Efficient chemoenzymatic synthesis of pelitrexol via enzymic differentiation of a remote stereocenter.
[structure: see text] An efficient chemoenzymatic process is described for the synthesis of pelitrexol, a novel GARFT inhibitor. The remoteness of this molecule's stereocenter in the tetrahydropterin moiety from the terminal carbonyl group provided a significant challenge in synthesis. The introduction of an oxalamic ester adjacent to the stereocenter dramatically enhanced an enzyme's enantioselectivity for hydrolysis at the terminal ester, producing the desired S-acid with high optical purity and yield. The recycling of the "wrong" enantiomer is achieved via a dehydrogenation/hydrogenation strategy.
Hu
Shanghui
S
Pfizer Global Research and Development, Chemical Research and Development, 10578 Science Center Drive, La Jolla, California 92121, USA. Shanghui.Hu@pfizer.com
Kelly
Sean
S
Lee
Steve
S
Tao
Junhua
J
Flahive
Erik
E
D002384:Catalysis; D005656:Fungal Proteins; D008049:Lipase / Q000378:metabolism; D015394:Molecular Structure; D051026:Phosphoribosylglycinamide Formyltransferase / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013876:Thiophenes / Q000138:chemical synthesis*
D005656:Fungal Proteins; D013876:Thiophenes; C516135:pelitrexol; D051026:Phosphoribosylglycinamide Formyltransferase; D008049:Lipase; C431349:lipase B, Candida antarctica