不对称有机催化MBH醇衍生物作为1-碳合成子的环化反应研究

Asymmetric annulation reactions have been established as the most synthetically useful and theoretically and mechanistically investigated transformations. Especially, chiral Lewis base-promoted annulation reactions with Morita–Baylis–Hillman alcohol derivatives (MBHADs) have emerged as a key platform for the construction of functionalized enantioselective carbo- and heterocycles. MBHADs, which are economical and readily available, exert diverse and amazing reactivity when reacted with a wide range of electrophiles. A variety of carbo and heterocycles, most of which are predominant in natural products and pharmaceuticals, could be constructed with high efficiency via the annulation of MBHADs. .However, the investigations on asymmetric annulation reactions of MBHADs as C1-synthons are very limited. Based on our experience, the project will focus on the asymmetric [1+n] reactions of MBHADs: 1) exploring the enantioselective [1+4] reaction of MBHADs with diversified electrophiles for the construction of benzohetercyclic rings, double heteroatomic rings, and axially chiral skeletons. 2) investigations on enantioselective [1+n] annulations and its applications: [1+2] reaction of MBHADs for the construction of cyclopropanes motifs and [1+5] reaction of MBHADs for the construction of six-member heterocyclic motifs. .The investigations would explore the reaction type of annulations of MBHADs and further broaden the application of enantioselective [1+n] annulation reactions in asymmetric organic synthesis.

不对称环化反应一直是有机化学研究和发展的前沿领域。特别是MBH醇衍生物参与的不对称环化反应为高效构建各种具有光学活性的功能化碳环或碳杂环提供了关键性技术。MBH醇衍生物廉价易得、使用方便；在与各种亲电试剂反应时表现出多样化的反应活性，可用于高效构建手性碳环和碳杂环等天然产物或药物分子的核心骨架。然而，关于MBH醇衍生物的不对称[1+n]环化反应的研究才刚刚起步。本项目拟围绕着有机催化MBH醇衍生物作为1-碳合成子的不对称环化反应开展研究：1）基于不对称[1+4]环化反应的拓展研究：拓展亲电试剂范围，构建具有生物活性的手性单杂原子并环、手性双杂原子杂环以及轴手性化合物；2）不对称[1+n]环化反应及其应用研究：通过MBH醇衍生物的[1+2]、[1+5]不对称环化反应构建手性环丙烷、六元杂环等生物活性分子的核心骨架;本项目将丰富环化反应的类型，进一步拓展[1+n]环化反应在有机合成中的应用。

围绕MBH碳酸酯的开发及应用展开工作：.1）将MBH碳酸酯的不对称[1+4]-环化反应中缺电子烯烃的范围拓展到α,β-不饱和亚胺 (40-87% yield, 87-93% ee, >20:1 dr)、2-烯羰基吡啶氮氧化物 (31-96% yield, 96->99% ee, >20:1 dr)、噻唑基烯酮 (49-96% yield, 92-99% ee, 6:1->20:1 dr)、1-戊烯-4-炔-3-酮 (73-89% yield, 88-96% ee, >20:1 dr)和1,4-戊二烯-3-酮 (70-88% yield, 93->99% ee, >20:1 dr)。.2）实现了MBH碳酸酯与2-偶氮萘的[3+2]-环化反应 (72-98% yield)、γ-取代的联烯酯与氮酰基偶氮化合物的不对称[2+4]-环化反应 (66-93% yield, 70-87% ee)、MBH碳酸酯与吲哚啉-2-亚胺的不对称烯丙基化反应 (21-99% yield, 80-95% ee)。.3）首次开发了含有1,3-茚二酮骨架的MBH碳酸酯，实现了其与含吲哚骨架的烯酮/烯酯的不对称[3+2]-环化反应 (47-99% yield, 90-99% ee, >20:1 dr)。.4）首次开发了苯并噁嗪合成子,实现了其与异氰酸酯的不对称[4+2]-环化反应 (61-84% yield, 61-92% ee)、与N-Ts-2-亚甲基-3-丁烯酯和2-亚甲基-3-氧代羧酸酯的不对称 [4+2]-环化反应 (47-97% yield, 81-93% ee, >20:1 dr)。..已发表第一标注论文12篇（SCI 9篇）、第二标注SCI论文12篇。申请中国发明专利1项。培养博士后1名，硕士研究生1名，技术骨干3名。.

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