Enantioselective Synthesis of an Azabicyclic Ring System by a Dynamic Kinetic Res

University Of California-Irvine, Irvine CA

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Abstract

DESCRIPTION (provided by applicant): Of the top fifteen pharmaceutical drugs in 2008, twelve contained a heterocyclic framework. As medicinal drugs yield over a hundred billion dollars of revenue a year, our ability to efficiently prepare or isolate medicinally important compounds is a significant goal for chemists. Some biologically active compounds are isolated from natural sources, rather than synthesized in the laboratory, because methods to access the drugs have not been developed or are not efficient for mass production. For many biologically important compounds, the natural sources where the drug is produced are becoming diminished or limited. Moreover, some compounds require the isolation of immense quantities of the natural source to be able to secure enough for biological testing. Therefore, a synthetic strategy may be the only route for mass production in some cases. Highlighted in my proposal is an outline for the preparation of enantiomerically enriched azabicycles. I will investigate a method involving dynamic kinetic resolution of amines by an aza-Cope rearrangement. The rearrangement will allow efficient access to the tricyclic core of medicinally important cephalotaxus alkaloids. Furthermore, I will apply the rearrangement to the enantioselective total synthesis of deoxyharringtonine. Deoxyharringtonine has demonstrated acute activity against plasmodial agents, murine lymphoma, and murine leukemia. This alkaloid and related derivatives have a promising future in pharmacological therapeutics if a practical means of production is realized. PUBLIC HEALTH RELEVANCE: The proposed research program consists of a concise and inexpensive route to biologically important alkaloids. The research that will be investigated is vital to the overall goal of synthetically preparing active pharmaceutical drugs in an inexpensive manner. The proposal will examine a rearrangement that will secure a heterocyclic motif that is found in a variety of medically relevant natural products, including the proposed target, deoxyharringtonine.