Synthesis of a Series of (–)-Quinic Acid-Derived Mimics of Phosphatidylinositol Dimannoside

Abstract

Two (–)-quinic acid derived mimics of phosphatidylinositol dimannoside (PIM2), termed PQM2s, were synthesised. (16:0/16:0)-PQM2 77 and (16:0/16:0)-PQM2 219 were synthesised from (‒)-quinic acid 71 in 13 and 16 steps in 3% and 1% yields respectively. PQM2 77 contains an n-butylamide group at the C-4 position of the core, whereas PQM2 219 contains a free amine attached to the core by a linker formed from a CuAAC reaction with the C-4 propargylamide.

Synthetic challenges in the synthesis of 77 were the formation of the α-glycosidic linkages, performing O-benzylation reactions in the presence of the n-butylamide moiety, and the hydrolysis of the cyclohexylidene protecting group. Synthesis of PQM2 219 required an extensive model study to select an appropriate O-1 protecting group which could be removed in the presence of the propargylamide moiety. Important synthetic steps in the formation of 219 were the CuAAC reaction to install an N-boc procted amine via a triazole linkage and the hydrolysis of the amine protecting group subsequent to the global hydrogenolysis reaction.

Two PQM2s were synthesised which carried biological probes. PQM2 220 was attached to biotin via an amide linkage and PQM2 221 was attached to fluorescein via a thiourea linkage. PQM2 220 will be used in biological assays in conjunction with fluorescently labelled avidin or streptavidin to determine the immunological mode of action of these compounds whereas fluorescently-labelled PQM2 221 could also be used in assays or in confocal microscopy experiments.