康 · 学术 | Pharmaron Launches the 27th Pharmaron Virtual Lecture

2022-10-17

康龙化成举办第二十七期“合成与药物化学前沿”名师线上讲座 2022年9月29日，北京—美国伊利诺伊大学厄巴纳-香槟分校的David Sarlah教授作客康龙化成第二十七期“合成与药物化学前沿”名师线上讲座，报告主题为“去芳官能化：从新颖的方法到复杂的天然产物”。Sarlah教授的报告详细介绍了去芳构化反应的最新进展。该反应以可见光介导的芳烃与亲芳烃体(arenophile, 含杂原子的有机小分子)之间的[4 + 2]环化反应为基础，并且可应用于具有生物活性的复杂天然产物的合成。去芳构化反应可以把简单易得的芳烃转化成饱和度更高的，更复杂的，在合成上应用更广泛的中间体。去芳构化反应可以分为下面几类：溶解金属还原方法（Birch还原）、氢化反应、苯酚氧化去芳构化、过渡金属介导的去芳构化、芳烃与烯烃之间的间位光环化反应和微生物氧化法。虽然上面这些已确立的方法很有效，但一般来讲，这些方法不能同时引入其他的官能团。Sarlah教授介绍了一种新的去芳构化方法，即用可见光激活含N-N键的亲芳烃体，然后与不同种类的芳烃发生对位环化反应，从而实现去芳构化的双羟化，还原，环氧化，反式1, 2碳胺基化，顺式1, 4-碳胺基化和顺式1, 4-双胺基化等反应。Sarlah教授还成功地将该去芳构化策略应用于具有抗癌活性的羟基异喹啉生物碱的不对称全合成，这些生物碱包括(+)-7-deoxypancratistatin, (+)-pancratistatin, (+)-lycoricidine, 和 (+)-narciclasine。合成这些生物碱的一个关键反应是镍催化的苯的去芳构化反应，生成反式的1, 2-碳胺基化的二烯中间体，接下来只需要两步烯烃的官能化反应就可以得到完全修饰的氨基环多醇核心结构。令人惊讶的是这些复杂的天然产物的合成以苯为起始原料，路线只有6-7步，并且可以顺利放大，Sarlah教授的实验室已经合成了克级的这四种生物碱。Sarlah教授还介绍了核糖霉素的化学合成方法。该合成方法以苯为起始原料，其中铜催化的不对称去芳构化氢胺化反应是关键步骤，整条合成路线只有10步。会后，Sarlah教授与听众开展了热烈的问答与讨论。Frontiers in Synthetic and Medicinal Chemistry-- Pharmaron Virtual Lecture 27Beijing China, September 29th, 2022 -Pharmaronheld its 27th virtual lecture in the Frontiers of Synthetic and Medicinal Chemistry series, which was delivered by Prof. David Sarlah from University of Illinois at Urbana-Champaign, IL, USA and titled Dearomative Functionalizations: From Novel Methods to Complex Natural Products. In this lecture, Prof. Sarlah introduced recent developments of dearomatization reactions based on visible-light mediated [4 + 2] cycloadditions between arenes and heteroatom-containing organic molecules-arenophiles and their applications in the synthesis of complex, biologically active natural products.Dearomatizatioin reactions provide a synthetic connection between readily available, simple arenesand more saturated intermediates of greater molecular complexity and synthetic utility. Several classes of these reactions exist, including the venerable dissolving metal (Birch) reduction, dearomatic hydrogenation, oxidative dearomatization of phenols, transition-metal-mediated dearomatizations, arene-alkene meta-photocycloaddition, and microbial oxidation. While these established dearomatization methods are exceptionally powerful, they generally do not result in introduction of additional functionality. Prof. Sarlah introduced a new dearomatization process that involved visible-light activation of N-N arenophiles, which resulted in their para-cycloaddition with a variety of arenesto enable dearomative dihydroxylation, reduction, epoxidation, trans-1,2-carboamination, syn-1,4-carboamination and syn-1,4-diamination.Prof. Sarlah successfully applied this dearomatic strategy in the enantioselective total syntheses of the anti-cancer isocarbostyril alkaloids, including (+)-7-deoxypancratistatin, (+)-pancratistatin, (+)-lycoricidine, and (+)-narciclasine. The key reaction was a Ni-catalyzed dearomativetrans-1,2-carboamination of benzene to provide a diene intermediate. Then only two additional olefin functionalizations were needed to construct the fully decorated aminocyclitol cores of these alkaloids. It is amazing to obtain these complex natural products from simple benzene in just 6-7 steps and several grams of each natural products were synthesized in Prof. Sarlah’s laboratory.Prof. Sarlah also described the chemical synthesis of antibiotic ribostamycin, which proceeded in ten linear operations from simple benzene. A key enabling transformation involved a copper-catalysed, enantioselective, dearomative hydroamination.After the lecture, there was an active discussion and Q&A with Prof. Sarlah.