An Enzymatic Platform for the Highly Enantioselective and Stereodivergent Construction of Cyclopropyl-δ-lactones.
An Enzymatic Platform for the Highly Enantioselective and Stereodivergent Construction of Cyclopropyl-δ-lactones.
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DOI：
10.1002/anie.202007953
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发表时间：
2020-11-23
期刊：
影响因子：
--
通讯作者：
Fasan R
中科院分区：
文献类型：
--
作者：
Ren X;Liu N;Chandgude AL;Fasan R
非生物酶为可持续化学提供了新的机遇。在这里，我们报告了源自抹香鲸肌红蛋白的生物催化剂的开发，该催化剂利用卡宾转移机制来不对称合成环丙烷稠合-δ-内酯，这是许多生物活性天然产物中发现的关键结构基序。虽然氯高铁血红素、野生型肌红蛋白和其他血红蛋白无法催化该反应，但可以通过蛋白质工程重塑肌红蛋白支架，以允许以高产率和高达 99% 对映体过量的方式对广谱高烯丙基重氮乙酸底物进行分子内环丙烷化。通过替代的进化轨迹，还获得了立体分歧的生物催化剂，用于提供所需双环产物的镜像形式。与全细胞转化相结合，基于肌红蛋白的生物催化剂很容易应用于克级的环丙基-δ-内酯支架的不对称构建，并且可以进一步精加工以提供各种对映体纯三取代环丙烷。 《指环王》：报道了一种通过高烯丙基重氮乙酸酯的分子内环丙烷化立体发散合成环丙基-δ-内酯的生物催化策略。肌红蛋白被重新设计成两种对映互补生物催化剂，能够产生一系列芳基和烷基取代的环丙烷稠合δ-内酯支架，可用于药物化学和天然产物合成。
Abiological enzymes offers new opportunities for sustainable chemistry. Here we report the development of biological catalysts derived from sperm whale myoglobin that exploit a carbene transfer mechanism for the asymmetric synthesis of cyclopropane-fused-δ-lactones, which are key structural motifs found in many biologically active natural products. While hemin, wild-type myoglobin, and other hemoproteins are unable to catalyze this reaction, the myoglobin scaffold could be remodeled by protein engineering to permit the intramolecular cyclopropanation of a broad spectrum of homoallylic diazoacetate substrates in high yields and with up to 99% enantiomeric excess. Via an alternate evolutionary trajectory, a stereodivergent biocatalyst was also obtained for affording mirror-image forms of the desired bicyclic products. In combination with whole-cell transformations, the myoglobin-based biocatalyst was readily applied to enable the asymmetric construction of a cyclopropyl-δ-lactone scaffold at a gram scale, which could be further elaborated to furnish a variety of enantiopure trisubstituted cyclopropanes. Lords of the Rings: A biocatalytic strategy for the stereodivergent synthesis of cyclopropyl-δ-lactones via the intramolecular cyclopropanation of homoallylic diazoacetates is reported. Myoglobin was re-engineered into two enantiocomplementary biocatalysts capable of producing a range of aryl- and alkyl-substituted cyclopropane-fused δ-lactone scaffolds useful for medicinal chemistry and natural product synthesis.
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影响因子：
64.8
作者：
Kan SBJ;Huang X;Gumulya Y;Chen K;Arnold FH
通讯作者：
Arnold FH
DOI：
10.1002/anie.201810059
发表时间：
2018-11-26
期刊：
Angewandte Chemie (International ed. in English)
影响因子：
--
作者：
Chandgude AL;Fasan R
通讯作者：
Fasan R
细胞色素 c 的定向进化促进碳-硅键形成：赋予硅生命。
DOI：
10.1126/science.aah6219
发表时间：
2016-11-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kan SB;Lewis RD;Chen K;Arnold FH
通讯作者：
Arnold FH
影响因子：
16.6
作者：
Srivastava P;Yang H;Ellis-Guardiola K;Lewis JC
通讯作者：
Lewis JC
影响因子：
16.6
作者：
France, Scott P.;Aleku, Godwin A.;Turner, Nicholas J.
通讯作者：
Turner, Nicholas J.