Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines.
Synthesis of Stereoenriched Piperidines via Chemo-Enzymatic Dearomatization of Activated Pyridines.
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DOI：
10.1021/jacs.2c07143
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发表时间：
2022-11-23
影响因子：
15
通讯作者：
Turner, Nicholas J.
中科院分区：
文献类型：
--
作者：
Harawa, Vanessa;Thorpe, Thomas W.;Marshall, James R.;Sangster, Jack J.;Gilio, Amelia K.;Pirvu, Lucian;Heath, Rachel S.;Angelastro, Antonio;Finnigan, James D.;Charnock, Simon J.;Nafie, Jordan W.;Grogan, Gideon;Whitehead, Roger C.;Turner, Nicholas J.
开发高效、可持续的氮杂环合成方法是化学工业的重要目标。特别是，取代的手性哌啶类化合物由于其在医药相关化合物及其前体中的普遍存在而成为重要的靶标。合成这种特殊支架的一种潜在的生物催化方法将是容易组装的吡啶的不对称脱芳构化。然而，自然界还没有产生一种专门用于该反应的合适的生物催化剂。本文通过化学合成和生物催化相结合的方法，对活性吡啶的不对称脱芳构化反应提出了一种通用的方法，并用精确的立体化学方法合成了取代的哌啶类化合物。关键步骤包括立体选择性的一锅胺氧化酶/烯亚胺还原酶级联反应，将N-取代四氢吡啶转化为立体定义的3-和3，4-取代哌啶。这种化学-酶方法已被证明对抗精神病药物倍拉莫和OSU-6162的合成中的关键转化以及卵巢癌单药尼拉帕利布合成路线中两个重要中间体的制备是有用的。
The development of efficient and sustainable methods for the synthesis of nitrogen heterocycles is an important goal for the chemical industry. In particular, substituted chiral piperidines are prominent targets due to their prevalence in medicinally relevant compounds and their precursors. A potential biocatalytic approach to the synthesis of this privileged scaffold would be the asymmetric dearomatization of readily assembled activated pyridines. However, nature is yet to yield a suitable biocatalyst specifically for this reaction. Here, by combining chemical synthesis and biocatalysis, we present a general chemo-enzymatic approach for the asymmetric dearomatization of activated pyridines for the preparation of substituted piperidines with precise stereochemistry. The key step involves a stereoselective one-pot amine oxidase/ene imine reductase cascade to convert N-substituted tetrahydropyridines to stereo-defined 3- and 3,4-substituted piperidines. This chemo-enzymatic approach has proved useful for key transformations in the syntheses of antipsychotic drugs Preclamol and OSU-6162, as well as for the preparation of two important intermediates in synthetic routes of the ovarian cancer monotherapeutic Niraparib.
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影响因子：
15
作者：
Hai Y;Chen M;Huang A;Tang Y
通讯作者：
Tang Y
影响因子：
4.5
作者：
Heath, Rachel S.;Pontini, Marta;Turner, Nicholas J.
通讯作者：
Turner, Nicholas J.
影响因子：
3.4
作者：
Chung, Cheol K.;Bulger, Paul G.;Emerson, Khateeta M.
通讯作者：
Emerson, Khateeta M.
影响因子：
7.3
作者：
KALGUTKAR, AS;CASTAGNOLI, N
通讯作者：
CASTAGNOLI, N
影响因子：
2.7
作者：
Baumann M;Baxendale IR
通讯作者：
Baxendale IR