【作者】 杨龙；

【导师】 谢剑波；

【作者基本信息】 西北农林科技大学 ， 化学， 2025， 硕士

【摘要】 螺环骨架广泛存在于手性配体和生物活性分子中,特别是含氮杂[5.5]和[5.6]螺环骨架的分子可作为药物先导化合物而备受关注。尽管已经报道了很多构建手性氮杂螺环的方法,但这些方法大多需要使用复杂结构的底物,限制了应用。因此,发展由简单原料合成手性氮杂螺环的方法是较为重要的。α,β-不饱和化合物结构简单、易于合成,是合成化学最常使用的底物之一。目前,过渡金属催化α,β-不饱和底物的串联“共轭加成-惰性键活化”反应鲜有报道。主要原因是反应产生的烯醇金属中间体容易质子化,难以克服惰性键活化与质子化之间的反应竞争问题。基于课题组前期报道铑催化环外双键α,β-不饱和酯的串联共轭加成-β-C消除反应,本文利用氮杂环外双键α,β-不饱和酯简化底物设计,突破传统方法依赖复杂前体的限制,经铑催化的不对称串联“共轭加成-C（sp²）-H键活化”反应,以优异的对映选择性实现了手性氮杂螺环茚酮的简洁不对称合成。本文对影响反应效率和选择性的因素如苯基硼试剂、底物构型、手性配体、反应体系干燥程度、温度和溶剂进行系统研究,确立了以（R）-H₈-BINAP作手性配体,[Rh（cod）Cl]₂作金属前体,苯硼酸作转移金属化试剂,叔丁醇钠作碱添加剂,乙二醇二甲醚作溶剂的最佳反应条件。该反应具有较好的官能团兼容性,一系列不同氮保护基的环外双键α,β-不饱和酯与芳基硼酸均能得到相应的手性氮杂螺环茚酮（23个例子,最高可达68%收率,98%ee值）。通过控制实验,对反应机理进行了初步探索。对产物的简单转化,以高对映选择性实现了一些含手性氮杂螺环骨架活性分子的便捷合成,证明该合成策略的应用价值。更多还原

【Abstract】 Spirocyclic skeletons are widely found in chiral ligands and bioactive molecules,and in particular,molecules containing aza[5.5]and[5.6]spirocyclic skeletons are of significant interest as drug lead compounds.Although many methods have been reported to construct chiral azaspirocycles,most require the use of structurally complex substrates,which significantly limits their applicability.Therefore,developing synthetic methods for chiral azaspirocycles from simple raw materials is of greater importance.α,β-Unsaturated compounds are structurally simple,readily accessible,and commonly used substrates in synthetic chemistry.Currently,the tandem“conjugate addition-inert bond activation”reactions have rarely been reported.The main reason for this is that the enol metal intermediates generated during the reaction are prone to protonation,making it challenging to overcome the competition between inert bond activation and protonation.Building upon our group’s previous work on rhodium-catalyzed tandem conjugate addition-β-C elimination reactions of exocyclicα,β-unsaturated esters,this thesis employs simplified aza-exocyclicα,β-unsaturated ester substrates to overcome the limitation of conventional methods that rely on complex precursors.Through a rhodium-catalyzed asymmetric tandem“conjugate addition-C（sp²）-H activation”reaction,we achieved a concise asymmetric synthesis of chiral aza-spirocyclic indanones with excellent enantioselectivity.In this thesis,the factors affecting the reaction efficiency and selectivity,such as phenyl boron reagents,substrate configuration,chiral ligands,dryness of the reaction system,temperature and solvents,were systematically investigated,and the optimal reaction conditions were established as follows:（R）-H₈-BINAP as chiral ligand,[Rh（cod）Cl]₂ as metal precursor,phenylboronic acid as transmetallation reagent,sodium tert-butoxide as alkaline additive,and dimethoxyethane as solvent.The reaction exhibited broad functional group tolerance,and a series of exocyclicα,β-unsaturated esters with different nitrogen protecting groups and arylboronic acids afforded the corresponding chiral aza-spirocyclic indanones（23examples,up to 68%yield,98%ee）.Control experiments provided preliminary mechanistic insights.Furthermore,derivatization studies demonstrated the practical utility of this strategy by enabling the facile synthesis of bioactive molecules featuring chiral azaspirocyclic scaffolds with high enantioselectivity.更多还原