Chiral Organocatalysis For(3+2) Cyclo Additions and Mannich Additions of Unsaturated Carbonyl Compounds with Cyclic Imines

张真真

张永娜;汪游清

硕士

河南大学

有机催化;;不对成称合成;;(3+2)环加成反应;;Mannich反应;;三氟甲基

手性有机小分子催化在不对称合成中有着广泛的应用,是继生物催化体系(如酶催化),金属有机配合物手性催化剂之后第三类用途广泛的手性催化剂。苯并[e]-[1,2,3]恶噻嗪2,2-二氧化物是一类N-磺酰基环状亚胺。三氟甲基基团具有高亲脂性和强吸电子性,因此可提高母体分子的极性、静电势、偶极矩、结合选择性、生物利用度和其它性质,在药物化学分子设计中具有重要意义。本论文研究了两类有机小分子催化作用下环状三氟甲基酮亚胺和不饱和羰基化合物的不对称反应:N-杂环卡宾(NHC)催化的不对称(3+2)环加成反应,手性伯胺和酸共催化的不对称Mannich反应。第一部分:手性NHC催化的不对称(3+2)环加成反应。通过N-杂环卡宾催化活化α,β-不饱和醛与酮亚胺的高烯醇中间体加成,实现了烯醛和环N-磺酰基三氟甲基酮胺的不对称(3+2)环化反应。以取代的三氟甲基酮亚胺和不同的α,β-不饱和醛为底物,对各种反应条件进行优化最终以中等至良好的产率,高的立体选择性>20:1 dr,94-99%ee有效地构建具有两个相邻手性中心的稠合N-杂环γ-内酰胺,其中一个手性中心为三氟甲基化的α-四取代碳立体中心。通过单晶衍射确定其中一个化合物绝对构型,化其它合物通过相似机理的化学类比法来确定。最后不损失立体选择性的实现了对环加成产物官能团的衍生化。第二部分:手性伯胺和酸共催化的不对称Mannich反应。手性伯胺和酸共催化活化α,β-不饱和酮形成烯胺中间体增加了其最高占据轨道(HOMO)的能量促进了与环状N-磺酰基三氟甲基酮亚胺的亲核加成,理论上接下来会发生aza-Michael反应,实验结果表明只进行了Mannich反应得到非关环产物。用取代的环状N-磺酰基三氟甲基酮亚胺和不同的非环烯酮为底物,经过对伯胺催化剂,共催化的酸,溶剂温度等实验条件的优化最终以良好的产率,高达97%ee构建了手性苯并稠合三氟甲基化的β-氨基羰基化合物。通过单晶衍射确定其中一个化合物绝对构型,化其它合物通过相似机理的化学类比法来确定。

Chiral organic catalysis is widely used in asymmetric synthesis.It is the third kind of chiral catalyst after biocatalysis(such as enzyme catalysis)and metal-organic complex chiral catalyst.Benzo[e][1,2,3]oxathiazine 2,2-dioxides can be considered as N-sulfonyl cyclic imines.The trifluoromethyl group represent lipophilicity and strong electron absorption,so it can improve the polarity,electrostatic potential,dipole moment,binding selectivity,bioavailability and other properties of the parents molecules.It shows great significance in the molecular design of pharmaceutical chemistry.In this paper,we studied the asymmetric reactions of cyclic trifluoromethyl ketoimines and unsaturated carbonyl compounds under the two kinds of chiral organic catalysis: Asymmetric(3+2)cycloaddition reaction catalyzed by N-heterocyclic carbene(NHC)and asymmetric Mannich reaction catalyzed by chiral primary amine and acid.Part Ⅰ: Asymmetric(3+2)cycloaddition reaction catalyzed by Chiral NHC.The enantioselective(3+2)cycloadditions of enals and cyclic N-sulfonyl trifluoromethylated ketimines via N-heterocyclic carbene-catalyzed homoenolate addition were developed.Using substituted trifluoromethyl ketonimines and different α,β-unsaturated aldehydes as substrates,various reaction conditions were optimized and finally fused N-heterocyclic γ-lactam with two adjacent chiral centers were effectively constructed with high stereoselectivity > 20:1 dr,94-99% ee,with one chiral center as a trifluoromethylated a-tetrasubstituted carbon stereocenter.The absolute configuration of one of the compounds was determined by single crystal diffraction,and the other compounds were determined by the chemical analogy method of similar mechanism.Finally,the functional groups of cycloaddition products were derivatized without loss of stereoselectivity.Patt Ⅱ: Asymmetric Mannich reaction catalyzed by chiral primary amine and acid.The chiral primary amines and acids co-catalyze to activate α,β-unsaturated ketones to form enamine intermediates increased the energy of the highest occupied orbital(HOMO)and promoted the nucleophilic addition with cyclic N-sulfonyl trifluoromethyl ketoimines.The cascade Mannich-Michael reaction will occur in theory.The experimental results show that only the Mannich reaction is carried out to obtain the unclosed ring product.Using substituted cyclic N-sulfonyl trifluoromethylated ketimines and different acyclic ketenes as substrates,After optimizing the experimental conditions such as primary amine catalyst,co-catalytic acid,solvent and temperature,the chiral benzo-fused trifluoromethylated β-aminocarbonyl compound was constructed with a good yield and up to 97% ee.The absolute configuration of one of the compounds was determined by single crystal diffraction,and the other compounds were determined by the chemical analogy method of similar mechanism.