Construction Of Fully Substituted Carbon Stereocenters Mediated By Asymmetric Nucleophilic Tertiary Amine Catalysis

Based on the n-π* and n-σ* interaction modes of nucleophilic tertiary amine catalysis, this thesis focused on the development of new enantioselective reactions through the activation of nucleophiles such as acrolein, isatin derived Morita-Baylis-Hillman (MBH) allyl bromide, trimethylsilyl cyanide (TMSCN) and fluorinated silyl enol ethers by tertiary amines, for the efficient construction of all-carbon or hetero-substituted quaternary carbon stereocenters, which paved a facile way for the synthesis of some value-added chiral building blocks. The related studies demonstrated that the merging of an appropriate H-bond donor with a tertiary amine to enable bifunctional catalysis might contribute to improved reactivity and stereochemical control in the construction of quaternary carbon stereocenters. By employment of the easily available cinchona alkaloid derivatives, this thesis has accomplished the following research work:1) By tertiary amine-phenol bifunctional catalysis, a highly efficient and selective asymmetric MBH reaction of acrolein and isatin was developed. This was the first example of using ketone as an electrophile and acrolein as a nucleophile in the asymmetric MBH reaction since its discovery in 1968. The corresponding 3-hydroxy quaternary oxindoles were achieved in up to 97% yield and 99% ee by using bifunctional tertiary amine catalyst β-ICD. The thus obtained adducts could be readily elaborated into lactone, furo-indoline derivative and MBH bromide. Mechanistic studies revealed that both the phenolic hydroxy group and rigid quinuclidine tertiary amine were indispensible for the success of this reaction. Based on these results, a possible stereochemical model was proposed.2) By nucleophilic tertiary amine catalysis, an asymmetric [3+2] cycloaddition reaction of isatin derived MBH bromides and ketones was realized. It was found that a β-ICD derivative enabled the efficient synthesis of spirooxindoles with two adjacent spiro carbon stereocenters, including the bisspirooxindoles and fluoroalkyl substituted spirooxindoles, in moderate to excellent stereoselectivities via y-regioselective annulation. We further combined the MBH reaction of isatin and acrolein with [3+2] cycloaddition reaction to develop an unprecedented one-pot MBH/bromination/[3+2] annulation cascade sequence. Control experiment revealed that the formyl group in the MBH bromide was crucial for the success of this [3+2] cycloaddition reaction. This represented the first example of using MBH bromides for asymmetric Lu’s [3+2] cycloaddition reaction, and the first one-pot tandem MBH/bromination/[3+2] annulation reaction. The reaction mechanism was investigated by means of DFT calculations and mass spectrographic analysis, and provided a reasonable explanation for the excellent regioselectivity and stereoselectivity that observed in this reaction.3) By bifunctional tertiary amine-hydrogen bond donor catalysis, the enantioselective Strecker reactions of some activated ketimines with TMSCN were developed, providing efficient synthesis of enantioenriched (α-quaternary amino acids.A newly designed quinine derived bifunctional tertiary amine-phosphoramide catalyzed Strecker reaction of N-aryl substituted isatin imines with TMSCN was first developed, with up to 71% ee obtained. This was the first catalytic asymmetric addition of nucleophiles to isatin imines, constituting a new strategy for the synthesis of optically active 3-substituted-3-aminooxindole. In view of the importance of this reaction, we further developed the bifunctional tertiary amine-thiourea catalyzed highly enantioselective cyanation of isatin derived N-Boc ketimines, and a cascade aza-Wittig/asymmetric Strecker reaction. Using this reaction as the key step, we realized the first catalytic asymmetric total synthesis of spirohydantoin I, a pain-killing compound that developed by AstraZeneca.By tertiary amine-urea bifunctional catalysis, we also realized highly enantioselective Strecker reaction of a-fluoroalkyl substituted ketimines with TMSCN under mild condition, affording the desired a-amino nitriles in up to 98% yield and 96% ee. The reaction had a wide substrate scope, and the thus obtained a-amino nitrile could be converted to optical active a-amino acid. We further designed a by-product water promoted one-pot ketimine formation/asymmetric Strecker cascade reaction of a-fluorinated ketones, aromatic amines and TMSCN. It was found that the yield and ee value were strongly influenced by the α-fluorine atom of ketimines. Based on the experiment results and DFT calculations, we proposed a new binding model of a-fluorinated ketimines with thio(urea) catalyst.4) Based on the finding that tertiary amines could efficiently activate fluorinated silyl enol ethers, we developed the bifunctional tertiary amine-urea catalyzed Mukaiyama-aldol reactions of difluorinated silyl enol ethers with isatins as well as β,γ-unsaturated-a-keto esters, which allowed the highly enantioselective synthesis of difluoroalkyl substituted tertiary alcohols. This method was successfully applied to the first catalytic asymmetric total synthesis of difluoro analogue of Convolutamydine E. We also developed a Mukaiyama-aldol reaction of monofluorinated silyl enol ethers and isatins to furnish the 3-hydroxyoxindoles containing two adjacent quaternary stereocenters with up to 94% yield, 15:1 dr and 94% ee. During the study on the aformentioned Mukaiyama-aldol reactions, we found that fluorinated silyl enol ethers were more reactive than non-fluorinated ones in the presence of bifunctional tertiary amine-H bond donor catalysts, but the reactivity between a-fluorinated ketones and non-fluorinated ones was reversed. In addition, the fluoro-substitution had a significant impact on the control of enantioselectivity. Currently, the reasons of fluorine substitution effect on the reactivity and stereoselectivity are not yet clear, and more work has to be done on this effect by theoretical calculations.