Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2-Substituted-Alkynyl-1-Sulfonyl Fluoride (SASF) Hubs

Christopher J. Smedley, Gencheng Li, Andrew S. Barrow, Timothy L. Gialelis, Marie Claire Giel, Alessandra Ottonello, Yunfei Cheng, Seiya Kitamura, Dennis W. Wolan, K. Barry Sharpless, John E. Moses

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

Diversity Oriented Clicking (DOC) is a unified click-approach for the modular synthesis of lead-like structures through application of the wide family of click transformations. DOC evolved from the concept of achieving “diversity with ease”, by combining classic C−C π-bond click chemistry with recent developments in connective SuFEx-technologies. We showcase 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs) as a new class of connective hub in concert with a diverse selection of click-cycloaddition processes. Through the selective DOC of SASFs with a range of dipoles and cyclic dienes, we report a diverse click-library of 173 unique functional molecules in minimal synthetic steps. The SuFExable library comprises 10 discrete heterocyclic core structures derived from 1,3- and 1,5-dipoles; while reaction with cyclic dienes yields several three-dimensional bicyclic Diels–Alder adducts. Growing the library to 278 discrete compounds through late-stage modification was made possible through SuFEx click derivatization of the pendant sulfonyl fluoride group in 96 well-plates—demonstrating the versatility of the DOC approach for the rapid synthesis of diverse functional structures. Screening for function against MRSA (USA300) revealed several lead hits with improved activity over methicillin.

Original languageEnglish (US)
Pages (from-to)12460-12469
Number of pages10
JournalAngewandte Chemie - International Edition
Volume59
Issue number30
DOIs
StatePublished - Jul 20 2020
Externally publishedYes

Keywords

  • cycloadditions
  • diversity oriented clicking
  • heterocycles
  • SuFEx click chemistry
  • sulfonyl fluorides

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)

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