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Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluoride (SASF) Hubs
Author(s) -
Smedley Christopher J.,
Li Gencheng,
Barrow Andrew S.,
Gialelis Timothy L.,
Giel MarieClaire,
Ottonello Alessandra,
Cheng Yunfei,
Kitamura Seiya,
Wolan Dennis W.,
Sharpless K. Barry,
Moses John E.
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202003219
Subject(s) - click chemistry , sulfonyl , cycloaddition , chemistry , pharmacophore , combinatorial chemistry , adduct , fluoride , stereochemistry , organic chemistry , inorganic chemistry , alkyl , catalysis
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‐ S ubstituted‐ A lkynyl‐1‐ S ulfonyl F luorides (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.