In the research proposal, I first describe the development of two general methodologies for use in the synthesis of furanocembranolides, a class of marine natural products possessing a range of biological activities. The first methodology involves the known reaction of alkynes with oxazoles to make furans; in the proposed research I will determine whether or not the reaction can be done regioselectively. Specifically, I will prepare a variety of unsymmetrically substituted oxazoles and react them with different alkynes, and observe which regiochemical products are favored. The second methodology will create butenolides from 3-hydroxy vinylsilanes by reaction with phosgene followed by Lewis acid-promoted ring closure. I will prepare a model substrate related to the furanocembranolide lophotoxin, and determine the ideal conditions for the desired ring closure. I will then incorporate these methodologies into a synthesis of the furanocembranolide lophotoxin, an irreversible inhibitor of nicotinic acetylcholine receptors. My proposed synthetic strategy will be amenable to the long-range goal of synthesizing analogs, in order to study the nicotinic acetylcholine receptor site through structure/activity relationships.
