Chem. Rev. 2003, 103, 977−1050 977 Stereoselective Cyclopropanation Reactions He´le`ne Lebel,* Jean-Franc¸ois Marcoux, Carmela Molinaro, and Andre´ B. Charette* De´partement de Chimie, Universite´ de Montre´al, Montre´al, Que´bec, Canada H3C 3J7 Received August 30, 2002 Contents cyclopropane-containing unnatural products have been prepared to test the bonding features of this I. Introduction 977 class of highly strained cycloalkanes3 and to study II. Halomethylmetal (Zn, Sm, Al)-Mediated 977 enzyme mechanism or inhibition.4 Cyclopropanes Cyclopropanation Reactions have also been used as versatile synthetic intermedi- A. Introduction 977 ates in the synthesis of more functionalized cyclo- B. Relative Diastereoselection 980 alkanes5,6 and acyclic compounds.7 In recent years, 1. Cyclic Alkenes 980 most of the synthetic efforts have focused on the 2. Acyclic Alkenes 983 enantioselective synthesis of cyclopropanes.8 This has C. Chiral Auxiliaries 989 remained a challenge ever since it was found that D. Stoichiometric Chiral Ligands 992 the members of the pyrethroid class of compounds 9 E. Chiral Catalysts 994 were effective insecticides. New and more efficient III. Transition Metal-Catalyzed Decomposition of 995 methods for the preparation of these entities in Diazoalkanes enantiomerically pure form are still evolving, and this A. Introduction 995 review will focus mainly on the new methods that have appeared in the literature since 1989. It will B. Intermolecular Cyclopropanation 996 elaborate on only three types of stereoselective cyclo- 1. Diazomethane 996 propanation reactions from olefins: the halomethyl- 2. Diazoalkanes Bearing an 997 metal-mediated cyclopropanation reactions (eq 1), the Electron-Withdrawing Group (N2CH- transition metal-catalyzed decomposition of diazo (EWG)) compounds (eq 2), and the nucleophilic addition-ring 3. Diazoalkanes Bearing Two 1006 closure sequence (eqs 3 and 4). These three processes Electron-Withdrawing Groups (N2C- (EWG) ) will be examined in the context of diastereo- and 2 enantiocontrol. In the last section of the review, other 4. Aryl- and Vinyldiazoester Reagents 1006 methods commonly used to make chiral, nonracemic C. Intramolecular Cyclopropanation 1008 cyclopropanes will be briefly outlined. 1. Diastereoselective Intramolecular 1008 Cyclopropanation of Chiral Substrates 2. Enantioselective Intramolecular 1011 Cyclopropanation: Chiral Catalysts IV. Michael-Initiated Ring Closure 1016 A. Introduction 1016 B. Relative Diastereoselection (Addition to Chiral 1018 Substrates) C. Removable Chiral Auxiliaries 1026 1. Chiral Michael Acceptors 1026 2. Chiral Nucleophiles 1031 D. Stoichiometric and Catalytic Promoters 1036 V. Other Methods 1036 A. Enzymatic Methods 1036 B. Chiral Stoichiometric Carbenes 1037 C. Other Ring-Closing Reactions of Chiral 1039 Precursors VI. References 1041 II. Halomethylmetal (Zn, Sm, Al)-Mediated Cyclopropanation Reactions I. Introduction A. Introduction Organic chemists have always been fascinated by The observation that diiodomethane reacts with the cyclopropane subunit.1 The smallest cycloalkane zinc to give an iodomethylzinc species was first is found as a basic structural element in a wide range reported in 1929 by Emschwiller.10 However, about of naturally occurring compounds.2 Moreover, many 30 years later, Simmons and Smith11 were the first 10.1021/cr010007e CCC: $44.00 © 2003 American Chemical Society Published on Web 04/09/2003 978 Chemical Reviews, 2003, Vol. 103, No. 4 Lebel et al. He´le`ne Lebel received her B.Sc. degree in biochemistry from the Universite´ Carmela Molinaro received her B.Sc. degree in biochemistry at the Laval in 1993. She performed graduate studies in organic chemistry in Universite´ de Montre´al in 1996 and stayed to study for her M.Sc. and the Chemistry Department of the Universite´ de Montre´al under the Ph.D. degree in organic chemistry (2002) with Professor Andre´ B. Charette. supervision of Professor Andre´ B. Charette as a 1967 Science and She has worked on the characterization of zinc cyclopropanating reagents Engineering NSERC fellow, during which she worked on stereoselective and the development of catalysts for the enantioselective cyclopropanation cyclopropanation reactions. In 1998, she joined the research group of reaction using these reagents. She has since joined the research group Professor Eric Jacobsen at Harvard University as a NSERC postdoctoral of Professor Timothy F. Jamison at the Massachusetts Institute of fellow, where she completed the total enantioselective synthesis of Technology as a FCAR postdoctoral fellow and is working on nickel- taurospongin A. She started her academic career in 1999 in the Chemistry catalyzed coupling reactions. Department of the Universite´ de Montre´al as an assistant professor. Her research activities involve the development of new transition metals containing catalysts that mediate fundamentally interesting and useful organic reactions. She recently developed a new olefination reaction via the transition metal-catalyzed synthesis of salt-free phosphorus ylides. Andre´ B. Charette received his Ph.D. (1987) from the University of Rochester under the supervision of Robert K. Boeckman, Jr., where he completed the total synthesis of the ionophore calcimycin. He then joined the research group of David A. Evans at Harvard University as a NSERC postdoctoral fellow, where he worked on the total synthesis of bryostatin. Jean-Franc¸ois Marcoux received a B.Sc. degree in chemistry from Since 1992, he has been professor at the Universite´ de Montre´al, and he Sherbrooke University, Canada, and went to Universite´ de Montre´alasa is currently the holder of the NSERC/Merck Frosst/Boehringer Ingelheim NSERC and FCAR predoctoral fellow, where he received his Ph.D. degree Research Chair on Stereoselective Drug Synthesis at the Universite´de in 1996. His graduate work, directed toward the development of chiral Montre´al. He has received a number of awards, including the Eli Lilly auxiliaries and catalysts for the stereoselective Simmons−Smith cyclo- Grantee Award, an Alfred P. Sloan Research Fellowship, the Astra Pharma propanation of olefins, was carried out under the mentorship of Professor Award, the Merck Frosst Centre for Therapeutic Research Award, a Andre´ B. Charette. He then joined the laboratory of Professor Stephen Steacie Fellowship, and the Rutherford Medal. His research interests are Buchwald at MIT, Massachusetts, as a NSERC postdoctoral fellow. There in the area of stereoselective synthesis of organic compounds. he was involved in the development of practical catalysts for the palladium- and copper-catalyzed formation of aromatic amines and ethers. He were quickly followed by the development of several currently is a Research Fellow in the department of Process Research at alternative methods to prepare related ZnCH2X spe- Merck & Co., Inc., Rahway, NJ. cies or to activate the zinc metal.14 to appreciate that this reagent (IZnCH2I) could be used for the stereospecific conversion of alkenes to cyclopropanes (eqs 5 and 6).12 The cyclopropanation reactions using these reagents are characteristically stereospecific, proceeding through a “butterfly-type” transition structure.13 One major advantage of the reaction is its excellent chemoselectivity, since it is applicable to a variety of olefins and compatible with several functional groups such as enamines, enol ethers, esters, ketones, etc. (vide infra). Simmons and Smith’s seminal studies Stereoselective Cyclopropanation Reactions Chemical Reviews, 2003, Vol. 103, No. 4 979 Table 1. Important Methods for the Preparation of Cyclopropanating Reagents reactants (ref) reagent Oxidative Addition Zn/activator, XCH2I (14) IZnCH2X(X) Cl, I) Sm/activator, CH2I2 (28) ISmCH2I Alkyl Exchange Et2Zn, CH2I2 (16) EtZnCH2I or Zn(CH2I)2 EtZnI, CH I (19,22a) IZnCH I Figure 2. Chem3D representation of the X-ray crystal 2 2 2 ‚ CF3COOH, Et2Zn, CH2I2 (23) CF3COOZnCH2I structure of the benzo-18-crown-6 IZnCH2I complex. 2,4,6-Cl3C6H2OH, Et2Zn, CH2I2 (24) 2,4,6-Cl3C6H2OZnCH2I C4F9C(O)OCH2I, Et2Zn, hν (26) C4F9C(O)OCH2ZnEt R3Al, CH2I2 (30) R2AlCH2I Nucleophilic Displacement ZnX2,CH2N2 (15) XZnCH2X ZnX2,CH2N2 (1:2) (15) Zn(CH2I)2 Figure 3. Chem3D representation of the X-ray crystal structure of the bis(quinoline)‚Zn(CH2I)2 complex. prepared by mixing equimolar amounts of trifluoro- acetic acid, diethylzinc, and diiodomethane, cyclo- propanates alkenes very effectively.23 Substituted Figure 1. Chem3D representation of the X-ray crystal iodomethylzinc aryloxides are also very effective structure of the bis(iodomethyl)zinc‚diether complex. reagents for the cyclopropanation of unfunctionalized alkenes.24 Shortly after Simmons and Smith’s seminal pub- Several other structures of zinc carbenoids, such 15 25 26 lication, Wittig reported that treatment of zinc as those of MeOZnCH2I and (PhC(O)OCH2)2Zn, iodide with either 1 or 2 equiv of diazomethane was were recently resolved, but these reagents are quite an alternative method to prepare IZnCH2Iorthe unreactive toward alkenes unless they are activated analogous bis(iodomethyl)zinc reagent (Zn(CH2I)2). In (vide infra). 1966, Furukawa and co-workers16 found that a In general, the classical Simmons-Smith reagent similar reactive species could be prepared by substi- in ether has been used in 90% of the zinc-mediated tuting a Zn/Cu couple with ZnEt2, to presumably cyclopropanation reactions. However, the use of the form EtZnCH2I. Denmark has further elaborated on Furukawa version, involving diethylzinc, is preferred