Multigram Synthesis of (–)-BMT-395137

Keywords

Diels–Alder cycloaddition - Curtius rearrangement - Wittig olefination

Significance

Bicyclo[2.2.1]heptane scaffolds can be found both in natural products and in pharmaceutical compound leads. BMS has disclosed the synthesis of (–)-BMT-395137, featuring a bicyclo[2.2.1]heptane skeleton, also containing a vinyl bromide and two amides. The first-generation synthesis led to the isolation of the product in milligram quantities, so its synthesis was optimized. This work highlights how careful choice of substrates and reagents can lead to operationally simpler procedures that are amenable towards scale-up. The final compound was separated through chiral SFC resolution to yield (–)-BMT-395137 in 4.1 % overall yield over 10 steps.

Comment

The synthesis starts by converting maleic anhydride into a benzylated maleic acid derivative, which served as the dienophile in the endo-selective Diels–Alder cycloaddition. Ferrocenium hexafluorophosphate underwent the cycloaddition in the presence of air at 400 g scale, and the cycloadduct was purified by crystallization. The carboxylic acid was then converted into an acyl azide, that underwent Curtius rearrangement to install a Teoc-protected amine. Hydrogenolysis cleaved the benzyl ester and reduced the alkene. The carboxylic acid was then coupled with a fluorinated aniline using propylphosphonic anhydride (T3P). The Teoc-protecting group was exchanged for a trifluoroacetamide in a sequence of three steps that were telescoped. Hydrolysis was required to release the alcohol. Swern oxidation, followed by Wittig olefination led to the diastereoselective formation of BMT-395137.

Publication History

Article published online:
30 October 2025