The principal objective of the proposed research is to develop a new, general, and efficient method for the synthesis of pyrrolidine-containing molecules of biological significance. It is noted that such compounds have the pyrrolidine ring incorporated into the structure in many different fashions. The principal investigator indicates that if a synthetic method were general enough in accessing this structural subfeature, it may be useful for the preparation of a wide variety of target molecules. The proposed research is to attempt to use the anionic (3+2) cycloaddition of 2-azaallyl anions with alkenes for the construction of a cross-section of biologically relevant target molecules. It is stated that examples include the acetyl choline receptor complex inhibitor (-)-indolizidine 209B, the ant venom and trail-following compound (+)-monomorine, the newly discovered anticancer alkaloid lapidaformine, the antimalarial, anticancer and antibacterial alkaloid crinamine, the anticancer compounds pretazettine and precriwelline, a component of a Chinese folk medicine used for the treatment of rheumatic heart disease known as scandine, the hypotensive and convulsive montanine-type alkaloids, the exciting new analgesic epibatidine, and the pharmacologically active tropane alkaloid (-)- cocaine. It is further noted that other compounds which have been targeted due to their structural novelty or their unexplored biological activity include lapidilectine B, augustamine, vittatine, aspidospermine, and homoerythratine. The principal investigator indicates that these targets will allow examination of the scope of the 2-azallyl anion cycloaddition method in several ways and notes that for example, the type of anionophile required varies considerably across the range of target molecules, from simple alkenes to conjugated alkenes such as dienes and styrenes. He reports that the types of anions required are also diverse. He suggests that simple aliphatic anions, heterosubstituted anions, conjugated anions, and cyclic anions will be required, each with their unique chemistry and method of preparation. The issue of stereocontrol, both absolute and relative is to be explored in detail. Information on the preferred transition state for these cycloadditions is to obtained as a result of these studies.
| Pearson, William H; Aponick, Aaron (2006) Formal synthesis of aspidosperma alkaloids via the intramolecular [3 + 2] cycloaddition of 2-azapentdienyllithiums. Org Lett 8:1661-4 |
