Repurposing enzymes to catalyze non‐natural asymmetric transformations that are difficult to achieve using traditional chemical methods is of significant importance. Although radical C‐O bond formation has emerged as a powerful approach for constructing oxygen‐containing compounds, controlling the stereochemistry poses a great challenge. Here we present the development of a dual bio‐/photo‐catalytic system comprising an ene‐reductase and an organic dye for achieving stereoselective lactonizations. By integrating directed evolution and photoinduced single electron oxidation, we repurposed engineered ene‐reductases to steer non‐natural radical C‐O formations (one C‐O bond for hydrolactonizations and lactonization‐alkylations while two C‐O bonds for lactonization‐oxygenations). This dual catalysis gave a new approach to a diverse array of enantioenhanced 5‐ and 6‐membered lactones with vicinal stereocenters, part of which bears a quaternary stereocenter (up to 99% enantiomeric excess, up to 12.9:1 diastereomeric ratio). Detailed mechanistic studies, including computational simulations, uncovered the synergistic effect of the enzyme and the externally added organophotoredox catalyst Rh6G.

中文翻译：

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重新利用可见光激发烯还原酶来合成非对映和对映选择性内酯

重新利用酶来催化使用传统化学方法难以实现的非天然不对称转化具有重要意义。尽管自由基C-O键形成已成为构建含氧化合物的有效方法，但控制立体化学却提出了巨大的挑战。在这里，我们展示了一种双生物/光催化系统的开发，该系统包含烯还原酶和有机染料，用于实现立体选择性内酯化。通过整合定向进化和光诱导单电子氧化，我们重新利用了工程烯还原酶来引导非天然自由基C-O形成（一个C-O键用于加氢内酯化和内酯化-烷基化，而两个C-O键用于内酯化-氧化）。这种双重催化为多种具有邻位立构中心的对映体增强的 5 元和 6 元内酯提供了一种新方法，其中部分具有季立构中心（对映体过量高达 99%，非对映体比率高达 12.9:1）。详细的机理研究，包括计算模拟，揭示了酶和外部添加的有机光氧化还原催化剂 Rh6G 的协同效应。