Dynamization strategies for the atroposelective synthesis of (hetero)biaryls

Abstract

The central objective in this PhD thesis has been the development of asymmetric catalysis methodologies for the atroposelective synthesis of (hetero)biaryls through dynamization strategies. These methodologies comprise resolution of both configurationally stable (DYKAT, for Dynamic Kinetic Asymmetric Transformation) or labile (DKR, for Dynamic Kinetic Resolution) heterobiaryl substrates. The obtained products possess appealing structures with potential applications as ligands for metal catalysis or precursors of bifunctional organocatalysts. Along Chapter I, the general considerations and contextualization of the developed work are first disclosed. Additionally, the state of the art of the different strategies for the atroposelective synthesis of (hetero)biaryls is reviewed. For that purpose, those approaches involving any dynamization process for the synthesis of the enantioenriched functionalized (hetero)biaryls are specially considered. In Chapter II, the first of the three developed methodologies during this PhD thesis is described. In this case, the Heck reaction (for which his discoverer was awarded with the Nobel Prize in Chemistry in 2010) has been combined with a DYKAT strategy, using configurationally stable heterobiaryl (pseudo)halides as substrates. This methodology has enabled the synthesis of highly functionalized heterobiaryls with the simultaneous generation of central and axial chirality elements, with an exquisite control on the regio-, diastereo-, and enantioselectivities. In Chapter III an alternative methodology for the synthesis of heterobiaryls bearing central and axial chirality is described. In this case, an asymmetric reduction of configurationally labile heterobiaryl ketones via dynamic kinetic resolution (DKR) was performed. Specifically, the zinc-catalyzed asymmetric hydrosilylation using chiral diamines as ligands has been employed to obtain the corresponding heterobiaryl carbinols with excellent diastereo- and enantioselectivities. Finally, the development of a methodology for the synthesis of axially chiral diamines is disclosed along Chapter IV. In this strategy, the configurational lability of biaryl aminals was exploited in Ru-catalyzed asymmetric transfer hydrogenation via dynamic kinetic resolution. This methodology is presented as an efficient pathway for the synthesis of homologues to BINAM and derivatives. All the developed methodologies during this PhD thesis have allowed for the efficient synthesis of a wide variety of (hetero)biaryl structures bearing central and axial chirality elements.