Date of Award

January 2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Alexei V. Novikov

Abstract

This research work consists of two independent studies. The first study is the development of a synthetic route to plakortethers A-E along with possible derivatives. The second study focuses on the synthetic applications of rhodium-catalyzed intramolecular C-H insertion on diazosulfonates.

Plakortethers (A-G) represent a set of marine natural products, which contain of a characteristic tetrasubstituted tetrahydrofuran fragment. This group of compounds was isolated from the Caribbean sponge Plakortis simplex. Their selective cytotoxic activity against the RAW 264-7 cell lines (murine macrophage) makes them promising candidates for biological studies and, along with their unusual structure, warrants the synthesis of these natural products. In the approach to plakortethers A-E, the key efforts were directed at the assembly of the important structural element: the tetrasubstituted tetrahydrofuran ring with three stereocenters. To achieve this goal, initially, it was intended to use trans-annular iodocyclization to obtain the embedded tetrasubstituted tetrahydrofuran backbone in plakortethers. Due to the synthetic difficulties encountered in preparation of the necessary intermediates, the construction of the tetrahydrofuran ring was proposed to be achieved via an acyclic intermediate using cyclization of an episulfonium ion onto an alcohol to control stereochemistry. Construction of the key precursor to the episulfonium ion with desired stereochemistry was envisioned from a

six-membered lactone (valerolactone) intermediate. The requisite lactones were prepared via enolate alkylation for the future studies of the episulfonium ion cyclization step.

The second study focuses on the use of rhodium-catalyzed intramolecular C-H insertion on diazosulfonates as a tool for the synthesis of organic molecules. Dirhodium-induced intramolecular C-H insertion on diazo carbonyl compounds is a relatively well-studied reaction. In a wide variety of cases it lead to the preferential formation of five-membered cycles. In the earlier work in our lab, it was found that sulfone and sulfonate diazocompounds undergo intramolecular C-H insertion to form predominantly six-membered cyclic sulfones and sulfonates (delta-sultones) over their five-membered counterparts. delta-Sultones can serve as viable synthetic intermediates. Preliminary work on the transformations of these compounds done in our research group has identified that, upon treatment with THBP and t-BuOK, delta-sultones undergo oxidative desulfonation to form five-membered lactones (gama-butyrolactones). Butyrolactones are a common fragment in natural compounds and are valuable as synthetic intermediates. In the current study, the conditions for this oxidative desulfonation of δ-sultones to gama-butyrolactones were optimized, along with testing of the scope of this transformation. Optimization studies resulted in satisfactory yields of -butyrolactones from delta-sultones with 5 eq of THBP and 6 eq of t-BuOK in THF or DME as a solvent at room temperature. These conditions have been utilized to synthesize a gama-butyrolactone key intermediate that was used in the previously reported total synthesis of natural product (-)-eburnamonine.

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