Development of New N,N-Ligands for the Enantioselective Copper(II)-Catalyzed Henry Reaction

Abstract

This account shows our efforts towards the development of new N, N-ligandsand their application in the asymmetric Henry reaction. Iminopyridineligands were prepared by the condensation of chiral monoterpeneketones and pyridinylalkylamines. The complexes of these ligandswith copper(II) ions catalyzed the enantio-selective additionof nitromethane to aldehydes with generally high yields and moderateenantioselectivities. The same reaction with other nitroalkanesgave racemic products. Stereoselective reduction of the imino groupallowed us to obtain new aminopyridine ligands. The new ligandswere shown to be more efficient, and they catalyzed the additionof nitromethane and also larger nitroalkanes to aldehydes to givethe corresponding products in generally very high yields and excellentenantiomeric excesses. We have used this aminopyridine catalyticsystem in the first catalytic enantioselective Henry reactions withbromo(nitro)methane and methyl 4-nitrobutanoate. The reaction involvingthe latter substrate gave multifunctional chiral building blocksthat were transformed into γ-lactams and δ-lactones.The application of the reaction to the synthesis of known amino(aryl)ethanolpharmaceuticals is also reported. Im-inopyridine ligands,however, were more efficient in the addition of nitromethane to α-ketoesters. 1 Introduction 1.1 Enantioselective Copper(II)-Catalyzed Henry Reaction 2 Enantioselective Henry Reaction with Aldehydes Catalyzed byCopper(II)-Iminopyridine Complexes 2.1 Design and Synthesis of Iminopyridine Ligands 2.2 Enantioselective Addition of Nitromethane to Aldehydes 2.3 Stereochemical Models 3 Enantioselective Henry Reaction with Aldehydes Catalyzed byCopper(II)-Aminopyridine Complexes 3.1 Design and Synthesis of Aminopyridine Ligands 3.2 Enantioselective Addition of Nitroalkanes to Aldehydes 3.3 Enantioselective Addition of Bromo(nitro)methane to -Aldehydes 3.4 Enantioselective Addition of Methyl 4-nitrobutanoate to Aldehydes 3.5 Synthesis of Chiral Amino(aryl)ethanol Derivatives 4 Enantioselective Henry Reaction with α-Keto Esters 5 Conclusion