Steric and Electronic Influences on the Diastereoselectivity of the Rh2(OAc)4-Catalyzed C−H Insertion in Chiral Ester Diazoanilides: Synthesis of Chiral, Nonracemic 4-Substituted 2-Pyrrolidinones

Abstract

A series of N-substituted N-(4-methoxyphenyl)-α-(alkoxycarbonyl)-α-diazoacetanilides, 10 and ent-10, wherein the alkoxy unit is a chiral auxiliary group [(−)-7 or (+)-8)], was prepared. The Rh2(OAc)4-catalyzed intramolecular C−H insertion reaction of 10 and ent-10, under optimized reaction conditions, was investigated as a route for the preparation of chiral, nonracemic 4-substituted 2-pyrrolidinones. The cyclization reaction led only to 2-pyrrolidinone and 2-azetidinone products; the former products were obtained as major and, in a few cases, as exclusive products. The type and nature of the N-substituent in 10 or ent-10 was found to govern the diastereoselectivity of the reaction. With N-alkyl groups, steric effects play an important role in determining the diastereoselectivity of the reaction. However, with N-arylethyl substituents, electronic effects transmitted by the aryl substituents influenced the diastereoselectivity of the C−H insertion reaction. Specifically, electron-donating substituents were found to markedly attenuate the diastereoselectivity of the reaction. The diastereoselectivity of the reaction ranged from moderate to high (37−98%). A transition-state model to explain the observed diastereoselectivity is provided. The synthetic utility of the method is demonstrated by the stereoselective synthesis of the medicinally important, unnatural amino acid trans-4-cyclohexyl-l-proline 23.