Modular Helical Foldamers to Drive a Rapid Asymmetric Catalyst Discovery Program

Catalysis is central to a wide range of endeavours within industry and academia. Estimated to be worth $433M to the UK economy in 2021 (which enables $188B of revenue in downstream sectors), it is an essential aspect in the pursuit of a sustainable society. Whilst the term 'catalysis' is a broad term that includes for example, the heterogeneous converters in cars, the purification of water, and carbon dioxide capture, a significant part of this field are the homogenous catalyst systems that can provide new ways of creating molecules that have never been made before. Some of these molecules are particularly challenging to make because the only difference between them is that they are mirror images that cannot be superimposed (such as the left and right hands). This phenomenon, known as chirality, has the consequence that differently handed molecules will interact with molecules within the body - which themselves are handed - with different efficacies or effects; think how easy it is to shake someone's right hand (the "biological receptor") with your own right hand (the correctly handed molecule) vs your left hand (the incorrectly handed molecule). This concept within chemistry is specifically known as "asymmetric catalysis" and has clearly an important role in the manufacture of safe and effective pharmaceuticals (an endeavour identified in the 2021 Innovate UK report as being a core benefit of investment). However, the discovery of catalyst systems can be a long process, because they are generally designed to be specific to a single, often fairly niche, reaction process. Many catalytic systems use relatively small molecules to help discriminate between left and right hands of a particular target. Successful catalyst optimisation relies on being able to derivatise those small molecules, which can be severely limited by their molecular structure - often these libraries are very small because there is only one position within the molecule where changes in the molecule can be made. Certainly the functionality within these small molecules - often derived from natural products - cannot be changed easily in either its position or its nature (for example an amine to a carboxylic acid). This proposal seeks to address this by generating highly preorganised catalysts that are modular in nature. There are two very important aspects to that design which give us confidence that this approach will speed up the catalyst discovery process beyond it existing cul-de-sac. First that these catalysts are helical. This means that they are intrinsically "handed" (the mirror image of helices are also non-superimposable) and that the orchestration of reaction processes around them will be highly defined in three-dimensional space (and thus the origin of asymmetry). The second important aspect is that the modularity of these helical scaffolds allows us to swap functionality with ease to whatever is required by the reaction we are trying to catalyse. Half of these modules are amino acids, which make up all of the proteins in our body and thus have a huge range of functionality. For example, we can swap an amine for a carboxylic acid as above by just changing one of the amino acids. We can also modify other aspects of the system very easily, such as the distances between functionalities. This approach will enable vast libraries to be made and will thus impact the catalysis industry in a groundbreaking way.