Smedley, C. J., Li, G., Barrow, A. S., Gialelis, T. L., Giel, M. C., Ottonello, A., Cheng, Y., Kitamura, S., Wolan, D. W., Sharpless, K. B., Moses, J. E. (April 2020) Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2-Substituted-Alkynyl-1-Sulfonyl Fluoride (SASF) Hubs. Angew Chem Int Ed Engl. ISSN 1433-7851
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 �-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 stereoselective 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.
| Item Type: | Paper |
|---|---|
| Additional Information: | Angewandte Chemie (International ed. in English) |
| Subjects: | chemistry > techniques > click chemistry > Accelerated SuFEx Click Chemistry chemistry chemistry > techniques > click chemistry chemistry > techniques |
| CSHL Authors: | |
| Communities: | CSHL labs > Moses lab |
| Depositing User: | Matthew Dunn |
| Date: | 16 April 2020 |
| Date Deposited: | 08 Jan 2021 17:21 |
| Last Modified: | 01 Feb 2024 18:37 |
| PMCID: | PMC7572632 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/39589 |
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