Synthesis of a Mycobacterium tuberculosis Tetra-acylated Sulfolipid Analogue and Characterization of the Chiral Acyl Chains Using Anisotropic NAD 2D-NMR Spectroscopy

Abstract

Tetra-O-acylated sulfolipids are metabolites found in the cell wall of Mycobacterium tuberculosis, the causative agent of tuberculosis. Their role in pathogenesis remains, however, undefined. Here we describe a novel access to model tetra-O-acylated trehalose sulfate derivatives having simple acyl chains. The trehalose core was regioselectively protected using a tandem procedure with catalytic iron(III) chloride hexahydrate and further desymmetrized. Model chiral fatty acids, prepared by a zinc-mediated cross-coupling, were incorporated into the trehalose core. The enantiomeric excess of the chiral fatty acids has been measured by natural abundance deuterium (NAD) 2D-NMR spectroscopy in a polypeptide based chiral liquid crystal. The synthetic approach established for the model compounds can easily be developed for the preparation of other analogues and natural sulfolipids.

Strategies for desymmetrising trehalose to synthesise trehalose glycolipids

“…Finally, C2′-sulfated 31a and 31b were respectively prepared from 27 in 20% and 8% yields in 10 steps. 20,21 In our study, we conducted per-O-trimethylsilylation using 1,1,1,3,3,3-hexamethyldisilazane (HMDS) as the silylating reagent and TMSOTf as the catalyst, thus obviating the production of a multiequivalent amount of solid ammonium salts. Thus, without requiring further purification, 4,6,4′,6′-dibenzylation, O3, O3′-benzylation, O2, O2′-acetylation, and O2, O2′-desilylation could be conducted from trehalose (9) directly to provide 32 or 33 in a one-pot manner in yields of 91% and 88%, respectively.…”

“…16 To solve the poor solubility problem of the free trehalose (9) in organic solvents, fully trimethylsilylated trehalose 27 is typically prepared by combining trimethylsilyl chloride with triethylamine or pyridine. [17][18][19][20][21] To benefit 6,6′-diester-hexatrimethylsilyl trehalose formation, both the O6 and the O6′ TMS groups were selectively removed using acetic acid at 8-10 °C or using K 2 CO 3 at 0 °C in pyridine. Because of the instability of the TMS groups under acidic conditions, the TMS groups were easily removed after esterification to obtain diesters 23, 28a, and 28b (Scheme 4).…”

Synthesis of chemical tools to label the mycomembrane of corynebacteria using modified iron(iii) chloride-mediated protection of trehalose

“…37,39 We have also used this inexpensive, easy to handle, and environmentally friendly catalyst for fast access to regioselectively protected trehalose derivatives in the synthesis of sulfolipid analogues from M. tuberculosis. [49][50][51] We therefore envisioned that this method could provide easy access to…”

Tailoring trehalose for biomedical and biotechnological applications

“…10,11 It is noted that since 2013, a number of new reports describing chemical syntheses of various mycobacterial glycolipids have been published as well. 12–18 Here, we emphasize recent advances in trehalose analogue synthesis using chemoenzymatic methods, which have been inspired by naturally occurring trehalose biosynthetic pathways. The bulk of this review is devoted to the various emerging applications of trehalose analogues, which range from the detection and treatment of pathogenic organisms to the development of non-digestible food additives.…”