Synthesis of 1-(tert-Butyl) 4-Methyl (1 R,2 S,4 R)-2-Methylcyclohexane-1,4-dicarboxylate from Hagemann's tert-Butyl Ester for an Improved Synthesis of BMS-986251

J Org Chem. 2020 Aug 21;85(16):10988-10993. doi: 10.1021/acs.joc.0c01169. Epub 2020 Aug 7.

Abstract

We describe an efficient synthetic route to differentially protected diester, 1-(tert-butyl) 4-methyl (1R,2S,4R)-2-methylcyclohexane-1,4-dicarboxylate (+)-1, via palladium-catalyzed methoxycarbonylation of an enol triflate derived from a Hagemann's ester derivative followed by a stereoselective Crabtree hydrogenation. Diester 1 is a novel chiral synthon useful in drug discovery and was instrumental in the generation of useful SAR during a RORγt inverse agonist program. In addition, we describe a second-generation synthesis of the clinical candidate BMS-986251, using diester 1 as a critical component.

MeSH terms

  • Carboxylic Acids*
  • Cyclohexanes
  • Esters*
  • Stereoisomerism

Substances

  • Carboxylic Acids
  • Cyclohexanes
  • Esters
  • methylcyclohexane