Identifier

etd-11112013-122916

Degree

Doctor of Philosophy (PhD)

Department

Chemistry

Document Type

Dissertation

Abstract

Theonellamides A-F were isolated from Theonella swinhoei by Fusetani and co-workers. Despite considerable synthetic effort to produce theonellamide F by the Shioiri group in the early 1990’s, the total synthesis of a theonellamide has yet to be reported. We report herein our efforts toward some of the required amino acid residues and construction of the western ring of theonellamide C. We describe the synthesis of an uncoded amino acid, (2S,4R)-ɣ-hydroxy-α-amino adipic acid (Ahad), a building block for theonellamide C. We initially investigated the Corey-Lygo method for the catalytic asymmetric generation of the Cα stereocenter. Unfortunately, the alkylation of glycine benzophenone imines with a series of electrophiles, including [(S)-benzyl-3-(tert-butyl dimethylsilyl)oxy]-4-iodobutanoate (104a), was unsuccessful due to low inherent reactivity and steric hindrance. A second approach was based on MacMillan’s enantioselective organocatalytic amine conjugate addition. Addition of CbzNHOTBS (136a) to (E)-benzyl-4-oxo-but-2-enoate (149), in the presence of catalytic (S)-2-diphenyl[trimethylsilyl)oxy]methylpyrrolidine (165) led to β-amino aldehyde (S)-benzyl 2-[(benzyloxycarbonyl)(tert-butyldimethylsilyloxy)amino-4-oxo-butanoate, (148a). A Wittig reaction between 148a and methyl-(triphenylphosphoranylidene)-acetate (142) afforded (2S,4E)-1-benzyl-2-[(benzyloxycarbonyl)(tert-butyldimethylsilyloxy)-amino-6-methyl-hex-4-enedioate (147a). The ɣ-hydroxy group was installed intramolecularly with 4:1 d.r. by treatment of 147a with TBAF. Hydrogenolysis was carried out to give unprotected Ahad. The next challenge was to find the right combination of protecting groups for Ahad that would be compatible with the synthesis of the western hemisphere of theonellamide C. We performed model studies on α-aminoadipic acid (α-AAA) which revealed that the δ-COOMe, introduced in the Wittig reaction, was incompatible with a Cα-acetol ester and a Nα-Alloc carbamate. α-AAA and Ahad bearing a δ-COOtBu group were synthesized in an analogous fashion. The Ahad building block was synthesized in 11 steps and 6.5% overall yield. In readiness for coupling; the tert-butyl ester was cleaved to afford the free δ-acid. Two tetrapeptides were assembled: Boc-Asn-HyAsn(OTBS)-Phe-β-Ala-OAll (249) and the simplified Fmoc-Asn(Trt)-Asn(Trt)-Phe-β-Ala-OAll (254). Removal of the N-terminal Fmoc-group from 254 and coupling with a suitably protected t-histidinoalanine acid afforded a linear hexapeptide that is a precursor to the western hemisphere of theonellamide C.

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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