The objective of this research is to develop an efficient unified synthetic strategy for construction, in chiral form, of five members of the architecturally novel class of tremorgenic alkaloids derived from the ergot fungus, Claviceps paspali and related species, which grow on a variety of food stuffs. The synthetic targets are: paspaline (1), paspalicine (2), paspalinine (3), paxilline (4), and penitrem D (11). Members of this class of toxins have been implicated in a wide variety of neurologic disorders, both in laboratory animals and in livestock; examples include Dallisgrass poisoning (the so called paspalin staggers) and ryegrass staggers. Symptoms are characterized by sustained tremors, especially upon voluntary initiation of movements and are accompanied by such effects as limb weakness, ataxia and convulsions. At high dose levels death results. These symptoms, particularly intentional tremors, are similar to those found in certain human disorders such as Wilson's Disease and multiple sclerosis, and may result at the molecular level from a common neurochemical mechanism. Subgoals of this research program will be the development of new synthetic methodology, such as the proposed cyclopentane-indole annulation sequence, which will have potential applicability to a wider range of pharmacologically important agents.
