Table Of ContentAsymmetric Synthesis of Three-Membered Rings
Asymmetric Synthesis of Three-Membered
Rings
Hélène Pellissier, Alessandra Lattanzi and
Renato Dalpozzo
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v
Contents
Preface ix
List of Abbreviations xi
1 Asymmetric Cyclopropanation 1
1.1 Introduction 1
1.2 Simmons–Smith Cyclopropanation 2
1.2.1 Chiral Substrates 3
1.2.1.1 Chiral Allylic Alcohols 3
1.2.1.2 Chiral Allylic Amines 7
1.2.1.3 Chiral Acetal-Directed Cyclopropanations 7
1.2.1.4 Simple Chiral Alkenes 9
1.2.2 Chiral Auxiliaries 11
1.2.3 Chiral Catalysts 15
1.2.3.1 Charette’s Ligand 15
1.2.3.2 Other Stoichiometric Ligands 20
1.2.3.3 Walsh’ Procedure 22
1.2.3.4 True Catalytic Procedures 24
1.3 Transition-Metal-Catalyzed Decomposition of Diazoalkanes 27
1.3.1 Intermolecular Cyclopropanation 28
1.3.1.1 Chiral Auxiliaries 28
1.3.1.2 Chiral Catalysts: Cobalt 32
1.3.1.3 Chiral Catalysts: Copper 38
1.3.1.4 Chiral Catalysts: Rhodium 56
1.3.1.5 Chiral Catalysts: Ruthenium 69
1.3.1.6 Chiral Catalyst: Other Metals 77
1.3.2 Intramolecular Cyclopropanation 80
1.3.2.1 Chiral Auxiliaries and Chiral Compounds 80
1.3.2.2 Chiral Catalysts 82
1.3.3 Chiral Stoichiometric Carbenes 93
1.4 Michael-Initiated and Other Ring Closures 94
1.4.1 Chiral Substrates 95
1.4.2 Chiral Auxiliaries 100
1.4.2.1 Chiral Michael Acceptors 100
1.4.2.2 Chiral Nucleophiles 106
vi Contents
1.4.3 Organocatalysis 115
1.4.3.1 Ylides 116
1.4.3.2 Nitrocyclopropanation 118
1.4.3.3 Halocarbonyl Compounds 128
1.4.4 Metal Catalysis 139
1.4.5 Other Ring Closures 140
1.5 Miscellaneous Reactions 148
1.5.1 Rearrangement of Chiral Oxiranes 148
1.5.2 Cycloisomerization of 1,n-Enynes 152
1.5.3 Denitrogenation of Chiral Pyrazolines 160
1.5.4 C–H Insertion 162
1.5.5 Addition to Cyclopropenes 164
1.5.6 Other Methods 167
1.6 Conclusions 172
References 172
2 Asymmetric Aziridination 205
2.1 Introduction 205
2.2 Aziridination Based on the Use of Chiral Substrates 206
2.2.1 Addition to Alkenes 206
2.2.1.1 Aziridination via Nitrene Transfer to Alkenes 206
2.2.1.2 Aziridination via Addition–Elimination Processes 219
2.2.1.3 Miscellaneous Reactions 224
2.2.2 Addition to Imines 225
2.2.2.1 Methylidation of Imines 226
2.2.2.2 Aza-Darzens and Analogous Reactions 248
2.2.2.3 Addition/Elimination Processes 255
2.2.2.4 Miscellaneous Reactions 266
2.2.3 Addition to Azirines 267
2.2.4 Aziridination via Intramolecular Substitution 270
2.2.4.1 From 1,2-Amino Alcohols 270
2.2.4.2 From 1,2-Amino Halides 278
2.2.4.3 From 1,2-Azido Alcohols 282
2.2.4.4 From 1,2-Amino Sulfides and 1,2-Amino Selenides 285
2.2.4.5 From Epoxides 286
2.2.5 Miscellaneous Reactions 287
2.3 Aziridination Based on the Use of Chiral Catalysts 296
2.3.1 Aziridination via Nitrene Transfer to Alkenes 296
2.3.1.1 Cu-Catalyzed Aziridination 296
2.3.1.2 Rh-Catalyzed Aziridination 310
2.3.1.3 Ru-Catalyzed Aziridination 312
2.3.1.4 Catalysis by Other Metals 314
2.3.1.5 Organocatalyzed Aziridination 318
2.3.2 Aziridination via Carbene Transfer to Imines 332
2.3.2.1 Carbene Methodology 332
2.3.2.2 Sulfur-Ylide-Mediated Aziridination 350
Contents vii
2.3.3 Miscellaneous Reactions 353
2.3.4 Kinetic Resolutions of Aziridines 357
2.4 Conclusions 363
References 364
3 Asymmetric Epoxidation 379
3.1 Introduction 379
3.2 Asymmetric Epoxidations Based on the Use
of Chiral Auxiliaries 380
3.3 Asymmetric Metal-Catalyzed Epoxidations 381
3.3.1 Ti-, Zr-, Hf-Catalyzed Epoxidations 381
3.3.2 V-, Nb-, Ta-Catalyzed Epoxidations 391
3.3.3 Cr-, Mo-, W-Catalyzed Epoxidations 397
3.3.4 Mn-, Re-, Fe-, Ru-Catalyzed Epoxidations 400
3.3.5 Pt-, Zn-, Lanthanoid-Catalyzed Epoxidations 412
3.4 Asymmetric Organocatalyzed Epoxidations 419
3.4.1 Phase-Transfer Catalyst 419
3.4.2 Polyamino Acids and Aspartate-Derived Peracids 423
3.4.3 Chiral Dioxiranes, Iminium Salts, and Alkyl Hydroperoxides 431
3.4.4 Chiral Amines 447
3.5 Kinetic Resolution of Racemic Epoxides 468
3.6 Asymmetric Sulfur-Ylide-Mediated Epoxidations 480
3.7 Asymmetric Darzens-Type Epoxidations 489
3.7.1 Chiral Auxiliary- and Reagent-Mediated Darzens Reactions 489
3.7.2 Catalytic Asymmetric Darzens Reactions 492
3.8 Other Ylide-Mediated Epoxidations 503
3.9 Asymmetric Biocatalyzed Synthesis of Epoxides 505
3.10 Conclusions 512
References 514
4 Asymmetric Oxaziridination
539
4.1 Introduction 539
4.2 Oxaziridination Using Chiral Substrates 540
4.3 Oxaziridination Using Chiral Catalysts 544
4.4 Kinetic Resolutions 551
4.5 Conclusions 554
References 555
5 Asymmetric Azirination and Thiirination
559
5.1 Introduction 559
5.2 Asymmetric Azirination 559
5.2.1 Neber Approaches 560
5.2.2 Elimination Approaches 565
5.2.3 Other Approaches 569
5.3 Asymmetric Thiirination 570
5.3.1 Conversion of Epoxides 571
viii Contents
5.3.2 Condensation of Sulfur‐Stabilized Carbanions to Carbonyl
Compounds 572
5.3.3 Intramolecular Nucleophilic Substitution 574
5.3.4 Miscellaneous Reactions 576
5.4 Conclusions 577
References 579
Index 583
ix
Preface
The importance of chirality is well recognized related to the fact that nearly all
natural products are chiral and their physiological or pharmacological properties
depend upon their recognition by chiral receptors, which will interact only with
molecules of the proper absolute configuration. Indeed, the use of chiral drugs in
enantiopure form is now a standard requirement for virtually every new chemi-
cal entity, and the development of new synthetic methods to obtain enantiopure
compounds has become a key goal for pharmaceutical companies. Asymmetric
synthesis constitutes one of the main strategies to gain access to enantioenriched
compounds, involving the use of either chiral auxiliaries or catalysts.
Even 134 years after the synthesis of the first cyclopropane derivative, the syn-
thesis of chiral three‐membered (hetero)cycles remains a considerable challenge.
Their strained structures, interesting bonding characteristics, and value as an
internal mechanistic probe have attracted the attention of the physical organic
chemistry community. Moreover, organic chemists have always been fascinated
by these subunits, which have been playing a prominent role in organic chemis-
try. In fact, while three‐membered rings are highly strained entities, they are
nonetheless found in a wide variety of naturally occurring compounds including
terpenes, pheromones, fatty acid metabolites, and unusual amino acids, among
others. Indeed, the prevalence of three‐membered‐containing (hetero)com-
pounds with biological activity, whether isolated from natural sources or ration-
ally designed pharmaceutical agents, has inspired chemists to find novel and
diverse approaches to their synthesis. The main strategy to gain access to these
enantioenriched compounds involve the use of either chiral auxiliaries or cata-
lysts that can in turn be metal‐centered, small organic asymmetric molecules or
enzymes.
This book collects all the developments achieved in the last 12 years in the
fields of asymmetric cyclopropanation, aziridination, epoxidation, oxaziridina-
tion, azirination, and thiirination reactions. In addition to describing the large
number of highly efficient processes based on the use of various chiral auxiliaries
or substrates, this book demonstrates that the most important achievements in
asymmetric synthesis of three‐membered rings are the spectacular expansion of
novel chiral catalysts, including the especially attractive chiral organocatalysts,
which have been recently applied to these reactions. Indeed, a collection of new
chiral Lewis‐acid catalysts and organocatalysts have provided new opportunities
for these enantioselective reactions and widely expanded their scope.
x Preface
Each chapter of the book covers issues related to the title reactions and includes
selected applications of the multiple synthetic methodologies discussed to prepare
pharmaceuticals, natural or biologically active compounds. All the chapters include
synthetic procedures based on the use of chiral pools and auxiliaries, which were
employed in the earlier times, but also more convenient catalytic approaches based
on the use of chiral metal catalysts and more recently organocatalysts.
Chapter 1, by R. Dalpozzo, deals with the synthesis of chiral cyclopropanes
through asymmetric cyclopropanation. The more efficient methodologies employed
are the well‐known Simmons–Smith reaction, the transition‐metal‐catalyzed
decomposition of diazo compounds, and the irreversible Michael‐initiated ring clo-
sure (MIRC), among others. For all these procedures, the use of chiral substrates or
auxiliaries as well as that of chiral metal‐ and organocatalysts is covered.
Chapter 2, by H. Pellissier, collects the recent developments in asymmetric
aziridination. The use of chiral substrates in addition reactions to alkenes, imines,
and azirines as well as in intramolecular substitutions among other reactions is
developed in a first section. The second section deals with enantioselective metal‐
and organocatalyzed carbene transfers to imines and nitrene transfers to alkenes
along with catalytic kinetic resolutions of racemic aziridines among other reac-
tions promoted by chiral catalysts of all types.
Chapter 3, by A. Lattanzi, demonstrates the important progress achieved in
the past decade in the vast area of asymmetric synthesis of epoxides. Important
enantioselective metal‐ and organocatalyzed epoxidations of alkenes are firstly
covered, while other sections deal with kinetic resolution of racemic epoxides,
asymmetric sulfur‐ylide‐mediated epoxidations of carbonyl compounds, asym-
metric Darzens reactions, and biocatalyzed synthesis of epoxides, among other
methodologies.
Chapter 4, by H. Pellissier, deals with asymmetric oxaziridination, which can
be achieved by using chiral substrates or chiral catalysts and kinetic resolutions.
It is the smallest chapter of the book, demonstrating that this field is still in its
infancy because it has been overshadowed for a long time by the fact that elec-
tron‐deficient oxaziridines can be employed as convenient and stable sources of
electrophilic oxygen.
Chapter 5, by H. Pellissier, collects the advances in asymmetric azirination and
thiirination using chiral reagents as well as chiral catalysts, focusing on those
published in the last 12 years.
The authors hope that this book will provide an insight into the present stage
of asymmetric synthesis of three‐membered rings and stimulate chemists to
future discoveries to fulfill the enormous potential in this area, opening the way
to the synthesis of a number of important products.
xi
List of Abbreviations
2,6‐DCPNO 2,6‐dichloropyridine N‐oxide
acac acetylacetonate
ACDC asymmetric counteranion‐directed catalysis
Ad 1‐adamantyl
AKR aminolytic kinetic resolution
Anth anthryl
Ar aryl
BARF tetrakis(3,5‐bis(trifluoromethyl)phenyl)borate
BHT 2,6‐di‐t‐butyl‐4‐methylphenyl
BINAM 1,1′‐binaphthyl‐2,2′‐diamine
BINAP 2,2′‐bis(diphenylphosphino)‐1,1′‐ binaphthyl
BINOL 1,1′‐bi‐2‐naphthol
BMEH Bacillus megaterium epoxide hydrolase
Bn benzyl
Boc tert‐butoxycarbonyl
Box bis(oxazoline)
Bs benzenesulfonyl
Bt benzotriazole
BUDAM tetra‐tert‐butyldianisylmethyl
Bz benzoyl (PhCO)
CAN ceric ammonium nitrate
CBS oxazaborolidine Corey–Bakshi–Shibata catalyst
Cbz benzyloxycarbonyl
CHP cumyl hydroperoxide
Cod 1,5‐cyclooctadiene
Cp cyclopentadienyl
CPO chloroperoxidase
CSA camphorsulfonic acid
Cy cyclohexyl
DABCO 1,4‐diazabicyclo[2.2.2]octane
DAM dianisylmethyl
DAP diaminopimelic acid
DBN 3,5‐dinitrobenzoyl
DBU 1,5‐diazabicyclo[5.4.0]undec‐5‐ene
DCC N,N′‐dicyclohexylcarbodiimide
