Enantioselective synthesis of "quaternary" 1,4-benzodiazepin-2-one scaffolds via memory of chirality
Enantioselective synthesis of "quaternary" 1,4-benzodiazepin-2-one scaffolds via memory of chirality
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DOI：
10.1021/ja0365781
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发表时间：
2003-09-24
影响因子：
15
通讯作者：
Lam, PCH
中科院分区：
文献类型：
--
作者：
Carlier, PR;Zhao, HW;Lam, PCH
甘氨酸衍生的1，4-苯二氮卓-2-酮，如地西潘，由于二氮杂环的船形构象而具有手性，并以构象对映体的外消旋混合物的形式存在。然而，苯二氮类化合物的C-3位手性中心的存在破坏了这一平衡，并优先稳定了一个环状构象。我们报道了由(S)-丙氨酸和(S)-苯丙氨酸衍生的N-i-Pr1，4-苯二氮卓-2-酮可以在86−99%ee中去质子化和烷基化，尽管在去质子化步骤中原手性中心被破坏。我们将这种高对映选择性的烷基化反应归因于苯二氮杂环的手性记忆。该方案提供了以前未探索的“四元”1，4-苯并二氮杂-2-酮的简单途径。
Glycine-derived 1,4-benzodiazepine-2-ones such as diazepam are chiral by virtue of the boat-shaped conformation of the diazepine ring and exist as a racemic mixture of conformational enantiomers. However, the presence of a chiral center at C-3 of the benzodiazepine perturbs this equilibrium and preferentially stabilizes one ring conformer. We report thatN-i-Pr 1,4-benzodiazepine-2-ones derived from (S)-Ala and (S)-Phe can be deprotonated and alkylated in 86−99% ee, despite the fact that the original chiral center is destroyed in the deprotonation step. We attribute this highly enantioselective alkylation to the chiral memory of the benzodiazepine ring. This protocol provides easy access to the previously unexplored “quaternary” 1,4-benzodiazepine-2-ones.