The conformational behaviour of 4,4a,5,6,7,8-hexahydropyrido[1,2-d][1,3,4]oxadiazine derivatives studied by NMR spectroscopy and molecular mechanics

The diastereomers (1'R*,2R*)- and (1'S*,2R*)-1-amino-2-(1'-hydroxypiperidin ebenzyl) and 1-amino-2-(1-hydroxy-1,1-diphenylmethyl) have been synthesized and transformed into the corresponding 4,4a,5,6,7,8-hexahydropyrido[1,2-d] [1,3,4]oxadiazines Similarly to the unsubstituted parent compound 2-phenylh exahydropyrido [1,2-d][1,3,3] oxadiazine, both the (4R*,4aR*)- and the (4S* ,4aR*)-2,4-diphenylhexahydropyrido [1,2-d][1,3,4]oxadiazines were found to be predominantly in the trans-annellated conformation. This was concluded f rom low temperature NMR measurements, the chemical shift differences of the methylene protons adjacent to the bridged nitrogen, or the Delta H degrees values derived from ab initio calculations. In 2,4,4-triphenylhexahydropyr ido[1,2-d][1,3,4]oxadiazine the conformational preference was switched to a slight predominance of the cis N-in conformation (53%). The conformational preference in the solid state for the (4R*,4aR*)- and the (4S*,4aR*)-2,4-d iphenylhexahydropyrido[ 1,2-d][ 1,3,4]oxadiazines was the same as in soluti on. The N-15 chemical shifts of the bridgehead nitrogens were found to corr elate to some extent with the conformational preference, while no correlati on was observed between the geminal coupling constant of the methylene prot ons adjacent to the bridgehead and the adopted ring annellation.