CHACTSCS · New metal catalised C–H bond activation strategies for chemical synthesis

New metal catalised C-H bond activation strategies for chemical synthesis

The use of catalysts to control the synthesis of architecturally complex and enantiopure molecules is a key aspect for the future of organic chemistry. Not only does this concept impact strongly on the area of natural product synthesis but also the continued development of chemical biology, medicinal chemistry and materials science. The challenge for the synthetic chemist is to develop novel strategies for complex molecule synthesis, that combine the factors of atom economy, catalysis and stereocontrol. One such challenge is represented by the arylation of enolate derivatives; a strategic C–C bond-forming process that has found widespread application in organic synthesis (eqn. 1). While transition metal catalysts have facilitated major breakthroughs in enolate arylation, the development of corresponding catalytic enantioselective methods remains a significant challenge. Pioneering studies from the Buchwald and Hartwig laboratories have resulted in transition metal–catalysed enantioselective enolate arylations which form all-carbon stereogenic centres. Conversely, related processes to generate tertiary α-aryl carbonyl compounds have not been forthcoming, presumably due to problems of product racemisation under the necessary basic reaction conditions. Despite some important advances, the demonstrated significance of the α-aryl carbonyl motif (in both pharmaceutical molecules and chiral building blocks) necessitates the development of new catalytic enantioselective methods for their preparation. Recently, our laboratory discovered that copper catalysts facilitate regioselective biaryl bond formation between diaryliodonium salts and simple arenes (eqn. 2). While the mechanism of these reactions remains unclear, we consider the reactive species to be a copper-activated aromatic electrophile. As a logical extension of this catalyst activation mode, we questioned whether the action of a chiral copper catalyst on a diaryliodonium salt would form an aryl electrophile species suitable for participation in an enantioselective arylation. Herein, we describe a copper-catalysed enantioselective arylation of an enolate equivalent with diaryliodonium triflates (eqn. 3). This mild and operationally simple process delivers versatile α-arylcarbonyl products in excellent yields and enantioselectivities, is tolerant of a range of functionality, and can be applied to the enantioselective synthesis of important therapeutic agents. At the outset of our studies we selected silylketenimides 1, derived from N-acyl oxazolidinones, as appropriate substrates for our designed catalytic enantioselective arylation process. N-acyl oxazolidinones possess several favorable features: (1) the derived silylketenimides can be formed as single (Z)-isomers; (2) the presence of the Lewis basic carbonyl oxygen of the oxazolidinone could rigidify a transition state via stabilising interactions with a chiral copper complex; (3) α-functionalised N-acyl oxazolidinones are less susceptible to post-reaction racemisation than other carbonyl compounds; and (4) the products catalytic enantioselective arylation Challenging strategic bond formation – catalytic enantioselective arylation (1) Copper catalyzed arylation of arenes with diaryliodonium salts (2) X R1 O R R1 O R H copper catalyst copper-catalyzed activation to form aromatic electrophile equivalents I Ph OTf + H H (–) Ar–H copper-catalyzed activation to form chiral aryl electrophile equivalents Ar previous work this project R O O N chiral Cu(II) catalyst O room temperature H diaryliodonium salt (2) enantioenriched α-aryl carbonyl (3) O R O N O SiMe3 silylketene imide (1) Mes I OTf Copper catalysed enantioselective arylation of silylketenimides (3) resulting from arylation can be readily transformed into useful intermediates – including carboxylic acids, esters, ketones, aldehydes, and alcohols – in a single step.

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