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

Organic molecules as well as metal complexes may exist as several geometric isomers1 which display distinct physical properties and chemical reactivities. A molecule containing two atoms (in general, two carbons) attached together by a double bond with substituents W-Z may be found as two isomeric † C.D. dedicates this review to Professor Andrée Marquet as a mark of his admiration and gratitude. * To whom correspondence should be addressed: Tel: (33) 169 08 52 25. Fax: (33) 169 08 90 71. E-mail: christophe.dugave@cea.fr. ‡ Present address: Département de Chimie, Institut de Pharmacologie, Université de Sherbrooke, 3001, 12e Avenue nord, Sherbrooke, Québec, J1H 5N4 Canada. 2475 Chem. Rev. 2003, 103, 2475−2532

Cis-trans isomerization of organic molecules and biomolecules: implications and applications.

Synthesis of cyclopropane containing natural products

Stereoselective synthesis of quaternary α-amino acids. Part 1: Acyclic compounds

The chemistry of 2-aminocycloalkanecarboxylic acids.

The syntheses of (−)-allo-coronamic acid, (−)-allo-norcoronamic acid, (−)-(Z)-2,3-methanohomoserine, (−)-(Z)-2,3-methanomethionine, and (2S,3R)-Cbz-cyclo-Asp-OMe have been achieved in 45–68% overall yields from suitable intermediates derived from homochiral aminopentenoates which were obtained, in turn, from D-glyceraldehyde. The key synthetic step involves the quantitative and highly diastereoselective cyclopropanation of such precursors. The factors dealing with the control of stereoselectivity are highlighted and the main features in side-chain functionalization to the respective target molecules are discussed.

Enantioselective total syntheses of cyclopropane amino acids: Natural products and protein methanologs

Stereoselective Synthesis of L-2-(Carboxycyclopropyl)glycines via Stereocontrolled 1,3-Dipolar Cycloadditions of Diazomethane on Z- and E-3,4-L-Didehydroglutamates OBO Esters.

Stereoselective Synthesis of C60-Based Cyclopropane Amino Acids

Versatile and stereocontrolled synthetic entries to novel types of cyclopropyl carbocyclic nucleosides are described. The target products have been synthesized from suitable cyclopropane precursors obtained, in turn, from olefinic compounds derived from D-glyceraldehyde as a chiral precursor. Selective manipulation of the functional groups has allowed the preparation of enantiopure nucleosides, some of them displaying opposite chirality. All these molecules contain a quaternary stereogenic carbon at C-1 or C-3 of the cyclopropane ring and bear an amino, a hydroxymethyl, or a methyl group as an additional substituent. In one instance, thymine is directly linked to the cyclopropane. A methylene unit serves as the spacer in the other synthesized nucleosides.

Stereoselective Synthesis of Novel Types of Cyclopropyl Carbocyclic Nucleosides Containing Quaternary Stereogenic Centers

Some title compounds have been synthesized in enantiomerically pure form starting from d - or l -glyceraldehyde as chiral precursors. A new synthesis of (+)-(Z)-methanohomoserine, one of the key intermediates employed, is also described. The target molecules are densely functionalized. Thus, in addition to one or two hydroxyl groups on a side-chain, an amino group is attached to a quaternary carbon of the cyclopropane ring, and the fourth substituent of such a stereogenic center contains a halogen atom, an alkyl group, or an alcohol, thioether or ester function. Some of these compounds are useful precursors in the synthesis of new cyclopropane nucleosides.

Joan Rifé

Papers

Enantioselective total syntheses of cyclopropane amino acids: Natural products and protein methanologs

Stereoselective Synthesis of L-2-(Carboxycyclopropyl)glycines via Stereocontrolled 1,3-Dipolar Cycloadditions of Diazomethane on Z- and E-3,4-L-Didehydroglutamates OBO Esters.

Stereoselective Synthesis of C60-Based Cyclopropane Amino Acids

Stereoselective Synthesis of Novel Types of Cyclopropyl Carbocyclic Nucleosides Containing Quaternary Stereogenic Centers

Enantioselective synthesis of cyclopropane aminoalcohols containing quaternary stereogenic centers