Myoglobin‐Catalyzed C−H Functionalization of Unprotected Indoles. Issue 31 (6th July 2018)

• Record Type: Journal Article
• Authors: Vargas, David A.; Tinoco, Antonio; Tyagi, Vikas; Fasan, Rudi
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 31(2018)
• Page Start: 9911
• Page End: 9915
• Publication Date: 2018-07-06
• Subjects: carbene transfer -- indole functionalization -- indomethacin -- myoglobin -- protein engineering; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201804779
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : Catalysis without protection : A biocatalytic strategy for the synthesis of C3‐functionalized indoles via myoglobin‐catalyzed carbene transfer is reported. This approach enabled the transformation of a broad range of indole derivatives bearing unprotected N−H groups with high efficiency and excellent chemoselectivity. This transformation could be integrated into a chemoenzymatic scheme for the synthesis of a drug molecule (indomethacin) at the preparative scale.