Synthetic Methods toward Antimicrobial tert-Alkylamino Carbocycles

描述（由申请人提供）：取代叔烷基胺碳环在许多抗菌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。我们的长期目标是针对这一特殊结构类开发新的合成方法，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altemicidin家族的氨基酰基trna合成酶抑制剂作为后续构效关系研究的目标结构。与altemicidin及其同系物的合成相关的主要挑战是：(1)构造一个立体定义的取代碳基环；(2)安装一个含胺的季碳中心。具体的工作假设是，在其他悬垂官能团存在的情况下，可以选择性地对以太C-H键进行亚硝基插入反应，这些官能团随后会参与分子内环化，形成叔烷基胺碳环。我们的假设是基于我们实验室的初步结果，表明某些多功能底物经过化学选择性亚硝基插入产生n -酰基氧胺，已知的亲电性亚胺离子的前体。

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.