2006 Ohio Student Research Forum

Abstract

Synthesis of Marine Natural Products
Charles M. Clay, Steve G. Ballmer, Benjamin K. Southerland, Brandon G. VanNess
Wright State University
Department of Chemistry
Mentor(s): Dr. Daniel M. Ketcha

Although pyrrole and reduced pyrrole ring systems constitute key structural elements of diverse families of natural products and pharmaceutically active agents, few synthetic routes to such target molecules are based on the selective functionalization of an extant pyrrole ring. This is perhaps attributable to the high reactivity of the pyrrole nucleus and the consequential lack of selectivity observed in many of its reactions. In this regard, early protection of the pyrrole nitrogen can play a pivotal role in synthetic planning, since the protecting group can serve to site-direct substitution as well as attenuate the normally high reactivity of this ?-excessive ring system. We have chosen to employ the 1-(phenylsulfonyl)-protecting group for pyrrole in synthetic approaches to epibatidine and dilemmaone A via Diels-Alder strategies wherein the pyrrole ring itself or a 3-vinyl pyrrole serves as the diene in each approach, respectively.
For some time now, we have been involved in synthetic efforts towards the poison-dart frog venom alkaloid epibatidine, a molecule demonstrated to be 500 times more potent than morphine as an analgesic and to exert it’s effects via agonism of the nicotinic acetylcholine receptor found to be involved in the mediation of disorders such as Alzheimer’s and Parkinson’s diseases. Although this molecule has been the subject of many synthetic efforts, the only possible route to this target remaining involves the Diels-Alder reaction of a 3-aryl pyrrole with an appropriate dienophile. In model studies, we are examining the microwave enhanced Diels-Alder reaction of NBSP with p-tosyl acetylene so as to optimize formation of the desired bicyclic core of epibatidine.
Another area of longstanding interest in our laboratory focuses on marine natural products with biomedical potential such as the dilemmaones A-C from an extract of a mixture of orange sponges collected near Cape Town, South Africa. Although secondary metabolites from marine sponges containing indole rings are not uncommon, the density of alkyl substituents about the benzene ring and the lack of C-3 substitution are unusual and call into question the biogenic origin of these alkaloids. Most notably, the lack of substitution at C-3 suggests that these alkaloids are not derived from tryptophan and thus have an unknown biosynthetic pathway. Whereas the majority of synthetic approaches to the indole nucleus involve formation of the pyrrole ring from an aromatic (benzenoid) nitrogen containing compound, methods entailing construction of the indole ring from pyrrole precursors have recently begun to emerge as versatile and efficient routes to this important class of heterocycle. This approach necessitates the Lewis acid catalyzed reactions of cycloalkenones bearing an enhancing group on the dienophilic carbon-carbon double bond. Extended to our case, reaction of the vinyl pyrrole with 2-(phenylselanyl)cylcopent-2-enone should provide an easy route to the dilemmanone family.