Date of Award
Fall 1998
Document Type
Dissertation - Restricted
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry
First Advisor
Donaldson, William A.
Second Advisor
Yi, Chae S.
Third Advisor
McKinney, Michael A.
Abstract
2-Deoxy-L-glucose and its derivatives are important structural components in numerous antifungal antibiotic agents and they were used as valuable chiral intermediates in natural products synthesis, including ambruticin. Ambruticin 39, W-7783, is an orally active antifungal antibiotic agent with a unique structure, produced by the soil inhabiting myxobacteriale Polyangium cellulosum var. Fulvum under appropriate conditions. Ambruticin shows in vitro and in vivo activity against a variety of pathogenic fungi including Histoplasma capsulatum and Coccidioide immitis . The structure was deduced from chemical and spectral evidence including single crystal X-ray analysis in 1977 by David T. Connor and his co-workers. "diagram" Ambruticin possesses not only unique biological properties, but also a complex architectural framework. The complex array of diverse functionality in ambruticin includes a tetrahydropyranyl ring, a dihydropyranyl ring, and a divinylcyclopropane ring moiety. Ambruticin has stimulated considerable synthetic interest among several research groups worldwide, but there is only a single laboratory synthesis of ambruticin reported in the literature to date. In this dissertation, a synthetic methodology for the preparation of 2-deoxy-L-glucosides was developed and this methodology was applied toward the synthesis of the tetrahydropyranyl ring (C1-C8) and the dihydropyranyl ring (C17-C24). A method for the synthesis of 2-deoxy-L-glucose, its tetraacetate and 1-methyl-2-deoxy-3,4,6-triacetyl-L-glucoside were accomplished by using L-arabinose as a starting material. A versatile synthetic route for the C1-C8 segment of ambruticin and its C3 epimer, both in optically pure form, were accomplished starting from the diethyldithioacetal of L-arabinose in 10 and 8 steps (10% and 16% yield) respectively. The overall yield of the C1-C8 segment of ambruticin reported herein (10%) is superior to that previously reported (4.6%). The C17-C24 carbon skeleton of ambruticin has also been prepared in 9 steps (5.37% yield) from dimethyl malate.