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.

来源：

JOURNAL OF ORGANIC CHEMISTRY | 1994年 / 59卷 / 23期

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.

引用

页码：7038 / 7045

页数：8

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