TitleI. New strategy for the synthesis of TMC-95A II. Selective ortho-substitution on substituted aryl rings III. Characterization of steroidal glycosides from easter lily
NameRamanathan, Ahalya (author), Jimenez, Leslie S (chair), Knapp, Spencer (internal member), Taylor, John (internal member), Colandrea, Vincent (outside member), Rutgers University, Graduate School - New Brunswick,
SubjectChemistry and Chemical Biology,
DescriptionTMC-95A is a natural product which has demonstrated inhibition activity against the proteasomal pathway. Though its biological activity is proven, the total synthesis of the molecule is challenging in many ways. In this thesis the synthetic strategy taken for the partial synthesis of the northern fragment of the TMC-95A is described. Part of the synthetic studies on the northern fragment involves selective ortho substitution on the indole aromatic ring. It was successfully achieved by protecting the para position with a bromo substituent. This selective ortho substitution was studied further on simple aromatic compounds. Bromides and chlorides at the para position were selectively removed in the presence of sensitive functional groups, which allowed this method to be utilized for selective ortho substitution. Model studies on 3-methyloxindole were carried out as part of the TMC-95A project. Although the model study gave very different results as opposed to the TMC-95A tryptophan intermediates, the outcome was interesting and turned out to be a project on its own. The halogen substitution at the α-position and sequential conversion of the halide to hydroxyl group was an interesting discovery. Several arylsulfonylhydroxylamines were investigated for the synthesis of the 1-propynamie, which will be used in the preparation of the TMC-95A Z-enamide sidechain. It was discovered that an arylsulfonylhydroxylamine with a dodecyl chain dissolved in THF and ether solvents at lower temperatures. This property should allow for the in situ synthesis of 1-propynamine. Synthesis of a TMC-278 model compound was successfully accomplished in 3 steps. The key step was the coupling of the pyrimidine intermediate with an aniline, which was achieved after oxidizing the sulfide substituent on the aminopyrimidine substrate. In contrast to literature reports with hydroxypyrimidines, the coupling with the sulfide itself does not occur with aminopyrimidines. A collaborative project with the Gianfagna group in the Department of Plant Science ¬- characterization of saponin compounds isolated from a species of Easter Lily by NMR was also accomplished.
NoteIncludes bibliographical references
Noteby Ahalya Ramanathan
CollectionGraduate School - New Brunswick Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.