Table of Contents
I. Conformational Analysis 1
A. Acyclic sp3–sp3Systems 1
B. Cyclohexane and Substituted Cyclohexanes, A Values (∆G°) 2
C. Cyclohexene 7
D. Decalins 7
E. Acyclic sp3–sp2 Systems 8
F. Anomeric Effect 12
G. Strain 14
H. pKa
of Common Organic Acids 16
II. Kinetics and Thermodynamics of Organic Reactions 17
A. Free Energy Relationships 17
B. Transition State Theory 18
C. Intramolecular Versus Intermolecular Reactions 18
D. Kinetic and Thermodynamic Control 20
E. Hammond Postulate 21
F. Principle of Microscopic Reversibility 22
III. Reaction Mechanisms and Conformational Effects on Reactivity 23
A. Ester Hydrolysis 23
B. Alcohol Oxidations 25
C. SN2 Reactions 25
D. Elimination Reactions 26
E. Epoxidation by Intramolecular Closure of Halohydrins 29
F. Epoxide Openings (SN2) 29
G. Electrophilic Additions to Olefins 30
H. Rearrangement Reactions 31
I. Pericyclic Reactions 33
J. Subtle Conformational and Stereoelectronic Effects on Reactivity 36
K. Methods for the Synthesis of Optically Active Materials 39
IV. Oxidation Reactions 41
A. Epoxidation Reactions 41
B. Additional Methods for Epoxidation of Olefins 51
C. Catalytic Asymmetric Epoxidation 56
D. Stoichiometric Asymmetric Epoxidation 67
E. Baeyer–Villiger and Related Reactions 67
F. Beckmann Rearrangement and Related Reactions 70
G. Olefin Dihydroxylation 74
H. Catalytic and Stoichiometric Asymmetric Dihydroxylation 81
I. Catalytic Asymmetric Aminohydroxylation 84
J. Ozonolysis 86
V. Oxidation of Alcohols 87
A. Chromium-based Oxidation Reagents 87
B. Manganese-based Oxidation Reagents 89
C. Other Oxidation Reagents 90
D. Swern Oxidation and Related Oxidation Reactions 93
VI. Reductions Reactions 95
A. Conformational Effects on Carbonyl Reactivity 95
B. Reactions of Carbonyl Groups 96
C. Reversible Reduction Reactions: Stereochemistry 96
D. Irreversible Reduction Reactions: Stereochemistry of Hydride Reduction Reactions 97
and Other Nucleophilic Additions to Carbonyl Compounds
E. Aluminum Hydride Reducing Agents 112
F. Borohydride Reducing Agents 113
G. Hydride Reductions of Functional Groups 115
H. Characteristics of Hydride Reducing Agents 118
I. Asymmetric Carbonyl Reductions 124
J. Catalytic Hydrogenation 127
K. Dissolving Metal Reductions 128
L. Amalgam-derived Reducing Agents 134
M. Other Reduction Methods 136
VII. Hydroboration–Oxidation 139
A. Mechanism 139
B. Regioselectivity 140
C. Diastereoselectivity 140
D. Metal-catalyzed Hydroboration 143
E. Directed Hydroboration 144
F. Asymmetric Hydroboration 144
VIII. Enolate Chemistry 147
A. Acidic Methylene Compounds 147
B. Enolate Structure 155
C. Enolate Alkylations 156
D. Enolate Generation 159
E. Alkylation Reactions: Stereochemistry 168
F. Asymmetric Alkylations 175
G. Aldol Addition (Condensation) 179
H. Aldol Equivalents 197
I. Enolate-imine Addition Reactions 199
J. Claisen Condensation 200
K. Dieckmann Condensation 201
L. Enolate Dianions 203
M. Metalloimines, Enamines and Related Enolate Equivalents 203
N. Alkylation of Extended Enolates 206
IX. Metalation Reactions 207
A. Directed Metalation 207
B. Organolithium Compounds by Metal–Halogen Exchnage 210
C. Organolithium Compounds by Metal–Metal Exchange (Transmetalation) 211
D. Organolithium Compounds from the Shapiro Reaction 211
E. Key Organometallic Reactions Enlisting Metalation or Transmetalation Reactions 212
X. Key Ring Forming Reactions 213
A. Diels–Alder Reaction 213
B. Robinson Annulation 271
C. Birch Reduction 287
D. Dieckmann Condensation 287
E. Intramolecular Nucleophilic Alkylation 287
F. Intramolecular Aldol Condensation 288
G. Intramolecular Michael Reaction 288
H. Cation–Olefin Cyclizations 289
I. Free Radical Cyclizations 301
J. Anionic Cyclizations 321
K. 1,3-Dipolar Cycloadditions 322
L. [1,3]-Sigmatropic Rearrangements 326
M. Electrocyclic Reactions 328
N. Nazarov Cyclization 328
O. Divinylcyclopropane Rearrangement 330
P. Carbene Cycloaddition to Alkenes 331
Q. [2 + 3] Cycloadditions for 5-Membered Ring Formation 336
R. Cyclopropenone Ketal Cycloaddition Reactions 339
S. [2 + 2] Cycloadditions 343
T. Arene–Olefin Photoadditions 346
U. Intramolecular Ene Reaction 347
V. Oxy–Ene Reaction: Conia Reaction 349
W. Cyclopentenone Annulation Methodology 350
X. Pauson–Khand Reaction 353
Y. Carbonylation Cyclizations 355
Z. Olefin Ring Closing Metathesis 356
XI. Olefin Synthesis 359
A. Wittig Reaction 359
B. Wadsworth–Horner–Emmons Reaction 365
C. Peterson Olefination 367
D. Tebbe Reaction and Related Titanium-stabilized Methylenations 370
E. Other Methods for Terminal Methylene Formation 371
F. Olefin Inversion Reactions 372
G. [3,3]-Sigmatropic Rearrangements: Claisen and Cope Rearrangements 374
H. [2,3]-Sigmatropic Rearrangements 378
I. Olefin Synthesis Illustrated with Juvenile Hormone 381
XII. Conjugate Additions: Organocuprate 1,4-Additions 395
XIII. Synthetic Analysis and Design 427
A. Classifications 428
B. Retrosynthetic Analysis 431
C. Strategic Bond Analysis 440
D. Total Synthesis Exemplified with Longifolene 443
XIV. Combinatorial Chemistry 461