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Title page for ETD etd-03192014-111714

Type of Document Dissertation
Author Doody, Amanda Blane
URN etd-03192014-111714
Title Synthetic Pursuit of the Tridecapeptide Feglymycin and the Manzamine Alkaloid Kauluamine
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Jeffrey N. Johnston Committee Chair
Brian O. Bachmann Committee Member
Gary A. Sulikowski Committee Member
Ned A. Porter Committee Member
  • Umpolung Amide Synthesis
  • UmAS
  • Feglymycin
  • Kauluamine
  • aryl glycine
  • arylglycine
Date of Defense 2014-03-10
Availability unrestricted
Feglymycin is a tridecapeptide that has been shown to act as an inhibitor of the formation of HIV syncytia as well as the cell-to-cell transmission of the virus. The natural product contains thirteen amino acid residues, four of which are unusual 4-hydroxy phenyl glycines and five of which are unusual 3,5-dihydroxy phenyl glycines. Aryl glycine residues are prone to epimerization during their installation into peptides using conventional amide bond-forming reactions. Feglymycin is therefore a good candidate for synthesis using Umpolung Amide Synthesis (UmAS), which mechanistically avoids this epimerization pathway. UmAS involves the reaction of a nucleophilic nitronate, derived from an α-bromo nitroalkane, with an electrophilically activated N-halo amine. The α-bromo nitroalkane donors can be prepared using an enantioselective aza-Henry reaction and serve as carboxylic acid surrogates in this sequence leading to amide formation. Retrosynthetically, feglymycin was divided into three peptide fragments (A-C) for synthesis using UmAS. Each fragment was further divided into the corresponding α-bromo nitroalkanes, which were prepared using an enantioselective aza-Henry reaction. Iterative UmAS coupling of the α-bromo nitroalkanes allowed for the synthesis of Fragment A, which contains three amino acid residues. Analogs of Fragments B and C, which contain six and four amino acid residues, respectively, were also prepared using this method. Fragments B and C were successfully coupled using a DEPBT-mediated amide-bond forming reaction, resulting in a decapeptide for coupling to Fragment A.

Kauluamine, a dimer of the manzamine class of natural product alkaloids, contains a cis-fused piperidine and cyclohexane core, six contiguous stereocenters, a β-carboline moiety, and unusually rigid 11- and 13-membered macrocycles. A model study for the total synthesis of this compound utilizing the Brønsted acid-promoted [3+2] cycloaddition and anti-aminohydroxylation reaction between an alkyl azide and an α-unsubstituted, α,β-unsaturated imide, followed by base-promoted cyclization, was successfully carried out to prepare the piperidine core of kauluamine. NMR-based structural elucidation was an essential tool used in the model study to confirm the diastereoselectivity of the cyclization. In a subsequent study, an alkyl azide and α-substituted, α,β-unsaturated cyclic imide were prepared for installation of a number of the carbons required for the kauluamine core. Through a series of experiments, it was determined that the reactivities of the α-substituted, α,β-unsaturated cyclic imide and alkyl azide were two low for coupling via the Brønsted acid-promoted [3+2] cycloaddition reaction.

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