Proteins fold into precise shapes that determine their function, and this project builds synthetic molecules that do the same—but with a chemical twist that lets chemists control the shape by choosing which catalyst to use during assembly. The problem is that natural proteins, while versatile, are limited by the 20 amino acids evolution provides. Synthetic foldamers can use a much wider chemical palette, but controlling their three-dimensional shape during synthesis has been difficult. This research introduces atropisomerism—a form of stereochemistry where certain bonds cannot rotate freely—to lock the foldamer's shape in place as it is built, step by step, using catalytic reactions. If successful, the work could produce artificial molecules that bind specific targets or catalyse reactions more reliably than natural enzymes. Potential applications include drug delivery, where a foldamer might carry a therapeutic molecule and release it only under the right conditions, and molecular sensors that detect specific chemicals. The shape of these atropisomeric foldamers also becomes flexible at higher temperatures, which the researchers plan to exploit to create "host" molecules moulded to fit a particular guest. This is primarily fundamental science in asymmetric synthesis and supramolecular chemistry, but the ability to design synthetic polymers with protein-like precision could eventually underpin new classes of responsive materials.
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Nature’s most remarkable functional molecules – proteins – are polymeric chains formed by bonding together amino acids. By simply changing the sequence of amino acids an incredible array of functions can be accessed, from structural proteins such as spider’s silk, to highly efficient enzyme catalysts. This proposal focuses on the development of atropisomeric foldamers, a novel class of synthetic molecules inspired by the natural folding behaviour of biomolecules such as proteins. Foldamers are artificial oligomers that can mimic the structures and functions of biological macromolecules. The primary innovation of this research is to incorporate atropisomerism—a form of stereochemistry where the shape of the molecule is determined by the restricted rotation around certain chemical bonds—into the design and synthesis of foldamers. A unique feature of our approach which differentiates it from natural systems, is that the shape of the polymer can be determined simply by the choice of catalysts used to form it. The methodology involves using a series of catalytic reactions to iteratively build these foldamers. By controlling the stereochemistry during synthesis, we hope to create foldamers with specific shapes and functions. This could lead to materials that are more versatile than natural biomolecules, with potential applications in drug delivery, catalysis, and molecular recognition. The research plan is divided into several work packages, each focusing on different aspects of the synthesis and analysis of these foldamers. Initial efforts will be directed toward synthesizing the core foldamer motifs and understanding their conformational behaviour using techniques like X-ray crystallography and NMR spectroscopy. Subsequent work will explore how the stereochemical configuration of the foldamers influences their function, particularly in binding to other molecules—a feature that could make them useful as molecular sensors or catalysts. One important feature of atropisomeric molecules is that their shape becomes flexible at higher temperatures: we will exploit this feature to develop new “host” molecules, moulded specifically to bind a particular guest. In summary, this research aims to create a new family of polymeric molecules with precise structural control, opening up possibilities for advanced materials with tailored functionalities. The work is positioned to contribute significantly to the fields of asymmetric synthesis, materials science, supramolecular chemistry and macromolecular chemistry.
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