Fu Wenzhen, Fu Yue, Zhao Yunlong, Wang Huanan, Liu Peng, Yang Yang
Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA.
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA.
Nat Chem. 2024 Dec;16(12):1999-2008. doi: 10.1038/s41557-024-01608-8. Epub 2024 Aug 28.
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-P450 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.
催化不对称去芳构化是一种将平面芳香族化合物转化为立体化学明确的三维分子骨架的有效方法。利用新型金属氧化还原生物催化，我们描述了一种通过具有挑战性的自由基机制进行催化不对称去芳构化的酶促策略，而小分子催化剂难以实现这种机制。通过定向进化，新型自由基去芳构酶P450-P450促进了包括吲哚、吡咯和苯酚在内的多种芳香族底物的不对称去芳构化，实现了对映收敛和对映发散的自由基去芳构化反应，并具有出色的酶促控制。计算研究表明，工程化金属酶与反应中间体之间额外的氢键相互作用对于提高酶活性和对映选择性控制至关重要。此外，发现设计的非离子表面活性剂可显著加速这种生物转化，为促进原本缓慢的新型生物转化提供了一种替代方法。总之，这个可进化的金属酶平台为推进涉及自由基中间体的具有挑战性的催化不对称去芳构化过程开辟了新途径。
