【作者】 黄丹；

【导师】 王彦广； 林旭锋；

【作者基本信息】 浙江大学 ， 化学， 2013， 博士

【摘要】 手性磷酸作为Brφnsted酸中重要的一员,在不对称有机催化领域得到了广泛的应用,特别在催化合成具有光学活性的含氮杂环化合物方面。本论文主要基于本课题组报道的手性螺环磷酸,探索其在一些含氮杂环化合物的不对称合成中的应用：1.研究了手性螺环磷酸在催化不对称Pictet-Spengler反应中的应用。以2mol%的(S)-6,6’-二-1-萘基螺环磷酸为催化剂、苯作溶剂、4A分子筛、30℃的最优反应条件下,Nb-萘甲基色胺与各种脂肪醛、芳香醛、杂芳醛反应,以最高99%的产率和最高98%的对映选择性合成了23个具有光学活性的四氢-β-咔啉类化合物。我们发现用Nb-萘甲基作为保护基团,可以提高底物的活性以及产物的对映选择性,并且Nb-萘甲基经Pd(OH)2/C很容易脱除。通过将产物Nb-萘甲基脱除后测定其旋光值并与文献值比较,我们确定产物的绝对构型为S,并提出了一个可能的反应机理：手性螺环磷酸在该体系中具有双功能作用,一方面活化了亲核基团,另一方面活化了亲电的亚胺中间体。我们还成功将此策略应用于合成(-)-quinolactacin B的关键中间体以及(-)-harmicine的全合成中。2.研究了手性螺环磷酸在催化不对称三组分Povarov反应中的应用。以5m01%的(S)-6,6’-二-对氯苯基螺环磷酸为催化剂、二氯甲烷为溶剂、-20℃的最优反应条件下,芳胺、N-乙烯基氨基甲酸苄酯和各种醛反应,以最高96%的产率和最高>20:1cisl/trans以及>99%ee值得到了19个具有光学活性的4-氨基四氢喹啉类产物。通过测定产物的旋光值并与文献值比较,我们确定产物的绝对构型为(2S,4S),并提出了一个可能的反应机理。我们还以93%的产率和99%的ee值合成得到了降血脂药物Torcetrapid的前体化合物并通过三步反应实现了苯并吲哚里西啶生物碱的不对称合成。3.研究了手性螺环磷酸在催化2,3-二氢喹唑啉-4(1H)-酮(DHQZs)不对称合成中的应用。邻氨基苯甲酰胺与醛在10mol%的螺环磷酸(S)-6,6’-二-9-蒽基螺环磷酸催化下反应,以最高99%的产率和最高98%的对映选择性获得了18个具有光学活性的DHQZs。通过测得产物的旋光值,并与文献值比较,最终确定产物DHQZs的绝对构型为S,并提出了一个可能的反应机理。更多还原

【Abstract】 As an important Brφnsted acid, chiral phosphoric acid has been extensively studied in the field of asymmetric organocatalysis, especially in the catalytic synthesis of optically active nitrogen-containing heterocyclic compounds. This dissertation mainly focuses on asymmetric synthesis of nitrogen-containing heterocyclic compounds catalyzed by chiral SPINOL-derived phosphoric acids, which were reported by our research group.1. A highly enantioselective Pictet-Spengler reaction catalyzed by SPINOL-phosphoric acids has been developed. Under the optimal reaction conditions of2mol%of (S)-6,6’-di-l-naphthyl-SPINOL-phosphoric acid、benzene、4A molecular sieves、30℃, twenty-three optically active tetrahydro-β-carbolines were obtained in up to99%yield with up to98%ee by the reaction of Nb-naphthylmethyl tryptamines with a variety of aliphatic aromatic and heteroaryl aldehydes. We found that the Nb-naphthylmethyl, which could be easily removed by Pd(OH)2/C, can improve the activity of the substrate and the enantioselectivity of the product. The absolute configuration of the products was confirmed to be S by comparing the optical rotation of its Nb-deprotected product with the literature. A possible mechanism was proposed that the bifunctional nature of the chiral phosphoric acid concurrently activates both the nucleophilic group and the electrophilic iminium intermediate. The utility of this method has also been successfully demonstrated in the preparation of the key intermediate of (-)-quinolactacin B and in the asymmetric total synthesis of (-)-harmicine.2. A highly enantioselective three-component Povarov reaction catalyzed by SPINOL-phosphoric acids has been developed. Under the optimal reaction conditions of5mol%of (S)-6,6’-di-4-chlorophenyl-SPINOL-phosphoric acid、methylene chloride、-20℃, nineteen optically active4-amino-tetrahydroquinoline derivates in high yields (up to96%) with excellent diastereo-(up to>20:1cisltrans) and enantioselectivities (up to>99%ee) were affored by the reaction of anilines、benzyl N-vinylcarbamate with a variety of aldehydes. The absolute configurations of the tetrahydroquinolines was confirmed to be (25,4S) by comparison of the optical rotation with the literature, and a possible mechanism was proposed. The precursor compound of the lipid-lowering drug Torcetrapid was also obtained in93%yield with99%ee. The synthetic utility of this protocol has also been demonstrated by the asymmetric synthesis of chiral benzo[e]indolizidine through three steps.3. A enantioselective synthesis of2,3-dihydroquinazoline-4(1H)-ketones (DHQZs) promoted by SPINOL-phosphoric acids has been developed. With10mol%(S)-6,6’-bi-9-anthryl-SPINOL-phosphoric acid loading, eighteen optically active DHQZs were obtained in up to99%yield with up to98%ee by the reaction of2-aminobenzamide with aldehydes. The absolute configurations of the dihydroquinazolinones was confirmed to be S by comparison of the optical rotation with the literature,and a possible mechanism was proposed.更多还原