Haloperidol

康龙化成举办第五十四期“合成与药物化学前沿”名师线上讲座2025年4月24日，北京——早稻田大学的山口润一郎教授做客康龙化成第五十四期“合成与药物化学前沿”名师线上讲座，报告主题为“探索环结构的转化：环的开环、成环与环交换”。报告重点介绍了：1）在路易斯酸和光氧化还原协同催化条件下，环状胺通过碳自由基中间体实现选择性的C-N键断裂以及后续衍生化；2）通过采用一种简单的多组分反应，生成了高活性的邻苯醌甲烷中间体，从而实现了多环结构的高效构建；3）一种简便的能够将烷基芳香酮底物中的芳香环替换为杂芳环的方法。首先，山口润一郎教授指出吡咯啉等未受环张力的氮杂环的C−N键断裂一直是合成化学中的难题，传统方法因吡咯啉缺乏环张力而难以适用。他们小组通过结合路易斯酸和光氧化还原催化，经由单电子转移和自由基中间体实现了N-苯甲酰吡咯啉的C−N键选择性的断裂。研究表明，路易斯酸在促进光氧化还原催化剂向酰胺羰基单电子转移过程中起着关键作用。山口润一郎教授还展示了该方法在多种吡咯啉衍生物中的广泛应用，包括通过分子间自由基加成实现C−C键形成，以及将吡咯啉转化为氮杂环丙烷、γ-内酯和四氢呋喃等结构，拓展了惰性C−N键断裂在合成策略中应用的潜力。然后，山口润一郎教授介绍了使用邻溴苯乙烯、三甲基硅基重氮甲烷在钯催化下形成邻苯醌甲烷中间体，并在碱的作用下进一步和连接有亲二烯体的丙二酸酯衍生物反应，经由分子内的狄尔斯–阿尔德反应，构建多环类化合物的新型方法。当底物中没有亲二烯体时，反应的产物变为苯并四元环的结构，该产物也可和亲二烯体发生分子间的狄尔斯–阿尔德反应形成上述多环类化合物。该分步合成的方法可以使用“一锅法”实现，并且更方便底物的扩展，从而用于构建更复杂的环状骨架分子。他们小组进一步利用该反应应用于天然产物“马萘雌甾酮”的高效合成。最后，山口润一郎教授在研究芳香酮的脱酰化转化过程中发现了将烷基芳香酮分子中的苯环直接替换为杂芳环的方法。如果底物是甲基芳香酮，在碱性条件下会和2-吡啶羧酸酯发生克莱森缩合和逆克莱森缩合反应形成新的芳香羧酸酯。如果底物是非甲基芳香酮，由于烷基的位阻增加，逆克莱森反应形成的烷基吡啶酮不会进一步反应，从而实现吡啶对烷基芳香酮中苯环的替换。该反应适用于多种杂芳环对芳香酮的替换，以及可以应用于复杂底物，如抗精神病药物氟哌啶醇中的芳环片段可直接替换为其它杂芳环。会后，山口润一郎教授在问答环节中与听众进行了热烈的讨论。Frontiers in Synthetic and Medicinal Chemistry--The 54th Pharmaron Virtual LectureBeijing, China, April 24th, 2025 - Pharmaron held its 54th virtual lecture in the Frontiers of Synthetic and Medicinal Chemistry series, which was delivered by Prof. Junichiro Yamaguchi from Waseda University in Japan. The presentation was titled “Exploring Ring Transformation: Opening, Formation, and Swapping of Cyclic Structures.” The talk focused on three areas: 1) under the conditions of Lewis acid and photo-redox cooperative catalysis, cyclic amines underwent selective C-N bond cleavage and subsequent derivatization through carbon radical intermediates; 2) by employing a simple multi-component reaction, a highly reactive ortho-quinodimethane intermediate was generated, enabling the efficient construction of polycyclic structures; 3) a facile method for replacing the aromatic ring in alkyl aromatic ketone substrates with heteroaromatic rings.Professor Junichiro Yamaguchi noted that the C-N bond cleavage in unstrained azacycles such as pyrrolidine has always been a challenge in synthetic chemistry. Traditional methods proved to be difficult to apply due to the lack of ring strain in pyrrolidine. His group achieved the selective cleavage of the C-N bond in N-benzoylpyrrolidine through single-electron transfer and radical intermediates by combining Lewis acid and photo-redox catalysis. The study showed that Lewis acid was key in promoting the single-electron transfer from the photo-redox catalyst to the amide carbonyl. Professor Junichiro Yamaguchi also demonstrated the wide application of this method in various pyrrolidine derivatives, including the formation of C-C bonds through intermolecular radical addition and the conversion of pyrrolidine to aziridine, γ-lactone, and tetrahydrofuran structures, expanding the potential of inert C-N bond cleavage in synthetic strategies.Professor Junichiro Yamaguchi introduced a novel method for constructing polycyclic compounds by using ortho-bromostyrene and trimethylsilyldiazomethane to form an ortho-quinodimethane intermediate under palladium catalysis, which further reacted with malonate derivatives bearing a dienophile in the presence of a base, followed by an intramolecular Diels-Alder reaction. When there was no dienophile in the substrate, the product became a benzannulated four-membered ring structure, which could undergo an intermolecular Diels-Alder reaction with a dienophile to form the polycyclic compounds. This stepwise synthesis method could be achieved in a "one-pot" process and was more convenient for substrate expansion, thus applicable to the construction of more complex cyclic skeleton molecules. His group further utilized this reaction to efficiently synthesize the natural product equilenin.Finally, Professor Junichiro Yamaguchi discovered a method for directly replacing the benzene ring in alkyl aromatic ketone molecules with heteroaromatic rings during the study of the deacylation transformation of aromatic ketones. If the substrate was a methyl aromatic ketone, it underwent Claisen condensation and retro-Claisen condensation with 2-pyridine carboxylic ester under alkaline conditions to form a new aromatic carboxylic ester. If the substrate was a non-methyl aromatic ketone, due to the increased steric hindrance of the alkyl group, the alkyl pyridine ketone was formed because there would be no further retro-Claisen reaction, thus achieving the replacement of the benzene ring in the alkyl aromatic ketone with pyridine. This reaction was applicable to the replacement of aromatic rings in aromatic ketones with various heteroaromatic rings and could be applied to complex substrates, such as the direct replacement of the aromatic ring fragment in the antipsychotic drug haloperidol with other heteroaromatic rings.Following the presentation, Prof. Junichiro Yamaguchi engaged in a Q&A session with the audience.