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

被引:33
作者
BARNETT, CJ
WILSON, TM
WENDEL, SR
WINNINGHAM, MJ
DEETER, JB
机构
[1] Chemical Process Research and Development Division, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis
[2] Crystallography Laboratory, Chemistry and Biotechnology Research Division, Lilly Research Laboratories, Eli Lilly and Co.
关键词
D O I
10.1021/jo00102a031
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
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.
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页码:7038 / 7045
页数:8
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