Catalytic Synthesis of alpha-Branched Carbonyl Compounds

Ut Southwestern Medical Center, Dallas TX

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Abstract

DESCRIPTION (provided by applicant): Synthetic organic molecules are the most effective tools to modulate biological systems dynamically. Small molecules find use as therapeutic agents and as reagents for biochemical studies. Our long-term goal is to develop new chemical reactions and apply them in the synthesis of natural products and small molecule libraries. The synthesis of compounds containing multiple substituents adjacent to a carbonyl compound remains an important but unsolved problem. We hypothesize that these a-branched carbonyl compounds will arise from a new catalytic substitution reaction. Specifically, a halogen adjacent to a carbonyl may be replaced by an alkyl group from an organometallic reagent. The use of an optically active catalyst may render this process enantioselective. This application describes our 4 related objectives: 1. Develop a catalytic cross-coupling of a-halo carbonyl compounds with organometallic reagents. Using copper catalysts, we will prepare a-branched carbonyl compounds from a wide variety of chlorinated substrates and organometallic reagents. 2. Determine the mechanism by which organometallic reagents react with a-halo carbonyl compounds. We will evaluate reaction kinetics and the structure of reactive intermediates. 3. Develop an enantioselective synthesis of a-branched carbonyl compounds. Most applications in medicine require single-enantiomer compounds. Accordingly, we seek to prepare optically active a-branched carbonyl compounds. 4. Develop an asymmetric catalytic chlorination of carbonyl compounds. Optically active carbonyl compounds are valuable chiral building blocks. They will find use in the copper-catalyzed cross-coupling reaction and a variety of other substitution reactions. These studies will uncover fundamental principles of chemical reactivity and lead to enantioselective syntheses of valuable chiral building blocks. Access to these compounds, in turn, will facilitate drug discovery and production.