5,10-Dideaza-5,6,7,8 tetrahydrofolic acid

It is important to note that 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (369) is, as prepared above by catalytic hydrogenation of (388) (followed by saponification), a mixture of two diastereomers (dl and ll). Their separation was achieved by reaction of (369) with ( + )-10-camphorsulphonic acid to give a mixture (ddl and dll) of salts separated by fractional crystallization. Subsequent hydrolysis then gave (369) (isomer A,[a]589 = +31.09) and (isomer B, [a]S89 = -21.06). The initially isolated mixture of diastereomers had [a]s89 = + 10-22. 

Two diastereomers of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid, DDATHF, 127, both potent inhibitors of folate metabolism114 and de novo purine synthesis115, have been synthesized116 by catalytic reduction of the unsaturated intermediate diethyl 2-acetyl-5,10-dideaza-9,10-didehydrofolate with Adams catalyst and carrier-free tritium gas in AcOH and 3H20 solution. Each of the separated (6R) and (65) diastereomers had specific activity 11.2 Ci mmol-1 and contained tritium almost exclusively at the metabolically stable positions C(5), C(6), C(7), C(9), C(10) and the phenyl ring of DDATHF. 

These results prompted the researchers to investigate the application of 2-CDMT 137 in synthetic applications, such as in the asymmetric synthesis of Lometrexol 297 ((6/ )-5,10-dideaza-5,6,7,8-tetrahydrofolic acid) <1994JOC7036>, or in the synthesis of 298, a precursor of LY303870, an NK-1 antagonist <1995JOC7033> (Scheme 58). 

Taylor, E.C., GiUespie, P. and Patel, M. (1992) Novel 5-desmethylene analogs of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid as potential anticancer agents. J. Org. Chem., 57, 3218-25. 

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