Synthetic Pursuit of the Tridecapeptide Feglymycin and the Manzamine Alkaloid Kauluamine

• Main Author: Doody, Amanda Blane
• Other Authors: Jeffrey N. Johnston
• Format: Others
• Language: en
• Published: VANDERBILT 2014
• Subjects: Chemistry
• Online Access: http://etd.library.vanderbilt.edu/available/etd-03192014-111714/

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.