Unsymmetrical ketones are common synthetic building blocks, and therefore numerous methods for their preparation have been developed; however, these strategies involve multiple synthetic steps, hazardous carbonyl electrophiles, or narrow reaction scopes. In light of these limitations, we have developed a bench-stable reagent (CLAmP) that serves as a sequentially dicationic carbonyl synthon that allows for the selective addition of two <i>different</i> organometallic nucleophiles in a single synthetic operation. The utility of CLAmP in unsymmetrical ketone synthesis appears to derive from the highly temperature-dependent persistence of the tetrahedral intermediate formed upon addition of an organometallic nucleophile to CLAmP.<br/><br/>Here, we will trace the origin and rational design of CLAmP from our previously developed reagent for the synthesis of Weinreb amides (WImC). The scope and limitations of the one-pot unsymmetrical ketone synthesis employing CLAmP will be described, as will mechanistic studies on the origin of the observed selectivity of nucleophilic additions to CLAmP.

Development of CLAmP: Rational design of a carbonyl dication synthon that facilitates the one-pot synthesis of unsymmetrical ketones

253rd National Meeting (2017)

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