D-mannitol-Derived Novel Chiral Thioureas:Synthesis And Application In Asymmetric Reactions

Chiral thiourea catalyst is a kind of double-hydrogen donor catalyst which have strong hydrogen bond activation ability and can facilitate the asymmetric reaction through effective activation of substrates through double-hydrogen bonding interactions. Currently, a variety of chiral thiourea catalysts have been reported, but the chiral thioureas that can catalyze a variety of catalytic asymmetric reactions with high enantioselectivity and can efficiently catalyze asymmetric reactions in water phase are rare. D-mannitol is a kind of sugar alcohol that widely exited in land and sea plants and it has a wide range of application in life, industry and medicine. In this thesis, five novel thiourea catalysts and one novel sulfonamide catalyst were obtained through multi-step reactions by using D-mannitol as starting material. They were used as organocatalysts in asymmetric Henry reaction and other asymmetric reactions, the results are good. The main contents of this thesis includes:1. An intermediate of chiral amine with 1,3-dioxane structure was obtained by a four-step reaction of condensation, alcoholysis, azidation and reduction, using D-mannitol as material. Five novel chiral thioureas（C₁-C₅） and one novel sulfonamide catalyst（C₆） were synthesized by the reaction of chiral amine with epiquinine isothiocyanate, quinidine isothiocyanate, hydroquinine isothiocyanate, cinchonin isothiocyanate, 3,5-bis-（trifluoromethyl）-phenyl isothiocyanate and paratoluensulfonyl chloride respectively. The structures were characterized by their IR, 1H NMR, 13 C NMR and HRMS.2. These novel catalysts were directly used in asymmetric catalytic Henry reaction. The optimal reaction conditions were determined after screening of catalysts, solvents, catalyst loading, additives, reaction temperature, and so on, using nitromethane and benzaldehyde’s Henry reaction as model reaction. Under the optimal reaction conditions, we extend fifteen substrates, the product（S）-1-（3-methoxyphenyl）-2-nitroethan-1-ol was obtained with 85% yield and 81% enantiomeric excess, the product（1S,2R）-2-phenyl-nitro-1-1-propanol with two chiral center get the better result（95% yield, 87% ee, 91:9 dr）. The catalyst can also catalyze the asymmetric Henry reaction of benzaldehyde and 1-nitro propane（70% yield, 87% ee, 77:23 dr） very well. In addition, the catalyst also show good catalytic effect in the presence of water, the chemical yield and enantioselectivity up to 75% and 87% ee and 95:5 dr under optimal reaction conditions.3. After a preliminary attempt in other asymmetric reactions, C₁ can also catalyze asymmetric Michael Addition reaction（65% yield, 73% ee） and asymmetric Aza-Henry reaction（45% yield, 35% ee）.