with alkyl halide leads to cis-product (20) [ 181, while aldehydes give trans-adducts (21)

The extent of asymmetric induction does not necessarily decrease if the double bond of the enolate is situated one bond further from the ring. This has been demonstrated in the elegant asymmetric syntheses of amino acids by Evans [19] and Trimble and Vederas [20]. It is likely that the enolate derived from (22) also exists as the chelated structure (23). Conformational fix- ation in the chelate permits the substituent R’

~171.

to direct the approaching reagent quite em- ciently ( > 97% ds). Di-tert-butylazodicarboxy- lic esters are also interesting electrophiles, giv- ing in enantiomerically pure form not only u- amino acids [after reduction of (241 but also the corresponding physiologically relevant a- hydrazino acids. Let us return, however, to the “covalent model”. A typical example of the application of six-membered endocyclic enolates occurs in the asymmetric synthesis of amino acids via bislactime ethers such as (25), as elab- orated by Schollkopf and cowerkers [21]. The nearly planar ion pair (26) obtained by depro- tonation of (25) reacts almost exclusively from the top of the molecule (>95% ds) to afford the top of the molecule (>95% ds) to afford the adduct (27). Methyl esters of valine and the desired amino acid bearing the variable substituents R’ and R2 are liberated by acidic hydrolysis in alcoholic solution in virtually enantiomerically pure form. Aldehydes, epoxides, and Michael acceptors can also be used suc- cessfully as electrophiles [21].

Dihydroazines such as (28) are obtained by condensation of chiral a-hydroxy acids and amino acids, such as phenylalanine and they can be deprotonated as in (29) with potassium tert-butoxide. Diastereoselectivity in this case

12 Stereodfferentiating Addition Reactions

0 0

BOC-N-N-BOC BocNH-NBoc

depends much more on the nature of the substituent R’ than in the case of the bislactime ethers (25). If alkylation is carried out with methyl halide only 60% ds is observed for R’ = isopropyl, but selectivity increases to 92% ds when R‘ = tert-butyl even with a residue as small as methyl. The fact that the steric influence of the substituent is so much less pronounced than in the case of the bislactime ethers may be a result of deviations from pla- narity in the dihydroazine system (26).

4 + H 3 3 F H 3

CH30 (27)

Fortunately, organic chemists have more than just monocyclic compounds in their trea- sure chests. Bicyclic systems comprising two five-membered rings are also very popular. For steric reasons the ring fusion in such systems is necessarily cis, which leads to particularly ef-

OCH,

(30)

fective shielding of the endo side. This circum- stance has been elegantly exploited by Meyers et al. [24] in the synthesis of chiral cyclopen- tenones. Selectivity remains relatively high even if one of the rings is expanded to six-members as demonstrated by extension of the synthesis to cyclohexenones with quarternary chiral centers [24].

The commercially available aminodiol (31) condenses with 5-oxohexanoic acid to yield bicyclic lactam (32) as the major product (84: 14) together with other isomers. An endolexo mixture is obtained in the first alkylation of (32) with RX, but this center becomes planar with subsequent formation of the enolate and the decisive second alkylation occurs with > 97% ds from the exo side to afford (33). The neigh- bouring hydroxymethyl group serves only to facilitate reduction of the lactam to an inter- mediate aminal (anchimeric effect). Further treatment with Bu4NH2P04 leads directly to the desired cyclohexenone (35) via the inter- mediate ketoaldehyde (34).

One might still wish to inquire about the re- liability of predictions based on the “covalent model” for the stereochemical outcome of cyclic enolate reactions. With the exception at the more flexible six-membered ring systems, in which other factors contribute to axial vs. equa- torial attack [26a], the examples presented here show quite good agreement between theory and

Reactions of Cyclic Enolates 13

2. IDA-HMPA Ph R’X 0

o R‘ Ph

(33) 1 OHC O b R ’ - R‘

(34)

4 R’ R (35)

experiment (for a recent theoretical treatment of enolate reactions see ref. 25). However, it is certainly dangerous to oversimplify, and factors such as enolate aggregation, the possibility of chelation, and the nature of the electrophile [e.g. (19)] must also be considered, as shown in the recent review by Seebach [26b].

References [I] B. K. Sharpless, lecture given at the Nobel Sym-

posium on “Asymmetric Organic Synthesis” Karlskoga/Schweden, Sept. 1984.

[2] C. H. Heathcock in J. D. Morrison (Ed.): “Asym- metric Synthesis”. Vol. 3, p. 111, Academic Press, Orlando. FL 1983.

[3] D. A. Evans, J. V. Nelson, and T. R. Taber, Top. Stereochem. 13, l(1982).

[4] a) T. Mukaiyama, Org. React. 28, 203 (1982); b) R. W. Hoffmann, Chem. Rev. 89, 1841 (1989).

[5] G. J. McGarvey, J. M. Williams, R. N. Hiner, Y. Matsubara, and T. Oh, J. Am. Chem. SOC. 108, 4943 (1986).

[6] a) P. Delongchamps: “Stereoelectronic Effects in Organic Chemistry”, Pergamon Pres, Oxford

1983; b) A. S. Cieplak, B. D. Tait, and C. R. Johnson, J . Org. Chem. 54, 8447 (1989).

[7] M. Reetz, Angew. Chem. 96,542 (1984). Angew. Chem. Int. Ed. 23, 556 (1984).

[8] C. Siege1 and E. R. Thornton, J . Am. Chem. SOC. 111, 5722 (1989).

[9] J. Mulzer and A. Chucholowski, Angew. Chem. 94,787 (1982), Angew. Chem. Int. Ed. Engl. 2f, 771 (1982). J. Mulzer and T. Kerkmann, J. A. Chem. SOC. 102, 3620 (1980).

[lo] J. Mulzer, A. Chucholowski, 0. Lammer, I. Ji- brill, and G. Huttner, J. Chem. SOC. Chem. Com- mun. 1983, 869.

[ I l l D. Seebach, R. NaeJ and G. Calderari, Tetra- hedron 40, 1313 (1984).

[I21 D. Seebach and A. Fadel, Helv. Chim. Acta 68, 1243 (1985).

[I31 J. D. Aebi and D. Seebach, Helv. Chim. Acta 68, 1507 (1985).

[14] D. Seebach, R. Irmwinkelried, and T. Weber in: “Modern Synthetic Methods 1986”. Vol. IV, p. 125. Springer Verlag, Berlin 1986.

[l5] R. Naef and D. Seebach, Liebigs Ann. Chem. 1983,1930; M. Braun, Nachr. Chem. Tech. Lab. 33, 392 (1985).

[I61 D. Seebach and M. Coquoz, Chimia 39, 20 (1985).

[I71 W. Ladner, Chem. Ber. 116, 3413 (1983). [I81 R. W. Hoffmann and W. Ladner, Chem. Ber. 116,

1631 (1983). [19] a) D. A. Evans, T. C. Britton, R. L. Dorow, and

J. F. Dellaria, J . Am. Chem. SOC. 108, 6395 (1986); b) D. A. Evans, J . S. Clark, R. Metternich, V. J. Novack. and G. S. Sheppard, J . Am. Chem. SOC. 112, 866 (1990).

[20] L. A. Trimble and J. C. Vederas, J . Am. Chem. SOC. 108, 6397 (1986).

[21] Review: U. Schollkopf in J. Streith, H . Prinzbach, and G. Schill (Eds): “Organic Synthesis, an interdisciplinary challenge” (Proc. 5th IUPAC Symp. Org. Synth., p. 101). Blackwell Scientific Publications, Oxforf 1985.

[22] U. Schollkopf and R. Scheuer, Liebigs Ann. Chem. 1984, 939.

[23] A. I. Meyers and K. T. Wanner, Tetrahedron Lett. 26, 2047 (1985).

[24] A. I. Meyers, B. A. Lejker, K. T. Wanner, and R. A. Aitken, J . Org. Chem. 51, 1936 (1986).

[25] Y. Li, M. N. Paddon-Row, and K. N. Houk, J . Am. Chem. SOC. 110, 3684 (1988).

[26] a) K. Tomioka, H. Kawasaki, K. Yasuda, and K. Koga, J . Am. Chem. SOC. 110, 3597 (1988); b) D. Seebach, Angew. Chem. 100, 1685 (1988). Angew. Chem. Int. Ed. Engl. 27, 1624 (1988).

Chiral Sulfoxides in the Synthesis of Enantiomerically Pure Compounds

Linguistic purists may not appreciate it, but ac- ronyms for chemical expressions are increas- ingly appearing in the chemical literature [ 13, and there can be no doubt that they facilitate rapid communication among specialists. Re- cently Seebach [2] introduced the expression “EPC synthesis” for the synthesis of “Enan- tiomerically Pure Compounds”. The advantage of this acronym is its conceptual breadth, which includes “synthesis of enantiomerically pure compounds via incorporation of chiral natural products” as well as “asymmetric synthesis” and “resolution of racemates”.

The application of sulfoxides in organic synthesis has long been documented [3] but the new goal of EPC synthesis has opened the door to novel perspectives [4-61 that are high- lighted here. Sulfoxides with two different alkyl- or aryl substituents [e.g., R. and R’ in (f)] are chiral; the remaining positions on the pyrami- dal structure are occupied by oxygen and a lone pair of electrons.

In contrast to the correspondingly substi- tuted tertiary amines, thermal racemization normally occurs only above 200°C (AH’ = 150 to 180 kJ mol-‘). Pyrolytic elimination be-

gins at lower temperatures and can serve as the basis for synthesizing chiral olefins [7]. Ally1 sulfoxides rearrange to ally1 sulfenates [S], a fact that has recently been skillfully exploited by Grieco et al. [9] in a synthesis of (+)-corn- pactin (Scheme 1).

Noteworthy are the mild conditions (room temperature) under which the sulfoxide (6) re- arranged to an allylic sulfenate, which was in turn reduced by trimethyl phosphite to the allylic alcohol (7). The chiral integrity of the neighboring centers was fully retained during the course of these reactions. The chiral building block (4) was derived from tri-0-acetyl-D- glucal [lo]. This was coupled via a Diels-Alder reaction with the enantiomerically pure dieno- phile (3), obtained by resolution of the corresponding racemate.

Similarly, no racemization is observed in the treatment of sulfoxides with base, a decisive fac- tor in this synthetic application. However, pre- liminary experiments (notably those of Tsuchi- hashi) [l 11 were disappointing. Rather low dia- stereoselectivities were observed in the reaction of carbanions from sulfoxides with carbonyl compounds. This was all the more disappointing since promising differences were measured in the kinetic acidities of the diastereomeric a- methylene protons. For example, the observed rate difference for base-catalyzed H-D exchange in the conformationally frozen centrosymmetric sulfoxide (8) is lo3 [12].



Chiral Sulfoxides 15

Scheme 1 A key step in the compactin synthesis of Grieco et al. [ 9 ]

1. MPBA + 0 SPh

S-Ph

1 rearragement

2 P(OME)~

0 R = M e o ~ o M e O=S- Ph

f 7) i

[#-R]

(6)

. o & H3C CH3

Facile acid-catalyzed isomerization served Solladie as a way of escaping this dilemma. At the same time, the enantiomerically pure sulfoxides became readily available thanks to an equilibration technique [13]. Thus, the sulfinate menthyl esters (9) and (10) could be equilibrated with hydrochloric acid, and the pure (S)-isomer (10) was easily isolated by crystallization (Scheme 2).

Scheme 2 Equilibration of diastereoisomeric sulfinate esters, synthesis of the enantiomerically pure sulfinyl acetate (ll), and stereoselective reaction of ( 1 1 ) with ketones.

(9) (crystallin) (10)

R = menthyl


The enantiomerically pure sulfinyl acetate (11) was obtained in 90% yield by substituting the magnesium enolate of tert-butyl acetate for the 0-menthyl group [13]. The ester group en- hances the acidity of the protons adjacent to the chiral sulfoxide, and excellent diastereoselectivity is observed in the reaction of the magnesium enolate of (If) with carbonyl compounds to afford (12). This high selectivity is once again due to formation of the magnesium chelate complex (14). Much better stereodifferentiation is possible here than with more conformationally flexible transition states [14]. The reversal of the normal stereochemical outcome in the reduction of P-ketosulfoxides with diisopropyl aluminum hydride (DIBAL) in the presence of zinc can be interpreted in a similar way [l5]. Finally, to conclude the general synthetic path outlined in Scheme 2, the P-hydroxy ester (13) is prepared with an ee of 66 to 95%

by reductive removal of the sulfoxide group using aluminum amalgam. Only the chiral information from the sulfoxide remains, and it is obtained at relatively low cost through use of the inexpensive reagent menthol.

The relatively low a- C - H acidity of a sulfoxide (about midway between the acidity of benzylic protons and protons c1 to an ester) can also be increased by a phosphonate group. The so-called Mikolajczyk phosphonate (15) [16] was elegantly incorporated in Solladit's EPC synthesis of the chromane ring of vitamin E [17] (Scheme 3).

Optically active sulfoxides result from the condensation of the doubly activated chiral sulfoxide (15) with the monoacetal of methyl- glyoxal. Unfortunately, however, the product is 1 : l mixture of E/Z-isomers. The route to the pure E-vinyl lithium compound (16) again in- volves an equilibration, this time under basic conditions with lithium diisopropylamine. The explanation for the shift of equilibrium in the direction of the E-vinyl compound (16) may lie in the favorable complexation of lithium with the two oxygen atoms of the neighboring acetal. The synthesis was completed as in the general reaction of Scheme 2, by diastereoselective ad-

Scheme 3 Synthesis of an enantiomerically pure formylchromane precursor to vitamin E.

(Equilibration)

j. h.-j. k. organic synthesis highlights€¦ · library of congress card no.: 90-13003 british...

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