ASYMMETRIC-SYNTHESIS OF LOMETREXOL ((6R)-5,10-DIDEAZA-5,6,7,8-TETRAHYDROFOLIC ACID)

An enantioselective synthesis of lometrexol (1) which utilizes (SR)-2-piperidone 18 as a key intermediate is described. Lipase-catalyzed enantioselective esterification of 1,3-propanediol derivative 5 provided (R)-(+)-6, the absolute configuration of which was established by X-ray analysis of the (S)-(alpha-methylbenzyl)carbamate derivative 8. By suitable choice of functional group protection strategies, (R)-(+)-6 could be converted to either enantiomer of azido alcohol 11. The S isomer of 11 was utilized to prepare 18 in three steps. Conversion of 18 to the thiolactam and cyclization with guanidine provided (6R)-5-deaza-5,6,7,8-tetrahydropterin 20. Cyanation of 20 (cuprous cyanide) followed by hydrolysis of the resulting nitrile 21 gave (6R)-5,10-dideaza-5,6,7,8-tetrahydropteroic acid (22). The synthesis of 1 was completed by reaction of 22 with diethyl glutamate via an active ester coupling procedure followed by hydrolysis of the resulting diester.