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

聚酮类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性质。它们的特点是具有不同的甲基和羟基立体生成中心的组装，从而使得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沙利马溴胺，这是一种独特的多环代谢物，也是从海洋粘液细菌中分离出来的第一种天然产物，以及高效呼吸链抑制剂阿贾达唑A，这是一种源于粘液细菌的独特的异色素酮聚酮。这些化合物具有重要的生物学特性，再加上其独特的、极具挑战性的结构，使其在合成和药物化学方面具有极大的吸引力。尽管复杂聚酮的化学研究取得了长足的进展，但人们仍然迫切需要更收敛、更有选择性的合成方法，尤其是自由基反应在复杂聚酮的合成中仍然不发达。该项目建议开发两种创新的以自旋为中心的方法，以有效地获取这两种复杂聚酮和重要天然产物的关键结构特征。第一种方法是以碘为载体的一锅法立体选择性合成异色满酮，而第二种方法是通过钛并茂催化的环氧化物开环和自由基烯丙基转移反应生成四元中心。这些程序将实现高度简明的首次全合成阿柔达唑A和沙利马溴胺，这对于明确的结构和立体化学指定也将是重要的。最后，将制备具有改进的生物和/或生物物理特性的设计类似物，以进一步评估和改进这些高度稀缺、有效的生物活性物质的全部生物潜力。

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.