Department of Chemistry, University of Rochester, 120 Trustee Road, Rochester, NY, 14627, USA.
Current address: School of Chemistry and Biochemistry, Thapar Institute of Engineering and Technology, Punjab, India.
Angew Chem Int Ed Engl. 2018 Jul 26;57(31):9911-9915. doi: 10.1002/anie.201804779. Epub 2018 Jul 6.
Functionalized indoles are recurrent motifs in bioactive natural products and pharmaceuticals. While transition metal-catalyzed carbene transfer has provided an attractive route to afford C3-functionalized indoles, these protocols are viable only in the presence of N-protected indoles, owing to competition from the more facile N-H insertion reaction. Herein, a biocatalytic strategy for enabling the direct C-H functionalization of unprotected indoles is reported. Engineered variants of myoglobin provide efficient biocatalysts for this reaction, which has no precedents in the biological world, enabling the transformation of a broad range of indoles in the presence of ethyl α-diazoacetate to give the corresponding C3-functionalized derivatives in high conversion yields and excellent chemoselectivity. This strategy could be exploited to develop a concise chemoenzymatic route to afford the nonsteroidal anti-inflammatory drug indomethacin.
功能化吲哚是生物活性天然产物和药物中常见的结构单元。虽然过渡金属催化的卡宾转移为合成 C3 功能化吲哚提供了一种有吸引力的方法，但这些方法仅在存在 N-保护吲哚的情况下才可行，因为 N-H 插入反应更容易发生。本文报道了一种用于实现未保护吲哚直接 C-H 功能化的生物催化策略。肌红蛋白的工程变体为该反应提供了高效的生物催化剂，这在生物界是前所未有的，使一系列广泛的吲哚在乙基-α-重氮乙酸酯的存在下转化为相应的 C3 功能化衍生物，转化率高，化学选择性好。该策略可用于开发简洁的化学酶法途径，以获得非甾体抗炎药吲哚美辛。
