转自：康龙化成
康龙化成举办第四十四期“合成与药物化学前沿”名师线上讲座
2024年03月28日，北京—美国宾夕法尼亚大学Marisa Kozlowski教授做客康龙化成第四十四期“合成与药物化学前沿”名师线上讲座，报告主题为“氧气驱动片段偶联在天然产物和抗菌药物合成中的应用”。在讲座中，Kozlowski教授分享了利用氧气为氧化剂，通过高通量筛选寻找具有化学选择性的高效催化剂的方法。目前，她的课题组通过催化策略在苯酚和萘酚的氧化偶联、烯醇的氧化偶联和烷基C-H活化选择性氧化偶联方面取得了很好的研究进展，并将其新发展的合成策略应用于天然产物和厚朴酚和pyrolaside B的全合成中。
首先，Kozlowski教授提到，氧化偶联反应被认为是一种简洁、高效的构建碳-碳、碳-杂、以及杂-杂键的方法。在过去10年里，氧化偶联反应取得了一系列重要进展。尽管利用氧化偶联高效构建碳-碳、碳-氧和碳-氮键在自然界中广泛存在，然而很少可以在实验室里能像生物体系一样具有优异的选择性及反应效率。因此，找到具有化学选择性的高效催化剂是十分必要的。Kozlowski教授分享了利用氧气为氧化剂，通过高通量筛选的方法，对72种金属催化剂进行筛选，最终发现：未报道的Cr-salen配合物在酚的氧化偶联反应中表现出独特的交叉偶联活性。Kozlowski教授课题组将Cr-salen配合物用于天然产物和厚朴酚的合成中。该策略大大提高了和厚朴酚的收率并节省了原料的成本。
其次，Kozlowski教授介绍了一种温和的铜催化体系氧化三聚酚的方法，并利用该方法首次实现了天然产物pyrolaside B的全合成。这种新方法的关键策略是螺缩酮三聚体中间体的一步合成，这样可以通过选择性还原来得到天然产物框架，并避免使用Ullmann和Suzuki偶联反应。利用该方法，Kozlowski教授通过5步反应，以16%的总收率合成了pyrolasideB。Kozlowski教授对这些化学转换的内在机理展开研究，理解其化学选择性和高催化效率的内在驱动力，以及如何利用其新发现的规律来发现更多新的化学转换。
最后，作为著名有机化学学术期刊-OrganicLetters的主编，Kozlowski教授对该期刊的稿件类型，研究方向等内容进行了介绍。
会后，Marisa Kozlowski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 44th Pharmaron Virtual Lecture
BeijingChina, March 28th,2024 -Pharmaron held its 44th virtual lecture in the Frontiers ofSynthetic and Medicinal Chemistry series, which was delivered by Prof. Marisa Kozlowski from University of Pennsylvania in theUS. The title of this presentation was “OxygenDriven Fragment Coupling for the Synthesis of Natural Products andAntibacterials.” Inthe lecture, Prof. Kozlowski shared the selective and efficient catalystscreening, phenol and naphthol coupling, enol coupling, and alkyl C–Hactivation. Applications of the oxidative coupling in the total synthesis of honokiol and pyrolasideB werealso presented.
Prof. Kozlowski first introduced thatnature uses oxidative couplings to construct carbon-carbon, carbon-oxygen, andcarbon-nitrogen bonds with a high degree of efficiency. However, few laboratoryequivalents are as selective or as efficient as the biological versions. Theuse of parallel microscale screening to discover selective and efficientcatalysts for such processes using oxygen as the terminal oxidant was shared.After screening 72 metal catalysts, Cr-salens appeared with uniquecross-coupling activity for cross coupling, which had not been reportedpreviously. The method was used for the total synthesis of honokiol. Thestrategy greatly improved the yield of honokiol synthesisand saved the cost of raw materials.
Then, Prof. Kozlowski presented a facilemethod to oxidatively trimerize phenols using a catalytic aerobic coppersystem. The mechanism of this transformation was probed, yielding insight thatenabled cross-coupling trimerizations. With this method, the natural product pyrolasideB wassynthesized for the first time. The key strategy used for this novel synthesisis the facile one-step construction of a spiroketal trimer intermediate, whichcould be selectively reduced to give the natural product framework, withoutrecourse, to stepwise Ullmann- and Suzuki-typecouplings. As a result, pyrolaside B could be obtained expeditiously in fivesteps with 16% overall yield. The studies on the mechanisms of thesetransformations were described with the goal of understanding the governingprinciples and how they might be used to discover further new transformations.
Finally, as the Editor-in-chief of OrganicLetters, thewell-known academic journal of organic chemistry, Prof. Kozlowski brieflyintroduced the types of manuscripts and research directions of the journal.
After the meeting, Prof. Kozlowski had adiscussion with the audience during the Q&A session.
