Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 31, Pages 9911-9915Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201804779
Keywords
carbene transfer; indole functionalization; indomethacin; myoglobin; protein engineering
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Funding
- U.S. National Institute of Health [GM098628]
- Ford Foundation Graduate Fellowship Program
- U.S. NSF grant [CHE-0946653]
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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 -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.
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