Enantioselective Chemical Synthesis. Methods, Logic, and Practice

330 Pages·2010·23.282 MB·English

by  Elias J. Corey and Laszlo Kurti (Auth.)

PART I.

TOOLS FOR
ENANTIOSELECTIVE SYNTHESIS

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COREY & KÜRTI: ENANTIOSELECTIVE CHEMICAL SYNTHESIS

Introduction The block diagram in Figure 1 depicts the standard
layout of sections in Part I of this book. Figure 2 illustrates
During the last three decades the field of a set of reactions as they usually appear in the
enantioselective methodology for chemical synthesis has subsequent sections of Part I. Each chemical
been transformed by a large number of important transformation is labeled with a roman numeral. The
discoveries and ideas. Those advances have markedly catalyst or ligand loading is shown above the arrow and
enhanced the ability of chemists to assemble complex the name or structure of the reagent or reactant appears
organic structures with multiple stereocenters. There are below along with the reaction conditions. The reported
now a very large number of reactions for generating new yield and enantiomeric excess are highlighted in bright
stereocenters by addition to the sp2 carbon of C=C, C=O, yellow boxes. If appropriate, the diastereomeric ratio is
C=N and Michael acceptors among others. These displayed under the structure of the major product. The
reactions can lead to C-C, C-O, C-N or C-heteroatom structures and identifying numbers of the catalysts and
bond formation. They may involve the use of chiral ligands appear in the lower part of the scheme. Finally, the
reagents or catalysts, either with or without metal centers. appropriate references are indicated for each reaction
The result, in addition to the generation of new entry.
stereocenters, may be chain-extension, functional group
introduction or addition, ring-formation, rearrangement or
appendage attachment. For all these reasons, the field of
multistep assembly of complex organic (i.e., carbogenic =
member of the family of carbon compounds) molecular
assembly has been both expanded and enriched.
One consequence of the intense activity in this area
by many research scientists has been a dramatic increase
in the possibilities for applying synthetic chemistry to
human needs and well-being. However, a less favorable
byproduct of recent progress is the ever-growing task for
synthetic chemists to identify or select the most effective
methods for solving a synthetic chemical problem. The
first part of this book is meant to alleviate this burden on
chemists by providing an extensive summary of the most
useful new tools for enantioselective synthesis.
Topics are presented in a standardized way with
generous use of structural formulas and examples. The
organization is both informal and intuitive, so as to
facilitate locating the needed information or comparing
alternative tools for a particular synthetic task. The
referencing is both recent and extensive to allow easy
access to the vast supporting literature. Particular
attention has been given to the inclusion of the most
useful review articles on each subject. An attempt has
been made to present each topic clearly and concisely. Figure 2
Another objective has been to serve the needs of both the
intermediate student of synthetic chemistry and the
References are given in a standard format throughout
experienced researchers.
the book, as exemplified in Figure 3. Each reference

contains a complete list of the authors, full title and full
StandardLayoutofSectionsinPartI
journal citation.

INTRODUCTION
GENERALOVERVIEW
SCOPE
Catalysts,Reagents&Structures
SYNTHETICEXAMPLES
REFERENCES

Figure 1 Figure 3

2
PART I. CONTENTS

1.1 Formation of C-H Bonds

Addition to C=C
Enantioselective Addition of H to C=C ................................................................................................................6
2
Enantioselective Reduction of C=C-C=O (Reduction of α,β-Unsaturated Compounds) ................................... 14
Enantioselective Reduction of C=C-C=O (“CuH”-Catalyzed Reduction of Activated Alkenes) ......................... 16

Addition to C=O
Enantioselective Addition of H to C=O (Homogeneous Hydrogenation of Prochiral Ketones) ........................ 17
2
Enantioselective Reduction of C=O (CBS Reduction of Prochiral Ketones) ..................................................... 24
Enantioselective Reduction of C=O (Hydrosilylation of Prochiral Ketones)....................................................... 27

Addition to C=N
Enantioselective Addition of H to C=N (Hydrogenation of Imines) ................................................................... 29
2
Enantioselective Reduction of C=N (Hydrosilylation of Imines) ......................................................................... 33
Enantioselective Reduction of C=N (Reduction of Imines Using 1,4-Dihydropyridines) ................................... 35
Enantioselective Reduction of C=N (Reduction of Oxime Ethers Catalyzed by Oxazaborolidines) .................. 37

1.2 Formation of C-O Bonds

Addition of Oxygen (O) to C=C
Enantioselective Epoxidation of C=C (Katsuki-Sharpless) ................................................................................ 38
Enantioselective Epoxidation of C=C (Jacobsen) .............................................................................................. 41
Enantioselective Epoxidation of C=C (Shi) ........................................................................................................ 43
Enantioselective Epoxidation of C=C-C=O (Julia-Colonna) .............................................................................. 45
Enantioselective Dihydroxylation of C=C ........................................................................................................... 47

1.3 Formation of C-N Bonds

Addition of Nitrogen (N) to C=C
Enantioselective Aziridination of C=C ................................................................................................................ 49

1.4 Addition of H-Y (Y= B, Si, CO, CN, vinyl) to C=C

Enantioselective Addition of H-Y to C=C ........................................................................................................... 50
Nucleophilic Addition of Heteroatoms to C=C .................................................................................................... 52
α-Funtionalization of Carbonyl Compounds (α-Amination, Oxidation, Halogenation and Sulfenylation) .......... 54

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COREY & KÜRTI: ENANTIOSELECTIVE CHEMICAL SYNTHESIS

1.5 Formation of C-C Bonds

α-Alkylation of Enolates
Enantioselective α-Alkylation – Part I. (Using Chiral Controller Groups) ........................................................... 56
Enantioselective α-Alkylation – Part II. (Catalytic Enantioselective α-Alkylation and α-Arylation) .................... 60

Aldol Reaction
Stereocontrolled Aldol Reaction ......................................................................................................................... 64

Nucleophilic Addition to C=O
Addition of sp3 C-Nucleophiles to C=O .............................................................................................................. 71
Addition of sp2 C-Nucleophiles to C=O .............................................................................................................. 74
Addition of sp C-Nucleophiles to C=O ............................................................................................................... 76
Addition of Allylic Nucleophiles to C=O .............................................................................................................. 78
Propargylation and Allenylation of C=O ............................................................................................................. 80
Additon of Stabilized Carbanions to C=O .......................................................................................................... 82
Enantioselective Cyanosilylation of C=O ........................................................................................................... 84
Enantioselective Carbonyl Ene-Reaction ........................................................................................................... 86

Nucleophilic Addition to C=N
Enantioselective Mannich Reaction ................................................................................................................... 88
Enantioselective Strecker Reaction ................................................................................................................... 92
Addition of sp3 C-Nucleophiles to C=N .............................................................................................................. 95
Addition of sp and sp2 C-Nucleophiles to C=N .................................................................................................. 98

Conjugate Addition
Metal-Catalyzed Conjugate Addition ................................................................................................................ 101
Conjugate Addition of Stabilized C-Anions ...................................................................................................... 104

Coupling Reactions of π-Allyl Metal Complexes ......................................................................................... 107

Metal-Catalyzed C-H Functionalization ........................................................................................................ 108

Sigmatropic Rearrangement
Enantioselective Claisen Rearrangement ........................................................................................................ 110
Stereoselective Cope Rearrangement ............................................................................................................. 112
Stereoselective [2,3]-Rearrangement .............................................................................................................. 113
Stereoselective All-Carbon Ene-Reaction ........................................................................................................ 114

Enantioselective Stetter Reaction ................................................................................................................1 15

Baylis-Hilman and Related Reactions .......................................................................................................... 117

Aromatic Substitution Reactions .................................................................................................................1 18
4
PART I. CONTENTS

1.6 Cyclization

Cycloaddition
Enantioselective Diels-Alder Reaction (Diels-Alder and Hetero Diels-Alder [4+2]-Cycloaddition) .................. 121
Enantioselective [3+2]-Cycloaddition ............................................................................................................... 128
Enantioselective All-C-[2+2]-Cycloaddition ...................................................................................................... 130
Hetero-[2+2]-Cycloaddition .............................................................................................................................. 131
Enantioselective [2+1]-Cycloaddition (Simmons-Smith Cyclopropanation) ..................................................... 133
Complex Pseudo-Cycloaddition Reactions ([4+3]-, [2+2+2]- and [5+2]-Cycloaddition) .................................. 135

Carbo- and Heterocyclization Reactions
Intramolecular Michael Addition ....................................................................................................................... 136
Intramolecular 1,2-Addition to C=O (Robinson Annulation) ............................................................................. 137
Enantioselective Pauson-Khand Reaction ....................................................................................................... 138
Cyclization Catalyzed by Rh-Complexes ......................................................................................................... 139
Enantioselective Heck Reaction ...................................................................................................................... 143
Cyclization via π-Allyl Metal Complexes .......................................................................................................... 145
Enantioselective Nazarov Cyclization .............................................................................................................. 147
Pictet-Spengler and Related Cyclizations ........................................................................................................ 148
Enantioselective Olefin Metathesis (RCM, ROM/RCM) ................................................................................... 150
Symmetry-Breaking Reactions ........................................................................................................................ 151

5
PART III. CONTENTS

PART III.

ENANTIOSELECTIVE
MULTI-STEP SYNTHESIS: EXAMPLES

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COREY & KÜRTI: ENANTIOSELECTIVE CHEMICAL SYNTHESIS

Introduction

The third and last part of this book provides an transformations. A section on further developments, if any,
overview of the practice of multistep enantioselective closes the topic. All the examples in Part III are taken from
synthesis in the form of specific examples. Each of these research in the Corey laboratory at Harvard over the past
molecular syntheses is described in a standardized format two decades and the reasoning behind the plan is,
(see illustration below). A brief introduction to the target therefore, not just surmise. Of course, there are many
molecule is followed by a concise description of the more synthetic sequences that have been developed in
thinking behind the retrosynthetic plan and comments on other laboratories all over the world that are at least as
any key or non-standard aspects of the planning process. interesting and noteworthy. It would be both instructive
The reaction sequence used for the synthesis of the target and useful if in the future these are compiled in formula
molecule is then outlined in graphical form with key data schemes of the type used in this collection.
on reaction conditions, yields and other details. Again,
concise comments are made on unusual or non-obvious
Standard Arrangement in Part III

174
PART III. CONTENTS

1. Glycinoeclepin…………………………………….179 7. Gracilin B and Gracilin C…………………….196

2. Ectanascidin 743…………………………………183

8. Nicandrenone 1………………………………..199

9. Okaramine N……………………………………203
3. Miroestrol………………………………................186

Me
Me
HN H O H N
Me N
Me N
OH
O H

4. Neotripterifordin…………………………………189 10. Austamide………………………………………205

5. Aflatoxin B2……………………………………......192 11. Aspidophytine………………………………….207

O O
O
H
O
MeO O H

6. Paeoniflorin……………………………................194 12. Dolabellanes……………………………………210

175
COREY & KÜRTI: ENANTIOSELECTIVE CHEMICAL SYNTHESIS

13. Salinosporamides……………………………...218 19. Atractyligenin…………………………………….241

14. Lactacystin & Omuralide……………………..223
20. Pseudopterosins…………………………………245

15. Antheliolide A………………………………….228
21. Pseudopteroxazole……………………………..251

16. Caryophylloids…………………………….........232
22. Desogestrel……………………………………....255

17. Oseltamivir (Tamiflu™)………………………..235 23. Estrone…………………………………………...258

24. Epibatidine…………………………………….....261
18. Pentacycloanammoxic acid…………………..237

176
PART III. CONTENTS

25. Eunicenone……………………………………...263 31. Dammerenediol………………………………..285

26. Cassiol…………………………………………..266
32. Lanostenol………………………………….......287

27. Ovalicin………………………………………….268

33. Protolimonoid…………………………………..289

28. Dysidiolide…………………………………........270

34. Onocerin………………………………………...293

29. Antheridic acid……………………………........273

35. Serratenediol…………………………………...296

30. 3β,20-Dihydroxyprotost-24-ene…………… 276

177