Organic chemists have always been fascinated by the cyclopropane subunit.1 The smallest cycloalkane is found as a basic structural element in a wide range of naturally occurring compounds.2 Moreover, many cyclopropane-containing unnatural products have been prepared to test the bonding features of this class of highly strained cycloalkanes3 and to study enzyme mechanism or inhibition.4 Cyclopropanes have also been used as versatile synthetic intermediates in the synthesis of more functionalized cycloalkanes5,6 and acyclic compounds.7 In recent years, most of the synthetic efforts have focused on the enantioselective synthesis of cyclopropanes.8 This has remained a challenge ever since it was found that the members of the pyrethroid class of compounds were effective insecticides.9 New and more efficient methods for the preparation of these entities in enantiomerically pure form are still evolving, and this review will focus mainly on the new methods that have appeared in the literature since 1989. It will elaborate on only three types of stereoselective cyclopropanation reactions from olefins: the halomethylmetal-mediated cyclopropanation reactions (eq 1), the transition metal-catalyzed decomposition of diazo compounds (eq 2), and the nucleophilic addition-ring closure sequence (eqs 3 and 4). These three processes will be examined in the context of diastereoand enantiocontrol. In the last section of the review, other methods commonly used to make chiral, nonracemic cyclopropanes will be briefly outlined.

Stereoselective Cyclopropanation Reactions

Large-scale applications of transition metal-catalyzed couplings for the synthesis of pharmaceuticals.

Synthesis of cyclopropane containing natural products

Methods for the synthesis of gem-difluoromethylene compounds

ConspectusDifluoroalkylated compounds play a remarkably important role in life and materials sciences because of the unique characteristics of the difluoromethylene (CF2) group. In particular, precise introduction of a CF2 group at the benzylic position can dramatically improve the biological properties of the corresponding molecules. As a consequence, difluoroalkylation of aromatic compounds has become a powerful strategy in modulating the bioactivities of organic molecules. However, efficient strategies to selectively synthesize difluoroalkylated arenes had been very limited before 2012. Traditional synthetic methods in this regard suffer from either harsh reaction conditions or narrow substrate scope, significantly restricting their widespread applications, particularly for late-stage difluoroalkylation of bioactive molecules. To overcome these limitations, a straightforward route to access these valuable difluoroalkylated skeletons is the direct introduction of the difluoroalkylated group (CF2R) onto ...

Transition-Metal (Cu, Pd, Ni)-Catalyzed Difluoroalkylation via Cross-Coupling with Difluoroalkyl Halides.

Synthesis of 2,2-difluoroesters by iododifluoroacetate-copper with organic halides

The Simmons-Smith reactions of Z- and E-allyl alcohol derivatives 6 derived from (R)-2,3-O-isopropylideneglyceraldehyde (6) were used for the synthesis of optically active cis- and trans-1,2-disubstituted cyclopropane derivatives. Reaction of 6 with diethyl zinc and diiodomethane gave cyclopropane derivatives 7 in 84% to quantitative yields with 35 to ≃100% des. Identical facial selectivities toward the double bonds, 1re-2si for Z-6 and 1re-2re for E-6, were observed in the cyclopropanations. The diastereoselectivity was dependent on the protecting group on the terminal allylic oxygen (R of 6, TBDPS>MOM>Bn) and on the stereochemistry of the double bond (Z >E). For TBDPS ethers Z-and E-6c, cis- and trans-7c were obtained as single distereomers, respectively. It was clearly demonstrated that the stereoselectivity of the cyclopropantion is controlled by the directing effect of the allylic oxygen (O-1) of the dioxolane ring, which coordinates to the reagent. The terminal allylic oxygen (O-2) lowered the diastereoselectivity. This reaction was applied to the synthesis of optically active cyclopropane analogs of γ-aminobutyric acid (GABA) 18,22, and ent-22

Synthesis of optically active cis- and trans-1,2-disubstituted cyclopropane derivatives by the Simmons-Smith reaction of allyl alcohol derivatives derived from (R)-2,3-O-isopropylideneglyceraldehyde

The oxidative coupling of ketone enolates and trimethylsilyl enol ethers by means of cupric trifluoromethanesulfonate [Cu(OTf)2] is described in detail. 1, 4-Diketones were effectively prepared by treating lithium enolates with Cu(OTf)2 in i-PrCN. 1, 3-Cyclopentanedione derivatives were synthesized through intramolecular coupling of 2, 4-pentanedione derivatives. Treatment of trimethylsilyl enol ethers with Cu(OTf)2 in i-PrCN also afforded the corresponding coupling products.

Studies on Organic Fluorine Compounds. XXXI. Oxidative Coupling of Ketone Enolates and Trimethylsilyl Enol Ethers by Means of Cu(OTf)2

Simmons-Smith reactions of fluoroallyl alcohols and their derivatives with excess Zn-Cu and CH2I2 or Et2Zn and CH2I2 provided fluorocyclopropane derivatives. Diastereoselective cyclopropanation of the fluoroallyl alcohol derivative obtained from (R)-2, 3-O-isopropylidene glyceraldehyde was successfully carried out to give the optically active fluorocyclopropane derivative in high selectivity (>98% de).

Tsutomu Morikawa

Papers

Synthesis of 2,2-difluoroesters by iododifluoroacetate-copper with organic halides

Synthesis of optically active cis- and trans-1,2-disubstituted cyclopropane derivatives by the Simmons-Smith reaction of allyl alcohol derivatives derived from (R)-2,3-O-isopropylideneglyceraldehyde

Studies on Organic Fluorine Compounds. XXXI. Oxidative Coupling of Ketone Enolates and Trimethylsilyl Enol Ethers by Means of Cu(OTf)2

Simmons-Smith Reactions of Fluoroallyl Alcohol Derivatives

Radical cyclization to fluorinated double bonds: 5-Exo ring closure of bromoacetals derived from fluoroallyl alcohols