A biomimetic approach to asymmetric acyl transfer catalysis

Small peptide catalysts containing modified histidine residues are reported that effect enantioselective acylation reactions. The catalysts described include octapeptide beta-hairpins (e.g., 11) that exhibit high selectivitie s (up to k(rel) = 51), tetrapeptide beta-turns (e.g., 7) that afford modera te selectivities (up to k(rel) = 28), and several simple derivatives of the modified histidine amino acid that do not exhibit appreciable enantioselec tivity. Supporting structural studies (H-1 NMR and X-ray) are presented whi ch lead to the proposal of a model in which catalyst rigidity and structura l complexity contribute to higher degrees of enantioselection. A covalently rigidified octapeptide (20) is prepared through solid-phase Ru-catalyzed r ing-closing metathesis; kinetic evaluation of this peptide reveals that sub stituents along the peptide backbone may be more important than covalent st abilization of a structural motif. Detailed kinetics studies on the most se lective peptide catalysts are presented that suggest the reactions are firs t order in catalyst and substrate. Additional kinetic studies indicate unam biguously that enantioselectivities are due to specific acceleration of rea ction for one substrate enantiomer, rather than the deceleration of the rea ction for the other. The results are presented in the context of a possible enantiomer-specific hydrogen-bonding interaction in the stereochemistry-de termining step for these processes.