Practical Strategies for Controlling Selectivity in Organic Reactions

Boston College, Chestnut Hill MA

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Abstract

DESCRIPTION (provided by applicant): There is a fundamental need to develop chemical transformations that are highly selective and atom-economical. Directing groups have played a pivotal role in controlling regio- and stereochemistry in a range of organic transformations. However, often directing-group strategies require the introduction of stoichiometric quantities of synthetically undesirable functional groups (such as phosphines) into the organic substrates. The long-term goal of this program is to address this limitation by developing ligands that have the ability to simultaneously and reversibly bind to a metal catalyst and common organic functional groups (such as alcohols, amines, and carboxylic acids). By using a ligand as a scaffold to temporarily join the catalyst and substrate together, the power of directing groups to control selectivity will be coupled to the practicality of catalysis. The value of the scaffolding strategy is that we can apply a synthetically useful functional group to bind to the ligand, and then tailor the ligand for optimal performance in the desired transformation. This concept will be applied towards the regio-, diastereo-, and enantioselective hydroformylation of a range of substrates. Successful application of this strategy will significantly broaden the scope of compounds accessible from hydroformylation, an efficient and practical metal-catalyzed reaction, and will provide access to biologically relevant heterocycles. Once this concept is established through application to catalytic hydroformylation, we will apply this idea to other significant transition metal- catalyzed reactions. PUBLIC HEALTH RELEVANCE: In 2002, single enantiomer pharmaceuticals made up 40% of worldwide drug sales. Over the last twenty years the number of enantiopure drugs approved worldwide has steadily increased, while the percentage of achiral drugs decreased from 43 to 34% of all approved drugs. These trends have created a need for methods that efficiently and selectively make single stereoisomer products. The proposed studies directly address this need by developing a new strategy for controlling stereoselectivity in organic transformations.