Stereoisomerically enriched N-protected β-lactams using candida antarctica
View Patent ↗The present disclosure provides enzymatic methods for generating stereoisomerically pure products by resolving a racemic mixture of N-protected β-lactams with a lipase from Candida antarctica with high stereospecificity. The presence of a carbamate protecting group, such as the tert-butoxycarbonyl group protecting group, on the β-lactam enhances enzyme catalysis and stereoselectivity.
1. A method for generating a stereoisomerically pure N-protected β-lactam from a mixture of diastereomers, comprising contacting an N-protected β-lactam mixture comprising enantiomers according to structural formulae (1) and (2):
wherein:
A represents a saturated or unsaturated, monocyclic, polycyclic or bridged polycyclic ring; and
R is a carbamate or thiocarbamate protecting group,
with a lipase from Candida antarctica under conditions in which the lipase selectively cleaves enantiomer 2, thereby yielding a mixture of reaction products according to structural formulae 1 and 4:
2. The method of claim 1 , wherein the carbamate protecting group is of the formula —C(O)OR 1 , where R 1 is selected from unsubstituted or substituted alkyl, unsubstituted or substituted (C6-C20) aryl and substituted or unsubstituted (C7-C26) arylalkyl.
3. The method of claim 2 , wherein R 1 is selected from t-butyl and benzyl.
4. The method of claim 1 , wherein A is selected from bicycloheptenyl, bicycloheptyl, cycloheptyl, cycloheptenyl, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, cyclopropyl, and cyclobutyl.
5. The method of claim 1 , wherein the lipase is a type B lipase.
6. The method of claim 1 , wherein the lipase is bound to a resin.
7. The method of claim 1 , wherein a catalytic amount of the lipase is used.
8. The method of claim 1 , wherein the contacting is carried out at a temperature in the range of about 0-80° C.
9. The method of claim 8 , wherein the temperature in the range of about 20-60° C.
10. The method of claim 1 , wherein the contacting is carried out in a solvent selected from diisopropyl ether, tetrahydrofuran, butanol, toluene, hexanes, acetonitrile, and mixtures thereof.
11. The method of claim 10 , wherein the solvent has a water content in the range about of 0.1 to 1.0 wt %.
12. The method of claim 1 , which further comprises the step of isolating compound 1 from compound 4.
13. The method of claim 12 , wherein the isolation is carried out by creating a base addition salt of compound 4 and removing said base addition salt via aqueous extraction of a mixture of an organic solution of compound 1 and said base addition salt.