Asymmetric Hydrogenation of Vinylthioethers: Access to Optically Active 1,5‐Benzothiazepine Derivatives

Abstract

A novel asymmetric hydrogenation of vinylthioethers was developed using a ruthenium(II) NHC complex. This method provides an efficient approach to optically active 1,5-benzothiazepines featuring stereocenters with C-S bonds. Excellent enantioselectivities (up to 95 % ee) and high yields (up to 99 %) were obtained for a variety of substrates bearing a range of useful functional groups. Moreover, this methodology could be directly applied to the synthesis of the antidepressant drug R-(-)-thiazesim.

Current advances on ruthenium(II) N-heterocyclic carbenes in hydrogenation reactions

“…An increase of the bulkiness of R 3 decreases the e.r. slightly After extending the substrate scope to various compounds that exhibit a natural product skeleton [94,95], investigations were directed to a more detailed mechanistic study. By exposing NHC 27 to Ru(cod)(2-methylallyl) 2 under catalytic conditions (KO t Bu, nhexane), bis-NHC 28a was formed (Fig.…”

“…The reaction is usually carried out with iso-propanol ( i PrOH), used as solvent, or formic acid as 93 hydrogen donors. Other examples of hydrogen donors, such as 94 glycerol, exist likewise, but appear only more recently in the liter- 95 ature and will not be part of this review. A detailed summary of 96 these advances is given by Voutchkova-Kostal et al [16].…”

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

“…[4] Nevertheless,c atalytic asymmetric reactions for the enantioselective synthesis of 1,5-benzothiazepine derivatives were realized only recently.Achiral ruthenium(II) Nheterocyclic carbene (NHC) complex was used to catalyze the hydrogenation of vinylthioethers, which was synthesizedf rom 2-amino-thiophenola nd b-substituted propiolica cid, was reported by the Glorius group to give optically active 1,5-benzothiazepinones (Scheme 1A). [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.…”

Catalytic Enantioselective Synthesis of Protecting‐Group‐Free 1,5‐Benzothiazepines

“…[9] One-pot multistep asymmetric procedures are highly attractive tools for the asymmetric synthesis of heterocyclic compounds, including pharmaceuticals.…”

“…[8] In 2016, Gloriusa nd colleagues devised ad ifferent approach based on the enantioselective ruthenium-Nheterocyclic-carbene-catalyzed hydrogenation of heterocyclic vinyl thioethers (Scheme 1b). [9] One-potm ultistep asymmetric procedures are highly attractive tools for the asymmetric synthesis of heterocyclic compounds, including pharmaceuticals. [10] Given the paucity of methods to access optically active 2,3-dihydro-1,5-benzothiazepinonesa nd our interest in developing stereoselective methodologies to prepareh eterocyclic compounds, [11] we embarked on as tudya imed at the development of as imple asymmetric synthesis of this versatile and relevant class of pharmacophores.…”