Journal
TETRAHEDRON LETTERS
Volume 58, Issue 45, Pages 4248-4250Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.tetlet.2017.09.070
Keywords
Kinetic resolution; Stereospecific; Enzyme inhibitor; Azole
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Funding
- National Institutes of General Health [GM 067871]
- Vanderbilt Institute of Chemical Biology
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The study and development of azole-based CYP51 inhibitors is an active area of research across disciplines of biochemistry, pharmacology and infectious disease. Support of in vitro and in vivo studies require the development of robust asymmetric routes to single enantiomer products of this class of compounds. Herein, we describe a scalable and enantioselective synthesis to VNI and VFV, the two potent inhibitors of protozoan sterol 14 alpha-demethylase (CYP51) that are currently under consideration for clinical trials for Chagas disease. A key transformation is the Jacobsen Hydrolytic Kinetic Resolution (HKR) reaction. The utility of the synthetic route is illustrated by the preparation of >25 g quantities of single enantiomers of VNI and VFV. (C) 2017 Published by Elsevier Ltd.
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