Ren Xinkun, Chandgude Ajay L, Carminati Daniela M, Shen Zhuofan, Khare Sagar D, Fasan Rudi
Department of Chemistry, University of Rochester Rochester New York 14627 USA
Department of Chemistry and Chemical Biology, Rutgers University New Brunswick New Jersey 08854 USA.
Chem Sci. 2022 Jun 6;13(29):8550-8556. doi: 10.1039/d2sc01965e. eCollection 2022 Jul 29.
Organophosphonate compounds have represented a rich source of biologically active compounds, including enzyme inhibitors, antibiotics, and antimalarial agents. Here, we report the development of a highly stereoselective strategy for olefin cyclopropanation in the presence of a phosphonyl diazo reagent as carbene precursor. In combination with a 'substrate walking' protein engineering strategy, two sets of efficient and enantiodivergent myoglobin-based biocatalysts were developed for the synthesis of both (1,2) and (1,2) enantiomeric forms of the desired cyclopropylphosphonate ester products. This methodology enables the efficient transformation of a broad range of vinylarene substrates at a preparative scale ( gram scale) with up to 99% de and ee. Mechanistic studies provide insights into factors that contribute to make this reaction inherently more challenging than hemoprotein-catalyzed olefin cyclopropanation with ethyl diazoacetate investigated previously. This work expands the range of synthetically useful, enzyme-catalyzed transformations and paves the way to the development of metalloprotein catalysts for abiological carbene transfer reactions involving non-canonical carbene donor reagents.
有机膦酸酯化合物一直是生物活性化合物的丰富来源，包括酶抑制剂、抗生素和抗疟剂。在此，我们报道了一种在膦酰基重氮试剂作为卡宾前体存在下进行烯烃环丙烷化的高度立体选择性策略。结合“底物步移”蛋白质工程策略，开发了两组高效且对映体发散的基于肌红蛋白的生物催化剂，用于合成所需环丙基膦酸酯产物的（1,2）和（1,2）对映体形式。该方法能够在制备规模（克级）上高效转化多种乙烯基芳烃底物，非对映体过量（de）和对映体过量（ee）高达99%。机理研究揭示了一些因素，这些因素使得该反应比先前研究的血红蛋白催化的用重氮乙酸乙酯进行的烯烃环丙烷化反应本身更具挑战性。这项工作扩展了合成上有用的酶催化转化的范围，并为开发用于涉及非经典卡宾供体试剂的非生物卡宾转移反应的金属蛋白催化剂铺平了道路。
