Polyketides via Redox-Triggered Alcohol C-H Functionalization

点击翻译按钮获取中文摘要

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.