Reducing Limitation in Probe Design: The Development of a Diazirine-Compatible Suzuki-Miyaura Cross Coupling Reaction.
| Autor: | Ichiishi N; Merck & Co., Inc., Discovery Chemistry, HTE and Lead Discovery Capabilities, Kenilworth, New Jersey 07033, United States., Moore KP; Merck & Co., Inc., Discovery Chemistry, Chemical Biology, West Point, Pennsylvania 19486, United States., Wassermann AM; Merck & Co., Inc., Discovery Chemistry, Chemistry Informatics, Boston, Massachusetts 02115, United States., Wolkenberg SE; Merck & Co., Inc., Discovery Chemistry, Chemical Biology, West Point, Pennsylvania 19486, United States., Krska SW; Merck & Co., Inc., Discovery Chemistry, HTE and Lead Discovery Capabilities, Kenilworth, New Jersey 07033, United States. |
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| Jazyk: | angličtina |
| Zdroj: | ACS medicinal chemistry letters [ACS Med Chem Lett] 2018 Dec 06; Vol. 10 (1), pp. 56-61. Date of Electronic Publication: 2018 Dec 06 (Print Publication: 2019). |
| DOI: | 10.1021/acsmedchemlett.8b00403 |
| Abstrakt: | 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. Competing Interests: The authors declare no competing financial interest. |
| Databáze: | MEDLINE |
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