The logic of chemical synthesis

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THE LOGIC OF CHEMICAL SYNTHESIS E. J. COREY AND XUEMIN 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 threepart 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 carbonbased 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, structuralmechanistic 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 flowcharts 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 1960’s (E. J. Corey and W. T. Wipke, Science, 1969, 166, 178192) 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 TransformBased Strategies 2.1 TransformGuided Retrosynthetic Search........................................................................17 2.2 DielsAlder Cycloaddition as a TGoal............................................................................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 TGoal Guidance.......................................23 2.7 Retrosynthetic Analysis of Squalene (57).........................................................................25 2.8 Enantioselective Transforms as TGoals..........................................................................26 2.9 Mechanistic Transform Application.................................................................................28 2.10 TGoal Search Using Tactical Combinations of Transforms...........................................31 CHAPTER THREE