To study the enantioselectivity of alternate substrate inhibition of chymotrypsin by chiral a- and 0-aryl-substituted enol lactones, we have prepared four of these lactones in homochiral form: 3-phenyl-6-methylenetetrahydro-2-pyranone («Ph6H, Ha), 3-(l-naphthyl)-6-methylenetetrahydro-2-pyranone (αNp6H, lIb), 4-phenyl-6-methylenetetrahydro-2-pyranone (βPh6H, IIIa) and 4-(l-naphthyl)-6-methylenetetrahydro-2-pyranone (βNp6H, IIIb). Their resolution was carried out on the acetylenic acid precursors α and β-aryl-5-hexynoic acids (2ab and 7ab, respectively) by silica gel chromatographic separation of the corresponding (R)-phenylglycinol amide derivatives. The homochiral acids, obtained by acid hydrolysis of the amides, have enantiomeric excesses of 94-100% and are readily converted to the enol lactones by mercury-catalyzed lactonization. The absolute configuration of the 0-aryl-substituted lactones was established by X-ray crystallographic analysis of one of the phenylglycinol amide diastereomers, cocrystallized with triphenylphosphine oxide; the configuration of the α-aryl-substituted lactones is based on a stereochemical correlation. In all cases, the assigned stereochemistry of the amides is consistent with their chromatographic elution order and the chemical shift of diagnostic resonances in the 1H NMR spectra. Both enantiomers of the Ilia hydrolysis product β-phenyl-substituted 5-oxohexanoic acid 10a were prepared by an asymmetric synthesis using the RAMP and SAMP hydrazones; their stereochemistry was correlated with that of the corresponding acetylenic acids.
ASJC Scopus subject areas
- Organic Chemistry