10.1021/jacs.5b02537.s001 Yukihiro Fukata Yukihiro Fukata Keisuke Asano Keisuke Asano Seijiro Matsubara Seijiro Matsubara Facile Net Cycloaddition Approach to Optically Active 1,5‑Benzothiazepines American Chemical Society 2015 sequential chemoselective nucleophilic attacks benzothiazepine assay evaluation cycloaddition approach Cycloaddition Approach derivative acylammonium intermediates enantioselective preparation chiral isothiourea catalysts 2015-04-29 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Facile_Net_Cycloaddition_Approach_to_Optically_Active_1_5_Benzothiazepines/2172163 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.