Synthesis of gluco-configured tertrahydroimidazolpyridine-2-phosphonate-derived lipids, potential glucosyl transferase inhibitors

The analogues 1-3 of dolichol monophosphatidyl beta-D-glucose have been pre pared as potential inhibitors of the glucosyl transferase Alg10p. Pd(PPh3)( 4)-catalysed phosphonylation of the iodoimidazole 4 with diethyl, dimethyl, and diphenyl phosphite led to the corresponding phosphonic acid diesters, which were transformed into deprotected and silyl-protected diesters, depro tected monoesters, and protected and unprotected phosphonic acids (Scheme). A N-methyl imidazolium salt was obtained as a by-product of the dimethyl p hosphonylation of the iodoimidazole, and prepared in high yields by methyla tion of the imidazole 8 with Mel; the corresponding deprotected salt 11 inh ibits sweet almond beta-glucosidases (IC50 = 308 mu M). Trichloroacetonitri le-promoted monoesterification of the acetylated mono-triethylammonium salt 19 with oleyl alcohol, phytanol, and dolichol-19, followed by deacetylatio n, gave the desired glycophospholipids.