Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China.
J Am Chem Soc. 2009 Oct 28;131(42):15301-10. doi: 10.1021/ja905320q.
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 Brønsted 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.
手性磷酸来源于 3,3′-二取代联萘酚，用于催化有机催化对映选择性的Biginelli 和类似的Biginelli 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′-取代基，可以反转 Biginelli 反应的立体化学。布朗斯特酸 12b 和 13 引发的这个有机催化的 Biginelli 反应适用于广泛的醛和各种β-酮酯，为 DHPMs 提供了一种高度对映选择性的方法。3,3′-二（三苯基硅基）联萘酚衍生的磷酸提供了具有广泛范围的醛和烯醇化酮的类似的 Biginelli 反应，与苯硫脲反应，得到具有极好光学纯度的结构多样的二氢嘧啶硫酮。通过 ONIOM 方法对立体中心形成步骤的过渡态进行理论计算表明，亚胺和烯醇通过氢键的形成同时被双功能手性磷酸激活。磷酸中 3,3′-取代基对 Biginelli 反应立体化学的影响也通过理论进行了合理化。该方案已应用于一些具有药用价值的化合物和中间体的合成，如手性硫脲、二氢嘧啶、胍和（S）-l-771688 的前体。
