Synthetic Methods toward Antimicrobial tert-Alkylamino Carbocycles

New Mexico State University Las Cruces, Las Cruces NM

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Abstract

[unreadable] 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. [unreadable] [unreadable] 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. [unreadable] [unreadable] 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. [unreadable] [unreadable] [unreadable]