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Supramolecular Modular Approaches to Asymmetric Catalysis: Synthesis of Ligands by a Metal-Ligand Mediated Assembly Process

Final Report Summary - SUPRASYMCAT (Supramolecular Modular Approaches to Asymmetric Catalysis: Synthesis of Ligands by a Metal-Ligand Mediated Assembly Process)

Our approach focuses mainly on the design and preparation of ligands capable of exploiting supramolecular interactions with the aim of modifying the geometry of the catalytic and/or recognition site through non-covalent interactions. Our interests within this research field involve the generation of organophosphorus-based supramolecular bidentate ligands capable of binding different cationic species and modulate the envisaged catalytic and/or binding activity through supramolecular interactions (ion-dipole interactions).
Allosteric modulation is a quite common feature in living systems and has allowed for structural and functional regulation. The term allosterism involves the modification of the properties of the biologically active site by the interaction of an external stimulus unit (effector) with a specific regulating site in the biological system. This effector can either enhance or decrease the functional properties of the system. The design of artificial allosteric systems is of great significance for controlling molecular function by external stimuli and we have developed within this research project new allosteric P=O-disubstituted receptors for dicarboxylic acids with appended crown ethers (Figure 1).

In this regard, a wide array of P=O-disubstituted receptors with appended crown ether cavities have been efficiently synthesized from easily available starting materials. Novel bisphosphine oxide derivatives bearing crown ethers cavitites of different size have been prepared in good isolated yields and have been fully characterized. The structure of these newly designed P=O-based allosteric receptors has unequivocally been established by single crystal X-ray diffraction analysis (Figure 2).
Binding studies consistently revealed that binding affinity of the receptor decreased upon increasing the spacer chain length of the dicarboxylic acid, thus the selectivity order being established as follows: HOOC-COOH > HOOC-CH2-COOH > HOOC-(CH2)2-COOH >> HOOC- (CH2)n>2-COOH. Li+ and Na+ cations turned out to be efficient allosteric effectors in the recognition of oxalic and malonic acids by our receptors. Binding of cationic effectors within the crown ether unit resulted in a positive "allosteric" effect, which has been determined to be Krel = 7 in the best case (binding of malonic acid with Li+ @ crown-4-receptor).

The development of chiral ligands that preserve most of the structural generalities but incorporate mechanisms to induce "subtle" changes in their three-dimensional structure by means of supramolecular interactions (allosterism) is an underexplored area of research. Work is in progress to develop efficient chiral catalysts based on this family of phosphorus compounds with an allosteric regulation mechanism suitable for enantioselective transformations of interest (enantioselective hydrogenation and hydroformylation, amongst others).