Enantioselective and regioselective desymmetrizations directed by the substrate employing Heck-Matsuda reactions

Abstract

Palladium-catalyzed cross-coupling reactions constitute an extremely useful and powerful class of reactions available for organic synthesis nowadays. Among these reactions involving aryl halides/tosylates/mesylates as one of the partner reagents, we could mention the following couplings: i) the Heck-Mizoroki reactions, with olefins; ii) the Negishi coupling, employing organozinc and organoaluminum reagents; iii) the Corriu-Kumada-Murashashi coupling, with Grignard reagents; iv) the Stille coupling, involving organostannes; v) the Suzuki-Miyaura coupling of organoboranes, vi) the Hiyama coupling, using organosilicon compounds; and vii) the Sonogashira coupling of terminal alkynes. Despite the reasonably large number of those coupling reactions, there is still plenty of chemical room for further development and applications of those processes in view of their broad scope. Several key features of these processes are still unclear or were not investigated in depth at all. Moreover, many of those reactions need more work to achieve a higher level of applicability in synthesis. Aiming at getting on the frontline of knowledge of these coupling reactions, we are proposing as goals of the present project: i) a deeper understanding of the mechanistic aspects of these processes promoted by Pd, in particular of those involving the Heck arylations using arenediazonium tetrafluoroborates (the Heck-Matsuda arylations); ii) a mild migration from homogeneous conditions of these coupling reactions to heterogeneous conditions, which prove themselves applicable to continuous flow; and iii) the development and application of less well-known couplings, with emphasis on C-H oxidative activation, such as the Fujiwara-Moritani reactions and the Tsutsui-Narasaka reactions to synthesize heterocyclic compounds. The project encompasses all three aspects mentioned above, posing as specific goals: 1) to expand the use of the cross-coupling methods catalyzed by palladium at the same time it investigates new frontiers, such as the chirality transfer in the Heck-Matsuda reactions (enantioselective Heck-Matsuda reactions employing arenediazonium salts) in batch as well as using reactions in flow; 2) new applications for the oxidative cross-couplings of aromatic systems; 3) the use of palladium for the construction of new functional organic materials; 4) the application of modern computational methods to study and elucidate the precise mechanism of these reactions catalyzed by palladium; 5) to evaluate the inhibition of the proteasome and other enzymatic targets aiming at neglected diseases and; 6) the development and application of new dyes for sensitized solar cells. (AU)