THE PREPARATION OF THE (6R)-DIASTEREOISOMERS AND (6S)-DIASTEREOISOMERS OF 5-FORMYL-TETRAHYDROFOLATE (LEUCOVORIN)

The separation of the (6R)- and (6S)-diastereoisomers of tetrahydrofol ic acid by derivatisation on N-5 with chiral auxiliary reagents follow ed by fractional crystallisation or extraction is described. Chlorofor mates of chiral alcohols were used as chiral auxiliaries and those der ived from cyclic terpene alcohols were found to be most effective for the separation. The cleavage of the derivative and conversion in situ into 5,10-methenyltetrahydrofolic acid which was subsequently hydrolys ed to afford 5-formyltetrahydrofolate (leucovorin) was investigated fo r the derivatised tetrahydrofolates; that from (-) -menthol was the on ly one that combined satisfactory separation with sufficient lability for efficient conversion into 5-formyltetrahydrofolate. The characteri sation and optical purity of the products is described.