Stereoselective hydrogenation of folic acid dimethyl ester benzenesulfonate: A new access to optically pure L-tetrahydrofolic acid

Folic acid was converted to the corresponding dimethyl ester benzenesulfonate and stereoselectively hydrogenated in organic solvents. An extended screening with rhodium- and iridium-diphosphine catalysts was performed. Under optimized conditions the asymmetric hydrogenation provided a solution of tetrahydrofolic acid dimethyl ester with up to 44% de. The de could be increased to 98% by fractional crystallization Of L-tetrahydrofolic acid dimethyl ester benzenesulfonate from the hydrogenation mixture. Hydrolysis of the ester afforded optically pure L-tetrahydrofolic acid, which can be isolated or converted into its 5- or 10- or 5,10-substituted derivatives.