Synthesis of Stable Dolichylphosphomannose Analogues.

Four oleyl or dolichyl thiophosphate esters 16, 17, 21, and 22, analogues of Dol-P-Man possessing C(1) - S and/or beta-S bonds, were synthesized as potential inhibitors of mannosyl transferases operating in the endoplasmic reticulum (ER). The beta-mannosyl derivatives were prepared by a Mitsunobu reaction of 2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranose (1) with the thiophosphate 2 that provided O- and S-glycosides with good-to-excellent diastereoselectivity. A second route to beta-mannosyl derivatives is based on the phosphitylation of the beta-D-mannopyranosyl thiol 3 with the phosphoramidites 4a and 4b. Oxidation of the intermediate oleyl thiophosphite with t-BuOOH led to mono- and dithiophosphates. The thiophospholipids 16, 21, and 22 were inactive as inhibitors of the Man(6)(GlcNAc)(2)-PP-Dol glycolipid elongation.