The aim of this study was to analyse different approaches for the synthesis of one of the most frequent a1-mycolic acids present in Mycobacterium smegmatis. These a-alkyl-~-hydroxylated fatty acids are major constituents of the cell envelope of this and other related organisms. They are thought to be implicated in the virulence of those species which are pathogenic, e.g. Mycobacterium tuberculosis .1-5 Many different methods were analysed for solving the three key problems encountered in the retro-synthesis of these compounds (Scheme 1).
Scheme 1: The three key problems.
In the preparation of the meromycolate moiety, the Julia reaction was a useful alternative to the Grignard reaction for the formation of long bifuntional chains. The double bond in the (£)-configuration was obtained through a Wittig reaction (Scheme 1). Three methods were tested for the preparation of the P-hydroxy ester (Scheme 1). Two were based on either the Sharpless epoxidation, or the Sharpless dihydroxylation. In the third approach, the chiral centre was already present in the initial starting material, D-Aspartic acid.6-8 Only the last two were successful. Three approaches were also attempted for the insertion of a C21 chain into the a-position (Scheme 1) using: either the Frater alkylation, or the regioselective and stereospecific introduction of a chain on reactive species, such as a cyclic sulphate; or an asymmetric anti-aldol condensation using a chiral auxiliary.