Catalytic asymmetric dearomatization represents a powerful means to convert flat aromatic compounds into stereochemically well-defined three-dimensional molecular scaffolds. Using new-to-nature metalloredox biocatalysis, we describe an enzymatic strategy for catalytic asymmetric dearomatization via a challenging radical mechanism that has eluded small-molecule catalysts. Enabled by directed evolution, new-to-nature radical dearomatases P450_rad1–P450_rad5 facilitated asymmetric dearomatization of a broad spectrum of aromatic substrates, including indoles, pyrroles and phenols, allowing both enantioconvergent and enantiodivergent radical dearomatization reactions to be accomplished with excellent enzymatic control. Computational studies revealed the importance of additional hydrogen bonding interactions between the engineered metalloenzyme and the reactive intermediate in enhancing enzymatic activity and enantiocontrol. Furthermore, designer non-ionic surfactants were found to significantly accelerate this biotransformation, providing an alternative means to promote otherwise sluggish new-to-nature biotransformations. Together, this evolvable metalloenzyme platform opens up new avenues to advance challenging catalytic asymmetric dearomatization processes involving free radical intermediates.

催化不对称脱芳构化是将平面芳香族化合物转化为立体化学明确的三维分子支架的有力手段。利用新颖的金属氧化还原生物催化，我们描述了一种通过小分子催化剂无法解决的具有挑战性的自由基机制催化不对称脱芳构化的酶促策略。通过定向进化，新型自由基脱芳构酶 P450 _rad1 –P450 _{rad 5}促进了广谱芳香族底物（包括吲哚、吡咯和苯酚）的不对称脱芳构化，从而可以通过出色的酶促完成对映会聚和对映发散的自由基脱芳构化反应控制。计算研究揭示了工程金属酶和反应中间体之间额外的氢键相互作用对于增强酶活性和对映体控制的重要性。此外，设计的非离子表面活性剂被发现可以显着加速这种生物转化，为促进原本缓慢的新自然生物转化提供了一种替代方法。总之，这种可进化的金属酶平台开辟了新的途径，以推进涉及自由基中间体的具有挑战性的催化不对称脱芳构化过程。