Cross-Aldol Reaction of Isatin with Acetone Catalyzed by Leucinol: A Mechanistic Investigation
Cross-Aldol Reaction of Isatin with Acetone Catalyzed by Leucinol: A Mechanistic Investigation
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DOI：
10.1002/chem.201500536
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发表时间：
2015-08-17
影响因子：
4.3
通讯作者：
Kocovsky, Pavel
中科院分区：
文献类型：
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作者：
Kabeshov, Mikhail A.;Kysilka, Ondrej;Kocovsky, Pavel
对l -亮醇（3a）催化isatin （1a）与丙酮之间的对映选择性醛醇反应进行了全面的机理研究，揭示了isatin除了作为底物外，还具有积极的催化作用。通过计算（类似的l -丙胺3b的G=26.1kcalmol(-1)）和动力学同位素效应(使用[D-6]丙酮的反应观察到k(H)/k(D)=2.7)，确定中间产物oxazolidine 4在isatin催化下转化为反应性的syn-enamine 6是决定速率的步骤。随后，syn-enamine 6与isatin反应生成(S)-2a（计算G=11.6kcalmol(-1)）。计算表明，整体立体化学是由两个关键事件控制的：1)isatin催化构-烯胺6的形成，在热力学上比它的反旋体7有利2.3kcalmol(-1)；2) syn-enamine 6更倾向于与isatin （1a）反应生成(S)-2a，而不是其对映体（G=2.6kcalmol(-1)）。
Comprehensive mechanistic studies on the enantioselective aldol reaction between isatin (1a) and acetone, catalyzed by L-leucinol (3a), unraveled that isatin, apart from being a substrate, also plays an active catalytic role. Conversion of the intermediate oxazolidine 4 into the reactive syn-enamine 6, catalyzed by isatin, was identified as the rate-determining step by both the calculations (G=26.1kcalmol(-1) for the analogous L-alaninol, 3b) and the kinetic isotope effect (k(H)/k(D)=2.7 observed for the reaction using [D-6]acetone). The subsequent reaction of the syn-enamine 6 with isatin produces (S)-2a (calculated G=11.6kcalmol(-1)). The calculations suggest that the overall stereochemistry is controlled by two key events: 1)the isatin-catalyzed formation of the syn-enamine 6, which is thermodynamically favored over its anti-rotamer 7 by 2.3kcalmol(-1); and 2)the high preference of the syn-enamine 6 to produce (S)-2a on reaction with isatin (1a) rather than its enantiomer (G=2.6kcalmol(-1)).