Tandem Michael addition and azanorbornane substance-P antagonists

Article abstract of DOI:10.1016/S0040-4020(97)00371-2

Tandem Michael addition product 5 provides a template for azanorbornane derivatives that display potent substance P receptor affinity. The advantages of this synthesis include: the straightforward preparation of both syn and anti azanorbornane diastereomers, access to two, and perhaps more, substituents at C-2 (a and b series), and the straightforward functionalization of the amine at C-3. Mechanistic studies suggest that the second 1,4-addition proceeds kinetically via syn-addition of the nitronate and ester. Conflicting results in the literature stem from a previously unobserved thermodynamic equilibrium which is described herein.