Creation of Proton Mediator Catalysts

在这项研究中，我们试图开发手性质子源，从而有可能人工控制质子的位置和反应活性，并在催化质子化反应中选择性地制备具有高光学纯度的目标有机化合物。在本项目期间，我们特别研究了基于手性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催化剂是一种高效的催化硅烯醇酸与甲醇不对称质子化反应的手性催化剂。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，当p-Tol-BINAP-AGF络合物作为催化剂时，不仅来自环酮而且来自非环酮的硅烯醇酸酯具有很高的对映选择性。此外，使用生物活性的α-芳基羧酸的烯酮硅基缩醛，如布洛芬和萘普生，导致适度的不对称诱导，最高可达30%ee。同时，在探索基于寡肽的有机质子介体催化剂方面，我们测试了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酸锂的不对称质子化反应，发现以大分子苯酚为非手性质子源的二肽催化剂可以得到相应的光学活性酮，ee高达88%。

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.