Synthesis Of Triptoquinone H Via Efficient Asymmetric Cyclization And Applications In Asymmetric Hydrogenation With Novel Chiral Phosphorus Ligands

Development of new highly efficient catalytic asymmetric methodologies for constructing chiral centers is of great significance. This dissertation mainly focuses on two research topics:1) Efficient synthesis of triptoquinone H and it's C5 epimer by palladium-catalyzed asymmetric dearomative cyclization.2) Development of new skeleton chiral phosphorus ligands and it's applications in the asymmetric hydrogenation of enamines. The following research results were obtained:(1)Triptoquinone H is a diterpenoid isolated from Tripterigyum hypoglaucum which possesses great immunosuppressive activity. Based on the methodology of asymmetric dearomative cyclization developed in our lab, we can easily obtain the precursor 2-7 via Wittig reaction, reduction and deprotection from commercial available aryl substrates. By employing mis strategy, we obtained the tricyclic compound 2-8 bearing a chiral all-carbon quaternary center in 85% ee and 87% yield when using chiral monophosphorus ligand AntPhos. The resulting chiral ketone 2-8 further proceeded through methylation, reduction of double bond, demethylation and oxidation by Fremy's salt. Finally, we accomplished the first synthesis of triptoquinone H and it's C5 epimer(trans:cw= 1:2) in 10 steps and 18% overall yield.(2) Based on the skeleton of chiral bisphosphorus ligands developed in our lab, we synthesized 6 new chiral bisphophorus ligands. L25-L28 bears chiral carbon centers and chiral phosphine centers and then were applied in the asymmetric hydrogenation of enamines. After the optimization of hydrogenate conditions:We can obtained 90% ee when compound 3-1 was the substrate, and Rh(cod)2SbF6 as the catalyst, L14 as the ligand, methanol as the solvent under the pressure of 300 psi at 40 ? was the optimized condition. We can obtained 92% ee when 3-20 was the substrate, and Rh(nbd)2BF4 as the catalyst, L26 as the ligand, methanol as the solvent under the pressure of 300 psi at 50 ? was the optimized condition. It provides great instruction for the efficient asymmetric synthesis of Pharmaceuticals lorcaserin and tofacitinib. It will be particularly possible and is of great pratical value for the industrialization of pharmaceutical molecular.