期刊
SCIENCE
卷 377, 期 6610, 页码 1104-+出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.add1383
关键词
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资金
- European Research Council under the European Union [757608]
- ETH Zurich
- Stipendienfonds der Schweizerischen Chemischen Industrie (SSCI)
- International Human Frontier Science Program Organization [LT000861/2020-L]
Reliable strategies for directly editing the core skeleton of pharmaceutical lead compounds are still scarce despite recent developments in the field. This study presents a method for skeletal editing of indoles through nitrogen atom insertion, demonstrating its utility in late-stage skeletal editing of several commercial drugs.
Compared with peripheral late-stage transformations mainly focusing on carbon-hydrogen functionalizations, reliable strategies to directly edit the core skeleton of pharmaceutical lead compounds still remain scarce despite the recent flurry of activity in this area. Herein, we report the skeletal editing of indoles through nitrogen atom insertion, accessing the corresponding quinazoline or quinoxaline bioisosteres by trapping of an electrophilic nitrene species generated from ammonium carbamate and hypervalent iodine. This reactivity relies on the strategic use of a silyl group as a labile protecting group that can facilitate subsequent product release. The utility of this highly functional group-compatible methodology in the context of late-stage skeletal editing of several commercial drugs is demonstrated.
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