Chapter 1 Retrosynthesis, Stereochemistry, and Conformations 1
1.1. Introduction 0001
1.2. The disconnection protocol 0005
1.3. Bond proximity and implications for chemical reactions 0011
1.4. Stereochemistry 0012
1.5. Conformations 0035
1.6. Conclusion 0071
Homework 0072
Chapter 2 Acids, Bases and Functional Group Exchange Reactions 77
2.1. Introduction 0077
2.2. Brønsted-Lowry acids and bases 0081
2.3. Lewis acids 0093
2.4 Hard-Soft acid-base theory 0096
2.5. Acyl addition, substitution and conjugate addition 0106
2.6. Substitution reactions 0112
2.7. Characteristics of reactions involving nucleophiles 0137
2.8. Substitution by halogen 0144
2.9. Elimination reactions 0153
2.10. Addition reactions 0177
2.11. Functional group manipulation by rearrangement 0188
2.12. Aromatic substitution 0193
2.13. Conclusion 0210
Homework 0211
Chapter 3 Oxidation 219
3.1. Introduction 0219
3.2. Alcohols to carbonyls (CH-OH -> C=O) 0226
3.3. Formation of phenols and quinones 0261
3.4. Conversion of alkenes to epoxides 0268
3.5. Conversion of alkenes to diols (C=C -> CHOH-CHOH) 0291
3.6. Baeyer-Villiger oxidation RCOR' -> RCO2R') 0307
3.7. Oxidative bond cleavage (C=C -> C=O + O=C) 0313
3.8. Oxidation of alkyl or alkenyl fragments (CH -> C=O or C-OH) 0324
3.9. Oxidation of sulfur, selenium, and nitrogen 0334
3.10. Conclusion 0340
Homework 0340
Chapter 4 Reduction 347
4.1. Introduction 0347
4.2. Reduction with complex metal hydrides 0348
4.3. Alkoxyaluminate reagents 0363
4.4. Reductions with borohydride 0369
4.5. Alkoxy- and alkylborohydrides 0377
4.6. Borane, aluminum hydride, and derivatives 0385
4.7. Stereoselectivity in reductions 0391
4.8. Catalytic hydrogenation 0422
4.9. Dissolving metal reductions 0451
4.10. Nonmetallic reducing agents 0472
4.11. Conclusion 0483
Homework 0484
Chapter 5 Hydroboration 491
5.1. Introduction 0491
5.2. Preparation of alkyl and alkenyl boranes 0491
5.3. Synthetic transformations 0505
5.4. Formation of oxygen-containing functional groups 0514
5.5. Amines and sulfides via hydroboration 0534
5.6. Conclusion 0537
Homework 0537
Chapter 6 Stereocontrol and Ring Formation 541
6.1. Introduction 0541
6.2. Stereocontrol in acyclic systems 0541
6.3. Stereocontrol in cyclic systems 0551
6.4. Neighboring group effects and chelation effects 0560
6.5. Acyclic stereocontrol via cyclic precursors 0563
6.6. Ring-forming reactions 0564
6.7. Conclusion 0582
Homework 0582
Chapter 7 Protecting Groups 587
7.1. Introduction 0587
7.2. When are protecting groups needed? 0589
7.3. Protecting groups for alcohols, carbonyls, and amines 0593
7.4. Conclusion 0619
Homework 0620
Chapter 8 Cd Disconnect Products: Nucleophilic Species That Form Carbon-Carbon Bonds 623
8.1. Introduction 0623
8.2. Cyanide 0623
8.3. Alkyne anions (R-C=C:-) 0629
8.4 Grignard reagents (C-Mg) 0636
8.5. Organolithium reagents (C-Li) 0670
8.6. Sulfur stabilized carbanions and umpolung 0696
8.7 Organocopper reagents (C-Cu) 0713
8.8. Ylids 0729
8.9. Other organometallic carbanionic compounds 0758
8.10. Allylic tin, alkyltitanium, and allylic silane complexes 0766
8.11. Phenolic carbanions 0771
8.12. Conclusion 0773
Homework 0774
Chapter 9 Cd Disconnect Products: Nucleophilic Species That Form Carbon-Carbon Bonds: Enolate Anions 781
9.1. Introduction 0781
9.2. Formation of enolate anions 0781
9.3. Reactions of enolate anions with electrophiles 0803
9.4. Enolate condensation reactions 0816
9.5. Stereoselective enolate reactions 0850
9.6 Enamines 0873
9.7. Michael addition and related reactions 0877
9.8. Enolate reactions of a-halo carbonyl derivatives 0883
9.9. Conclusion 0888
Homework 0889
Chapter 10 Synthetic Strategies 897
10.1. Introduction 0897
10.2. Target selection 0898
10.3. Retrosynthesis 0907
10.4. Synthetic strategies 0914
10.5 The strategic bond approach 0920
10.6. Strategic bonds in rings 0934
10.7. Selected synthetic strategies: pancratistatin 0942
10.8. Biomimetic approach to retrosynthesis 0948
10.9. The chiral template approach 0954
10.10. Computer generated strategies 0961
10.11. Degradation techniques as a tool for retrosynthesis 0973
10.12. Combinatorial chemistry 0978
10.13. Conclusion 0988
Homework 0989
Table of Contents vi
Chapter 11 Pericyclic Carbon-Carbon Bond Forming Reactions: Multiple Bond Disconnections 999
11.1. Introduction 0999
11.2. Frontier molecular orbital theory 0999
11.3. Allowed and forbidden reactions 1010
11.4. [4 + 2]-cycloadditions 1013
11.5. Inverse electron demand and the retro Diels-Alder 1032
11.6. Rate enhancement in Diels-Alder reactions 1037
11.7. Heteroatom Diels-Alder reactions 1049
11.8. Intramolecular Diels-Alder reactions 1059
11.9. Enantioselective Diels-Alder reactions 1066
11.10. [2+2]-Cycloaddition reactions 1076
11.11. Electrocyclic reactions 1097
11.12. [3+2]-Cycloaddition reactions 1101
11.13. Sigmatropic rearrangements 1116
11.14. The ene reaction 1143
11.15. Conclusion 1152
Homework 1153
Chapter 12 Ca Disconnect Products: Electrophilic Carbon-Carbon Bond Forming Reactions 1161
12.1. Introduction 1161
12.2. Carbocations 1161
12.3. Carbon-carbon bond forming reactions of carbocations 1182
12.4. Friedel-Crafts reactions 1192
12.5. Friedel-Crafts reactions: formation of heteroatom-containing derivatives 1210
12.6. p-Allyl palladium complexes 1225
12.7. Named palladium coupling reactions 1236
12.8. p-Allyl nickel complexes 1245
12.9. Electrophilic iron complexes 1248
12.10. Conclusion 1250
Homework 1251
Chapter 13 Carbon Radical Disconnect Products: Formation of Carbon-Carbon Bonds Via Radicals and Carbenes 1257
13.1. Introduction 1257
13.2. Structure of radicals 1258
13.3. Formation of radicals by thermolysis 1259
13.4. Photochemical formation of radicals 1262
13.5. Reactions of free radicals 1267
13.6. Intermolecular radical reactions 1278
13.7. Intramolecular radical reactions (radical cyclization) 1283
13.8. Metal-induced radical reactions 1296
13.9. Carbenes and carbenoids 1311
13.10. Metathesis reactions 1334
13.11. Pauson-Khand reaction 1342
13.12. Conclusion 1345
Homework 1346
Chapter 14. Student Syntheses: The First Synthetic Problem 1353
14.1. Introduction 1353
14.2. Total synthesis of securamine C 1355
14.3. Total synthesis of variecolol 1364
Disconnection Index 1377
General Index 1383
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