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. Issue 50 (6th August 2020)

• Record Type: Journal Article
• Authors: Teloxa, Saul F.; Kennington, Stuart C. D.; Camats, Marc; Romea, Pedro; Urpí, Fèlix; Aullón, Gabriel; Font‐Bardia, Mercè
• Is Part Of: Chemistry. Volume 26:Issue 50(2020)
• Page Start: 11540
• Page End: 11548
• Publication Date: 2020-08-06
• Subjects: asymmetric synthesis -- catalysis -- C−C bond forming reactions -- lacosamide -- synthetic methods; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202001057
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: A 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. Abstract : One step ahead : A direct, enantioselective, and catalytic approach to the synthesis of α‐amino acids in which an achiral 1, 3‐thiazolidine‐2‐thione is used for the sake of attaining high yields is reported. Such a scaffold also acts as coupling reagent to give, in a single step, enantiomerically pure amide derivatives, which can then be converted into biologically active compounds as lacosamide in a rapid and straightforward manner.