Resolution and Determination of the Absolute Stereochemistry of α and β-Aryl-Substituted γ-Methylenevalerolactones, Alternate Substrate Inhibitors for Serine Proteases

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.