Logic of Organic synthesis by Corey

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  1. 1. 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
  2. 2. PART ONE GENERAL APPROACHES TO THE ANALYSIS OF COMPLEX SYNTHETIC PROBLEMS
  3. 3. PREFACE The title of this three-part volume derives from a key theme of the bookthe 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 ChemDrawTM 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 1960s (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
  4. 4. 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
  5. 5. Structure-Based and Topological Strategies 3.1 Structure-goal (S-goal) Strategies .................................................................................33 3.2 Topological Strategies ...................................................................................................37 3.3 Acyclic Strategic Disconnections ...................................................................................37 3.4 Ring-Bond Disconnections-Isolated Rings .....................................................................38 3.5 Disconnection of Fused-Ring Systems ...........................................................................39 3.6 Disconnection of Bridged-Ring Systems .......................................................................42 3.7 Disconnection of Spiro Systems ....................................................................................43 3.8 Application of Rearrangement Transforms as a Topological Strategy .........................44 3.9 Symmetry and Strategic Disconnections .......................................................................44 CHARTER FOUR Stereochemical Strategies 4.1 Stereochemical SimplificationTransform Stereoselectivity..........................................47 4.2 Stereochemical ComplexityClearable Stereocenters....................................................51 4.3 Stereochemical StrategiesPolycyclic Systems..............................................................54 4.4 Stereochemical StrategiesAcyclic Systems...................................................................56 CHAPTER FIVE Functional Group-Based and Other Strategies 5.1 Functional Groups as Elements of Complexity and Strategy............................................59 5.2 Functional Group-Keyed Skeletal Disconnections.............................................................60 5.3 Disconnection Using Tactical Sets of Functional Group-Keyed Transforms.....................62 5.4 Strategic Use of Functional Group Equivalents.................................................................64 5.5 Acyclic Core Group Equivalents of Cyclic Functional Groups..........................................67 5.6 Functional Group-Keyed Removal of Functionally and Stereocenters...............................68 5.7 Functional Groups and Appendages as Keys for Connective Transforms..........................71 5.8 Functional Group-Keyed Appendage Disconnection..........................................................75 5.9 Strategies External to the Target Structure......................................................................76 5.10 Optimization of a Synthetic Sequence...............................................................................78 CHAPTER SIX Concurrent Use of Several Strategies
  6. 6. 6.1 Multistrategic Retrosynthetic Analysis of Longifolene (215)...........................................81 6.2 Multistrategic Retrosynthetic Analysis of Porantherine (222).........................................83 6.3 Multistrategic Retrosynthetic Analysis of Perhydrohistrionicotoxin (228)......................83 6.4 Multistrategic Retrosynthetic Analysis of Gibberellic Acid (236)....................................84 6.5 Multistrategic Retrosynthetic Analysis of Picrotoxinin (251)..........................................86 6.6 Multistrategic Retrosynthetic Analysis of Retigeranic Acid (263)...................................88 6.7 Multistrategic Retrosynthetic Analysis of Ginkgolide B (272).........................................89 References........................................................................................................................92 Glossary of Terms............................................................................................................96 CONTENTS OF PART TWO SPECIFIC PATHWAYS FOR THE SYNTHESIS OF COMPLEX MOLECULES Introduction ................................................................................................................99 Abbreviations ............................................................................................................100 CHAPTER SEVEN Macrocyclic Structures 7.1 Erythronolide B .................................................................................................................104 7.2 Erythronolide A .................................................................................................................108 7.3 Recifeiolide ........................................................................................................................112 7.4 Vermiculine ........................................................................................................................113 7.5 Enterobactin ......................................................................................................................114 7.6 N-Methylmaysenine ..........................................................................................................116 7.7 (-)-N-Methylmaysenine .....................................................................................................120 7.8 Maytansine ........................................................................................................................122 7.9 Brefeldin A ........................................................................................................................124 7.10 Aplasmomycin ..................................................................................................................128 CHAPTER EIGHT Heterocyclic Structures 8.1 Perhydrohistrionicotoxin ..................................................................................................136 8.2 Porantherine .....................................................................................................................138 8.3 Biotin ................................................................................................................................140 8.4 Methoxatin .......................................................................................................................141
  7. 7. 8.5 20-(S)-Camptothecin .........................................................................................................143 CHAPTER NINE Sesquiterpenoids 9.1 Insect Juvenile Hormones and Farnesol ...........................................................................146 9.2 Longifolene .......................................................................................................................151 9.3 Caryophyllenes .................................................................................................................153 9.4 Caryophyllene Alcohol .....................................................................................................155 9.5 Cedrene and Cedrol ..........................................................................................................156 9.6 Humulene .........................................................................................................................159 9.7 Dihydrocostunolide ...........................................................................................................161 9.8 Elemol ..............................................................................................................................162 9.9 Helminthosporal ...............................................................................................................163 9.10 Sirenin ..............................................................................................................................165 9.11 Sesquicarene .....................................................................................................................168 9.12 Copaene and Ylangene .....................................................................................................170 9.13 Occidentalol ......................................................................................................................172 9.14 Bergamotene .....................................................................................................................173 9.15 Fumagillin .........................................................................................................................174 9.16 Ovalicin ............................................................................................................................176 9.17 Picrotoxinin and Picrotin .................................................................................................178 9.18 Isocyanopupukeananes .....................................................................................................180 9.19 Bisabolenes ........................