The Logic of Chemical Synthesis - E. J. Corey(1).pdf - ANGIELSKIE - Nekromantis

THE LOGIC OF

CHEMICAL SYNTHESIS

E. J. COREY AND XUE-MIN CHELG

Department of Chemistry

Harvard University

Cambridge, Massachusetts

JOHN WILEY & SONS

New York . Chichester . Brisbane . Toronto . Singapore

PART ONE

GENERAL APPROACHES TO THE ANALYSIS OF COMPLEX

SYNTHETIC PROBLEMS

PREFACE

The title of this three-part volume derives from a key theme of the bookthe logic underlying

the rational analysis of complex synthetic problems. Although the book deals almost exclusively with

molecules of biological origin, which are ideal for developing the fundamental ideas of multistep

synthetic design because of their architectural complexity and variety, the approach taken is fully

applicable to other types of carbon-based structures.

Part One outlines the basic concepts of retrosynthetic analysis and the general strategies for

generating possible synthetic pathways by systematic reduction of molecular complexity. Systematic

retrosynthetic analysis and the concurrent use of multiple independent strategies to guide problem

solving greatly simplify the task of devising a new synthesis. This way of thinking has been used for

more than two decades by one of the authors to teach the analysis of difficult synthetic problems to

many hundreds of chemists. A substantial fraction of the intricate syntheses which have appeared in

the literature in recent years have been produced by these individuals and their students. An effort has

been made to present in Part One the essentials of multistrategic retrosynthetic analysis in a concise,

generalized from with emphasis on major concepts rather than on specific facts of synthetic

chemistry. Most of the key ideas are illustrated by specific chemical examples. a mastery of the

principles which are developed in Part One is a prerequisite to expertise in synthetic design. Equally

important is a command of the reactions, structural-mechanistic theory, and reagents of carbon

chemistry. The approach in Part One is complementary to that in courses on synthetic reactions,

theoretical carbon chemistry, and general organic chemistry.

Part Two, a collection of multistep syntheses accomplished over a period of more than three

decades by the Corey group, provides much integrated information on synthetic methods and pathways

for the construction of interesting target molecules. These syntheses are the result of synthetic

planning which was based on the general principles summarized in Part One. Thus, Part Two serves to

supplement Part One with emphasis on the methods and reactions of synthesis and also on specific

examples of retrosynthetically planned syntheses.

The reaction flow-charts of Part Two, and indeed all chemical formulae which appear in this

book, were generated by computer. The program used for these drawings was ChemDraw TM adapted

for the Macintosh  personal computer by Mr. Stewart Rubenstein of the Laboratories from the

molecular graphics computer program developed by our group at Harvard in the 1960’s (E. J. Corey

and W. T. Wipke, Science , 1969 , 166 , 178-192) and subsequently refined.

Part Three is intended to balance the coverage of Parts One and Two and to serve as a

convenient guide to the now enormous literature of multistep synthesis. Information on more than five

hundred interesting multistep syntheses of biologically derived molecules is included. It is hoped that

the structural range and variety of target molecules presented in Part Three will appeal to many

chemists.

Synthesis remains a dynamic and central area of chemistry. There are many new principles,

strategies and methods of synthesis waiting to be discovered. If this volume is helpful to our many

colleagues in the chemical world in their pursuit of discovery and new knowledge, a major objective of

this book will have been met.

CONTENTS OF PART ONE

GENERAL APPROACHES TO THE ANALYSIS OF COMPLEX

SYNTHETIC PROBLEMS

CHAPTER ONE

The Basis for Retrosynthetic Analysis

1.1 Multistep Chemical Synthesis .......................................................................................... ...1

1.2 Molecular Complexity .........................................................................................................2

1.3 Thinking About Synthesis ....................................................................................................3

1.4 Retrosynthetic Analysis .......................................................................................................5

1.5 Transforms and Retrons ......................................................................................................6

1.6 Types of Transforms ............................................................................................................9

1.7 Selecting Transforms ..........................................................................................................15

1.8 Types of Strategies for Retrosynthetic Analyses ................................................................15

CHAPTER TWO

Transform-Based Strategies

2.1 Transform-Guided Retrosynthetic Search........................................................................17

2.2 Diels-Alder Cycloaddition as a T-Goal............................................................................18

2.3 Retrosynthetic Analysis of Fumagillol (37)......................................................................19

2.4 Retrosynthetic Analysis of Ibogamine (49).......................................................................22

2.5 Retrosynthetic Analysis of Estrone (54)...........................................................................23

2.6 Retrosynthetic Analysis by Computer Under T-Goal Guidance.......................................23

2.7 Retrosynthetic Analysis of Squalene (57).........................................................................25

2.8 Enantioselective Transforms as T-Goals..........................................................................26

2.9 Mechanistic Transform Application.................................................................................28

2.10 T-Goal Search Using Tactical Combinations of Transforms...........................................31

CHAPTER THREE

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