CATFOLD · Cooperatively enhanced asymmetric hydrogen bonding catalysis

Cooperatively enhanced asymmetric hydrogen bonding catalysis

Introduction: Hydrogen bonding is ubiquitous throughout nature, from its role in maintaining the secondary structure of proteins to assisting in the specific recognition of enzyme substrates. It is known that in nature enzymes utilize specific non-covalent interactions to facilitate efficient catalysis. The presence of specific secondary structures is very important for these enzymes to perform various reactions. Although the number of non-covalent interactions in enzymes are manifold, various small molecules can be designed based on cooperative H-bonding interactions to act as efficient catalysts. The development of small molecule organocatalysis in the last decade has been immense as evident from the recent literature. Transformations mediated by hydrogen-bonding organocatalysts typically require a reactive electrophile due to the low levels of activation on offer and hence there is significant scope for increasing reactivity and efficiency through the design and application of new catalytic entities. Objectives: Taking a lead from nature, the aim of this project was to exploit the notion of cooperativity – namely that a hydrogen bond donor is made stronger if it is also involved as an acceptor – to increase catalytic efficiency and facilitate challenging asymmetric transformations. This will require the development and investigation of a series of folded materials, the probing of a series of non-covalent interactions and application of this information to the development of new folded catalysts. The work programme comprises three main interrelated elements. (i) Development of new folded structures: we have demonstrated that a reverse-turn comprising an amino acid derived alcohol conjoined with an aromatic amine can promote parallel sheet structure in a γ-peptide sequence designed to fold with the aid of C-H…O hydrogen-bonds. In designing this parallel-turn motif, we reasoned that incorporating an ortho-amino phenol derivative would restrict the ψ(i+2) torsion to angles consistent with natural β-turns. An N-aryl amide proton would also possess a greater hydrogenbond donor ability than a conventional amide, and the presence of the aryl trifluoromethyl group may offer further conformational control through acidification of the ortho-proton, facilitating its participation in a hydrogen-bond with the adjacent carbonyl group (scheme 1). We have made a series of simple turn structures and then extended this to larger, more complex structures with repeat their hydrogen bonding patterns along a chain. As such we have generated materials with repeating turn stuctures stabilized by urea and amide hydrogen bonds, and have also synthesized larger materials containing two isolated turn structures.

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