手性膦酸催化3-取代吲哚不对称F-C烷基化反应构建手性双吲哚基烷烃类化合物

Asymmetric synthesis of bis(indolyl)alkanes by phosphoric acid catalyzed F-C alkylation of 3-substituted indoles with 3-indolylmethanols

双吲哚基烷烃类化合物是一类具有生物活性的天然产物中间体,其合成研究已经成为目前热门研究领域。吲哚3-甲醇在酸性条件下可以失去一分子水形成吲哚基稳定的烯基亚胺正离子,这种烯基亚胺正离子可以和多种亲核试剂发生反应。因此,我们设想,在手性膦酸催化下,高活性的3-取代吲哚应该可以和这类烯基亚胺正离子发生不对称F-C烷基化反应。本文通过手性膦酸催化的3-取代吲哚与吲哚3-甲醇的不对称F-C烷基化反应构建手性双吲哚基烷烃类化合物,经过筛选各种结构的手性膦酸,发现3,3'-双(2-萘基)-联二萘酚膦酸为最佳催化剂,在此最佳催化剂催化下,反应可获得高达95%的产率以及67%ee。该合成策略为开发新药如新的抗生素药物提供了新的思路。

Bis（indolyl）alkanes are important intermediates of many bioactive natural products. Consequently, synthesis of bis（indolyl）alkanes is one of the popular research areas currently. 3-indolylmethanols are able to participate in a dehydration reaction in the presence of the acids to generate transient vinyliminium intermediates, which are principally reactive toward nucleophiles. Therefore, we envisioned that, as highly active nucleophiles, 3-substituted indoles could undergo asymmetric F-C alkylation with such kind of vinyliminium intermediates under the catalysis of the chiral phosphoric acids. Hererin we presented a chiral phosphoric acid catalyzed F-C alkylation of 3-substituted indoles with 3-indolylmethanols. A variety of chiral phosphoric acids were initially evaluated for the reaction. As a result, the 3,3＇-bis（2-naphthyl）BINOL-phosphoric acid proved to be the optimal catalyst. In the presence of the optimal catalyst, the reactions proceeded quickly（5 minutes）to afford a series of enantiosnriched bis（indolyl） alkanes in good yields（up to 95%）with moderate enantioselectivities（up to 67% ee）. This transformation enabled us to provide a wide range of structurally novel compounds for the research and development of new drugs, especially new antibiotics.