Li, Renzhe, Hu, Chao, Liu, Chang, Lyness, Thomas, Li, Wenyuan, Cai, Chenyan, Kanda, Yuzuru, Merchant, Rohan, Matsuura, Bryan, Williams, Noelle and Qin, Tian (2025) Modular Access to N‑SF5 Azetidines. Journal of American Chemical Society. ISSN 10.1021/jacs.5c10954

Abstract

Synthetic accessible novel scaffolds and chemical functional groups with drug-like properties offer a fresh approach to pharmaceutical molecule design. The introduction of the N-pentafluorosulfanyl (N–SF₅) group may overcome the limited aqueous stability often seen with N-alkyl substitutions—thanks to its larger steric volume, stronger electron-withdrawing effect, and increased lipophilicity. However, the lack of a general, operational simple and efficient synthetic strategy for N–SF₅ compounds has significantly hindered their broader application. To address this, we developed a modular coupling approach using bench-stable, scalable SF₅-transfer reagents, enabling efficient access to N–SF₅-azetidines. This method provides a user-friendly protocol with mild reaction conditions and broad functional group tolerance, making it well-suited for the late-stage modification of commercial drugs and other complex molecules. The resulting scaffolds demonstrate excellent stability and permeability, representing a novel class of potential (bio)isosteres in medicinal chemistry.

Item Type:	Article
Date Deposited:	27 Sep 2025 00:45
Last Modified:	27 Sep 2025 00:45
URI:	https://oak.novartis.com/id/eprint/57516