Preface ................................................... XIII
List of Contributors ........................................ XV
Part One Asymmetric Synthesis of Nitrogen Heterocycles
Containing Only One Heteroatom ......................... 1
1 Asymmetric Synthesis of Three- and Four-Membered Ring
Heterocycles ................................................. 3
Giuliana Cardillo, Luca Gentilucci and Alessandra
Tolomelli
1.1 Substituted Aziridines .................................. 3
1.1.1 Generalities ..................................... 3
1.1.2 Asymmetric Aziridination via Cyclization
Methods .......................................... 6
1.1.2.1 Cyclization of a Nucleophilic N on an
Electrophilic С (Pathway A) ............. 7
1.1.2.2 Cyclization of a Stabilized Anion on
an Electrophilic N (Pathway B) .......... 9
1.1.3 Asymmetric Aziridination via Cycloaddition
Methods ......................................... 12
1.1.3.1 Addition of Nitrenes to Alkenes ........ 12
1.1.3.2 Reaction between Carbenes and Imines ... 16
1.1.4 Ring Transformation Methods ..................... 27
1.1.4.1 Aziridines from Epoxides ............... 27
1.1.4.2 Aziridines from Other Heterocycles ..... 30
1.1.5 Racemate Resolution ............................. 31
1.1.6 Asymmetric Synthesis of Azirines ................ 33
1.1.6.1 The Neber Reaction ..................... 33
1.1.6.2 Thermal or Photochemical Treatment of
Vinyl Azides ........................... 34
1.1.6.3 Elimination from Aziridines ............ 34
1.1.6.4 Resolution of Racemic Azirines ......... 35
1.1.6.5 Oxidation of Aziridines ................ 36
1.2 Substituted Monocyclic Azetidines and Carbocyclic-
Fused systems .......................................... 36
1.2.1 Generalities .................................... 36
1.2.2 Cyclization Methods: Introduction ............... 38
1.2.2.1 Cyclization methods: Enantiopure
Azetidines via Formation of C-N Bond ... 39
1.2.2.2 Cyclization Methods: Enantiopure
Azetidines via Formation of C-C Bond ... 40
1.2.3 Azetidines by Resolution of Racemates ........... 42
1.2.4 Azetidines by Ring Transformation ............... 44
References .................................................. 45
2 Asymmetric Synthesis of Five-Membered Ring Heterocycles ..... 51
Pei-Qiang Huang
2.1 Monocyclic Pyrrolidines and Pyrrolidinones ............. 51
2.1.1 Generalities .................................... 51
2.1.2 Cyclization Methods ............................. 52
2.1.2.1 Cyclization via C1/C5-N Bond
Formation .............................. 52
2.1.2.2 Cyclization via C2-C3 Bond Formation ... 61
2.1.2.3 Cyclization Involving C3-C4 Bond
Formation .............................. 62
2.1.3 Cycloaddition Methods ........................... 64
2.1.3.1 Cycloaddition Approach ................. 64
2.1.3.2 Annulation Approach .................... 66
2.1.4 Ring Transformation Methods ..................... 67
2.1.4.1 Ring Expansion Methods ................. 67
2.1.4.2 Ring Contraction Methods ............... 68
2.1.5 Substitution of Already Formed Heterocycle ...... 68
2.1.5.1 By Nucleophilic Reaction of
Pyrrolidinium Ions ..................... 71
2.1.5.2 By Nucleophilic Reaction of Cyclic
Imides ................................. 72
2.1.5.3 By Nucleophilic Addition/
Cycloaddition of Pyrrolidine
Nitrones ............................... 74
2.1.5.4 By Functionalization of 2-Pyrrolines ... 76
2.1.5.5 By Enantioselective Reactions .......... 77
2.1.5.6 By Functionalization at C3/C4
Positions of Pyrrolidines .............. 77
2.2 Pyrrolines ............................................. 79
2.2.1 Synthesis of Pyrrolines by Cyclization and
Annulation Reactions ............................ 79
2.2.2 Synthesis of Pyrrolines by Substitution of
Already Formed Heterocycles ..................... 80
2.3 Fused Bicyclic Systems with Bridgehead Nitrogen ........ 82
2.3.1 Pyrrolizidines .................................. 82
2.3.1.1 Through Extension of Methods for
the Synthesis of Pyrrolidines .......... 82
2.3.1.2 Other Methods for the Synthesis of
Pyrrolizidines ......................... 83
2.3.1.3 Asymmetric Synthesis of
Polyhydroxylated Pyrrolizidines ........ 85
2.4 Acknowledgments ........................................ 87
References .................................................. 87
3 Asymmetric Synthesis of Six-Membered Ring Heterocycles ...... 95
Naoki Toyooka
3.1 Introduction ........................................... 95
3.2 Dihydropyridines ....................................... 95
3.3 Tetrahydropyridines .................................... 98
3.3.1 Ring-Closing Metathesis (RCM) ................... 98
3.3.2 Reduction of Pyridine Derivatives .............. 101
3.3.3 Deracemization Processes ....................... 101
3.3.4 Michael Addition Followed by Elimination ....... 102
3.3.5 Enamine Reaction ............................... 102
3.3.6 Electrocyclization ............................. 105
3.4 Monocyclic Piperidines and Carbocyclic Fused
Systems ............................................... 107
3.4.1 Generalities ................................... 107
3.4.2 Cyclization Methods ............................ 107
3.4.2.1 Nitrogen as a Nucleophile ............. 108
3.4.2.2 C-C Bond Formation .................... 113
3.4.3 Cycloaddition Methods .......................... 117
3.4.3.1 [4 + 2] Azadiene Cycloaddition ........ 117
3.4.3.2 [4 + 2] Acylnitroso Cycloaddition ..... 117
3.4.3.3 [3 + 2] Cycloaddition ................. 119
3.4.4 Ring Transformation Methods .................... 119
3.4.4.1 Ring Enlargement of Pyrrolidines
to Substituted Piperidines ............ 120
3.4.4.2 Ring Transformation of Lactones to
2-Piperidones ......................... 121
3.4.4.3 Ring Enlargement of γ-Lactam to
2-Piperidones ......................... 122
3.4.5 Substitution of Already Formed Heterocycle ..... 123
3.4.5.1 Phenylglycinol-Derived Oxazolidine .... 123
3.4.5.2 Asymmetric Michael Addition ........... 125
3.4.5.3 Nitrone Cycloaddition ................. 127
3.4.5.4 Iminium Strategies .................... 128
3.4.5.5 Oxidative Methods ..................... 131
3.5 Fused Tri- or Bicyclic System with Bridgehead
Nitrogen .............................................. 132
References ............................................ 135
4 Asymmetric Synthesis of Seven- and More-Membered Ring
Heterocycles ............................................... 139
Yves Troin and Marie-Eve Sinibaldi
4.1 Substituted Azepines .................................. 139
4.1.1 Generalities ................................... 139
4.1.2 Cyclization Methods ............................ 142
4.1.2.1 Lactamization: C-N Bond Formation ..... 142
4.1.2.2 Radical Cyclization ................... 146
4.1.2.3 Intramolecular Cyclization ............ 149
4.1.2.4 Oxidative Phenol Coupling Reaction .... 155
4.1.2.5 The Ring Closure Metathesis ........... 155
4.1.3 Cycloaddition Methods .......................... 161
4.1.3.1 [5 + 2] Cycloaddition ................. 162
4.1.3.2 [4 + 3] Cycloaddition ................. 162
4.1.3.3 Nitrone Cycloaddition ................. 162
4.1.3.4 Intramolecular Diels-Alder Reactions
(IMDA) - [4 + 2] Cycloaddition ........ 163
4.1.4 Ring Transformation Methods .................... 163
4.1.4.1 Classical Methods ..................... 164
4.1.4.2 Ring Expansion ........................ 166
4.1.4.3 Substitution of Already Formed
Heterocycles .......................... 169
4.2 Substituted Azocines .................................. 171
4.2.1 Azocines from Intramolecular Nucleophilic
Substitution ................................... 172
4.2.2 Ring Transformations Methods ................... 173
4.2.3 Cycloaddition Approaches to Azocines ........... 174
4.2.4 Ring-Closing Metathesis ........................ 175
4.3 Substituted Large Nitrogen-Containing Rings ........... 177
References ................................................. 181
Part Two Asymmetric Synthesis of Nitrogen Heterocycles with
More Than One Heteroatom ............................. 187
5 Asymmetric Synthesis of Three- and Four-Membered Ring
Heterocycles with More Than One Heteroatom ................. 189
Steve Lanners and Gilles Hanquet
5.1 Introduction .......................................... 189
5.2 Three-Membered N-Heterocycles with Two Heteroatoms .... 189
5.2.1 Diaziridines ................................... 190
5.2.1.1 Substrate-Controlled
Diastereoselective Diaziridination
Using Chiral Enantiomerically Pure
Amines ................................ 191
5.2.1.2 Substrate-Controlled
Diastereoselective Diaziridination
Using Chiral Enantiomerically Pure
Ketones ............................... 192
5.2.2 Diazirines ..................................... 193
5.2.3 Oxaziridines ................................... 194
5.2.3.1 Chiral Peracidic Oxidation of
Achiral Imines ........................ 195
5.2.3.2 Achiral Peracidic Oxidation of
Chiral Nonracemic Imines .............. 196
5.2.3.3 Photocyclization of Nitrones .......... 207
5.3 Four-Membered N-Heterocycles with Two Heteroatoms ..... 208
5.3.1 Diazetidines ................................... 208
5.3.2 Oxazetidines ................................... 210
5.3.2.1 Thiazetidines ......................... 212
5.4 Conclusions ........................................... 217
References ................................................. 217
6 Asymmetric Synthesis of Five-Membered Ring Heterocycles
with More Than One Heteroatom .............................. 223
Catherine Kadouri-Puchot and Claude Agami
6.1 Five-Membered Heterocycles with N and О Atoms ......... 223
6.1.1 Oxazolidines ................................... 223
6.1.1.1 N-Alkyloxazolidines ................... 224
6.1.1.2 N-Tosyl and N-Boc Oxazolidines ........ 228
6.1.2 Oxazolines (4,5-dihydrooxazoles) ............... 230
6.1.3 Oxazolidinones ................................. 235
6.1.3.1 Oxazolidin-2-ones ..................... 235
6.1.3.2 Oxazolidin-4-ones and 5-ones .......... 242
6.1.4 Isoxazolines and Isoxazolidines ................ 243
6.1.4.1 Isoxazolidines ........................ 244
6.1.4.2 Isoxazolines .......................... 246
6.2 Five-Membered Heterocycles with Two N Atoms ........... 249
6.2.1 Imidazolidines and Imidazolidinones ............ 249
6.2.1.1 Imidazolidines ........................ 249
6.2.1.2 Imidazolidinones ...................... 252
6.2.2 Pyrazolidines and Pyrazolines .................. 255
6.2.2.1 Pyrazolidines ......................... 255
6.2.2.2 Pyrazolines ........................... 257
6.2.3 Pyrazolidinones ................................ 260
6.3 Five-Membered Heterocycles with N and S Atoms ......... 263
6.3.1 Thiazolidines .................................. 263
6.3.1.1 Iminothiazolidines .................... 267
6.3.1.2 Thiazolidinethiones ................... 268
6.3.1.3 Thiazolidinones ....................... 269
6.3.2 Thiazolines .................................... 270
6.3.2.1 2-Thiazolines ......................... 270
6.3.2.2 3-Thiazolines ......................... 275
6.3.3 Sultams ........................................ 276
References ..................................... 281
7 Asymmetric Synthesis of Six-Membered Ring Nitrogen
Heterocycles with More Than One Heteroatom ................. 293
Péter Mátyus and Pál Tapolcsámyi
7.1 Six-Membered Rings with Another Heteroatom in the
Same Ring ............................................. 293
7.1.1 Pyridazines .................................... 293
7.1.1.1 Ring Closure of Optically Active
Precursors ............................ 294
7.1.1.2 Diels-Alder Reactions ................. 299
7.1.2 Pyrimidines .................................... 302
7.1.2.1 Formation of the Pyrimidine Ring ...... 302
7.1.2.2 Stereoselective Transformation by
the Involvement of the Pyrimidine
Ring .................................. 307
7.1.3 Piperazines .................................... 311
7.1.3.1 Formation of the Piperazine Ring ...... 311
7.1.3.2 Stereoselective Transformation of
the Piperazine Ring ................... 327
7.1.4 Oxadiazines .................................... 332
7.1.4.1 1,2,5-Oxadiazines ..................... 332
7.1.4.2 1,3,4-Oxadiazines ..................... 332
7.1.5 Morpholines .................................... 335
7.1.5.1 Formation of the Morpholine Ring ...... 335
7.1.5.2 Asymmetric Transformations with
the Involvement of the Morpholine
Ring .................................. 352
References ................................................. 359
8 Asymmetric Synthesis of Seven-Membered Rings with More
Than One Heteroatom ........................................ 367
Jacques Royer
8.1 Diazepines ............................................ 367
8.1.1 1,2-Diazepines ................................. 367
8.1.2 1,3-Diazepines ................................. 368
8.1.3 1,4-Diazepines ................................. 371
8.1.3.1 1,4-Benzodiazepines ................... 371
8.1.3.2 Other 1,4-Diazepines .................. 376
8.2 Oxazepines ............................................ 378
8.2.1 1,2-Oxazepine .................................. 378
8.2.1.1 Diels-Alder Cycloaddition ............. 378
8.2.1.2 Intramolecular 3 + 2 Cycloaddition .... 379
8.2.1.3 Pd-Catalyzed 4 + 3 Cycloaddition ...... 379
8.2.1.4 Rearrangements ........................ 379
8.2.2 1,3-Oxazepines ................................. 380
8.2.2.1 N,O-Acetals ........................... 380
8.2.3 1,4-Oxazepines ................................. 383
8.2.3.1 Amino Alcohol Double Condensation ..... 383
8.2.3.2 Other Cyclization Methods ............. 383
8.2.3.3 Pd-Catalyzed Allene Cyclization ....... 384
8.2.3.4 Radical Cyclization ................... 385
8.2.3.5 Ring Enlargement ...................... 385
8.2.3.6 Cycloaddition ......................... 386
8.3 Thiazepines ........................................... 386
8.3.1 1,2-Thiazepines ................................ 387
8.3.2 1,3-Thiazepines ................................ 387
8.3.3 1,4-Thiazepines ................................ 388
8.3.3.1 From Mercaptopropionic Acid
Derivatives ........................... 388
8.3.3.2 From Amino Thiols ..................... 390
8.3.3.3 Others ................................ 391
References ................................................. 392
Index ...................................................... 399
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