Foldamer sequences as self-organized molecular capsules – FOLDAPSULES

A work plan was implemented that includes : (i) the production of a range of units to constitute a tool box of building blocks having specific properties to construct molecular strands ; (ii) the development of methods allowing the stepwise chemical synthesis and the purification of strands having 10-20 units arranged in a precise order ; (iii) the elucidation of the helically folded structures with an extreme accuracy, in particular using X-ray diffraction methods ; (iv) the investigation of molecular recognition properties of the helices in solution, especially their affinity and selectivity for various organic guest molecules; (v) the establishment of relationships between the structures of the helices and their molecular recognition properties to allow the computer-aided design of new capsule by molecular modelling. All these methods allow to reach a great variety of capsules with predictable shapes. The production of a capsule selective for a given target molecule is a stepwise process that requires several iterations to progressively improve the properties of a first generation.

The project has delivered a major progress in the field of molecular recognition, i.e. the clear validation of the helical folded molecular capsule concept. A large number of these structures has been produced and characterized, culminating with the selective encapsulation of monosaccharides (fructose, glucose, mannose, galactose…). Important other developments include the delivery of new synthetic methodologies to prepare monomers, some of which have been patented, or the serendipitous discovery of the first artificial organic molecular structure folded in a triple helix.

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The scientific output reflects the excellent progress made during the project implementation and its collaborative aspect. It includes two patents and twelve accepted publications among which six have appeared in the most prestigious journals in the field of chemistry (J. Am. Chem. Soc. and Angew. Chem. Int. Ed.), as well as numerous presentations at conferences (over twenty five). In addition, the most important results concerning molecular recognition of saccharides are yet to appear.

This project proposes to explore a new, bio-inspired approach to the design and synthesis of artificial receptors for sizeable polar and chiral organic molecules. These receptors are constructed from helically folded oligomers that completely surround (i.e. encapsulate) their guest and can release it in a controlled fashion, in protic or non-protic solvents. The project stems from the observations that: (i) Nature's receptors rely on the folded, self-organized structures of proteins or peptides; (ii) artificial receptors are generally based on rigid molecular or supramolecular polycyclic structures that do not exploit the unmatched modularity of oligomeric strands in which each and every individual monomer may be varied in order to tune the overall properties; (iii) multiple synthetic folded oligomers (foldamers) have been described in the last decade, which offer a vast array of opportunities for the design of synthetic receptors using non-natural scaffolds. This project proposes to go beyond the current state of the art both in synthetic receptor and in foldamer design through the use and combination of the properties of two foldamer families: aromatic oligoamides, and oligo aza-aromatics. These oligomers have compatible folding motifs. They form exceptionally stable and predictable helical architectures possessing a cavity of tunable size in which guest molecules can be encapsulated. The original design on which the proposal rests is a helically folded structure whose diameter is narrow at the ends and wide in the center, which results in a hollow space with specific recognition properties. Each monomer of the sequence brings its own features to the final folded helical capsule: cavity size, helix stability, recognition properties. The targeted guests are chiral and polar organic molecules, typically mono- or di-saccharides. This choice is driven by the high biological relevance of these compounds (receptors for saccharides would be useful biochemical tools), by the fact that our capsule design makes it easy to introduce polar recognition function, by the fact that helices are intrinsically chiral objects, and by the fact that the partners involved possess extensive experience of these guests. In essence, this project amounts to creating new, artificial, codes between primary one-dimensional sequences of aromatic monomers, tertiary three-dimensional folded structures of oligomers, and molecular recognition properties. In the medium term, this project may deliver receptors suitable as sensors or for controlled substance release applications. In the long run, it paves the way towards foldamers structurally as complex and functionally as efficient as enzymes. The two teams assembled to reach these objectives combine advanced and complementary expertise in aromatic amide foldamers (partner 1), in synthetic methodology, in particular of aza-aromatic oligomers (partner 2), in state of the art physical and crystallographic characterization (partner 1), saccharide chemistry (partner 2) and saccharide molecular recognition (partner 1), and electrochemical transformations of aromatics directly relevant to guest release processes (partner 2).