Synthetic studies toward Mycobacterium tuberculosis sulfolipid-I

Abstract

Sulfolipid-I (SL-I) is an abundant metabolite found in the cell wall of Mycobacterium tuberculosis that is comprised of a trehalose 2-sulfate core modified with four fatty acyl substituents. The correlation of its abundance with the virulence of clinical isolates suggests a role for SL-I in pathogenesis, although its biological functions remain unknown. Here we describe the synthesis of a SL-I analogue bearing unnatural lipid substituents. A key feature of the synthesis was application of an intramolecular aglycon delivery reaction to join two differentially protected glucose monomers, one prepared with a novel alpha-selective glycosylation. The route developed for the model compound can be readily extended to the synthesis of native SL-I as well as additional analogues for use in the investigation of SL-I's functions.

FIGURE 1

Sulfolipid-I from Mycobacterium tuberculosis (average lipid lengths shown).

FIGURE 2

Structure and retrosynthesis of model compound 1.

SCHEME 1

Preparation of Glucose Monomer 4

SCHEME 2

Construction of the Trehalose Core

SCHEME 3

Synthesis of Intermediate 2

SCHEME 4

Initial Deprotections and Acylations of Intermediate 2

SCHEME 5

Completion of Compound 1