Scalable Synthesis of the Potent HIV Inhibitor BMS-986001 by Non-Enzymatic Dynamic Kinetic Asymmetric Transformation (DYKAT)

• Published in: Angewandte Chemie (International ed.) Vol. 54; no. 24; pp. 7185 - 7188
• Main Authors: Ortiz, Adrian, Benkovics, Tamas, Beutner, Gregory L., Shi, Zhongping, Bultman, Michael, Nye, Jeffrey, Sfouggatakis, Chris, Kronenthal, David R.
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 08.06.2015; WILEY‐VCH Verlag; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Asymmetry; Catalysis; Chemistry; Chemistry, Multidisciplinary; Chromatography; Dynamics; HIV; Inhibitors; kinetic resolution; Levamisole - chemistry; organocatalysis; Physical Sciences; Science & Technology; Stereoisomerism; Synthesis; synthesis design; tautomerism; Thymidine - analogs & derivatives; Thymidine - chemical synthesis; Thymidine - chemistry; Transformations; organocatalysis; tautomerism; inhibitors; CATALYSIS; COMPOUND; kinetic resolution; synthesis design
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201502290

Described herein is the synthesis of BMS‐986001 by employing two novel organocatalytic transformations: 1) a highly selective pyranose to furanose ring tautomerization to access an advanced intermediate, and 2) an unprecedented small‐molecule‐mediated dynamic kinetic resolution to access a variety of enantiopure pyranones, one of which served as a versatile building block for the multigram, stereoselective, and chromatography‐free synthesis of BMS‐986001. The synthesis required five chemical transformations and resulted in a 44 % overall yield. Good dynamic: Described is the synthesis of BMS‐986001 by employing two novel organocatalytic transformations: a highly selective pyranose to furanose ring tautomerization, and an unprecedented small‐molecule‐mediated dynamic kinetic asymmetric transformation (DYKAT) to access enantiopure pyranones. BMS‐986001 was synthesized in five steps in an overall yield of 44 %. Bz=benzoyl.