Stereoselective synthesis of the rat selective toxicant norbormide

Norbormide [5-(α-hydroxy-α-2-pyridylbenzyl)-7-(α-2-pyridylbenzylidene)-5-norbornene-2,3-dicarboximide] (NRB, 1), an existing but infrequently used rodenticide, is known to be uniquely toxic to rats but relatively harmless to other rodents/mammals. However, as an acute vasoactive, NRB has a rapid onset of action which makes it relatively unpalatable to rats, often leading to sub-lethal uptake/accompanying bait shyness. It is recognized that the pharmacological profile of NRB is highly sensitive to its stereoisomeric composition, yet no comprehensive endeavor has been made to impart any stereochemical control in its manufacture. The effect of temperature/concentration/reaction solvent/Lewis acid on the Diels–Alder synthesis of NRB is investigated. An attempted stereoselective synthesis of key NRB precursor 2-fulvenylmethanol 4 is also described. Palatability/efficacy data in rats is reported for novel NRB batches 1a–1e. Disappointingly, given the level of stereocontrol now available in the synthesis of NRB as a result of this research, no clear relationship between stereoisomeric composition and palatability was observed.