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 PS bonds, were synthesized as potential inhibitors of mannosyl transferases operating in the endoplasmic reticulum (ER). The β ‐mannosyl derivatives were prepared by a Mitsunobu reaction of 2,3,4,6‐tetra‐ O ‐acetyl‐ α ‐ D ‐mannopyranose ( 1 ) with the thiophosphate 2 that provided O ‐ and S ‐glycosides with good‐to‐excellent diastereoselectivity. A second route to β ‐mannosyl derivatives is based on the phosphitylation of the β ‐ 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.