Highly Enantioselective Organocatalytic Biginelli and Biginelli-Like Condensations: Reversal of the Stereochemistry by Tuning the 3,3′-Disubstituents of Phosphoric Acids
Highly Enantioselective Organocatalytic Biginelli and Biginelli-Like Condensations: Reversal of the Stereochemistry by Tuning the 3,3′-Disubstituents of Phosphoric Acids
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DOI：
10.1021/ja905320q
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发表时间：
2009-10-28
影响因子：
15
通讯作者：
Gong, Liu-Zhu
中科院分区：
文献类型：
--
作者：
Li, Nan;Chen, Xiao-Hua;Gong, Liu-Zhu
研究了源自 3,3'-二取代联萘酚的手性磷酸的有机催化对映选择性 Biginelli 和 Biginelli 类反应。催化剂的3,3'-取代基的大小能够控制Biginelli反应的立体化学。通过调整磷酸的 3,3'-二取代基，可以逆转 Biginelli 反应的立体化学。这种布朗斯台德酸 12b 和 13 的有机催化 Biginelli 反应适用于多种醛和各种 β-酮酯，为获取 DHPM 提供了一种高度对映选择性的方法。 3,3'-二（三苯基甲硅烷基）联萘酚衍生的磷酸可以使多种醛和烯醇化酮与苄基硫脲发生类似 Biginelli 的反应，从而得到结构多样的具有优异光学纯度的二氢嘧啶硫酮。用ONIOM方法对立体中心形成步骤的过渡态进行理论计算表明，亚胺和烯醇同时被双功能手性磷酸通过形成氢键激活。磷酸中的 3,3'-取代基对 Biginelli 反应立体化学的影响也得到了理论上的合理化。目前的方案已应用于一些药学上有趣的化合物和中间体的合成，例如手性硫脲、二氢嘧啶、胍和(S)-L-771688的前体。
Organocatalytic enantioselective Biginelli and Biginelli-like reactions by chiral phosphoric acids derived from 3,3'-disubstituted binaphthols have been investigated. The size of 3,3'-substituents of the catalysts is able to control the stereochemistry of the Biginelli reaction. By tuning the 3,3'-disubstituents of the phosphoric acids, the stereochemistry of the Biginelli reaction can be reversed. This organocatalytic Biginelli reaction by Bronsted acids 12b and 13 is applicable to a wide range of aldehydes and various beta-keto esters, providing a highly enantioselective method to access DHPMs. 3,3'-Di(triphenylsilyl) binaphthol-derived phosphoric acid afforded Biginelli-like reactions of a broad scope of aldehydes and enolizable ketones with benzylthiourea, giving structurally diverse dihydropyrimidinethiones with excellent optical purity. Theoretical calculations with the ONIOM method on the transition states of the stereogenic center forming step showed that the imine and enol were simultaneously activated by the bifunctional chiral phosphoric acid through formation of hydrogen bonds. The effect of the 3,3'-substituents in phosphoric acids on the stereochemistry of the Biginelli reaction was also theoretically rationalized. The current protocol has been applied to the synthesis of some pharmaceutically interesting compounds and intermediates, such as chiral thioureas, dihydropyrimidines, guanidines, and the precursor of (S)-L-771688.