Synthesis of 2-Deoxy-L-glucosides and studies directed toward the synthesis of ambruticin

Luping Liu, Marquette University


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 an 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.* 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. Please refer to dissertation for diagram.

Recommended Citation

Liu, Luping, "Synthesis of 2-Deoxy-L-glucosides and studies directed toward the synthesis of ambruticin" (1998). Dissertations (1962 - 2010) Access via Proquest Digital Dissertations. AAI9912730.