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Application of Functionalised Oligoprolines in Asymmetric Catalysis

Final Report Summary - FUNCTOPROLASYMMCAT (Application of Functionalised Oligoprolines in Asymmetric Catalysis)

Asymmetric catalysis has been among the fastest developing disciplines in modern organic chemistry in the past twenty years. Driven by the desire to mimic nature’s catalytic machinery – enzymes, the quest towards efficient, robust, reusable synthetic catalysts suitable for a range of transformations has led to the development of a wide array of chiral organic compounds and transition metal complexes suitable for this purpose. Yet there is still the need for new designs which would improve the efficacy of existing systems. One of the recently emerging pathways in the development of novel catalytic systems concerns incorporation of small molecule catalysts into the structure of dynamic, supramolecular architectures to achieve an even higher degree of control over the outcome of catalysed processes (e.g. allosteric regulation, tunable selectivities) and thus mimic the properties of enzymes even closer. Amino-acids and peptides are among the most attractive building blocks to construct such catalytic systems due to their structural and functional diversity and the natural propensity to form defined, three dimensional architectures. The ultimate goal of this project was to create a catalytic, supramolecular assembly, based on rigid, helical oligoproline scaffolds, that would template the formation of an oligomeric species with a high degree of control over the length of the formed product, thus in a simplified way mimic the events which occur during the synthesis of biopolymers (DNA, proteins). Successful creation of such system would be a major achievement in both supramolecular chemistry and catalysis and a milestone in the development of artificial systems mimicking the behaviour of natural ones.

Accomplishment of the above outlined goal required an intricate design of an oligoproline-based supramolecular architecture, functionalised with complementary recognition sites, driving the assembly process (through covalent linkages or non-covalent interactions) and orthogonal catalytic sites, responsible for the activation of the bifunctional, monomeric species for the oligomerisation reaction.

Taking advantage of the synthetic toolbox, developed in the Wennemers Lab, allowing to functionalise oligoproline backbones with wide variety of substituents through chemically orthogonal transformations, we prepared a wide range of compounds with potential catalytic activity. Similarly we accessed a series of derivatives capable of forming larger aggregates or assemblies through cooperative covalent or non-covalent interactions. Studying the properties of the obtained molecules allowed us to demonstrate the potential of oligoproline-based systems to function as efficient organocatalysts and building blocks for large supramolecular architectures.

As the design, synthesis and fine-tuning of the target structure required the ability to position functional groups along the oligoproline backbones with high degree of control over their mutual spatial arrangement, structural studies, allowing to determine the crucial parameters of oligoproline PPII helices both in solid-state (X-ray crystallography) and solution (EPR spectroscopy) have been simultaneously carried out. They allowed to determine with unprecedented precision the distances between residues in the oligoproline backbone (helical pitch of 0.89nm) and confirmed that the PPII helix is a well-defined (backbone amide bonds almost exclusively in trans conformation), rigid structure (persistence length of 3.5nm at room temperature), thus perfectly suited to be used as a scaffold to construct the target, catalytic assembly.

With the above results in hand we focused our efforts on the successful combination of the previous findings and constructing an oligoproline-based, self-assembled template for oligomerisation reaction. For this purpose an orthogonal set of catalytic moieties and recognition sites was selected, following a careful screening process, to avoid the disruption of both the self-assembly properties and the catalytic performance of the device. Using a combination of state-of-the-art synthetic and analytical techniques, the target compound has been successfully prepared. The most ambitious and challenging task was however finding the optimal reaction conditions for the final, supramolecular catalytic system. A promising set of conditions has been developed and is currently being fine-tuned to increase the efficiency and selectivity of the transformation towards the oligomer of desired length.

Understanding the way in which nature controls and performs tasks as fundamental as enzymatic catalysis, biopolymer synthesis and replication will in the future allow us to precisely design every aspect of artificial functional molecules and materials. Successful realisation of the ultimate goal of this project – creating a supramolecular assembly line templating length-controlled oligomerisation will be the first example of what can be considered a simple mimic of replication process occurring in nature and will contribute to our ability to understand and follow the great complexity of biological systems. As such it will constitute a landmark achievement of modern organic chemistry enabling new areas of biochemistry, nanotechnology and materials science to develop.