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

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.

Direct and Asymmetric Aldol Reactions of N‐Azidoacetyl‐1,3‐thiazolidine‐2‐thione Catalyzed by Chiral Nickel(II) Complexes. A New Approach to the Synthesis of β‐Hydroxy‐α‐Amino Acids

“…In agreement with this, the nickel atom presents a distorted square‐planar environment ( S SQ‐4 =3.7), further away from the tetrahedral one by continuous shape measures (78 %). For instance, P−Ni‐S and P−Ni‐O opposite angles are 159° and 160°, respectively, influenced by the diphosphane bite angle (97°) [16,18c] …”

Stereocontrolled Aldol-Like Reactions Involving Oxocarbenium Intermediates

“…Indeed, the reaction with trimethyl orthoformate catalyzed by [( S )-Tol-BINAP]NiCl 2 ( 169 ) and treatment of the resultant adduct with benzyl amine produced enantiomerically enriched ( ee 96%) amide 170 in an 88% yield, from which the total synthesis of the antiepileptic agent lacosamide was completed in a few steps. 64…”

“…tiomerically enriched (ee 96%) amide 170 in an 88% yield, from which the total synthesis of the antiepileptic agent lacosamide was completed in a few steps. 64 The successful installation of the C stereocenter in so many processes encouraged us to tackle further challenges. In particular, we envisaged that the appropriate silyl triflate activation of an aldehyde might lead to an oxocarbeniumlike intermediate (Route B in Scheme 31) able to react with simultaneously generated nickel enolates to provide the corresponding silyl-protected aldol products and thus selectively introduce two new stereocenters.…”