Creation of Proton Mediator Catalysts

本研究尝试开发手性质子源，使其能够人工控制质子的位置和反应性，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。在本项目中，我们重点考察了基于手性刘易斯酸催化剂的具有质子介体能力的新型手性不对称催化剂。我们以前发现BINAP-AgF催化剂是一种有效的手性催化剂，用于催化烯醇化硅酯与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能够提供比BINAP更高的对映选择性。此外，高的对映选择性，观察到甲硅烷基烯醇化物衍生自不仅环状酮，但也无环酮时，p-Tol-BINAP-AgF复合物用作催化剂。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甲硅烷基缩醛导致适度的不对称诱导，高达30%ee。同时，对于基于寡肽的有机质子介体催化剂的探索，我们测试了由天冬氨酸和苯丙氨酸组成的二肽作为烯醇化锂的不对称质子化的手性催化剂，催化剂与作为非手性质子源的大体积苯酚的组合得到具有高达88%ee的相应光学活性酮。

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.