Late-stage diversification of indole skeletons through nitrogen atom insertion

2022/09/01 by Julia C. Reisenbauer, Ori Green, Allegra Franchino +2 · 10 citations
Biochemistry, Genetics and Molecular Biology · Chemistry · #Phenothiazines and Benzothiazines Synthesis and Activities #Quinazolinone synthesis and applications #Synthesis and Biological Evaluation

paper · doi:10.1126/science.add1383

openalex publication_date 2022/09/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30

Abstract

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.

Citations

• <i>OLEX2</i>: a complete structure solution, refinement and analysis program
• Effect of the damping function in dispersion corrected density functional theory
• Automated exploration of the low-energy chemical space with fast quantum chemical methods
• Extended <scp>tight‐binding</scp> quantum chemistry methods
• Prescribed drugs containing nitrogen heterocycles: an overview
• Skeletal editing through direct nitrogen deletion of secondary amines
• Late-stage C–H functionalization offers new opportunities in drug discovery
• Software update: The <scp>ORCA</scp> program system—Version 5.0
• Single-atom logic for heterocycle editing

Cited by

• Unifying principles for the design and evaluation of natural product-inspired compound collections
• Photogeneration and Visualization of a Surface‐Stabilized Dinitrene
• Rational Molecular Editing: A New Paradigm in Drug Discovery
• Selective synthesis of [6-6-7]/[6-6-6] core polycyclic heterocycles via Lewis acid-mediated cascade annulation of 1,6-enynols with aminonitriles
• Atom-swapping skeletal editing of benzo[c]oxepines for the construction of 2-benzodiazepines via a continuous manufacturing one-pot synthesis
• Direct transformation of azaarenes into aromatic aldehydes and QUINAP-like atropisomers
• Suppressing Inversion of a Chiral Polycyclic Aromatic Aza Monkey Saddle by Molecular Editing
• Lactam Framework Editing via Formal Methylene Deletion
• Photocatalytic furan-to-pyrrole conversion
• Skeletal editing by tip-induced chemistry

Related

• Visible-Light-Promoted Metal-Free Approach for the N-H Insertions by Using Donor/Donor Diazo Precursors
• Annulative Skeletal Diversification of Pyrimidines to Expanded Heteroaromatic Space
• Cheminformatic Analysis of Core-Atom Transformations in Pharmaceutically Relevant Heteroaromatics
• Synthesis of Pharmacologically Relevant Indoles with Amine Side Chains via Tandem Hydroformylation/Fischer Indole Synthesis
• Formal nitrogen-to-carbon replacement in isoindolines to form indenes <i>via N</i> -alkyl tetrahydroisoquinolines