Synthetic Methods toward Antimicrobial tert-Alkylamino Carbocycles

描述(申请人提供)：取代叔烷基氨基碳环在许多抗菌天然产品中具有特征，使其化学合成方法成为发现新疗法的关键组成部分。我们的长期目标是为这一特权结构阶层开发新的合成方法，并将这些方法应用于发现细菌蛋白质生物合成的小分子抑制剂。为了实现这些目标，我们选择了青蒿素家族的氨基酰-tRNA合成酶抑制剂作为后续构效关系研究的目标结构。与合成青蒿素及其同系物相关的主要挑战是(1)构建立体定义的取代碳基环和(2)安装含胺的四元碳中心。具体的工作假设是，选择性地对醚化C-H键进行硝化插入反应可以在存在其他侧基官能团的情况下进行，这些官能团随后将参与分子内的环化反应形成叔烷基氨基碳环。我们的这一假设是基于我们实验室的初步结果，即某些多功能底物经过化学选择性的硝基插入得到N-酰氧基胺，这是已知的亲电亚胺离子的前体。 因此，我们的具体目标是：(1)开发新的硝基插入-亚胺离子碳环化策略，用于合成含四元中心的碳环。我们将在生物相关靶标的背景下确定该反应序列的范围，并开发有效的串联过程和新的重排反应。(2)完成青蒿素、SB-203207、SB-203208的全合成。这些研究将作为设计和合成结构相关的氨基酰-tRNA合成酶抑制剂的发射台。3.在新的小分子抗生素的化学和生物学方面建立外部资助的跨学科研究计划。 合成障碍往往限制获得重要的天然先导化合物进行生物评估。以目标为导向的青蒿素努力将成为开发新方法的有用平台。这项研究的结果应该在合成其他重要的抗菌剂天然产物方面得到广泛应用，这些产品尚未成为结构-活性关系研究的主题。

DESCRIPTION (provided by applicant): Substituted tert-alkylamino carbocycles feature in a number of antimicrobial natural products, making methods for their chemical synthesis a key component in the discovery of new therapeutics. Our long-term goals are to develop new synthetic methodologies toward this privileged structural class, and to apply these methods to the discovery of small-molecule inhibitors of bacterial protein biosynthesis. To achieve these objectives, we have selected the altemicidin family of aminoacyl-tRNA synthetase inhibitors as target structures for subsequent structure-activity relationship studies. The principle challenges associated with the synthesis of altemicidin and its congeners are (1) the construction of a stereo-defined, substituted carbon- based ring and (2) the installation of an amine-bearing quaternary carbon center. The specific working hypothesis is that nitrene insertion reactions selective for ethereal C-H bonds can be carried out in the presence of other pendant functionalities, which will subsequently participate in intramolecular cyclizations to form tert-alkylamino carbocycles. We base this hypothesis on preliminary results in our laboratory showing that certain polyfunctional substrates undergo chemoselective nitrene insertion to give N-acyloxyaminals, known precursors to electrophilic iminium ions. Thus, our specific aims are to: (1) develop novel nitrene insertion-iminium ion carbocyclization strategies for the synthesis of carbocycles bearing quaternary centers. We will determine the scope of this reaction sequence within the context of biologically relevant targets and develop efficient tandem processes and novel rearrangement reactions. (2) Complete the total synthesis of altemicidin, SB-203207, and SB-203208. These studies will serve as a launch pad for the design and synthesis of structurally related inhibitors of aminoacyl-tRNA synthetases. 3. Build an externally funded interdisciplinary research program in the chemistry and biology of new small-molecule antibiotics. Synthetic obstacles often limit access to important natural lead compounds for biological evaluation. A target-driven effort toward the altemicidins will serve as a useful platform for the development of new approaches. Results emanating from this research should find wide application in the synthesis of other important antimicrobial natural products that have yet to be the subject of structure-activity relationship studies.