In this project funded by the Chemical Synthesis program of the Chemistry Division, Professor Don M. Coltart of the Department of Chemistry at Duke University will explore the development of new methods for the regiocontrolled asymmetric alpha-alkylation of ketones. The central hypothesis of the planned research is that activated hydrazones - those having at least one electron withdrawing group on the distal nitrogen - and oximes will provide the basis for a variety of new approaches to the asymmetric alpha-alkylation of ketones. From this work, fundamentally new regiochemical substitution patterns that cannot be generated using existing technology will be accessible in an asymmetric manner. Moreover, it will be possible to conduct asymmetric alpha-alkylation in an umpolung sense, thus enabling the incorporation of functionality that cannot be introduced using enolate-based methods.
This work could lead to facile methods for the asymmetric alpha-alkylation of ketones. The ability to easily and effectively prepare single enantiomer forms of alpha-alkylated ketones will contribute greatly to our ability to synthesize optically pure natural products, drugs and related compounds, thus impacting science and society in important ways. In addition, this project will provide excellent training of undergraduate and graduate students, including those from groups historically underrepresented in the sciences.
The first asymmetric total synthesis of the marine natural product apratoxin D, a highly potent inhibitor of H-460 human lung cancer cell growth (IC50 value of 2.6 nM), was achieved under this award. Asymmetric N-amino cyclic carbamate (ACC) a,a-bisalkylation was developed and utilized to establish the isolated C-37 methyl group with excellent selectivity. Other key asymmetric transformations employed were an Evans syn-aldol and a Paterson anti-aldol, both of which also proceeded with excellent stereoselectivity. The synthetic material was evaluated in collaboration with the NCI using its 60 cell line screen, which reveled that it is highly active across a range of cancer cell lines. The first asymmetric anti-aldol addition of a ketone-derived donor that is not limited by the structure of the ketone has been achieved through the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. Not only does this transformation exhibit essentially perfect anti-diastereoselectivity and enantioselectivity but, remarkably, it also proceeds via thermodynamic, rather than kinetic control. To our knowledge this is the first report of a thermodynamically controlled ketone-based aldol addition involving a chiral auxiliary. Significantly, by merging the known procedure of asymmetric a,a-bisalkylation of ACC hydrazones with this new aldol transformation, it is now possible to gain access to ketone-based aldol addition products that have previously been inaccessible via direct aldol methods.
