Tethered aza-Wacker Technology for Complex Antibiotic Assembly

项目摘要 对临床使用的抗生素产生抗药性的细菌数量继续以惊人的速度增加， 这些细菌感染缺乏可行的一线治疗方法，迫使临床医生考虑第二- 选择抗生素，如多粘菌素和氨基糖苷类。这种备用抗生素通常带有以下风险 严重的毒性和随后对病人的伤害。因此，及时开发新的抗菌剂， 最好是采取不同于目前所采用的行动模式，这对全球减少 人类发病率和死亡率。已知的抗菌天然产物的化学合成是一种策略 在过去产生了巨大的红利，并在现在继续提供重要的临床疗法。 通常，在构筑如此复杂的分子时，合成实践者会面对 受现有技术的限制。因此，新的有机方法论的发展往往是密切相关的 加入了对生物活性天然产品的追求。指导本R35提案的主要主题 是新的束缚氮杂-瓦克环化反应的发展及其在合成中的应用 含氮抗生素。束缚反应的重要性在于它将合成实践者从 需要预先存在的C-N键才能形成新的C-N键的限制，我们的实验室已经发表了 这方面的几项研究。我们计划将这一技术应用于合成不寻常的二氯化 从培养物中首次分离到聚酮类抗生素杆菌素A-B和杆菌素A。 吉多美假单胞菌发酵液和已被证明具有广泛的抗菌活性 各种致病的革兰氏阳性和革兰氏阴性生物。最近的研究准确地指出了 杆菌素A通过与一种前所未有的结合抑制细菌蛋白翻译的抗菌活性 位于50s原核亚单位(L2)上；存在显示这种相互作用的晶体结构。尽管他们很有钱 生物活性，只有一种外消旋合成(Weinreb)和一种对映异构体合成(Švenda)。 Acybolin A是一种新近分离的抗生素，对B型芽孢杆菌耐药株具有抗菌活性。 枯草杆菌，这表明尽管结构上有同源性，但作用模式与杆状芽孢杆菌完全不同。目前在那里 不存在天然产物Acybolin家族的合成，没有类似物的探索，也没有有限的分析 生物活性。我们提出的合成这些化合物的关键步骤是最近开发的一种反应 在我们实验室，磺酸盐氮杂-瓦克环化反应。这一系列研究的预期结果包括 发展有效的新方法用于烯烃部分的位置选择性胺化和获得 通过精确的立体控制合成多种新的抗菌化合物。总体而言，这项工作将 在我的实验室建立一个广泛和强有力的合成化学创新和抗生素设计计划。

Project Summary The number of bacterial strains resistant to clinically used antibiotics continues to increase at a frightening pace, and the lack of viable first-line treatments of these bacterial infections has forced clinicians to consider second- line antibiotic options such as polymyxins and aminoglycosides. Such reserve antibiotics often carry the risk of significant toxicity and subsequent patient harm. Thus, the timely development of new antibacterial agents, preferably with modes of action distinct from ones currently employed, is essential for the global decrease of human morbidity and mortality. The chemical synthesis of known antibacterial natural products is a strategy that has yielded great dividends in the past and continues to furnish important clinical therapeutics in the present. Often, while entrenched in the construction of such complex molecules, the synthetic practitioner is confronted by the limitations of available technology. Thus, the development of new organic methodology is often intimately joined with the pursuit of biologically-active natural products. The overarching themes guiding this R35 proposal are the development of new tethered aza-Wacker cyclization reactions and their use in the synthesis of nitrogenous antibiotics. The importance of a tethered reaction is that it frees the synthetic practitioner from the constraint of needing a pre-existing C–N bond in order to forge a new one, and our laboratory has published several studies in this area. We plan to apply this technology for the synthesis of the unusual dichlorinated polyketide antibiotics Bactobolins A-B and Acybolin A. Bactobolins A and B were first isolated from the culture broth of Pseudomonas yoshidomiensis and have been demonstrated to have broad antibacterial activity against a variety of pathogenic gram-positive and gram-negative organisms. Recent work has pinpointed the antibacterial activity of Bactobolin A to inhibition of bacterial protein translation via binding to an unprecedented site on the 50s prokaryotic subunit (L2); a crystal structure exists showing this interaction. Despite their rich biological activity, there exists only one racemic synthesis (Weinreb) and one enantiospecific synthesis (Švenda) of Bactobolin A. Acybolin A is a recently isolated antibiotic with activity against Bactobolin-resistant strains of B. subtilis, suggesting a disparate mode of action from Bactobolins despite structural homology. There currently exists no synthesis of the Acybolin family of natural products, no exploration of analogues, and limited analysis of biological activity. A key step in our proposed synthesis of these compounds is a reaction recently developed in our laboratory, the sulfamate aza-Wacker cyclization. The expected outcomes of this line of research include the development of powerful new methods for the site-selective amination of alkene moieties and access to a variety of new antibacterial compounds through precise stereocontrolled synthesis. Collectively, this work will establish a broad and robust program of synthetic chemical innovation and antibiotic design in my laboratory.