基于手性联萘的胍类季铵盐相转移催化剂设计、合成及其在不对称Michael串联反应中的应用

Chiral guanidine as an effective group widely exists in many natural products and molecules which have biological activity. In addition, the raw material and method for synthesis of chiral guanidine is easily available. Moreover, as chiral organic acids or bases, chiral guanidines show highly catalytic activity and selectivity in many reactions. But until now, there are little reports about chiral guanidinium salts which are employed as phase transfer catalysts. So, there are still many opportunities in this area. The project is aim to design and synthesize a novel chiral guanidinium salt phase transfer catalyst based on binaphthyl group. These classes of chiral guanidinium salt phase transfer catalysts which are sp2-quaternized ammonium salts have some advantages, such as high degree of dispersion of the charge, high chemical and thermal stability, convenience to modify the R group in both nitrogen and binaphthyl groups, easy to get raw materials and so on. We will screening and optimize the structure of catalysts to achieve high enatioselective tandem Michael reaction, and develop a new methodology for synthesis of chiral indan and α-fluoro-β-carbonyl ester. We hope to found a novel glass of high efficient chiral guanidinium salt phase transfer catalysts which have our own intellectual property rights, and have potential applications in chemical industry.

手性胍作为一种有效基团，广泛的存在于具有生物活性的分子中。由于原料易得，合成方法成熟，手性胍也经常被用作有机酸或碱来催化不对称反应，表现出很好的催化活性和选择性。但是目前人们对手性胍类季铵盐作为相转移催化剂的研究较少，因此该领域还存在较大的发展空间。本项目拟合成一类基于C2轴手性联萘的胍类季铵盐相转移催化剂。该类手性胍盐相转移催化剂是一类sp2季铵化的季铵盐，具有电荷分散程度高、化学和热稳定性好、氮原子以及联萘上的基团可以进行设计和调节等特点，不仅结构新颖、而且原料简单易得。我们将对催化剂进行筛选和结构优化，然后考察其在两类新型的Michael串联反应中的应用，发展一种新型的合成多取代手性茚满和手性α-氟代-β-羰基酯的方法。本项目的成功实施，有望发展一类具有中国知识产权、催化活性高的手性胍盐相转移催化剂，并实现其在医药工业和精细化工领域，潜在的应用价值。

本项研究发展了手性胍类相转移催化剂, 用于不对称二苯亚甲基甘氨酸叔丁酯与二烯酮类化合物的Michael/Michael串联环化反应, 取得了高达91%对映选择性和大于99：1的非对映选择性；首次实现了苯亚甲基甘氨酸叔丁酯与邻醛基查尔酮的高非对映选择性Michael/Aldol串联反应以及苯亚甲基甘氨酸叔丁酯与邻亚胺基查尔酮的高非对映选择性Michael/Mannich串联反应，为后续不对称催化研究奠定了坚实的基础。在此基础上，我们成功实现了苯亚甲基甘氨酸叔丁酯与邻胺基查尔酮和醛的三组分Michael/Mannich串联反应，合成了一列新型多取代吡咯并喹啉化合物。该项目的实施对于具有茚满和喹啉环结构的天然产物及其类似物的合成具有很好的指导意义,为手性茚满和喹啉类化合物提供切实可行的合成方案，对于发现具有生物活性的新型茚满和喹啉类化合物具有很好的学术价值，在合成含有茚满和喹啉结构单元的手性药物方面也具有光明的应用前景。