Exploring the Aldol Reaction using Catalytic Antibodies and “On?Water” Organocatalysts from QM/MM Calculations

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• 作者：Kira Armacost ; Orlando Acevedo
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：January 8, 2014
• 年：2014
• 卷：136
• 期：1
• 页码：147-156
• 全文大小：582K
• ISSN：1520-5126

文摘

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鈥揅 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 鈥渙n water鈥?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 鈥渘eat鈥?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 鈥渃losed state鈥?steric barrier compared to an 鈥渙pen state鈥?for the re-face. New insight into the synthetically important aldol reaction and state-of-the-art methodology is presented herein.