Date of Award

2-7-2011

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Alexi Novikov

Abstract

This work consists of two independent studies. The first part of the dissertation focuses on the total synthesis of two marine based natural products, Plakortether F and G which represent a class of non-peroxide derivatives of Plakortin related metabolites that are isolated from the Caribbean sponge Plakortis simplex. The selective cytotoxic activity of Plakortethers against the RAW 264-7 cell line (murine macrophage) makes them promising candidates for biological studies. A strategy utilizing desymmetrization of a C2 symmetric intermediate was proposed and demonstrated to be effective for the synthesis of the core of Plakortethers. Initially, the symmetric intermediate could only be prepared in low yields but this was overcome by optimizing the reaction conditions. In order to improve the yield, different chiral auxiliaries were tested; camphor, pseudoephedrine, oxazolidine and oxazolidinone. The latter was found to have a better yield in the bis-alkylation step (generation of the C2 symmetric intermediate). Reductive cleavage of the chiral auxiliary in order to synthesize the trisubstituted lactone alcohols resulted in problems with yield, reproducibility and over-reduction of the substrate. These challenges were overcome by changing the approach of desymmetrization preceded by peroxide assisted hydrolysis. This modification not only corrected the above stated issues but also simplified the synthetic route. The completion of the synthesis required asymmetric aldol followed by hydrolysis and esterification. Initially, the aldol products were obtained from the titanium assisted aldol reaction. Due to the poor reproducibility, low diastereoselectivity and an unidentifiable impurity profile of the titanium based aldol reaction, efforts were focused on finding a suitable methodology to obtain the desired aldol products. Samarium(II) iodide mediated Reformatsky reaction proved to be an excellent alternative to the titanium based aldol reaction providing better yield and diastereoselectivity.The second part of the study focuses on the selectivity aspect of a well known methodology, C–H insertion reactions. Our research showcases the findings of the intramolecular C–H insertion on the synthetically useful substrates such as diazosulfones and diazosulfonates. Initially, it was found that these substrates conveniently undergo intramolecular C–H insertion to form predominantly six-membered cyclic sulfones and sulfonates. Several examples through our research have demonstrated the feasibility of the preferential formation of six-membered cyclic sulfones and sulfonates. However, a careful analysis of the reaction mixtures revealed that the intramolecular C–H insertion reactions of the diazosulfones resulted in isomerization and formation of five-membered ring systems. Different kinds of rhodium(II) catalysts were tested for this transformation and it was found that the electronic environment of the catalytic core greatly affected the selectivity and yield. It was observed that a relatively electron deficient metallic core tends to prefer five-membered ring formation. Another noteworthy aspect of this study is the effect of substitution next to the sulfone center. It was found that increased substitution tends to cause the selectivity to favor the five-membered ring formation.

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