Department of Chemistry, Biochemistry, Auburn University , Auburn, Alabama 36849, United States.
J Am Chem Soc. 2014 Jan 8;136(1):147-56. doi: 10.1021/ja405614p. Epub 2013 Dec 17.
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.
苯甲醛和丙酮的醛醇缩合反应已通过 QM/MM 蒙特卡罗计算和自由能微扰理论进行了研究，以确定基于烯胺的催化抗体 33F12 和手性有机催化剂衍生的增强速率和对映选择性（%ee）的起源。TrpH103、SerH100 和 AsnL34 静电稳定了通用酸/碱 TyrL36，使 33F12 活性位点能够仅采用 si-面苯甲醛取向与 LysH93-烯胺进行 C-C 键形成。虽然抗体中的预组织负责获得唯一的（S）-醛醇产物，但具有手性二苯基氨基醇部分的有机催化剂则通过立体和电子稳定之间的相互作用获得其首选的（R）-醛醇产物。与 re-面相比，si-面苯甲醛构象与有机催化剂之间存在不利的相互作用。气相计算预测 ee 值为 73%；然而，尽管反应几何形状相似，但溶液会提高 ee 值。与在“纯”丙酮中计算的 87% ee（实验 85% ee）相比，定义为在水有机乳液中进行的反应的“在水中”环境产生了计算出的 94% ee（实验 93% ee）。发现界面水与催化剂上酰胺氧之间的特定氢键控制 ee 值。与 re-面的“开态”相比，si-面过渡态结构的紧凑性降低了酰胺氧的溶剂可及性，具有“闭态”位阻。本文提出了对合成上重要的醛醇反应和最先进方法的新见解。
