The indole diterpene tremorgens comprise a rapidly growing family of architecturally novel natural products. 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 Dallis-grass poisoning (the so-called paspaline 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. The overall objecuves of this research program are: (A) to complete the total syntheses of paspalicine (2), paspalinine (3), paxilline (4), and penitrem D (11); (B) to devise a viable synthetic strategy for the newly isolated emindoles DA (19), SA (20), and DB (21); (C) to explore biomimetic approaches to both the simple tremorgens and emindoles, employing polyolefinic substrates, thereby offering both simplified synthetic approaches and insight into possible biosynthetic pathways; and (D) to initiate a structure-activity analysis directed at defining the pharmacophore of these novel tremorgens. Information obtained from these studies may help to elucidate the neurochemical origins of certain human diseases such as Wilson's disease and multiple sclerosis, as well as provide new leads for the design of improved anti-tremorgenic agents. Second, given the highly selective effects displayed by these toxins on various neurotransmitter release mechanisms, the availability of these agents in useful amounts would provide potentially important pharmacological research tools. Third, the proposed syntheses would be the first for each of these complex natural products. Finally, new synthetic methods and strategies in general will emanate from this program.
