Asymmetric Synthesis of Nitrogen Heterocycles

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DESCRIPTION (provided by applicant): Modern drug discovery mandates the rapid and modular assembly of increasingly complex substances. Medicinally relevant molecules overwhelmingly bear nitrogen functionality with 179 of the top 200 brand name drugs containing at least one N-atom. Increasingly, the nitrogen atom is not merely a functional substituent, such as a pendant amine or linking amide, but is present in the form of a heterocycle, often bearing stereocenters. The development of methods to access these heterocycles from easily accessible precursors is an attractive goal. The resultant heterocycles will facilitate the pace of drug discovery, with the common motifs visible in biologically active agents ranging from antibiotics, antidepressants as well as agonists and antagonists of protein-protein interactions such as Hsp40-Hsp70. The specific goals of this research are as follows: 1) develop temporary tethering strategies for [2+2+2] cycloadditions; 2) Investigate the oxidative coupling of amides and alkene/alkyne ? systems to assemble piperidines by a catalyzed/oxidative protocol; 3) Exploit readily available aza-dienes in metal-catalyzed [4+2] reactions; and 4) Implement isocyanate cycloadditions to involve allenes and vinyl cyclopropanes. The long-term impact of this science is to enable chemists to rapidly assemble complex structures with high efficiency.