Chiral Spirocyclic Phosphoric Acids-catalyzed Asymmetric Synthesis Of Some Nitrogen-containing Heterocvcles

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.