Synthesis of 1‑(<i>tert</i>-Butyl) 4‑Methyl (1<i>R</i>,2<i>S</i>,4<i>R</i>)‑2-Methylcyclohexane-1,4-dicarboxylate from Hagemann’s <i>tert</i>-Butyl Ester for an Improved Synthesis of BMS-986251

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.