McDonald Benjamin R, Scheidt Karl A
Department of Chemistry, Department of Pharmacology, and Center for Molecular Innovation and Drug Discovery, Northwestern University, 2145 Sheridan Road, Evanston, Illinois 60208, United States.
Acc Chem Res. 2015 Apr 21;48(4):1172-83. doi: 10.1021/ar5004576. Epub 2015 Mar 6.
Natural products continue to provide a wealth of opportunities in the areas of chemical and therapeutic development. These structures are effective measuring sticks for the current state of chemical synthesis as a field and constantly inspire new approaches and strategies. Tetrahydropryans and tetrahydropyran-4-ones are found in numerous bioactive marine natural products and medicinal compounds. Our interest in exploring the therapeutic potential of natural products containing these motifs provided the impetus to explore new methods to access highly functionalized, chiral pyran molecules in the most direct and rapid fashion possible. This goal led to exploration and development of a Lewis acid-mediated Prins reaction between a chiral β-hydroxy-dioxinone and aldehyde to produce a pyran-dioxinone fused product that can be processed in a single pot operation to the desired tetrahydropyran-4-ones in excellent yield and stereoselectivity. Although the Prins reaction is a commonly employed approach toward pyrans, this method uniquely provides a 3-carboxy-trisubstituted pyran and utilizes dioxinones in a manner that was underexplored at the time. The 3-carboxy substituent served as a key synthetic handhold when this method was applied to the synthesis of highly functionalized pyrans within the macrocyclic natural products neopeltolide, okilactiomycin, and exiguolide. When employed in challenging macrocyclizations, this tetrahydropyranone forming reaction proved highly stereoselective and robust. Another major thrust in our lab has been the synthesis of benzopyranone natural products, specifically flavonoids, because this broad and diverse family of compounds possesses an equally broad range of biological and medicinal applications. With the goal of developing a broad platform toward the synthesis of enantioenriched flavonoid analogs and natural products, a biomimetic, asymmetric catalytic approach toward the synthesis of 2-aryl benzopyranones was developed. A bifunctional hydrogen bonding/Brønstead base catalyst was ultimately found to enable this transformation in analogous manner to the biosynthesis via the enzyme chalcone isomerase. Employing thiourea catalysts derived from the pseudoenantiomeric quinine and quinidine, alkylidene β-ketoesters can be isomerized to 3-carboxy flavanones and decarboxylated in a single pot operation to stereodivergently provide highly enantioenriched flavanones in excellent yield. This method was applied to the synthesis of the abyssinone family of natural products, as well as the rotenoid, deguelin. An analogous method to isomerize chalcones was developed and applied to the synthesis of isosilybin A. In both of these related endeavors, the need for novel enabling methodologies toward the efficient creation of targeted molecular complexity drove the discovery, development and deployment of these stereoselective catalytic transformations.
天然产物在化学和治疗学开发领域持续提供丰富的机会。这些结构是化学合成领域当前状态的有效衡量标准，并不断激发新的方法和策略。四氢吡喃和四氢吡喃 -4- 酮存在于众多具有生物活性的海洋天然产物和药用化合物中。我们对探索含有这些结构基序的天然产物的治疗潜力的兴趣，促使我们探索以最直接、最快速的方式获得高度官能化的手性吡喃分子的新方法。这一目标促使我们探索并开发了一种路易斯酸介导的手性β - 羟基二氧杂环己酮与醛之间的普林斯反应，以生成吡喃 - 二氧杂环己酮稠合产物，该产物可以通过一锅法操作以优异的产率和立体选择性转化为所需的四氢吡喃 -4- 酮。尽管普林斯反应是合成吡喃常用的方法，但该方法独特地提供了一种3 - 羧基三取代吡喃，并以当时未充分探索的方式利用了二氧杂环己酮。当该方法应用于大环天然产物新佩托利德、奥基拉西霉素和埃西古利德中高度官能化吡喃的合成时，3 - 羧基取代基成为关键的合成手柄。当用于具有挑战性的大环化反应时，这种形成四氢吡喃酮的反应证明具有高度的立体选择性且稳健。我们实验室的另一个主要研究方向是苯并吡喃酮天然产物的合成，特别是黄酮类化合物，因为这个广泛多样的化合物家族具有同样广泛的生物和药用应用。为了开发一个广泛的平台用于合成对映体富集的黄酮类类似物和天然产物，我们开发了一种仿生、不对称催化方法来合成2 - 芳基苯并吡喃酮。最终发现一种双功能氢键/布朗斯特碱催化剂能够以类似于通过查尔酮异构酶进行生物合成的方式实现这种转化。使用源自假对映体奎宁和奎尼丁的硫脲催化剂，亚烷基β - 酮酯可以异构化为3 - 羧基黄烷酮，并在一锅法操作中脱羧，以立体发散的方式提供高产率的高度对映体富集的黄烷酮。该方法应用于阿比西诺酮类天然产物以及鱼藤酮类化合物鱼藤素的合成。还开发了一种类似的使查尔酮异构化的方法并应用于异水飞蓟宾A的合成。在这两项相关的研究中，对高效创建目标分子复杂性的新型有效方法的需求推动了这些立体选择性催化转化的发现、开发和应用。
