Direct, enantioselective, and nickel(II) catalyzed reactions of N-azidoacetyl thioimides with trimethyl orthoformate: a new combined methodology for the rapid synthesis of lacosamide and derivatives

Teloxa, Saul F.Kennington, Stuart C. D.Camats Gangonells, MarcRomea, PedroUrpí Tubella, FèlixAullón López, GabrielFont Bardia, Ma. Mercedes2020-09-092021-04-082020-04-080947-6539https://hdl.handle.net/2445/170414A direct and highly enantioselective reaction of N-azidoacetyl-1,3-thiazolidine-2-thione with trimethyl orthoformate catalyzed by Tol-BINAPNiCl2 in the presence of TESOTf and 2,6-lutidine is reported. The heterocyclic scaffold can be easily removed by addition of a wide array of amines to give the corresponding enantiomerically pure 2-azido-3,3-dimethoxypropanamides in high yields. Appropriate manipulation of the N-benzyl amide derivative provides an efficient access to the antiepileptic agent lacosamide through a new enantioselective C−C bond-forming process. DFT computational studies uncover clues for the understanding of the remarkable stereocontrol of the addition of a nickel(II) enolate to a putative oxocarbenium intermediate from trimethyl orthoformate.9 p.application/pdfeng(c) Wiley-VCH, 2020AnticonvulsiusSíntesi asimètricaCompostos de níquelAnticonvulsantsAsymmetric synthesisNickel compoundsDirect, enantioselective, and nickel(II) catalyzed reactions of N-azidoacetyl thioimides with trimethyl orthoformate: a new combined methodology for the rapid synthesis of lacosamide and derivativesinfo:eu-repo/semantics/article7029862020-09-09info:eu-repo/semantics/openAccess