Asymmetric synthesis of trifluoro- and difluorochloro- methyl-containing epoxides

Abstract

One of the inherent limitations of the well established chiron approach to the synthesis of fluoroorganic compounds of biological interest remains the limited number of chiral and enantiomerically pure starting materials, which should be both readily available and easily adaptable. An improved high yield procedure for transferring a methylene group from diazomethane to β-keto-γ-fluoro sulphoxides has been found, giving the corresponding epoxides as main compounds [G. Cavicchio, P. Bravo, V. Marchetti and C. Zappalà, J. Fluorine Chem., 54 (1991) 244]. The reaction has been now extended to polyhalogenated derivatives ( 1). Although those compounds are present as an equilibrium mixture of keto and gem-diol form, they react fast to give mainly the corresponding epoxides ( 2) along with minor amounts of methyl enolethers ( 3). Chemical yields range from 35 to 60%. When a substituent is present on the α position, a crude mixture of diastereoisomers ( 1) can be used since partial equilibration occurs during the reaction and the epoxidcs ( 2) are still the predominant products. The reaction medium does not influence diastereoselection but greatly influences the final epoxides ( 2)/enolethers ( 3) ratio. The mechanism of epoxide formation, stereochemical details and the possibilities of employing epoxides ( 2) in the synthesis of natural product analogues will be discussed. ▪