Veglin

康龙化成举办第四十八期“合成与药物化学前沿”名师线上讲座 2024年07月25日，北京—美国芝加哥大学Mark Levin教授做客康龙化成第四十八期“合成与药物化学前沿”名师线上讲座，报告主题为“骨架编辑的单原子逻辑”。在讲座中，Levin教授介绍了其团队的“骨架编辑”策略——即通过在合成后期对分子中单个原子的快速扩展、改变或修剪，简洁、化学特异性地有效实现所需的化学转换。本次讲座主要围绕通过插入和删除单个重原子(C、N等)选择性变换芳香环中的单个原子，以及利用这些基本转换的组合实现更复杂的C原子到N原子(C-to-N)的转换进行展开。 Levin教授首先展示了通过光化学转化对氮杂芳环进行“碳删除”，使喹啉骨架变为吲哚骨架的方法。该方法使用390 nm光照令喹啉氮氧化物发生选择性光解，然后经酸促进的重排得到N-酰基吲哚，实现2位碳原子的删除。该反应在兼容如杂芳基、卤素、氨基甲酸酯、膦酸酯、砜和硼酸酯等多种官能团取代的同时，也兼容被删除的2位碳原子上包括氰基、酯基、杂芳基、烯基等在内的不同取代基。此外，当对得到的吲哚使用Levin教授课题组先前报道的碳插入试剂α-chlorodiazirines时，又可以在3位重新引入碳原子，实现喹啉环上3位碳到2位碳的迁移和交换。最后，如果该吲哚通过已报道的N-胺化和氧化芳构化进行2位氮插入，便可以得到对应的噌啉，即起始喹啉形式上的C-to-N交换产物。 随后，Levin教授介绍了他们的选择性芳环C-to-N置换反应，该两步一锅反应从芳基叠氮化物出发，在光催化下将其转化为3H-吖庚因，后者在氧化作用下生成螺环中间体并选择性释放2位的碳，实现从芳环到吡啶环的转变。该方法能够以25%到60%的收率实现多数底物的转化。同时，采用该方法可以经3步10%的总收率完成雌酮分子中芳环到吡啶环的转化，实现这一先前报道中需要11步且总收率不到1%的合成。 最后，Levin教授介绍了杂芳族碳原子直接转化为氮原子的C-to-N置换反应。该方法首先将喹啉转化为对应的氮氧化物，其在光照下可以生成苯并恶嗪，再经由臭氧氧化实现3位和4位碳碳键的断裂开环，这时外加的氮原子能够进攻碳2位形成的酰亚胺酸酐官能团并使3位的碳能够以羧酸酯形式被释放离去，之后经缩合完成C-to-N置换反应，实现喹啉到喹唑啉的一步转化。该反应在耐受芳基、杂芳基、酯基和烷基等2位碳取代基和烷基、芳基、杂芳基、氰基和磺酰基等3位碳取代基的同时，也兼容喹啉骨架上的三氟甲基、甲氧基氨基甲酸酯、膦酸酯等取代。此外，从3-(喹啉-2-基)苯酚出发，经两步转化获得喹啉前体并进行N氧化后，便可经C-to-N置换反应以克级规模制备能够用于合成药物贝舒地尔的喹诺酮中间体。 会后，Levin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 48th Pharmaron Virtual Lecture Beijing China, July 25, 2024 - Pharmaron held its 48th virtual lecture in the Frontiers of Synthetic and Medicinal Chemistry series, which was delivered by Prof. Mark Levin from The University of Chicago, USA. The title of this presentation was “Single Atom Logic for Skeletal Editing.” In this lecture, Prof. Levin detailed the "skeleton editing" strategy, which could effectively achieve desired chemical transformations in a concise and chemospecific fashion through rapidly building, changing or pruning molecules, one atom at-a-time, using transformations at the late stage. This lecture focused on how to enable single-atom changes to aromatic systems through the insertion and deletion of single heavy atoms (C, N, etc.), as well as more complex manipulations leveraging combinations of these elementary transformations toward carbon to nitrogen (C-to-N) exchange. Professor Levin first demonstrated the method of "carbon deletion" of nitrogen-containing aromatic rings through photochemical conversion, transforming the quinoline skeleton into an indole skeleton. This method used 390 nm light to selectively photodecompose quinoline N-oxides, followed by acid-promoted rearrangement to obtain N-acylindoles, achieving the deletion of the 2-position carbon atom. This reaction was compatible with various functional group substitutions such as heteroaromatic, halogen, carbamate, phosphonate, sulfone and boronic acid ester, as well as different substitutions on the deleted 2-position carbon atom, including cyano, ester, heteroaromatic, and vinyl groups. Additionally, when using their previously reported C3-selective carbon reagent α-chlorodiazarines, the carbon atom could be reintroduced at the 3-position of the obtained indoles to achieve the migration of the carbon atom from 3-C to 2-C on the quinoline rings. Finally, when indole was subjected to 2-N insertion through a precedented N-amination and oxidative aromatization, cinnolines, as the formal C-to-N exchange product of starting quinolines, could also be accessed. Subsequently, Professor Levin introduced their selective aromatic C-to-N replacement reaction. In a two-step, one-pot procedure, aryl azides were first photochemically converted to 3H-azepines, which then underwent an oxidatively triggered C2-selective cheletropic carbon extrusion through a spirocyclic azanorcaradiene intermediate to afford the pyridine products. This method worked on most substrates with 25% to 60% yield. Meanwhile, compared to the previously reported synthesis in 11 steps and <1% overall yield, using this method, the conversion of the aromatic ring to the pyridine ring in estrone could be completed in 3 steps and 10% overall yield. Finally, Professor Levin introduced a transformation that enabled the direct conversion of a heteroaromatic carbon atom into a nitrogen atom. This method initially converted quinolines into nitrogen oxides, which then rearranged to benzoxazepines under light irradiation. Subsequently, through ozone oxidation, the C-C bonds between 3-C and 4-C could be cleaved, leading to ring opening. The external nitrogen atom could then attack the acyl anhydride functional group at 2-C, allowing the release of 3-C as carboxylic esters. The resulting intermediate underwent condensation to complete the C-to-N replacement reaction, achieving a one-step conversion from quinoline to quinazoline. This reaction was tolerant to 2-carbon substituents such as aryl, heteroaromatic, ester, alkyl, etc., as well as 3-carbon substituents including alkyl, aryl, heteroaromatic, cyano, sulfonyl, etc. It was also compatible with trifluoromethyl, methoxycarbamate, phosphonate, and other substituents on the quinoline skeleton. Additionally, starting from 3-(quinolin-2-yl)phenol, the quinoline precursor could be obtained through a two-step conversion, followed by N-oxidation to produce the corresponding quinolone intermediate. This intermediate could be utilized for gram-scale synthesis of the drug belumosudil through a C-to-N displacement reaction. After the meeting, Prof. Levin led a Q&A session with the audience for further discussion.