基于“可控张力释放”策略的多取代环丙烷衍生物的合成新方法

Cyclopropane moiety is prevalent in many natural products, drugs and bioactive molecules. Development of efficient strategies for cyclopropane construction has been a challenge and attracted significant attention for decades. Even though many strategies have been developed, the state-of-the-art processes still cannot meet the requirements for structurally diverse cyclopropane moieties in natural products, many of which still invoke multiple-step, inefficient synthetic routes to access. Current strategies mainly focus on “de novo” construction of this stained scaffold, enforcing restrictions on substrate structure and reagent reactivities. Alternatively, the thermodynamically more favored cyclopropane synthesis from cyclopropene is a highly attractive alternative for being atom economical and enabling the coupling of non-reactive reagents. However, the due to its large strain, under transition metal catalysis cyclopropene often undergoes other more favored processes, such as ring-opening, oligerization, et. al. Thus, “ring-retentive” cyclopropane synthesis from cyclopropene still faces many challenges, such as lack of reaction modes and very limited product diversity. Evolution of efficient cyclopropane synthesis by way of multicomponent reactions of cyclopropene is thus highly challenging. In this proposal we propose to leverage the reactivities of a few novel cyclopropyl copper intermediates discovered or developed in our own group to develop efficient, highly enantioselective catalytic three-component reactions. The products derived from these studies will be preliminarily evaluated for their anti-cancer and anti-neurodegenerative activities. The successful implementation of this project will offer highly efficient and highly enantioselective methodologies for multi-substituted cyclopropanes otherwise difficult to obtain or difficult to access with traditional approaches. For these reasons, the research projects outlined have significance from both theoretical and practical aspects.

环丙烷是广泛存在于具有重要药理活性的天然产物和生物活性分子中的结构单元。构建环丙烷的方法学研究一直是有机化学发展的热点和难点之一。目前环丙烷合成大都基于热力学上不利的“从头构建”张力环的方式，对底物结构和试剂活性要求较高；从环丙烯出发构建多取代环丙烷的方法因热力学有利、原子经济性高而极具吸引力。然而，环丙烯的金属催化反应因张力释放的不可控而易导致骨架开环、寡聚等过程，使得“环保留型”的环丙烷合成模式单一、产物多样性极为受限。发展基于环丙烯可控张力释放过程的环丙烷的多组分合成方法因而极具挑战性。本项目拟基于申请人课题组发现或发展的一些新型环丙基铜中间体，探索和发展高效、高对映选择性的催化三组分反应，并将一些典型产物用于抗肿瘤等疾病的药物的初步筛选。项目的顺利实施将为一些传统方法难以获得的多取代环丙烷提供绿色高效的方法学，丰富环丙烷衍生物的多样性和化学空间，具有重要的理论意义和应用价值。

尽管环丙烷是极为重要的结构单元，目前多取代环丙烷骨架的高效合成仍然效率低下且缺乏高效的催化策略。另外，含氮氧的杂环，如硝酮和肟醚的合成也仍然存在重要问题。从稳定且易得的高张力环丙烯分子出发，发展高效的多组分反应实现多取代环丙烷的合成具有重要发展潜力。受到环丙烯的碳铜化和课题组前期发现的环丙烯Cope型氢胺化的活性的启发，本项目发展了：（1）基于硼试剂为碳源的碳铜化策略实现三组分环丙烷的高效合成，分别实现了环丙烯的顺式选择性芳胺化（Org. Lett. 2019）、芳基烯丙基（苄基）化（Org. Chem. Front. 2019）以及高对映选择性烯基胺化（Chem. Commun, 2020），并将这一策略扩充到了张力较小的氧杂双环二烯（Org. Biomol. Chem. 2021）；（2）将Cu催化剂用于非张力烯烃的分子内Cope-型氢胺化反应，实现了一系列环状硝酮的高效合成，部分底物实现了高的不对称诱导（Chem. Eur. J., 2019，Hot paper）；对部分环状硝酮进行了抗癌活性测试，发现了具有较高癌细胞毒性的环状硝酮化合物（Med. Chem. Res. 2021）；（3）鉴于Cu催化剂活化烯烃进行Cope-型氢胺化能力较弱的问题，发展了Pd催化的烯基肟化合物的分子内环化（Asian J. Org. Chem，2019）和分子间偶联环化反应合成环状硝酮和肟醚（Org.Chem. Front. 2019；Org. Lett., 2020；Asian J. Org. Chem. 2023), 并在Pd催化的手性硝酮的对映选择性合成上取得了一些进展，目前正在进行之中。部分结果项目负责人作为第一完成人获批国家专利2件。在环丙烯的三组分碳官能化反应发展中，研究揭示了协调多个基元步骤的动力学匹配性在优化反应中的重要性，并在芳基烯丙基（苄基）化反应发展中，利用电子效应适中的配体协调了碳铜化和后续亲电官能化的矛盾。这些发现为其它三组分反应的发展具有一定的借鉴意义。手性硝酮的高对映选择性的合成也是杂环化学领域发展的一个挑战，其成功实现将具有较为重要的意义。