Asymmetric Synthesis of the Major Metabolite of a Calcitonin Gene-Related Peptide Receptor Antagonist and Mechanism of Epoxide Hydrogenolysis

An asymmetric synthesis of the major
metabolite of the calcitonin
gene-related peptide recepotor antagonist BMS-846372 is presented.
The variously substituted cyclohepta­[b]­pyridine ring
system represents an underexplored ring system and showed some unexpected
chemistry. Reactivities of epoxide and ketone functional groups on
the cycloheptane ring were extensively controlled by a remote bulky
TIPS group. The rate difference of the hydrogenolysis between two
diastereomeric epoxide intermediates shed some light on the mechanism
of epoxide hydrogenolysis, and further, deuterium labeling studies
revealed more mechanistic details on this well-known chemical transformation
for the first time.