College of Chemistry & Materials Engineering, Wenzhou University, Wenzhou 325035, China.
Jiangsu Key Laboratory of Pesticide Science and Department of Chemistry, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China.
J Am Chem Soc. 2022 Apr 20;144(15):6981-6991. doi: 10.1021/jacs.2c01985. Epub 2022 Apr 8.
Significant advances have been achieved for the construction of chiral skeletons containing 1,2,3-triazoles via transition-metal-catalyzed asymmetric azide-alkyne cycloaddition; however, most of them have been limited to terminal alkynes in the synthesis of central chirality via desymmetrization and dynamic/dynamic kinetic resolution. Enantioselective transition-metal-catalyzed azide-internal-alkyne cycloaddition is extremely limited. Moreover, the construction of a challenging five-membered (hetero)biaryl axially chiral molecule via transition-metal-catalyzed asymmetric azide-internal-alkyne cycloaddition is still underexplored. Herein, we first report an atroposelective and atom-economical synthesis of axially chiral 1,4,5-trisubstituted 1,2,3-triazoles, directly acting as core chiral units of challenging five-membered atropisomers, via the enantioselective Rh-catalyzed azide-alkyne cycloaddition (E-RhAAC) of internal alkynes and azides. The reaction demonstrates excellent functional group tolerance, forging a variety of C-C axially chiral 1,2,3-triazoles under mild conditions with moderate to excellent yields (up to 99% yield) and generally high to excellent enantioselectivities (up to 99% ee) along with specific regiocontrol. The origin of regio- and enantioselectivity control is disclosed by density functional theory (DFT) calculations, providing new guidance for the facile construction of axially chiral compounds.
通过过渡金属催化的不对称叠氮-炔环加成反应，在手性骨架的构建方面已经取得了显著进展，其中包含 1,2,3-三唑；然而，大多数方法仅限于通过去对称化和动态/动态动力学拆分来合成中心手性的末端炔烃。对映选择性过渡金属催化的内炔环加成反应极为有限。此外，通过过渡金属催化的不对称叠氮-内炔环加成反应构建具有挑战性的五元（杂）联芳基轴手性分子的研究仍未得到充分探索。在此，我们首次报道了通过对映选择性 Rh 催化的内炔和叠氮化物的环加成反应（E-RhAAC），直接作用于具有挑战性的五元轴手性异构体的核心手性单元，原子经济性地合成轴手性 1,4,5-三取代 1,2,3-三唑。该反应表现出优异的官能团容忍性，在温和条件下能够构建各种 C-C 轴手性 1,2,3-三唑，产率中等至优异（高达 99%），对映选择性高至优异（高达 99%ee），并具有特定的区域选择性。密度泛函理论（DFT）计算揭示了区域和对映选择性控制的起源，为轴手性化合物的简便构建提供了新的指导。
