Kinetic investigations provide additional evidence that an enzyme-like binding pocket is crucial for high enantioselectivity in the bis-cinchona alkaloid catalyzed asymmetric dihydroxylation of olefins
Kinetic investigations provide additional evidence that an enzyme-like binding pocket is crucial for high enantioselectivity in the bis-cinchona alkaloid catalyzed asymmetric dihydroxylation of olefins
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DOI：
10.1021/ja952567z
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发表时间：
1996-01-17
影响因子：
15
通讯作者：
Noe, MC
中科院分区：
文献类型：
--
作者：
Corey, EJ;Noe, MC
使用催化手性配体（DHQD）(2)PYDZ (1)， OsO4对末端烯烃的Sharpless对映选择性二羟基化反应遵循Michaelis-Menten动力学，表明烯烃、OsO4和1的络合物在限制性转化为Os（VI）酯中间体之前快速可逆形成。观察到的结合常数K-m与二羟基化的对映选择性之间存在良好的相关性，表明底物的范德瓦尔斯结合率为1。OsO4对提高对映选择性速率很重要。各种化合物对氧化的抑制作用已经用动力学的Dixon分析数据证明了，K-i值已经确定并与抑制剂的结构相关。最强的抑制剂是能够与1的Os（VIII）配位的化合物。OsO4络合物同时结合在由芳香亚基组成的配体口袋中。K-m和K-i值之间的平行关系及其与结构的关系表明底物和抑制剂配合物与1的结合相似。OsO4。如表1和表3所示，动力学、结构和立体化学数据支持一种对映选择性二羟基化反应机制，该机制包括：(1)烯烃- os (VIII) pi-d络合物的快速、可逆形成；(2)缓慢重排至[3 + 2]环加成过渡态，如图12所示。根据这一机制，对映选择性加速是两个因素的结果：(1)酶-底物样络合作用，使反应物以适当的几何形状聚集在一起，以便进一步转化为主要的对映体，从而提供较高的有效反应物浓度（熵效应）；(2)由于OsO4-N键的重叠应变减轻，降低了活化焓，这是下一步的驱动力。结合Sharpless对映选择性二羟基化的现有数据，本研究结果有力地支持了先前提出的[3 + 2]环加成途径和u形结合袋。
The Sharpless enantioselective dihydroxylation of terminal olefins by OsO4 using the catalytic chiral ligand (DHQD)(2)PYDZ (1) has been shown to follow Michaelis-Menten kinetics, demonstrating fast reversible formation of a complex of olefin, OsO4, and 1 prior to the rate-limiting conversion to the Os(VI) ester intermediate. There is a good correlation between the observed binding constants, K-m, and the degree of enantioselectivity of the dihydroxylation indicating that van der Waals binding of the substrate by 1 . OsO4 is important to enantioselective rate enhancement. Inhibition of the oxidation by various compounds has been demonstrated kinetically using Dixon analysis of the data, and K-i values have been determined and correlated with inhibitor structure. The strongest inhibitors are compounds with the ability to coordinate to Os(VIII) of the 1 . OsO4 complex while simultaneously binding in the pocket formed by the aromatic subunits of the ligand. Parallelism between K-m and K-i values and their relationship with structure indicate similar binding in the substrate and inhibitor complexes with 1 . OsO4. The kinetic, structural, and stereochemical data, as summarized in Tables 1 and 3, support a mechanism for the enantioselective dihydroxylation which involves (1) rapid, reversible formation of an olefin-Os(VIII) pi-d complex and (2) slow rearrangement to the [3 + 2] cycloaddition transition state which is exemplified in Figure 12. In terms of this mechanism, enantioselective acceleration is the result of two factors: (1) enzyme-substrate-like complexation which brings the reactants together in the appropriate geometry for further conversion to the predominating enantiomer, thereby providing a high effective reactant concentration (entropic effect) and (2) a driving force in the next step due to relief of eclipsing strain about the OsO4-N bond which lowers the activation enthalpy. Taken together with existing data on the Sharpless enantioselective dihydroxylation, the present results strongly support the [3 + 2] cycloaddition pathway and the U-shaped binding pocket which was advanced earlier.