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Monday, October 18, 2004
Douglass Taber
University of Delaware

Enantioselective Ring Construction: Part Two of Two

As new drug entities must be usually be prepared as single enantiomers, and as many contain one or more heterocyclic or carbocyclic rings, there is an increased emphasis on the development of practical methods for the construction of enantiomerically pure cyclic systems. In this three-part series, we will cover the most important recent advances. (Part One)

Enantiomerically-pure ternary stereogenic centers, often readily available, can be used to set the helicity of ring-forming reactions, leading to diastereomerically- and so enantiomerically-pure products. In the course of a synthesis of the antifungal sesquiterpene (-)-alliacol A 5, Kevin Moeller of Washington University (J. Am. Chem. Soc. 2004, 126, 9106. ) set the absolute configuration of 2 by chiral catalytic conjugate addition to the prochiral 1. Electrochemical oxidation of 2 gave 3, which was cyclized to 4. Further manipulation of 4 gave 5.

Another approach to the preparation of enantiomerically-pure ring systems is to start with the prochiral preformed ring, and perform an asymmetric transformation. Mauro Pineschi of the UniversitÓ di Pisa has reported (J. Org. Chem. 2004, 69, 2099. ) a study of a series of racemic cyclic epoxides, represented here by 6. Exposure of 6 to Bu2Zn in the presence of an enantiomerically-pure Cu complex derived from 7 converts one enantiomer of 6 to 8, and the other enantiomer to 9, each in high enantiomeric excess. Several other classes of cyclic epoxides showed similar selectivity.

Epoxides such as 10 can be prepared in high enantiomeric purity, by, inter alia, kinetic resolution. David Hodgson of Oxford University has demonstrated (J. Am. Chem. Soc. 2004, 126, 8664. ) that on exposure to LTMP, monosubstituted epoxides are smoothly converted into the corresponding alkoxy carbene or alkoxy carbenoid. When an alkene is available for insertion, the cyclopropane, in this case 11, is formed with high diastereocontrol. This represents a powerful new approach to enantioselective ring construction. It is possible that in the absence of a target alkene, the intermediate alkoxy carbene could divert to intramolecular C-H insertion, which might also proceed with substantial diastereocontrol.

D. F. Taber, Org. Chem. Highlights 2004, October 18.