Studies Of Reactions Based On Ketone/Ketimine

Nitrogen or oxygen-substituted tetrasubstituted carbon centers are widely present in natural products and pharmaceutically active compounds.The absolute configuration of the chiral center greatly influences the biological activity of these molecules.Therefore,much attention has been paid to the catalytic enantioselective synthesis of such frameworks.For this purpose,the inter-and intramolecular addition of nitroalkanes to aryl?-ketoester-or isatin-derived ketimines was explored,as well as the addition reaction of TMSCF₂PO?OEt?₂ to ketones,providing a facile access to?-amino-?^2,2-amino acid moiety,quaternary aminooxindole derivatives and?-hydroxy-?,?-difluorophosphonates.This thesis has accomplished the following research work:?1?Aza-Henry reaction of nitroalkanes to ketiminesBy using 5 mol%of DBU as Br?nsted base catalyst,we realized an efficient aza-Henry reaction of nitroalkanes to aryl?-ketoester-derived N-tosyl ketimines or N-Boc isatin ketimines,allowing the smooth synthesis of racemic?-amino-?^2,2-amino acid derivatives and quaternary aminooxindoles.Under the catalysis of quinine-derived tertiary amine-H-bond donor catalyst,up to 78%ee was achieved for the addition of nitromethane to phenyl?-ketoester-derived N-tosyl ketimine.The use of similar bifunctional catalyst could achieve up to 98%yield and 91%ee in the reaction of N-Boc isatin ketimines and nitroalkanes.Control experiments demonstrated that the phenolic hydroxyl group was essential to the reactivity.The methyl protection on the phenolic hydroxyl group led to catalyst deactivation.Mechanism study revealed that the reaction proceeded via a dual activation model:the?-H of nitroalkane was abstracted by tertiary amine,while the merging of an appropriate H-bond donor activated the substrate.?2?Ambident electrophilic addition reaction based on ketiminesWe took advantage of the ambident electrophilicity of C=N double bond to develop new reactions,and realized the controllable regiodivergent intramolecular addition of nitroalkanes to the C=N bond of ketimines derived from?-ketoesters or isatins.The electron-withdrawing group at the?-position of the ketimine could enhance the electrophilicity of the N terminus of the C=N double bond,so that the nitroalkane attacked the C=N double bond in a 5-exo mode.When ketimine was coordinated with a Lewis acid or a H-donor based catalyst,it was more likely to be attacked in a 6-endo manner.When isatin-derived ketimine-nitro compounds were subjected to an excess amount of Na₂CO₃ and MeOH,the N-selective addition took place.After releasing one equivalent of HNO₂,3-indolyl oxindole was accessible.Then,a one-pot ketimine formation/N-selective addition sequence of isatins and aniline derivatives was developed,giving the desired products in up to 96%yield.This method was successfully applied to the formal synthesis of natural product?-?-Psychotrimine,involving an asymmetric Michael addition using nitroethene as key step.Besides,under the catalysis of cinchona alkaloid derived tertiary amine catalyst,the C3 position of the product could be modified via asymmetric electrophilic sulfuration or hydroxyl methylation,establishing the nitrogen-substituted quaternary carbon centers in high ee.On the other hand,when the reaction was carried out in the presence of?R,R?-Ph-BOX/Cu?BF₄?₂ along with ⁱPr₂NH,the aza-Henry adducts could be achieved in up to 100%yield,7.6:1 dr and 94%ee,which allowed the highly enantioselective synthesis of spirocyclic aminoxindoles.DFT study showed thermodynamic factors were found to contribute to the better N-selectivity.When?-ketoester-derived ketimines were treated with inorganic bases and MeOH,N-selective reaction occurred likewise to afford 2-indolyl-2-arylacetate,in which ortho substituents on the aryl group greatly improved the selectivity.Furthermore,we managed to achieve the aza-Henry adduct in>20:1 dr and 53%ee,when this ketimine was catalyzed by thiourea-ammonium salt derived from cinchona alkaloids in combination with K₃PO₄.?3?Addition of diethyl difluoro?trimethylsilyl?methylphosphonate to ketonesWe have developed a difluoromethylenation reaction of ketones with diethyl difluoro?trimethylsilyl?methylphosphonate facilitated by the combination of 18-crown ether-6 and potassium acetate,furnishing the?-hydroxy-?,?-difluoromethylphosphonate moiety.Compared with the precedents appeared in the literature,the utility of oxygen-based Lewis base promoters avoided a rearrangement reaction that might occur when using fluoride promoters.The cheap and easily available promoters,along with the mild reaction conditions made our methodology very attractive.In particular,various ketone substrates,such as isatins,acetophenone analogs,?,?-unsaturated carbonyl compounds and alkyl ketones could work efficiently under the optimized condition.Then two strategies were applied to the asymmetric addition of TMSCF₂PO?OEt?₂ withisatin,including chiral crown ether/KOAc and 18-crown ether-6/chiral potassium salts.However,neither strategies were successful.