title: Exploring the aldol reaction using catalytic antibodies and "on water" organocatalysts from QM/MM calculations.
abstract: The aldol reaction between benzaldehyde and acetone has been investigated using QM/MM Monte Carlo calculations and free-energy perturbation theory to determine the origin of the enhanced rates and enantioselectivities (% ee) derived from an enamine-based catalytic antibody 33F12 and a chiral organocatalyst. Electrostatic stabilization of the general acid/base TyrL36 by TrpH103, SerH100, and AsnL34 enabled the 33F12 active site to exclusively adopt an si-face benzaldehyde orientation for C-C bond formation with the LysH93-enamine. Whereas preorganization was responsible for the exclusive (S)-aldol product in the antibody, the organocatalyst featuring a chiral diphenyl amino alcohol moiety instead derived its preferred (R)-aldol product from an interplay between sterics and electronic stabilization. The si-face benzaldehyde conformation had unfavorable interactions with the organocatalyst in contrast to the re-face. Gas-phase calculations predicted a 73% ee; however, solution boosted the % ee values despite similar reaction geometries. An "on water" environment, defined as a reaction that proceeds in an aqueous organic emulsion, yielded a computed 94% ee (exptl 93% ee) compared to a calculated 87% ee in "neat" acetone (exptl 85% ee). Specific hydrogen bonding between the interfacial waters and an amide oxygen on the catalyst was found to control the % ee. A more compact si-face transition structure reduced solvent accessibility to the amide oxygen with a "closed state" steric barrier compared to an "open state" for the re-face. New insight into the synthetically important aldol reaction and state-of-the-art methodology is presented herein.
authors.affiliation: Department of Chemistry, Biochemistry, Auburn University , Auburn, Alabama 36849, United States.
authors.forename: Kira
authors.initials: K
authors.lastname: Armacost
authors.forename: Orlando
authors.initials: O
authors.lastname: Acevedo
mesh_terms: D000096:Acetone / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry*; D017151:Antibodies, Catalytic; D001547:Benzaldehydes / Q000737:chemistry; D002384:Catalysis; D020134:Catalytic Domain; D008956:Models, Chemical; D015394:Molecular Structure; D011789:Quantum Theory; D013237:Stereoisomerism; D014867:Water / Q000737:chemistry*
chemical_list: D000447:Aldehydes; D017151:Antibodies, Catalytic; D001547:Benzaldehydes; D014867:Water; D000096:Acetone; C116609:3-hydroxybutanal; C032175:benzaldehyde