The Logic of Chemical Synthesis

by Corey, E. J.; Cheng, Xue-Min

• ISBN13: 9780471115946
• ISBN10: 0471115940
• Edition: 1st
• Format: Paperback
• Copyright: 1995-06-29
• Publisher: Wiley-Interscience

Summary

The Logic of Chemical Synthesis 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 logical 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. Part Two, a collection of multistep syntheses, 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 reactions of synthesis and on specific examples of retrosynthetically planned syntheses. 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 six 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.

Author Biography

ELIAS JAMES COREY, winner of the 1990 Nobel Prize in Chemistry, is Sheldon Emery Professor in the Department of Chemistry at Harvard University. XUE-MIN CHENG is a Research Associate specializing in cardiovascular medicinal chemistry at Parke-Davis/Warner-Lambert Company.

Table of Contents

PART ONE GENERAL APPROACHES TO THE ANALYSIS OF COMPLEX SYNTHETIC PROBLEMS
The Basis for Retrosynthetic Analysis
Multistep Chemical Synthesis	1	(1)
Molecular Complexity	2	(1)
Thinking About Synthesis	3	(2)
Retrosynthetic Analysis	5	(1)
Transforms and Retrons	6	(3)
Types of Transforms	9	(6)
Selecting Transforms	15	(1)
Types of Strategies for Retrosynthetic Analyses	15	(2)
Transform-Based Strategies
Transform-Guided Retrosynthetic Search	17	(1)
Diels-Alder Cycloaddition as a T-Goal	18	(1)
Retrosynthetic Analysis of Fumagillol (37)	19	(3)
Retrosynthetic Analysis of Ibogamine (49)	22	(1)
Retrosynthetic Analysis of Estrone (54)	23	(1)
Retrosynthetic Analysis by Computer Under T-Goal Guidance	23	(2)
Retrosynthetic Analysis of Squalene (57)	25	(1)
Enantioselective Transforms as T-Goals	26	(2)
Mechanistic Transform Application	28	(3)
T-Goal Search Using Tactical Combinations of Transforms	31	(2)
Structure-Based and Topological Strategies
Structure-goal (S-goal) Strategies	33	(4)
Topological Strategies	37	(1)
Acyclic Strategies Disconnections	37	(1)
Ring-Bond Disconnections---Isolated Rings	38	(1)
Disconnection of Fused-Ring Systems	39	(3)
Disconnection of Bridged-Ring Systems	42	(1)
Disconnection of Spiro Systems	43	(1)
Application of Rearrangement Transforms as a Topological Strategy	44	(1)
Symmetry and Strategic Disconnections	44	(3)
Stereochemical Strategies
Stereochemical Simplification---Transform Stereoselectivity	47	(4)
Stereochemical Complexity---Clearable Stereocenters	51	(3)
Stereochemical Strategies---Polycyclic Systems	54	(2)
Stereochemical Strategies---Acyclic Systems	56	(3)
Functional Group-Based and Other Strategies
Functional Groups as Elements of Complexity and Strategy	59	(1)
Functional Group-Keyed Skeletal Disconnections	60	(2)
Disconnection Using Tactical Sets of Functional Group-Keyed Transforms	62	(2)
Strategic Use of Functional Group Equivalents	64	(3)
Acyclic Core Group Equivalents of Cyclic Functional Groups	67	(1)
Functional Groups-Keyed Removal of Functionality and Stereocenters	68	(3)
Functional Groups and Appendages as Keys for Connective Transforms	71	(4)
Functional Group-Keyed Appendage Disconnection	75	(1)
Strategies External to the Target Structure	76	(2)
Optimization of a Synthetic Sequence	78	(3)
Concurrent Use of Several Strategies
Multistrategic Retrosynthetic Analysis of Longifolene (215)	81	(2)
Multistrategic Retrosynthetic Analysis of Porantherine (222)	83	(1)
Multistrategic Retrosynthetic Analysis of Perhydrohistrionicotoxin (228)	83	(1)
Multistrategic Retrosynthetic Analysis of Gibberellic Acid (236)	84	(2)
Multistrategic Retrosynthetic Analysis of Picrotoxinin (251)	86	(2)
Multistrategic Retrosynthetic Analysis of Retigeranic Acid (263)	88	(1)
Multistrategic Retrosynthetic Analysis of Ginkgolide B (272)	89	(15)
References	92	(4)
Glossary of Terms	96	(3)
PART TWO SPECIFIC PATHWAYS FOR THE SYNTHESIS OF COMPLEX MOLECULES
Introduction	99	(1)
Abbreviations	100	(4)
Macrocyclic Structures
Erythronolide B	104	(4)
Erythronolide A	108	(4)
Recifeiolide	112	(1)
Vermiculine	113	(1)
Enterobactin	114	(2)
N-Methylmaysenine	116	(4)
(-)-N-Methylmaysenine	120	(2)
Maytansine	122	(2)
Brefeldin A	124	(4)
Aplasmomycin	128	(8)
Heterocyclic Structures
Perhydrohistrionicotoxin	136	(2)
Porantherine	138	(2)
Biotin	140	(1)
Methoxatin	141	(2)
20-(S)-Camptothecin	143	(3)
Sesquiterpenoids
Insect Juvenile Hormones and Farnesol	146	(5)
Longifolene	151	(2)
Caryophyllenes	153	(2)
Caryophyllene Alcohol	155	(1)
Cedrene and Cedrol	156	(3)
Humulene	159	(2)
Dihydrocostunolide	161	(1)
Elemol	162	(1)
Helminthosporal	163	(2)
Sirenin	165	(3)
Sesquicarene	168	(2)
Copaene and Ylangene	170	(2)
Occidentalol	172	(1)
Bergamotene	173	(1)
Fumagillin	174	(2)
Ovalicin	176	(2)
Picrotoxinin and Picrotin	178	(2)
Isocyanopupukeananes	180	(3)
Bisabolenes	183	(5)
Polycyclic Isoprenoids
Aphidicolin	188	(3)
Stemodinone and Stemodin	191	(2)
K-76	193	(2)
Tricyclohexaprenol	195	(3)
Atractyligenin	198	(3)
Cafestol	201	(3)
Kahweol	204	(1)
Gibberellic Acid	205	(7)
Antheridic Acid	212	(3)
Retigeranic Acid	215	(3)
Diisocyanoadociane	218	(3)
Ginkgolide B and Ginkgolide A	221	(6)
Bilobalide	227	(3)
Forskolin	230	(4)
Venustatriol	234	(3)
Pseudopterosin A	237	(2)
α-Amyrin	239	(2)
β-Amyrin	241	(2)
Pentacyclosqualene	243	(3)
Dihydroconessine	246	(4)
Prostanoids
Structures of Prostaglandins (PG's)	250	(1)
(±)-Prostaglandins E1, F1α, F1β, A1 and B1	251	(2)
Prostaglandins E1, F1α and Their 11-Epimers	253	(2)
General Synthesis of Prostaglandins	255	(3)
Refinements of the General Synthesis of Prostaglandins	258	(4)
Prostaglandins E3 and F3α	262	(3)
Modified Bicyclo [2.2.1] heptane Routes to Prostaglandins	265	(2)
Synthesis of Prostaglandin A2 and Conversion to other Prostaglandins	267	(5)
Alternative Synthesis of Prostaglandins F1α and E1	272	(1)
Conjugate Addition-Alkylation Route to Prostaglandins	273	(3)
Bicyclo [3.1.0] hexane Routes to Prostaglandins	276	(2)
Prostaglandins F2α from a 2-Oxabicyclo [3.3.0] octenone	278	(2)
11-Desoxyprostaglandins	280	(2)
Prostacycline (PGI2)	282	(2)
Major Human Urinary Metabolite of Prostaglandin D2	284	(2)
Analogs of the Prostaglandin Endoperoxide PGH2	286	(5)
12-Methylprostaglandin A2 and 8-Methylprostaglandin C2	291	(2)
Synthesis of Two Stable Analogs of Thromboxane A2	293	(2)
Synthesis of (±)-Thromboxane B2	295	(2)
Synthesis of Prostaglandins via an Endoperoxide Intermediate Stereochemical Divergence of Enzymatic and Biomimetic Chemical Cyclization Reactions	297	(6)
(±)-Clavulone I and (±)-Clavulone II	303	(2)
(-)-Preclavulone-A	305	(2)
Hybridalactone	307	(5)
Leukotrienes and Other Bioactive Polyenes
Formation of Leukotrienes from Arachidonic Acid	312	(1)
Leukotriene A4	313	(5)
Leukotriene C4 and Leukotriene D4	318	(2)
Leukotriene B4	320	(4)
Synthesis of Stereoisomers of Leukotriene B4	324	(4)
Leukotriene B5	328	(2)
5-Desoxyleukotriene D4	330	(1)
Synthesis of the 11,12-Oxido and 14,15-Oxido Analogs of Leukotriene A4 and the Corresponding Analogs of Leukotriene C4 and Leukotriene D4	331	(3)
12-Hydroxy-5,8,14-(Z)-10-(E)-eicosatetraenoic Acid (12-HETE)	334	(3)
Hepoxylins and Related Metabolites of Arachidonic Acid	337	(2)
Synthesis of 5-, 11-, and 15-HETE's Conversion of HETE's into the Corresponding HPETE's	339	(4)
Selective Epoxidation of Arachidonic Acid	343	(2)
Synthesis of Irreversible Inhibitors of Eicosanoid Biosynthesis, 5,6-, 8,9-, and 11,12-Dehydroarachidonic Acid	345	(6)
Synthesis of a Class of Sulfur-Containing Lipoxygenase Inhibitors	351	(2)
Synthesis of a Putative Precursor of the Lipoxins	353	(2)
Bongkrekic Acid	355	(4)
PART THREE GUIDE TO THE ORIGINAL LITERATURE OF MULTISTEP SYNTHESIS
Chapter Thirteen
Introduction	359	(2)
Abbreviations of Journal Names	361	(1)
Acyclic and Monocarbocyclic Structures	362	(4)
Fused-Ring Bi- and Tricarbocyclic Structures	366	(11)
Bridged-Ring Carbocyclic Structures	377	(7)
Higher Terpenoids and Steroids	384	(3)
Nitrogen Heterocycles (Non-bridged, Non-indole)	387	(8)
Fused-Ring Indole Alkaloids	395	(4)
Bridged-Ring Non-Indole Alkaloids	399	(4)
Bridged-Ring Non-Indole Alkaloids; Porphrins	403	(4)
Polycyclic Benzenoid Structures	407	(3)
Oxygen Heterocycles	410	(7)
Macrocyclic Lactones	417	(5)
Macrocyclic Lactams	422	(3)
Polyethers	425	(2)
Index	427