Postgraduate Researcher, University of Sheffield
Maleimides are an excellent starting material for the asymmetric synthesis of pyrrolidinones, a key moiety in a number of pharmaceuticals and natural products, such as Berkeleyamide A, a caspase inhibitor and Salinosporamide A, which has shown to be cytotoxic to cancer cells. Due to the two planes of symmetry that maleimides possess, enantioselective functionalisation can be difficult. Temporary attachment of a maleimide to an anthrone template removes both of these planes of symmetry and can allow chemical manipulations to proceed selectively at the distal carbonyl and from the top face. This attachment has been shown to occur via various organocatalysed Diels-Alder reactions in high enantioselectivity. In this work, quinidine has been used to catalyse this Diels-Alder reaction between a wide range of maleimide substrates and anthrone, at low temperatures and with fast reaction times. These reactions have occurred with high selectivity (79% ee). Investigations into improving the enantioselectivity of this reaction are ongoing, including the exploration of various factors including solvent and temperature. This strategy means that after manipulations, the functionalised pyrrolidinone can be easily relieved from the anthrone template via a room temperature, base-catalysed retro-Diels-Alder reaction.
Abstract: A highly enantioselective (>95% ee) strategy to affect the desymmetrization of a maleimide has been performed by temporary attachment to an anthracene template followed by asymmetric reduction with an oxazaborolidine catalyst. A stereoablative over-reduction process was partially responsible for the high levels of enantioselectivity. Exemplification of the strategy by stereoselective functionalization and retro-Diels-Alder reaction provided the natural product pyrrolam A.
Pub.: 28 Jun '14, Pinned: 27 Apr '18