Department of Material Chemistry, Graduate School of Engineering, Kyoto University , Kyotodaigaku-Katsura, Nishikyo, Kyoto 615-8510, Japan.
J Org Chem. 2017 Dec 1;82(23):12655-12668. doi: 10.1021/acs.joc.7b02451. Epub 2017 Nov 14.
In this study, the isothiourea-catalyzed enantioselective formal [4+3] cycloaddition of various α,β-unsaturated carboxylic acid derivatives with 2-aminothiophenols was developed. Mechanistic studies suggested that the reaction proceeds via a reversible sulfa-Michael addition to α,β-unsaturated acylammonium intermediates, followed by the enantioselective formation of a seven-membered ring, enabling the facile and divergent synthesis of optically active 2- and 3-substituted 1,5-benzothiazepines. This process was demonstrated to be highly versatile, affording the corresponding products in excellent regioselectivities and high enantioselectivities. Furthermore, this method enabled the synthesis of chiral 2,3-disubstituted 1,5-benzothiazepines in high regio-, enantio-, and diastereoselectivities. Hence, this protocol can be applied for the construction of a library of useful pharmaceutical candidates.
在这项研究中，开发了一种异硫脲催化的各种α，β-不饱和羧酸衍生物与 2-氨巯基苯酚的对映选择性形式[4+3]环加成反应。机理研究表明，反应通过α，β-不饱和酰基铵中间体的可逆亚磺酰迈克尔加成进行，然后对映选择性地形成一个七元环，从而实现了光学活性 2-和 3-取代的 1,5-苯并噻嗪的简便和发散合成。该过程表现出很高的多功能性，以优异的区域选择性和高对映选择性得到相应的产物。此外，该方法还能够以高区域选择性、对映选择性和非对映选择性合成手性 2,3-二取代的 1,5-苯并噻嗪。因此，该方案可用于构建有用的药物候选物文库。
