Journal
SCIENCE
Volume 356, Issue 6342, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aam7355
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Funding
- China Scholarship Council
- Shanghai Institute of Organic Chemistry
- Zhejiang Medicine Co.
- Pharmaron
- Crohn's and Colitis Foundation of America
- Deutsche Forschungsgemeinschaft
- NIH [GM-118176]
- Bristol-Myers Squibb
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The widespread use of alkyl boronic acids and esters is frequently hampered by the challenges associated with their preparation. We describe a simple and practical method to rapidly access densely functionalized alkyl boronate esters from abundant carboxylic substituents. This broad-scope nickel-catalyzed reaction uses the same activating principle as amide bond formation to replace a carboxylic acid moiety with a boronate ester. Application to peptides allowed expedient preparations of alpha-amino boronic acids, often with high stereoselectivity, thereby facilitating synthesis of the alkyl boronic acid drugs Velcade and Ninlaro as well as a boronic acid version of the iconic antibiotic vancomycin. The reaction also enabled the discovery and extensive biological characterization of potent human neutrophil elastase inhibitors, which offer reversible covalent binding properties.
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