APPLICATION OF PROTEASE-CATALYZED REGIOSELECTIVE ESTERIFICATION IN SYNTHESIS OF 6'-DEOXY-6'-FLUOROLACTOSIDE AND 6-DEOXY-6-FLUOROLACTOSIDE

Subtilisin-catalyzed esterification of methyl 4-O-beta-D-galactopyranosyl-beta-D-glucopyranoside (methyl beta-lactoside) (1) with 2,2,2-trichloroethyl butyrate (3) distinguished between the two primary hydroxyl groups of 1, yielding exclusively the 6'-O-monobutyryl derivative 6 from which 6'-deoxy-6'-fluoro- and 6-deoxy-6-fluorolactosides (22 and 29, respectively) were efficiently synthesized. A key feature in the synthesis of 22 was the use of the 2,4,6-trimethylbenzoyl (mesitoyl) group to protect the remaining free hydroxyl groups. A mesitoate ester, in addition to being inert to the condition that hydrolyzed a butyrate ester, could be easily cleaved by reduction with AlH3 without hydrogenolysis of a C-F bond. The steric bulk of a mesitoyl group suppressed the C-4' --> C-6' acyl migration during the fluorination with (diethylamino)sulfur trifluoride (DAST). The success in the synthesis of 29 depended on the choice of solvent employed for the DAST fluorination. With diglyme the desired 6-fluoro derivative 28 was the only product, whereas the use of CH2Cl2 yielded 6-O-methyl-beta-lactosyl fluoride 30 concomitantly through a C-1 --> C-6 migration of the methoxyl group.