Expanding the conformational space accessed by dipole-controlled foldamers

Abstract

Foldamers are artificial oligomers that utilise a range of non-covalent interactions to adopt well-defined conformations akin to the secondary and occasionally tertiary structures of biomacromolecules. With this mimicry, foldamers are therefore seen as a potential platform to replicate the vast array of functions that biomacromolecules perform such as molecular recognition, catalysis, and signalling.

Taking inspiration from Hamilton et al.’s utilisation of dipole-control to enforce conformational control in a class of imidazolidin-2-one based β-strand mimetics, previous research conducted by the Knipe group examined the conformational relationship between imidazolidin-2-one and a variety of isomeric azine-arene linkers, finding that either a linear or curved shape could be occupied via judicious choice of aromatic linker. However, due to the strict conformational control enforced by the dipolar repulsion, the repeating units are locked in a planar conformation and therefore place limitations on the exploration of the conformational space, since substituents can only be directed about one axis (yaw), rather than in perpendicular directions.

Being able to fully explore the conformational space is imperative to expand the range of biomolecular structures and functions that can be mimicked. The principal aim of this project was therefore to develop novel dipole-controlled motifs that could be incorporated within the previously developed foldamer framework, and enable selective manipulation of each principal axis, allowing for further diversity in the folded conformations accessed.

Chapter 2 explores the modification of the roll axis with the creation of a spiro-bislactam motif, whose spirocentre enabled a 90° twist between each monomer in the backbone, allowing for the projection of substituents along both the yaw and pitch axes. Compatibility with the previous imidazolidin-2-one based foldamers was then demonstrated, allowing greater structural complexity and function in future hybrid foldamer designs.

Chapter 3 explores the use of diketopiperazine motifs as dipole-controlled units. When combined with a pyridine linker these adopted a zig-zag conformation, and allowed for manipulation of both the yaw and roll axes due to the interplay of dipolar repulsion and torsional strain interactions. Due to the unique symmetry of the diketopiperazine foldamer, it could be then exploited to enable stimulus-responsive sidechain reconfiguration. Treatment with acid disrupts the dipolar repulsion and forms a pyridine-centred hydrogen-bond network, resulting inversion of the sidechains but with retention of the zig-zag conformation.

Chapter 4 explores the attempt to develop dipole-controlled units that would manipulate the last remining principal axis, pitch. Two potential candidates were proposed to achieve this, either an envelope-like fused bislactam motif, or puckered bridged diketopiperazine, whose ring curvature would enable raising or lowering of the backbone in the vertical axis. Efforts were therefore made to incorporate these motifs within the dipole-controlled foldamer system. This involved attempting to develop a novel synthetic route to the fused bislactam, as to date despite its simple appearance, a literature method is not known. However, despite several approaches, a successful route was not established. As for the bridged diketopiperazine motif, although a literature route to the structure was known and the motifs easily synthesised, attempts to form the dipole-controlled monomer units were largely unsuccessful. The highly strained bridged species instead favouring decomposition under the typical Pd or Cu catalysed coupling conditions.

Alongside the research conducted into novel dipole-controlled monomer units, the synthesis of spiro[pyrrolidin-3,2’-oxindoles] was explored, having become of interest due to their presence in a variety of naturally and synthetically derived compounds displaying numerous biological activities. Amongst the most prevalent method for their synthesis is via a 1,3-dipolar cycloaddition, with numerous catalytic asymmetric approaches having been developed.

Chapter 5 discusses the development of a 1,3-dipolar cycloaddition between isatin-derived N-trifluoroethyl ketimines and a range of benzylidenemalononitrile and benzylideneindandione dipolarophiles, affording a series of functionalised spiro[pyrrolidin-3,2’-oxindoles] with up to four contiguous stereocentres in excellent yields, ee and dr (up to 98% yield, 97% ee, and >100:1 dr)

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy & Royal Society of Chemistry Research Fund
Supervisor	Peter Knipe (Supervisor) & Stephen Cochrane (Supervisor)