NMR-spectroscopic investigations towards the reasons for selectivity in peptide catalysis

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NMR spectroscopy is a powerful tool to obtain information on the structure and dynamics of organic, organometallic, inorganic or biomolecular compounds in solution at atomic resolution. Information about the three dimensional structure in solution can in turn be linked to activity and/or selectivity. This can also be true for catalysis, provided compounds or intermediates relevant for the catalytic cycle can be subjected to analysis at conditions as close to reality as possible. Furthermore, NMR spectroscopy allows the investigation of intermolecular interactions via a series of techniques. These are mostly based on magnetisation transfer from a ‘ligand’ to a ‘binder’ or vice versa. In drug discovery these techniques are used to search for pharmacologically relevant leads. The ‘binder’ usually is the target biomacromolecule (protein, e.g.) and the ‘ligand’ a proposed drug; in terms of catalysis this could be the catalyst and the substrate.It is proposed here to use NMR-spectroscopic methods to (further) investigate the importance of hydrogen bonds and London dispersion interactions in the kinetic resolution of trans-1,2-cycloalkane diols by a (series of) peptide catalyst(s). The Thiele and Schreiner groups showed previously that intermolecular interactions can be observed NMR-spectroscopically between catalyst and substrate for this particular system. Within this project the reasons for the extraordinary selectivity shall be investigated. The individual contributions of hydrogen bonds vs. dispersion interactions shall be tracked down NMR-spectroscopically employing different NMR spectroscopic techniques on a series of diols (exhibiting different selectivities and dispersion interaction surfaces but the same hydrogen bonding ability vs. the same dispersion interactions surfaces and different hydrogen bonding abilities). Additionally, different peptide catalysts with increasing polarizabilities of the amino acid, which mainly provides the interaction surface (so called Dispersion Energy Donating Amino Acids) shall be investigated. Applications of the methods used and developed herein to other (peptide) catalysed reactions - the enantioselective Dakin-West reaction, e.g. – shall then be envisioned.