Synthesis of 4,6:2′,3′:4′,6′-tri- O-cyclohexylidene-α,α′-trehalose 2-palmitate: an intermediate for the synthesis of mycobacterial 2,3

Abstract

The aim was to `triprotect' trehalose by placing various acetals, or related protecting groups, across the 4,6-, 2′,3′-, and 4′,6′-positions, leaving the 2,3-positions free for subsequent acylation. Isopropylidene and ethylidene acetals were studied, with the formation of a small amount of 4,6:2′,3′:4′,6′-tri- O-isopropylidene- α,α′-trehalose. 4,6:4′,6′-Di- O-benzylidene-2′,3′- O-(tetraphenyldisiloxane-1,3-diyl)-α,α′- trehalose 2,3-diacetate was prepared in low yield. 1,1-Dimethoxycyclohexane reacted with methyl α- d-glucopyranoside to afford the 4,6- O-cyclohexylidene derivative, isolated as the diacetate; mild acid cleavage of the acetal gave the 2,3-diacetate. 4,6:2′,3′:4′,6′-Tri- O-cyclohexylidene-α,α′-trehalose is the major product of the reaction between α,α′-trehalose and 1,1-dimethoxycyclohexane. 2,3:4,6:2′,3′:4′,6′-Tetra- O- cyclohexylidene-, 4,6:4′,6′-di- O-cyclohexylidene-, and 4,6- O-cyclohexylidene-α,α′-trehaloses were also isolated in lower yields, all acetals being characterised as their peracetates. The proportions of the different trehalose acetals were dependent upon the molar ratio of 1,1-dimethoxycyclohexane and particularly on the reaction temperature. The triprotected trehalose acetal was acylated with palmitic acid, with excellent regioselectivity, affording the 2- O-palmitoyl ester. This 2-monoacylated, triprotected trehalose is a key intermediate for the synthesis of 2,3-di- O-aryl-α,α′-trehalose glycolipid antigens, isolated from Mycobacterium fortuitum and Mycobacterium tuberculosis.