Scalable Synthesis of the Potent HIV Inhibitor BMS-986001 by Non-Enzymatic Dynamic Kinetic Asymmetric Transformation (DYKAT).
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.
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA). Adrian.Ortiz@bms.com.
Adrian
A
Ortiz
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA).
Tamas
T
Benkovics
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA).
Gregory L
GL
Beutner
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA).
Zhongping
Z
Shi
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA).
Michael
M
Bultman
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA).
Jeffrey
J
Nye
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA).
Chris
C
Sfouggatakis
Chemical Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, NJ 08903 (USA).
David R
DR
Kronenthal
D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002384:Catalysis; D007978:Levamisole / Q000737:chemistry; D013237:Stereoisomerism; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry
D019380:Anti-HIV Agents; C583040:BMS-986001; D007978:Levamisole; D013936:Thymidine
inhibitors; kinetic resolution; organocatalysis; synthesis design; tautomerism