Synthetic Methods toward Antimicrobial tert-Alkylamino Carbocycles

描述（由申请人提供）：取代的叔烷基氨基碳环化合物在许多抗微生物天然产物中具有特征，使其化学合成方法成为发现新疗法的关键组成部分。我们的长期目标是开发新的合成方法对这个特权的结构类，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，我们选择了氨酰-tRNA合成酶抑制剂的altemicidin家族作为后续构效关系研究的靶结构。与合成阿替西丁及其同类物相关的主要挑战是（1）立体限定的取代的碳基环的构建和（2）带有胺的季碳中心的安装。具体的工作假设是，氮烯插入反应的醚C-H键的选择性，可以进行在其他悬垂功能的存在下，这将随后参与分子内环化，形成叔烷基氨基碳环。我们基于这个假设在我们的实验室的初步结果表明，某些多功能基板进行化学选择性氮烯插入给N-酰氧基胺，亲电亚胺离子的前体。 因此，我们的具体目标是：（1）发展新的氮宾插入-亚胺离子碳环化策略，用于合成含季中心的碳环。我们将在生物相关目标的背景下确定此反应序列的范围，并开发有效的串联过程和新型重排反应。(2)完成阿替西啶、SB-203207和SB-203208的全合成。这些研究将作为一个发射台的设计和合成结构相关的氨酰-tRNA合成酶抑制剂。3.在新的小分子抗生素的化学和生物学方面建立一个外部资助的跨学科研究计划。 合成障碍往往限制了获得重要的天然先导化合物进行生物评价。目标驱动的努力对altemicidins将作为一个有用的平台，为开发新的方法。从这项研究中产生的结果应该找到广泛的应用在其他重要的抗菌天然产物的合成，尚未成为主题的结构-活性关系的研究。

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.