Theoretical study of the catalysis of cyanohydrin formation by the cyclic dipeptide catalyst cyclo[(S)-His-(S)-Phe].
Dipeptide cyclo[(S)-His-(S)-Phe] 1, first applied by Inoue et al. in 1981, catalyzes the hydrocyanation of aromatic aldehydes very efficiently. Enantioselective autoinduction has also been reported for the process. We have employed QM (density functional theory and MP2), molecular mechanics (MM), and molecular dynamics (MD) methods to (i) derive a mechanistic picture for catalysis and (ii) reveal the origin of stereochemistry and autoinduction. A dimer is proposed to be the catalytic species, in which one imidazole group is essential for the delivery of the nucleophile and the second imidazole group acts as an acid, accompanied with pi-interaction for most favorable substrate binding. Hydrogen-bonding via hydroxy groups is crucial for catalysis also. MD studies indicate stability of the dimer only in non-polar media, which is consistent with the need of the experimental (heterogeneous) reaction conditions to achieve high enantioselectivities. DFT and MP2 results suggest the incorporation of the product cyanohydrin via extended edge-to-face pi-interaction over three aromatic units. Transition states derived from this model are in good agreement with experimental findings and enantioselectivities.
Schoenebeck
Franziska
F
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, USA.
Houk
K N
KN
D000447:Aldehydes / Q000737:chemistry; D055162:Biocatalysis; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism; D004583:Electrons; D008958:Models, Molecular; D009570:Nitriles / Q000737:chemistry*; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism; D011789:Quantum Theory; D055672:Static Electricity; D013237:Stereoisomerism; D013379:Substrate Specificity
D000447:Aldehydes; D004151:Dipeptides; D009570:Nitriles; D010456:Peptides, Cyclic; C430593:cyanohydrin