Protoglobin-Catalyzed Formation of cis-Trifluoromethyl-Substituted Cyclopropanes by Carbene Transfer.
Protoglobin-Catalyzed Formation of cis-Trifluoromethyl-Substituted Cyclopropanes by Carbene Transfer.
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DOI：
10.1002/anie.202208936
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发表时间：
2022-12
影响因子：
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通讯作者：
Lucas Schaus;Anuvab Das;A. M. Knight;Gonzalo Jiménez‐Osés;K. Houk;M. Garcia‐Borràs;F. Arnold;Xiong Huang
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作者：
Lucas Schaus;Anuvab Das;A. M. Knight;Gonzalo Jiménez‐Osés;K. Houk;M. Garcia‐Borràs;F. Arnold;Xiong Huang
三氟甲基取代的环丙烷（CF 3-CPA）是一类重要的药物发现化合物。虽然已经开发了几种方法用于合成反式-CF 3-CPA，但立体选择性地产生相应的顺式-非对映异构体仍然是一个巨大的挑战。我们报道了一种生物催化剂，用于非对映体和对映体选择性合成顺式-CF 3-CPA，并对多种烯烃具有活性。我们发现，来自Aeropyrnum pernix的工程改造的原球蛋白（ApePgb）可以在制备规模下以低至优异的产率（6- 55%）和对映选择性（17- 99%ee）催化这种不寻常的反应，这取决于底物。计算结果表明，在原球蛋白的活性位点的空间环境迫使铁卡宾和底物采取一个pro-cis近攻击构象。这项工作证明了酶催化剂解决具有挑战性的化学问题的能力，并为扩大CF 3-CPA的结构多样性以用于药物发现提供了有力的手段。
Trifluoromethyl-substituted cyclopropanes (CF3 -CPAs) constitute an important class of compounds for drug discovery. While several methods have been developed for synthesis of trans-CF3 -CPAs, stereoselective production of corresponding cis-diastereomers remains a formidable challenge. We report a biocatalyst for diastereo- and enantio-selective synthesis of cis-CF3 -CPAs with activity on a variety of alkenes. We found that an engineered protoglobin from Aeropyrnum pernix (ApePgb) can catalyze this unusual reaction at preparative scale with low-to-excellent yield (6-55 %) and enantioselectivity (17-99 % ee), depending on the substrate. Computational studies revealed that the steric environment in the active site of the protoglobin forced iron-carbenoid and substrates to adopt a pro-cis near-attack conformation. This work demonstrates the capability of enzyme catalysts to tackle challenging chemistry problems and provides a powerful means to expand the structural diversity of CF3 -CPAs for drug discovery.