Synlett 2014; 25(3): 324-335
DOI: 10.1055/s-0033-1340342
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© Georg Thieme Verlag Stuttgart · New York

Synthesis of Oligobenzamide α-Helix Mimetics

George M. Burslem
a   School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK   Fax: +44(113)3431409   Email: A.J.Wilson@leeds.ac.uk
b   Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK
,
Andrew J. Wilson*
a   School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK   Fax: +44(113)3431409   Email: A.J.Wilson@leeds.ac.uk
b   Astbury Centre for Structural Molecular Biology, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK
› Author Affiliations
Further Information

Publication History

Received: 04 October 2013

Accepted after revision: 05 November 2013

Publication Date:
17 December 2013 (online)


Abstract

The development of inhibitors of protein–protein interactions (PPIs) represents a major challenge in chemical biology. α-Helix-mediated PPIs represent a subclass that might be amenable to inhibition using scaffolds that reproduce the spatial projection of recognition groups produced by the helix; these ligands are termed proteomimetics. Such a generic scaffold approach requires robust chemistry that can be used to synthesize reasonably large libraries of compounds. Foldamers are defined as oligomers that adopt well-defined folded structures. An ultimate goal of research in this area is to be able to reproduce and surpass the functionality of natural biopolymers; again a key enabling technology in this pursuit is robust synthetic methodology with a broad substrate scope. When we started our research program in this area seven years ago, we were drawn to aromatic oligoamide foldamers as potential proteomimetic scaffolds; however, in contrast to more widely studied β-peptide- and peptoid-based foldamers, the synthesis of aromatic oligoamides was less well developed in terms of monomer diversity and amenability to library synthesis. This account describes our efforts and, more generally, the development of methodologies for the synthesis of aromatic oligoamides during this period.

1 Introduction

1.1 Helix Mimetics-Based on Aromatic Oligoamides

1.2 Issues with Amide Bond Formation

2 N-Alkylated Oligobenzamides

3 O-Alkylated Oligobenzamides

4 Concluding Remarks