Chemoselective Cyclopropanation over Carbene Y–H Insertion Catalyzed by an Engineered Carbene Transferase,The Journal of Organic Chemistry

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Chemoselective Cyclopropanation over Carbene Y–H Insertion Catalyzed by an Engineered Carbene Transferase
The Journal of Organic Chemistry ( IF 3.3 ) Pub Date : 2018-06-15 00:00:00 , DOI: 10.1021/acs.joc.8b00946
Eric J. Moore ₁ , Viktoria Steck ₁ , Priyanka Bajaj ₁ , Rudi Fasan ₁

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Hemoproteins have recently emerged as promising biocatalysts for promoting a variety of carbene transfer reactions including cyclopropanation and Y–H insertion (Y = N, S, Si, B). For these and synthetic carbene transfer catalysts alike, achieving high chemoselectivity toward cyclopropanation in olefin substrates bearing unprotected Y–H groups has proven remarkably challenging due to competition from the more facile carbene Y–H insertion reaction. In this report, we describe the development of a novel artificial metalloenzyme based on an engineered myoglobin incorporating a serine-ligated Co-porphyrin cofactor that is capable of offering high selectivity toward olefin cyclopropanation over N–H and Si–H insertion. Intramolecular competition experiments revealed a distinct and dramatically altered chemoselectivity of the Mb(H64V,V68A,H93S)[Co(ppIX)] variant in carbene transfer reactions compared to myoglobin-based variants containing the native histidine-ligated heme cofactor or other metal/proximal ligand substitutions. These studies highlight the functional plasticity of myoglobin as a “carbene transferase” and illustrate how modulation of the cofactor environment within this metalloprotein scaffold represents a valuable strategy for accessing carbene transfer reactivity not exhibited by naturally occurring hemoproteins or transition metal catalysts.

中文翻译：

工程化的碳转移酶催化的碳氢Y–H插入上的化学选择性环丙烷化

血红蛋白最近已成为有希望的生物催化剂，可用于促进各种卡宾转移反应，包括环丙烷化和Y–H插入（Y = N，S，Si，B）。对于这些和合成卡宾转移催化剂，由于与更简便的卡宾Y–H插入反应之间的竞争，事实证明，在带有未保护的Y–H基团的烯烃底物中，对环丙烷化具有很高的化学选择性。在本报告中，我们描述了一种基于工程化的肌红蛋白的新型人工金属酶的开发，该酶结合了丝氨酸连接的卟啉辅因子，能够通过NH和Si-H插入对烯烃环丙烷化提供高选择性。分子内竞争实验显示Mb（H64V，V68A，卡宾转移反应中的H93S）[Co（ppIX）]变体与含有天然组氨酸连接的血红素辅因子或其他金属/近端配体取代的基于肌红蛋白的变体相比。这些研究突出了肌红蛋白作为“卡宾转移酶”的功能可塑性，并说明了在该金属蛋白支架内调节辅因子环境如何代表获得天然血红蛋白或过渡金属催化剂未表现出的卡宾转移反应性的有价值的策略。

更新日期：2018-06-15

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