Stereoselective Cyclopropanation of Electron-Deficient Olefins with a Cofactor Redesigned Carbene Transferase Featuring Radical Reactivity
Stereoselective Cyclopropanation of Electron-Deficient Olefins with a Cofactor Redesigned Carbene Transferase Featuring Radical Reactivity
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DOI：
10.1021/acscatal.9b02272
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发表时间：
2019-10-01
期刊：
影响因子：
12.9
通讯作者：
Fasa, Rudi
中科院分区：
文献类型：
--
作者：
Carminati, Daniela M.;Fasa, Rudi
工程肌红蛋白和其他血红素蛋白最近出现作为有前途的催化剂的不对称烯烃环丙烷化反应通过卡宾转移化学。尽管取得了这一进展，但使用这些系统转化贫电子烯烃已被证明是非常具有挑战性的。在这里，我们描述了一个肌红蛋白为基础的碳烯转移酶的设计，将一个非天然的铁卟啉辅因子和轴向配体，作为一个有效的催化剂的不对称环丙烷化的缺电子烯烃。使用这种金属酶，一个广泛的富电子和缺电子的烯烃环丙烷化，高效率和高非对映体和对映体选择性（高达>99%的de和ee）。机理研究表明，这种卡宾转移酶的扩大的反应范围是依赖于收购作为结果的重新配置的配位环境周围的金属中心的二卡宾自由基的反应性。自由基为基础的反应性，这个系统偏离亲电反应性的肌红蛋白和大多数已知的有机金属卡宾转移催化剂。这项工作展示了辅助因子重新设计对调节和扩大金属蛋白在非生物反应中的反应性的价值，并且它为缺电子烯烃的不对称环丙烷化提供了生物催化解决方案。预期这种生物催化剂所表现出的β-卡宾自由基反应性在各种其他合成转化的背景下证明是有用的。
Engineered myoglobins and other hemoproteins have recently emerged as promising catalysts for asymmetric olefin cyclopropanation reactions via carbene-transfer chemistry. Despite this progress, the transformation of electron-poor alkenes has proven to be very challenging using these systems. Here, we describe the design of a myoglobin-based carbene transferase incorporating a non-native iron-porphyrin cofactor and axial ligand, as an efficient catalyst for the asymmetric cyclopropanation of electron-deficient alkenes. Using this metalloenzyme, a broad range of both electron-rich and electron-deficient alkenes are cyclopropanated with high efficiency and high diastereo- and enantioselectivity (up to >99% de and ee). Mechanistic studies revealed that the expanded reaction scope of this carbene transferase is dependent upon the acquisition of metallocarbene radical reactivity as a result of the reconfigured coordination environment around the metal center. The radical-based reactivity of this system diverges from the electrophilic reactivity of myoglobin and most of the known organometallic carbene-transfer catalysts. This work showcases the value of cofactor redesign toward tuning and expanding the reactivity of metalloproteins in abiological reactions, and it provides a biocatalytic solution to the asymmetric cyclopropanation of electron-deficient alkenes. The metallocarbene radical reactivity exhibited by this biocatalyst is anticipated to prove useful in the context of a variety of other synthetic transformations.