N-Glyoxylamides as versatile precursors for peptide mimics and heterocycles

by Duc Le

Institution: University of New South Wales
Department: Chemistry
Year: 2015
Keywords: Heterocycles; N-glyoxylamide; Peptide mimics; Isatin
Record ID: 1073669
Full text PDF: http://handle.unsw.edu.au/1959.4/54235


The work presented in this thesis aims to highlight the versatile reactions of N-acylisatins as precursors for the synthesis of novel peptide mimics and heterocycles. N-arylisatins were prepared via Chan-Lam coupling of various electron-deficient arylboronic acids with isatin. Attempts to ring-open these N-arylisatins with primary alcohols were unsuccessful. However, when subjected to tert-butylamine in refluxing conditions, the corresponding N-glyoxylacid salts were obtained along with the N-glyoxylamides as minor products. A novel series of first generation amphiphilic peptide mimics were prepared from the ring-opening reactions of hydrophobic N-acylisatins by various amines. Further modification allowed for the introduction of cationic moieties such as those mimicking positively charged amino acids as well as tertiary ammonium groups. An extension of this chemistry was used to prepare a series of second generation peptide mimics from terephthaloyl chloride. By altering the core structure of these compounds the balance of charge and hydrophobicity could be controlled. The N-acylisatin ring-opening strategy was applied to the synthesis of benzene-1,3,5-tricarboxamides (BTA) allowing access to both novel BTA-N-glyoxylesters and amides with peripheral alkyl chains. Furthermore BTA-N-glyoxylamides with peripheral amino acid esters were prepared in a similar fashion demonstrating the ease with which BTAs can be functionalized using this strategy. Various N-protected amino acids were coupled to isatin forming N-amino acyl isatins. These novel N-acylisatins participate in ring-opening reaction with either alcohols or amines to give the corresponding N-glyoxylesters or amides. Upon deprotection these precursors cyclize to form1,4-benzodiazepin-2-ones bearing C5 pendant amide or ester groups. This is a novel synthetic strategy that provides access to these biologically relevant molecules from cheap and readily accessible starting materials. A number of strategies were investigated for the design and synthesis of novel cyclic peptide mimics incorporating the N-glyoxylamide moiety. Macrocyclization via ring closing metathesis (RCM) and macrolactonization were attempted with little success. Macrolactamization of aN-glyoxylmethylester containing a β-alanine moiety 6-26 afforded the first cyclic dimer containing two N-glyoxylamide units.