Selective Spin Transfer in Complex Polyketide Synthesis: Total Synthesis of Ajudazol A and Salimabromide

复杂聚酮化合物合成中的选择性自旋转移：Ajudazol A 和 Salimabromide 的全合成

• 批准号: 400173102
• 负责人: Professor Dr. Dirk Menche
• 金额: --
• 依托单位: Kekulé-Institut für Organische Chemie und Biochemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/400173102?language=en
• 关键词: Selective; Spin; Transfer; Complex; Polyketide

Polyketides are prevalent structural features in numerous natural products with a broad range of biological activities and pharmacological properties. They are characterized by diverse assemblies of methyl and hydroxyl-bearing stereogenic centers, thus enabling very large numbers of stereochemical permutations and structures with extraordinary complexity and diversity. Prominent examples include the antibiotic salimabromide, a unique polycyclic metabolite and first natural product that was isolated from a marine myxobacterium and the highly potent respiratory chain inhibitor ajudazol A, a singular isochromanone polyketide of myxobacterial origin. The important biological properties in combination with their unique and synthetically challenging architectures render these compounds attractive targets from the perspective of synthetic and medicinal chemistry. Despite considerable progress in the chemistry of complex polyketides, there remains a high need for more convergent as well as more selective synthetic methods and in particular radical reactions are still underdeveloped in complex polyketide synthesis. This project proposes the development of two innovative spin-centered methods to access key structural features of these two complex polyketides and important natural products in general in an efficient manner. The first procedure focuses on an iodine-mediated one-pot process for stereoselective isochromanone synthesis, while the second method concentrates on the generation of quaternary centers by a titanocene-catalyzed epoxide opening followed by a radical allyltransfer reaction. These procedures will then enable highly concise first total syntheses of ajudazol A and salimabromide, which will also be important for an unambiguous structural and stereochemical assignment. Finally, designed analogs with improved biological and/or biophysical properties will be prepared to further evaluate and improve the full biological potential of these highly scarce, potent bioactive agents.

聚酮化合物是许多天然产物中普遍存在的结构特征，具有广泛的生物活性和药理学性质。它们的特征在于具有甲基和羟基的立体中心的不同组装，从而使得非常大量的立体化学排列和结构具有非凡的复杂性和多样性。突出的例子包括抗生素salimabromide，一种独特的多环代谢物和第一种天然产物，是从海洋粘细菌中分离出来的，以及高效呼吸链抑制剂ajudazol A，一种粘细菌来源的异色满酮聚酮化合物。重要的生物学特性与其独特的和具有合成挑战性的结构相结合，使得这些化合物从合成和药物化学的角度来看是有吸引力的目标。尽管在复杂聚酮化合物的化学方面取得了相当大的进展，但仍然高度需要更收敛以及更选择性的合成方法，特别是自由基反应在复杂聚酮化合物合成中仍然不发达。该项目提出了两种创新的自旋为中心的方法，以有效的方式访问这两个复杂的聚酮化合物和重要的天然产物的关键结构特征。第一个程序侧重于碘介导的一锅法立体选择性异苯并二氢吡喃酮合成，而第二种方法集中在生成季中心的二茂钛催化的环氧化物开放，然后由一个自由基烯丙基转移反应。然后，这些程序将使高度简洁的第一次全合成的Ajudazol A和salimabromide，这也将是重要的明确的结构和立体化学分配。最后，将制备具有改善的生物和/或生物物理性质的设计类似物，以进一步评估和改善这些高度稀缺的有效生物活性剂的全部生物潜力。