Design And Synthesis Of Novel Chiral Ligands Based On Privileged Skeleton Cinchona Alkaloids And Ferrocene And Their Applications In Asymmetric Reactions

This thesis is concerned with the design and synthesis of novel chiral ligands based on privileged chiral skeleton Cinchona alkaloids and ferrocene and their applications in metal-catalyzed asymmetric reactions. The main content contains three parts.1. Preparation of Cinchona alkaloids based Schiff base ligands and their Cu(II) complex catalyzed asymmetric Henry reactionBased on our previous study, we designed and synthesized four kinds of Cinchona alkaloids based Schiff base ligands featuring obvious steric and electronic effects. Their catalytic performance was investigated in Cu(II) catalyzed asymmetric Henry reaction of aldehydes and nitroalkanes(nitromethane and nitroethane). The results indicated that with 5 mol% of Cu(OTf)21:1 complex of sterically hindered tertiary butyl group substituted ligands 94, the b-nitroalcohols adducts could be obtained in high activity andenantioselectivities(up to 97% isolated yield, 99% ee, 84:16 dr) under optimized conditions. In addition, the mechanism of the reaction was initially studied via the absolute configuration of the products, the X-ray crystal structure of ligand 94 and IR, HR-MS spectra of the metal complex. Based on these preliminary studies, the possible transition state has been reasonably speculated.2. Design and synthesis of a novel type of ferrocene-based N, N-ligands and their application in asymmetric allylic alkylation reactionOverall 19 kinds of novel ferrocene based N,N-ligands have been designed and synthesized via the combination of pyridine and oxazoline into the skeleton. Their structures are fully characterized by NMR, HRMS and X-ray crystal structures. These types of ligands contain multi-chiral elements, also featuring in easily tunable of steric and electronic factors and a plausible secondary interaction with substrate through a free hydroxyl group. Besides, these ligands are stable and the synthesis steps are concise and the starting materials are readily available. To the best of our knowledge, this is the first example of ferrocene-based N,N- bidentate ligands bearing both oxazoline and pyridine. The catalytic performance of the ligands was investigated in Pd(II)-catalyzed allylic alkylation reactions of(E)-1,3-diaryl allyl acetate and malonate. The results indicated that the absolute configuration of the hydroxyl-attached carbon has a key effect to the activity and the chiral induction, as well as the existence of the free hydroxyl group. The study of the planar chirality showed that ligands with S planar chirality performed better than the R ones. However, the TMS group on the ferrocene or the variation of substituent on the oxazoline has relatively little effect to the catalytic performance. Under the optimized conditions, using 5 mol% of the Pd(II)/(S,Sp,R)-107 a complex, the allylic alkylation products could be obtained in up to 99% yield and 98% ee. Besides, the initial assumption of possible hydrogen bonding between the free hydroxyl group and the substrate was preliminary verified via hydroxy alkyl experiment, the absolute configuration of the ligands and the chiral allylic alkylation products. Based on these preliminary studies, a possible transition state has been reasonably proposed.3. Highly enantioselective hydrogenation of α-oxy functionalized α, β-unsaturated acids catalyzed by a Chen Phos-Rh complexEnantiomerically pure α-oxy functionalized carboxylic acids are useful synthetic intermediates and have important applications in the medicine and agrochemical fields. Transition metal catalyzed asymmetric hydrogenation of α-oxy functionalized α,?-unsaturated carboxylic acids is the most economic and effective way to form these acids. Herein, we successfully applied the Rh(I) complex of ferrocene derived chiral bisphosphine ligand Chenphos, which developed by our group, in asymmetric hydrogenation of α-oxy functionalized α,?-unsaturated carboxylic acids(up to 5000 TON, 99% yield, 99% ee). The catalytic system features in mild conditions and no base additive is needed. Besides, we also found that the choice of the solvents is vital in the reaction, and it is demonstrated that the interaction between ligand and substrate and solvent plays an important role for achieving high enantioselectivities and high activity. In addition, the developed catalytic system was successfully employed in synthesis of the key intermediate of the Sacubitril(AHU 377), which is one of the components of a new drug Entresto(LCZ 696) for treatment of cardiovascular disease(up to 99:1 dr).