An improved synthesis of trehalose 6-mono and 6,6′-dicorynomycolates and related esters

Abstract

A simplified synthesis of 6-mono and 6,6′-di-corynomycolate esters of α,α-trehalose, and related compounds, was achieved by coupling the (hydroxyl-protected) acids to the partially trimethylsilylated sugar in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine. As acid reactants, (2- RS,3- RS)-3-hydroxy-2-tetradecyloctadecanoic acid ( dl-corynomycolic acid) and its 2 RS,3 SR diastereomer were prepared from methyl palmitate by sequential Claisen condensation, reduction, chromatographic separation, and saponification. Reaction with tert-butylchlorodimethylsilane (imidazole) gave the disubstituted ether-ethers, which were converted into the required 3- tert-butyldimethylsilyl ethers by partial hydrolysis. 6-Linked monocorynomycolate was obtained in excellent yield (78%) from the reaction of the RS, SR acid with the known heptakis- O-(trimethylsilyl)trehalose, and in good yield from equimolar portions of RS, RS acid and hexakis- O-(trimethylsilyl)trehalose. An excess (2.5-molar portions) of the RS, RS acid gave the 6,6′-diester (69%). The mono- and di-palmitate were similarly obtained from (Me 3Si) 6-trehalose. The mono ( RS, RS)-(Me 3Si) 6-trehalose coupling product was partially resolved on a silica gel column into its RR and SS diastereomers, the former corresponding to the naturally occurring trehalose monocorynomycolate. All coupling products were deprotected to free trehalose esters by treatment first with K 2CO 3 in methanol, then tetrabutylammonium fluoride-trifluoroacetic acid in oxolane.