Facile Net Cycloaddition Approach to Optically Active 1,5-Benzothiazepines

Abstract

The 1,5-benzothiazepine moiety is well-known as a versatile pharmacophore, and its derivatives are expected to have antagonism against numerous diseases. Thus, it is desirable to develop a synthetic route that enables facile enantioselective preparation of a wide range of such derivatives. Although the cycloaddition approach could be considered a possible route to these compounds, to date, there has been no precedent of such a protocol. We therefore present the first example of a highly enantioselective net [4 + 3] cycloaddition to afford 1,5-benzothiazepines by utilizing α,β-unsaturated acylammonium intermediates generated by chiral isothiourea catalysts, which undergo two sequential chemoselective nucleophilic attacks by 2-aminothiophenols. This protocol provided cycloadducts in extremely high regioselectivity, with a good-to-excellent stereoselectivity being achieved regardless of the steric and electronic properties of the substrates. This method therefore offers promising synthetic routes for the construction of a library of optically active 1,5-benzothiazepines for assay evaluation.

Enantioselective Synthesis of N−H‐Free 1,5‐Benzothiazepines

“…A chiral ruthenium(II) N‐heterocyclic carbene (NHC) complex was used to catalyze the hydrogenation of vinylthioethers, which was synthesized from 2‐amino‐thiophenol and β‐substituted propiolic acid, was reported by the Glorius group to give optically active 1,5‐benzothiazepinones (Scheme A) . Asano and Matsubara utilized a chiral isothiourea accelerated enantioselective net [4+3] cycloaddition through α,β‐unsaturated acylammonium intermediates to afford the desired targets (Scheme B) . These strategies give direct access to 2‐substituted 1,5‐benzothiazepines, but N‐protection and deprotection processes are inevitable in order to obtain ( R )‐Thiazesim.…”

“…[5] Asano and Matsubara utilized ac hiral isothiourea accelerated enantioselective net [4+ +3] cycloaddition through a,b-unsaturated acylammonium intermediates to afford the desired targets (Scheme 1B). [6] These strategies give direct access to 2-substituted1 ,5-benzothiazepines, butN-protection and deprotection processes are inevitable in order to obtain (R)-Thiazesim. Although sequential sulfa-Michael addition and cyclization reactions between thiols and a,b-unsaturated carboxylic acid derivatives could give NÀH-free 1,5-benzothiazepines,n evertheless the presentm ethods are substrate-dependent and unusuall eaving groups are required (Scheme 1B).…”

Theoretical Density Functional Theory insights into the nature of chalcogen bonding between CX2 (X = S, Se, Te) and diazine from monomer to supramolecular complexes

“…Nevertheless, the importance of noncovalent interactions was demonstrated by the increasing number of studies in the fields of supramolecular architecture, synthesis, molecular recognition, catalysis and materials science . Among the various noncovalent interactions, chalcogen bonding has found application in several areas such as synthesis, catalysis and crystal engineering . The chalcogen bond is the noncovalent chalcogen‐chalcogen interaction in which one of the chalcogens acts as the acceptor of electron density.…”

Stereodivergent, Diels–Alder-initiated organocascades employing α,β-unsaturated acylammonium salts: scope, mechanism, and application

“…Most recently, Matsubara described the first example of a highly enantioselective net [4 + 3] cycloaddition to afford 1,5-benzothiazepines by utilizing α,β-unsaturated acylammonium intermediates generated by a chiral isothiourea catalyst. 32 …”