Facile Net Cycloaddition Approach to Optically Active 1,5-Benzothiazepines
Facile Net Cycloaddition Approach to Optically Active 1,5-Benzothiazepines
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DOI：
10.1021/jacs.5b02537
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发表时间：
2015-04-29
影响因子：
15
通讯作者：
Matsubara, Seijiro
中科院分区：
文献类型：
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作者：
Fukata, Yukihiro;Asano, Keisuke;Matsubara, Seijiro
1,5-苯并硫氮杂卓部分是众所周知的多功能药效基团，其衍生物预计对多种疾病具有拮抗作用。因此，需要开发一种能够容易地对映选择性制备多种此类衍生物的合成路线。尽管环加成方法可以被认为是获得这些化合物的可能途径，但迄今为止，还没有这样的方案的先例。因此，我们提出了第一个高度对映选择性网[4 + 3]环加成的例子，通过利用手性异硫脲催化剂产生的α，β-不饱和酰基铵中间体提供1,5-苯并硫氮杂卓，该中间体经历2-氨基苯硫酚的两次连续化学选择性亲核攻击。该方案提供了具有极高区域选择性的环加合物，无论底物的空间和电子性质如何，都可以实现良好至优异的立体选择性。因此，该方法为构建用于测定评估的光学活性 1,5-苯并硫氮杂卓库提供了有前途的合成路线。
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 alpha,beta-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.