Selective Protection Strategies in the Synthesis of TRIS-Fatty Ester Derivatives

Abstract

A methodology for the selective synthesis of lipophilic acyl derivatives of the glycinamido triol (1) with either one, two, or three fatty ester groups has been established. Peracylation of (1), with palmitoyl chloride gave the triacylated derivative. Conversion of (1) into the acetonide, followed by acylation with either palmitoyl chloride or lauroyl chloride, and acetal hydrolysis provided the monoacylated derivatives. Treatment of (1) with trimethyl orthoacetate gave the orthoacetate derivative. Mild hydrolysis provided the monoacetate/diol. Acylation of the two hydroxyl groups with palmitoyl chloride gave the dipalmitate/acetate. Selective cleavage of the acetate group afforded the dipalmitate of (1). Analogous chemistry with trimethyl orthoformate provided the same dipalmitate via the orthoformate, monoformate/diol, and dipalmitate/formate. A more robust synthesis of the dipalmitate was achieved by converting the hydroxyl group of the acetonide of (1) into a tert-butyldiphenylsilyl ether, followed by acetal hydrolysis, palmitoylation of the liberated hydroxyl groups, and desilylation.