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Reducing Limitation in Probe Design: The Development of a Diazirine-Compatible Suzuki-Miyaura Cross Coupling Reaction. | LitMetric

Reducing Limitation in Probe Design: The Development of a Diazirine-Compatible Suzuki-Miyaura Cross Coupling Reaction.

ACS Med Chem Lett

Merck & Co., Inc., Discovery Chemistry, HTE and Lead Discovery Capabilities, Kenilworth, New Jersey 07033, United States.

Published: January 2019

AI Article Synopsis

  • - Researchers identified that the synthesis of high-quality photoaffinity probes is limited by challenges in adding diazirine groups, and found the Suzuki-Miyaura (S-M) coupling reaction to be underused in this area.
  • - They conducted a screening of different conditions for S-M couplings using an aromatic diazirine fragment, discovering effective conditions that yielded good results while keeping the diazirine intact.
  • - The optimized conditions were found to be scalable and applicable to a variety of compounds, and were successfully used to produce a known diazirine probe molecule more efficiently.

Article Abstract

Access to high quality photoaffinity probe molecules is often constrained by synthetic limitations related to diazirine installation. A survey of recently published photoaffinity probe syntheses identified the Suzuki-Miyaura (S-M) coupling reaction, ubiquitous in drug discovery, as being underutilized to incorporate diazirines. To test whether advances in modern cross-coupling catalysis might enable efficient S-M couplings tolerant of the diazirine moiety, a fragment-based screening approach was employed. A model S-M coupling reaction was screened under various conditions in the presence of an aromatic diazirine fragment. This screen identified reaction conditions that gave good yields of S-M coupling product while minimally perturbing the diazirine reporter fragment. These conditions were found to be highly scalable and exhibited broad scope when applied to a chemistry informer library of 24 pharmaceutically relevant aryl boron pinacol esters. Furthermore, these conditions were used to synthesize a known diazirine-containing probe molecule with improved synthetic efficiency.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6331167PMC
http://dx.doi.org/10.1021/acsmedchemlett.8b00403DOI Listing

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