Catalytic enantioselective synthesis of O- and N-substituted quaternary carbon stereogenic centers

Abstract

Chapter 1: We disclose an Al-catalyzed enantioselective method for additions of Me2Zn and Et2Zn to α-ketoesters bearing aromatic alkenyl, and alkyl substituents. These transformations are promoted in the presence of a readily available amino acid-based ligand, and afforded the desired products in excellent yields and in up to 95% ee. In addition, we discovered a remarkable enhancement of efficiency and selectivity in the presence of an achiral phosphoramidate additive. Chapter 2: An efficient diastereo- and enantioselective Ag-catalyzed method for additions of a commercially available siloxyfuran to α-ketoimine esters is disclosed. Catalytic transformations require an inexpensive metal salt (AgOAc) and an air stable chiral ligand that is readily prepared in three steps from commercially available materials in 42% overall yield. Aryl- as well as heterocyclic substituted ketoimines can be used effectively in the Ag-catalyzed process. Additionally, two examples regarding reactions of alkyl-substituted ketoimines are presented. An electronically modified N-aryl group is introduced that is responsible for high reaction efficiency (>98% conversion, 72–95% yields after purification), diastereo- (up to >98:2 dr) and enantioselectivity (up to 97:3 er or 94% ee). The new N-aryl unit is also crucial for conversion of the asymmetric vinylogous Mannich products to the unprotected amines in high yields. Spectroscopic and X-ray data are among the physical evidence provided that shed light on the identity of the Ag-based chiral catalysts and some of the mechanistic subtleties of this class of enantioselective C–C bond forming processes.