Tethered aza-Wacker Technology for Complex Antibiotic Assembly

项目摘要 对临床使用的抗生素具有耐药性的细菌菌株的数量继续以惊人的速度增加， 缺乏可行的第一线治疗这些细菌感染迫使临床医生考虑第二- 线抗生素的选择，如多粘菌素和氨基糖苷类。这些储备抗生素通常会带来以下风险： 严重毒性和随后的患者伤害。因此，及时开发新的抗菌药物， 最好是与目前使用的不同的作用方式，对于全球减少 人类发病率和死亡率。已知抗菌天然产物的化学合成是一种策略， 在过去已经产生了巨大的红利，并且在现在继续提供重要的临床治疗。 通常，在构建如此复杂的分子时，合成实践者面临着 受到现有技术的限制。因此，新的有机方法学的发展往往与 与追求生物活性天然产品相结合。指导R35提案的总体主题 是新的系留氮杂-Wacker环化反应的发展及其在合成 含氮抗生素拴系反应的重要性在于，它将合成从业者从 需要一个预先存在的C-N键才能形成一个新的键，我们的实验室已经发表了 这方面的几项研究。我们计划将这项技术应用于合成不寻常的二氯 聚酮抗生素Bactobolin A-B和Acybolin A。首先从培养物中分离细菌毒素A和B 发酵液，并已被证明具有广泛的抗菌活性， 各种致病性革兰氏阳性和革兰氏阴性微生物。最近的工作已经指出， Bactobolin A的抗菌活性通过与前所未有的 50 s原核亚基（L2）上的位点;存在显示这种相互作用的晶体结构。尽管他们富有 生物活性，仅存在一种外消旋合成（Weinreb）和一种对映体特异性合成（Švenda） Bactobolin A. Acybolin A是最近分离的抗生素，对B的Bactobolin耐药菌株具有活性。 枯草芽孢杆菌，表明尽管结构同源，但与Bactobolins的作用模式不同。目前， 没有合成Acybolin家族的天然产物，没有探索类似物，分析有限 的生物活性。我们提出的合成这些化合物的关键步骤是最近开发的反应 在我们的实验室中，氨基磺酸盐氮杂-瓦克环化。这一系列研究的预期成果包括 开发了强有力的新方法，用于烯烃部分的位点选择性胺化，并获得了 通过精确的立体控制合成多种新的抗菌化合物。总的来说，这项工作将 在我的实验室建立一个广泛而强大的合成化学创新和抗生素设计项目。

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.