Galantamine derivatives: Synthesis, NMR study, DFT calculations and application in asymmetric catalysis

Abstract

In a search of effective ligands for asymmetric catalysis (−)-galantamine has been selected as a complex chiral framework for the synthesis of four novel diphenylphosphino-benzenecarboxamides. Their application in Pd-catalyzed asymmetric allylic alkylation proceeded with excellent conversion and moderate enantioselectivity due to the conformational flexibility of the galantamine derived compounds. To get insights into their molecular structure and conformational behaviour in solution a combination of experimental NMR methods and theoretical DFT calculations has been employed. The ligands exist as four conformers due to restricted rotation around the amide bond and due to flexibility of the 2,3,4,5-tetrahydro-1H-azepine ring. The experimentally measured barriers of C–N rotation (17.1 ÷ 17.7 kcal/mol) are higher than the barriers of observed exchange process in azepine ring (13.7 ÷ 14.0 kcal/mol). Their BOC precursors exist in solution as two conformers due to restricted rotation around the carbamate C–N bond. The experimentally measured barrier is lower than the amide barriers in ligands (16.1 ÷ 16.5 kcal/mol).