Department of Chemistry and Biochemistry, University of California, Santa Barbara, CA, USA.
Department of Biochemistry, Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Nat Commun. 2023 Sep 14;14(1):5704. doi: 10.1038/s41467-023-40980-w.
Catalytic asymmetric α-alkylation of carbonyl compounds represents a long-standing challenge in synthetic organic chemistry. Herein, we advance a dual biocatalytic platform for the efficient asymmetric alkylation of α-keto acids. First, guided by our recently obtained crystal structures, we develop SgvM as a general biocatalyst for the enantioselective methylation, ethylation, allylation and propargylation of a range of α-keto acids with total turnover numbers (TTNs) up to 4,600. Second, we mine a family of bacterial HMTs from Pseudomonas species sharing less than 50% sequence identities with known HMTs and evaluated their activities in SAM regeneration. Our best performing HMT from P. aeruginosa, PaHMT, displays the highest SAM regeneration efficiencies (TTN up to 7,700) among HMTs characterized to date. Together, the synergistic use of SgvM and PaHMT affords a fully biocatalytic protocol for asymmetric methylation featuring a record turnover efficiency, providing a solution to the notorious problem of asymmetric alkylation.
羰基化合物的催化不对称 α-烷基化反应是合成有机化学中长期存在的挑战。在此，我们提出了一种用于高效不对称酮酸烷基化的双生物催化平台。首先，根据我们最近获得的晶体结构，我们开发了 SgvM 作为一种通用的生物催化剂，用于对一系列 α-酮酸进行对映选择性的甲基化、乙基化、烯丙基化和炔丙基化，总转化数 (TTN) 高达 4600。其次，我们从假单胞菌属中挖掘了一组与已知 HMT 相似度低于 50%的细菌 HMT，并评估了它们在 SAM 再生中的活性。我们从铜绿假单胞菌中得到的表现最好的 HMT，PaHMT，在迄今为止表征的 HMT 中具有最高的 SAM 再生效率（TTN 高达 7700）。SgvM 和 PaHMT 的协同使用为不对称甲基化提供了一种完全生物催化的方案，具有创纪录的转化率效率，为解决不对称烷基化的臭名昭著问题提供了一种解决方案。
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