摘要：2025年01月09日，北京—瑞士洛桑联邦理工学院的祝介平教授做客康龙化成第五十二期“合成与药物化学前沿”名师线上讲座，报告主题为“揭示基于钯的Dyotropic重排：从偶然发现到理性设计与合成应用”。本次讲座主要介绍了基于Pd(IV)的Dyotropic重排

转自：康龙化成

康龙化成举办第五十二期“合成与药物化学前沿”名师线上讲座

2025年01月09日，北京—瑞士洛桑联邦理工学院的祝介平教授做客康龙化成第五十二期“合成与药物化学前沿”名师线上讲座，报告主题为“揭示基于钯的Dyotropic重排：从偶然发现到理性设计与合成应用”。本次讲座主要介绍了基于Pd(IV)的Dyotropic重排—即两个σ-键在分子内同时迁移，一个协同的[σ2s+σ2s]历程，通过合理的底物设计，可以分别实现1,2-芳基，杂原子，烷基/Pd(IV)的重排，对产物的立体化学给出了详细的解释，也对反应的机理进行了深入的研究。同时基于祝教授发展的方法，可以实现DOBCO类天然产物的全合成。

祝教授首先介绍了他们在Pd催化的三组分反应过程中偶然发现了1,2-C/Pd(IV)-Dyotropic重排的发生，首次证实了在I型的Dyotropic重排里，Pd可以作为迁移基团。利用该发现，他们发展了一种简单易操作的方法，顺利解决了1,1-二取代烯烃的Wacker氧化难题。反应可以兼容一系列对称的和非对称的1,1-二取代烯烃。对于非对称的1,1-二取代烯烃，取代基更多的碳原子会优先迁移。通过向链状非对称端烯底物里引入羧酸作为导向基，可以有效提高反应的区域选择性。在机理研究中，通过外加羧酸，得到了α-酰氧基氟化合物，推测反应经历了Dyotropic重排。

随后，祝教授介绍了他们组在基于Pd的Dyotropic重排反应的研究。反应的历程一般为：1）C-Pd键产生（C-Pd化；C(sp3)-H活化；亲核Pd化；烷氧基Pd化；酰氧基Pd化；胺基Pd化等），2）Pd(II)物种的选择性氧化为Pd(IV)，3）基于Pd(IV)的Dyotropic重排，4）还原消除再生Pd(II)催化剂。通过合理的底物设计，可以分别实现1,2-芳基，杂原子，烷基/Pd(IV)的重排。当以带有α-季碳的Weinreb酰胺为底物时，经历芳基或胺基从α-到β-碳的迁移，可以生成一系列的α-三级氟化合物，反应官能团兼容性好，立体化学专一。当以γ-羟基烯烃为底物时，反应经历关键的5-exo-trig氧钯化，可以合成官能团化的3-氟四氢吡喃衍生物；而在烯烃一端合适的位置上引入杂原子则可以实现双杂螺环的构建。机理研究表明：Dyotropic重排是协同的反式共平面迁移，这也解释了产物的立体化学。因此作者通过巧妙地调节Pd催化剂的配位环境，可以实现1,2-O/Pd(IV)重排向1,2-C(sp3)/Pd(IV)重排的转变，构建一系列氟取代的四氢吡喃醇，当以γ,δ-双羟基烯烃为底物，则可以构建一系列DOBCO类化合物，实现了多种信息素的全合成，展现了该方法的应用潜力。

最后，祝教授展望了基于Pd(II)物种的选择性氧化，未来还能做哪些研究工作，并对Dyotropic重排反应是否会在未来会成为基元反应之一也提出了殷切期望。

会后，祝教授在问答环节与听众进行了热烈的讨论。

Frontiers in Synthetic and Medicinal Chemistry

--The 52nd Pharmaron Virtual Lecture

Beijing China, Jan. 9, 2025 - Pharmaron held its 52nd virtual lecture in the Frontiers of Synthetic and Medicinal Chemistry series, which was delivered by Professor Jieping Zhu from the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland. The title of this presentation was "Unveiling Pd-Based Dyotropic Rearrangement: From Serendipity to Rational Design and Synthetic Application." In this lecture, Prof. Zhu introduced Pd(IV)-based dyotropic rearrangement, two σ-bonds simultaneously migrate intramolecularly—a concerted [σ2s+σ2s] pericyclic process. By rationally designing the substrates, 1,2-aryl, heteroatom, and alkyl/Pd(IV) rearrangements could be achieved, respectively. Detailed explanations were provided regarding the stereochemistry of the products, and an in-depth investigation into the reaction mechanism was also conducted. Furthermore, based on the method developed by Professor Zhu, the total synthesis of DOBCO-type natural products could be realized.

ProfessorZhu first introduced their serendipitous discovery of the1,2-C/Pd(IV)-Dyotropic rearrangement during a Pd-catalyzed three-componentreaction process, which for the first time confirmed that Pd can serve as amigrating group in a Type I Dyotropic rearrangement. Leveraging this discovery,his group developed a general and reliable method that successfully addressedthe challenge of Wacker oxidation of 1,1-disubstituted alkenes. The reactionwas compatible with a range of symmetric and unsymmetric 1,1-disubstitutedalkenes. For unsymmetric 1,1-disubstituted alkenes, the carbon atom with moresubstituents preferred to migrate. By introducing carboxylic acid as directinggroup into linear unsymmetric terminal alkenes, the regioselectivity of the reactionwould be effectively improved. In the mechanistic study, the addition ofexogenous carboxylic acid resulted in the formation of α-acyloxyfluorocompounds, leading to the speculation that the reaction proceeds through aDyotropic rearrangement.

Subsequently,Professor Zhu presented his group's research on Pd-based Dyotropicrearrangement. The reaction pathway generally involves: 1) Generation of C-Pdbond (Carbopalladation; C(sp3)-H activation; nucleopalladation; alkoxypalladation; acyloxypalladation; aminopalladation,etc.), 2) selective oxidation of Pd(II) species to Pd(IV), 3) Pd(IV)-basedDyotropic rearrangement, and 4) reductive elimination to regenerate the Pd(II)catalyst. Through rational substrate design, 1,2-aryl, heteroatom, andalkyl/Pd(IV) rearrangements could be achieved respectively. When α-quaternarycarbon of Weinrebamides were used as substrates, migration of aryl or amino groups from the α-to β-carbon occurred, leading to the formation of a series of α-tertiaryfluorides with good functional group compatibility and stereochemicalspecificity. When γ-hydroxyalkenes wereused as substrates, the reaction underwent a key 5-exo-trig oxypalladation,enabling the synthesis of functionalized 3-fluorotetrahydropyran derivatives;whereas, introducing a heteroatom at an appropriate position on the end of thealkene allowed for the construction of bis-heterospirocycles. Themechanistic studies demonstrated that the Dyotropic rearrangement was aconcerted antiperiplanar migration, which explained the stereochemistry of theproducts. Therefore, by cleverly adjusting the Pd catalyst’s coordinationsphere, the shifting group can be modulated from 1,2-O/Pd(IV) rearrangement to1,2-C((sp3)/Pd(IV)rearrangement, constructing a series of fluorinated tetrahydropyranols.When γ,δ-dihydroxyalkenes wereapplied, a series of DOBCO could be obtained, demonstrating the applicationpotential of this method through the total synthesis of various pheromones.

ProfessorZhu discussed the potential future research work that can be done based on theselective oxidation of Pd(II) species, and expressed his earnest hope that theDyotropic rearrangement reaction might become one of the elementary reactionsin the future.

Afterthe meeting, Professor Zhu met with the audience during the Q&A session.

来源：新浪财经