Antimetabolites have been used for some years as chemotherapeutic agents in the treatment of cancer, as well as in the treatment of other conditions such as rheumatoid arthritis. One such drug, methotrexate, is now one of the most widely used anticancer drugs, and many other compounds in the folic acid family have been made, tested and discussed in the chemical and medical literature. The compounds have various activities at the enzymatic level; they inhibit enzymes such as dihydrofolate reductase and folate polyglutamate synthetase, to varying degrees and in varying combinations.
More recently, a series of derivatives of 5,10-dideaza-5,6,7,8-tetrahydrofolic acids has been disclosed and shown to be particularly useful anti-folate drugs. See, for example, U.S. Pat. No. 4,684,653, of E. C. Taylor et al., and European Patent Publication 0248573, of Taylor, Shih et al. Those compounds have two or more asymmetric centers. The asymmetric center at the 6-position (the junction of the tetrahydropyrimidine ring and the two-carbon bridge) is of particular interest and concern. It has been shown in the above EPO publication that the two stereoisomers wherein the 6-position center is in the R and the S configuration have different activities. Both forms are effective drugs, but their efficacies are different and one or the other would be preferred for various purposes. The patent publication shows a method for preparing and separating the two stereoisomers by use of a chiral salt. That procedure, however, is wasteful if only one of the stereoisomers is wanted in the circumstances. An enantioselective method of preparing either the 6R or the 6S stereoisomer of those compounds is provided by the present invention.