Asymmetric Catalysis, 105 . Stereoselective Hydrogenation of Folic Acid with Immobilized Optically Active Rhodium(I)/Diphosphane Catalysts

For the hydrogenation of the CN bonds in the pyrazine ring of the vitamin folic acid ( 1 ) optically active rhodium(I)/diphosphane complexes immobilized on supports such as silica gel or Al 2 O 3 were used. The reduction was carried out at 50 bar hydrogen pressure in an aqueous solution buffered to pH 7. Thus, 5,6,7,8‐tetrahydrofolic acid ( 2 ) was obtained which contains a new asymmetric center at C‐6 of the pterine system. Therefore, in combination with the ( S ) configuration of the natural L ‐glutamic acid part of the molecule two diastereomers with (6 S,S ) and (6 R,S ) configuration arise. The relatively unstable tetrahydrofolic acid ( 2 ) was converted into its 5‐formyl derivative folinic acid ( 4 ) by treatment with methyl formate/formic acid in a 5:1 mixture of DMSO/pyridine. The Ca salt of folinic acid ( 4 ) is the widely used drug leucovorin. The diastereomers were separated by silica gel HPLC. To the column bovine serum albumine (BSA) is covalently bound. With optically active rhodium(I)/diphosphane catalysts, immobilized on silica gel supports, a diastereoselectivity of up to 90% could be achieved in the hydrogenation of folic acid ( 1 ).