Double rings made with heme Cyclic organic structures with adjacent three-carbon rings—bicyclobutanes—are useful starting materials for chemical and materials synthesis owing to their extreme ring strain. Constructing these molecules is a challenging task for organic chemists, especially if a single stereoisomer is desired. Chen et al. engineered a heme-containing enzyme to catalyze sequential carbene insertion reactions using an alkyne substrate. Starting with an enzyme that could only catalyze a single carbene insertion, a series of mutations led to variants that catalyzed efficient, stereoselective production of bicyclobutanes. By using a less reactive alkyne substrate and screening more variants with active site mutations, the authors found enzymes that stop at either enantiomer of the intermediate cyclopropene. Science, this issue p. 71 An engineered heme-containing enzyme catalyzes asymmetric formation of strained bicyclobutanes and cyclopropenes. Small carbocycles are structurally rigid and possess high intrinsic energy due to their ring strain. These features lead to broad applications but also create challenges for their construction. We report the engineering of hemeproteins that catalyze the formation of chiral bicyclobutanes, one of the most strained four-membered systems, via successive carbene addition to unsaturated carbon-carbon bonds. Enzymes that produce cyclopropenes, putative intermediates to the bicyclobutanes, were also identified. These genetically encoded proteins are readily optimized by directed evolution, function in Escherichia coli, and act on structurally diverse substrates with high efficiency and selectivity, providing an effective route to many chiral strained structures. This biotransformation is easily performed at preparative scale, and the resulting strained carbocycles can be derivatized, opening myriad potential applications.

中文翻译：

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高应变碳环的酶促构建

由血红素制成的双环 具有相邻三碳环（双环丁烷）的环状有机结构由于其极端的环应变，是化学和材料合成的有用起始材料。构建这些分子对有机化学家来说是一项具有挑战性的任务，尤其是在需要单一立体异构体的情况下。陈等人。设计了一种含血红素的酶，以使用炔底物催化连续的卡宾插入反应。从只能催化单个卡宾插入的酶开始，一系列突变导致变体催化高效、立体选择性地生产双环丁烷。通过使用反应性较低的炔烃底物并筛选更多具有活性位点突变的变体，作者发现了终止于中间体环丙烯的任一对映异构体的酶。科学，这个问题 p。71 一种工程化的含血红素酶催化不对称形成的张力双环丁烷和环丙烯。小碳环在结构上是刚性的，并且由于它们的环应变而具有高内能。这些特征导致了广泛的应用，但也给它们的构造带来了挑战。我们报告了通过连续卡宾加成到不饱和碳-碳键来催化手性双环丁烷形成的血红素蛋白工程，这是最紧张的四元系统之一。还鉴定了产生环丙烯（双环丁烷的假定中间体）的酶。这些基因编码的蛋白质很容易通过定向进化优化，在大肠杆菌中发挥作用，并以高效率和选择性作用于结构多样的底物，为许多手性应变结构提供了有效途径。这种生物转化很容易在制备规模上进行，产生的应变碳环可以衍生化，开启无数潜在的应用。