Conformational Studies of Muscarone Analogs - X-ray-analysis and Molecular Mechanics Calculations

The X-ray structure of muscarone analogues 3 and 4 was determined and compared with that of muscarone (1, iodide and picrate salts), muscarine 2, dioxalane 5, oxathiolane 6, and tetrahydrofuran 7. In order to better define the pharmacological stereoselectivity of muscarone, the conformational profiles of compounds 1, 2, 3, and 5 were analyzed using Allinger's MM2(85) progam or, in the case of 4, by H-1 NMR spectroscopy. The conformation of the ring in 1 provided similar to that of the other derivatives. MM2 calculations predicted a preferred gauche arrangement of the sides chain for 1 and its analogues; such an arrangement was also observed in the solid state of muscarone picrate. Thus, the antiperiplanar arrangement reported for crystaline muscarone iodide appears to be due to crystallographic packaging forces. As a consequence, the rationalization of the phasrmacological profile of 1 based on the antiperiplanar arrangement is now highly questionable. The lack of stereoselectivity of 4 can be attributed to the absence of a stereocenter at C-2 whereas, in our opinion, there are currently no sound explanations for the low values of eudismic ratios for the muscarone enantiomers.