Creation of Proton Mediator Catalysts

在本研究中，我们试图开发手性质子源，使人工控制质子的位置和反应活性成为可能，并在催化质子化反应中选择性地制备高光学纯度的目标有机化合物。在本项目研究期间，我们重点研究了基于手性Lewis酸催化剂的具有质子介体能力的新型手性不对称催化剂。我们已经发现BINAP-AgF催化剂是一种有效的手性催化剂，用于催化硅烯醇酯与MeOH的不对称质子化反应。因此，我们研究了相关的手性膦配体，发现p-Tol-BINAP比BINAP具有更高的对映选择性。此外，当p-Tol-BINAP-AgF配合物作为催化剂时，不仅环酮衍生的硅烯醇酯有很高的对映选择性，而且非环酮衍生的硅烯醇酯也有很高的对映选择性。此外，使用具有生物活性的α-芳基羧酸（如布洛芬和萘普生）的烯酮硅基缩醛，可导致高达30% ee的中度不对称诱导。同时，在探索基于寡肽的有机质子介质催化剂方面，我们测试了一种由天冬氨酸和苯丙氨酸组成的二肽作为手性催化剂，用于烯醇化锂的不对称质子化反应，发现该二肽催化剂与体积较大的苯酚作为非手性质子源结合，可以得到相应的具有高达88% ee的旋光性酮。

In this research we attempted to develop chiral proton sources which make it possible to artificially control the position and reactivity of the proton and to prepare targeted organic compounds selectively with high optically purity in catalytic protonation reaction. During the term of this project, we especially examined novel chiral asymmetric catalysts possessing proton-mediator ability based on chiral Lewis acid catalysts. We have previously discovered that BINAP-AgF catalyst is an efficient chiral catalyst for catalytic asymmetric protonation of silyl enolates with MeOH. Thus, we investigated related chiral phosphine ligands and found that p-Tol-BINAP is able to provide higher enantioselectivity than that given by BINAP. In addition, high enantioselectivity was observed for silyl enolates derived from not only cyclic ketones but also acyclic ketones when a p-Tol-BINAP-AgF complex was used as a catalyst. Furthermore, use of ketene silyl acetals of biologically active α-aryl carboxylic acids such as ibuprofen and naproxen resulted in moderate asymmetric induction with up to 30% ee. In the meanwhile, as for exploration of organic proton-mediator catalysts based on oligopeptides, we tested a dipeptide consisting of aspartic acid and phenyl alanine as a chiral catalyst in the asymmetric protonation of lithium enolates and found that the dipeptide catalyst in combination of a bulky phenol as an achiral proton source gave the corresponding optically active ketones with up to 88% ee.