Polyketides via Redox-Triggered Alcohol C-H Functionalization

聚酮化合物在人类医学中的使用频率高于任何其他类别的次级化合物。 代谢物，占畅销小分子药物的约20%。尽管他们 重要性：（a）人类医学中使用的所有聚酮化合物都来自土壤细菌， 通过发酵或半合成制备（尽管是艾日布林），（B）<5%的土壤细菌 适合培养，许多门逃避培养，少数细菌适合培养。 （c）尽管海洋聚酮化合物具有生物合成基因， 惊人的生物活动，商业发酵过程，涉及海洋 细菌（通常是共生体）仍然非常罕见。从头化学 合成可能提供进入否则难以获得的聚酮化合物及其同系物，然而， 目前的合成方法通常不能利用足够简洁的路线进行大规模生产。 为了克服这一挑战，我们的实验室开创了一个广泛的，新的催化系列， 将低级醇直接立体选择性和位置选择性转化为高级醇的方法。 如在许多全合成中所记载的，这些方法简化了聚酮化合物的构建， 使得目标化合物的制备步骤比以前少得多 可能 在拟议的供资期内，提出了三个具体目标： 新霉素B和唐菖蒲苷的聚酮化合物将使用我们的催化方法进行。新霉素B 是U87人胶质母细胞瘤的飞摩尔抑制剂。唐菖蒲苷显示出强有力的选择性活性 分支杆菌对一线抗生素异烟肼耐药的结核菌株， 利福平(b)II型聚酮抗生素甲酸霉素G、H和J，阿雷尼霉素A和 将使用我们的催化方法制备葡萄球菌毒素的类似物。抗菌 这些化合物的性质将与巴里威尔金森教授合作进行评估 Jean Chmielewski教授(c)钌催化的聚酮化合物反应 构建（烯丙基化、巴豆基化、炔丙基化等）将被开发。优化这些 方法将由Kuo-Wei Huang教授进行的计算研究提供帮助。因此，在本发明中， 我们的研究推进了一个综合方案，其中方法创新通知 合成和合成告诉药物化学。

Polyketides are used more frequently in human medicine than any other class of secondary metabolites, and comprise roughly 20% of top-selling small-molecule drugs. Despite their importance: (a) All polyketides used in human medicine are derived from soil bacteria and are prepared via fermentation or semi-synthesis (notwithstanding eribulin), (b) <5% of soil bacteria are amenable to culture, many phyla have eluded culture, and the few bacteria amenable to culture express <10% of their biosynthetic genes, (c) although marine polyketides possess an astonishing array of biological activities, commercial fermentation processes involving marine bacteria (which are often symbionts) remain exceptionally uncommon. De novo chemical synthesis potentially offers entry to otherwise inaccessible polyketides and their congeners, yet current synthetic methods often do not avail sufficiently concise routes for large scale production. To overcome this challenge, our laboratory has pioneered a broad, new family of catalytic methods for the direct stereo- and site-selective conversion of lower alcohols to higher alcohols. As documented in numerous total syntheses, these methods streamline polyketide construction, allowing the target compounds to be prepared in significantly fewer steps than previously possible. In the proposed funding period, 3 specific aims are proposed: (a) Total syntheses of the type I polyketides neaumycin B and gladiolin will be pursued using our catalytic methods. Neaumycin B is a femtomolar inhibitor of U87 human glioblastoma. Gladiolin displays potent, selective activity against M. tuberculosis strains that are resistant to the frontline antibiotics isoniazid and rifampicin. (b) The type II polyketide antibiotics formicamycins G, H and J, arenimycin A and analogues of viridicatumtoxin will be prepared using our catalytic methods. Antibacterial properties of these compounds will be evaluated in collaboration with Prof. Barrie Wilkinson and Prof. Jean Chmielewski. (c) Ruthenium-catalyzed reactions relevant to polyketide construction (allylation, crotylation, propargylation, etc.) will be developed. Optimization of these methods will be assisted by computational studies performed by Prof. Kuo-Wei Huang. Thus, our studies advance an integrated program in which methodological innovation informs synthesis, and synthesis informs medicinal chemistry.