Identifier

etd-11112013-181807

Degree

Doctor of Philosophy (PhD)

Department

Chemistry

Document Type

Dissertation

Abstract

The theonellamides (TNMs) A-F are bicyclic dodecapeptides isolated from marine sponges of the genus Theonella and were shown to display potent antifungal activity. Despite considerable synthetic effort to produce TNM F by the Shioiri group in the early 1990s, a total synthesis of a TNM has yet to be reported. This dissertation describes our efforts toward some of the required amino acid residues of TNM C and the eastern hemisphere. The production of erythro-β-hydroxyasparagine (eHyAsn) followed the synthesis of threo-β-HyAsn by Boger and co-workers, utilizing a key Sharpless aminohydroxylation reaction. The eHyAsn building block, Boc-eHyAsn(OTBS)-OH, was coupled with HCl.Phe.OMe using EDC/HOBt/NEt3/THF to afford Boc-eHyAsn(OTBS)-Phe-OMe in 68% yield. Our two early approaches toward the (3S,4S,5E,7E)-3-amino-8-(4-bromophenyl)-4-hydroxy-6-methylocta-5,7-dienoic acid (Aboa) residue are presented. The first relied on a challenging regioreversed Sharpless aminohydroxylation reaction and the second on a nitroaldol condensation. Results from individual model systems indicated that the levels of diastereo- and enantioselectivity for each approach were not acceptable. The most recent approach to Apoa and Aboa utilized a key Horner-Wadsworth Emmons reaction followed by two conceptual sets of protecting group manipulations. The optimized conditions for the HWE reaction of (4S,5R)-tert-butyl 5-formyl-4-(2-(4-methoxyphenoxy)ethyl)-2,2-dimethyloxazolidine-3-carboxylate with (E)-diethyl (4-phenylbut-3-en-2-ylphosphonate led to a 40% yield with a 4.5:1 E/Z ratio of olefin products. Currently, an advanced primary alcohol intermediate (three steps from Apoa) has been verified by HRMS. We also briefly explored an approach whereby the conjugated system could potentially be introduced after the oxidative removal of the PMP group. The preparation of the Fmoc-allo-Thr(OTBS)-Ser(OTBS)-Phe-OBn tripeptide resulted from coupling commercially available amino acid residues in an N→C stepwise fashion followed by exchange of both OtBu protecting groups with their TBS counterparts. Since the Apoa and Aboa residues were not yet available, we sought to synthesize an analog of the eastern hemisphere of TNM C containing β-Phe as this would generate a macrocycle with the same ring size. Synthetic efforts toward this analog have produced the cyclization precursor as verified by HRMS. Once Apoa/Aboa is complete, the deprotection and coupling conditions outlined for the β-Phe analog can be applied towards the assembly of both Apoa- and Aboa-containing eastern hemispheres.

Date

2013

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Taylor, Carol

Included in

Chemistry Commons

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