Date of Award
Summer 2004
Document Type
Dissertation - Restricted
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Donaldson, William A.
Second Advisor
Hossenlopp, Jeanne
Third Advisor
Steinmetz, Mark
Abstract
Natural products (+)-decarestrictine L and (+)-ambruticin are tetrahydropyran containing molecules that were isolated from different soil inhabiting bacteria. They possess important biological properties and make interesting synthetic targets."diagram" Decarestrictine L is a tetrahydropyran that was isolated from bacteria of the species Penicillium simplicissimum and Penicillium corylophilum that were present in soil samples collected in the United States and Portugal. Initial investigations revealed that cholesterol biosynthesis in HEP-G2 liver cells of normolipidemic rats was significantly inhibited in the presence of Decarestrictine L. Previously, five total syntheses were described in the literature. Our synthesis begins with commercially available tri- O -acetyl-D-glucal, relies upon a C -glycosidation reaction, and prepares (+)-decarestrictine L in 13 steps and 8.5% overall yield. Ambruticin contains a tetrahydropyran ring, a divinylcyclopropane, and a dihydropryan ring that are joined via three E -olefinic bonds. Ambruticin was isolated from the myxobacteria Polyangium Cellulosum var. fulvum and has been found to be an orally active antifungal agent that exhibits pronounced activity against Coccidioides immitis , Histoplasma capsulatum , and Blastomyces dermatitidis and has been shown to kill the yeast strain Hansenula anomala . To date four total syntheses and numerous partial syntheses have been reported. Our synthesis of the C17-C24 dihydropryan containing segment relies upon a dienealdehyde cyclocondensation reaction and a C -glycosidation reaction. The synthesis begins with a known diene and known optically active aldehyde and results in the dihydropryan in 6 total steps and 33% overall yield. The C9-C16 cyclopropane containing segment was prepared using organoiron methodology with the C13-C14 E -olefin formed via olefin cross metathesis. The cyclopropane containing segment was synthesized from a known optically active iron cation in three steps and 24% overall yield.