Alpha-tertiary amines have quaternary centers bearing a nitrogen atom. They are found in natural products and therapeutic agents but they represent a remarkably challenging synthetic motif to access when stereochemical control is required. The development of efficient asymmetric approaches towards substituted azepanes and benzazepines is desirable due to their relevance as pharmaceuticals as well as alkaloids. In this oral presentation we will describe our work towards the development of an innovative approach that – by combining biocatalysis with organolithium chemistry – allows the first synthesis of enantiopure 2,2-diaryl azepanes. Our strategy relies on the initial enzymatic asymmetric synthesis of 2-aryl azepanes. We have identified a few complementary pathways: by means of kinetic resolution, deracemisation with monoamine oxidase (MAO-N) or enantioselective reduction with imine reductase (IRED). With the series of enantiopure 2-aryl azepanes in hand, we have converted the amines to the corresponding ureas and subsequent organolithium-mediated stereospecific aryl migration gave rise to enantiomerically pure α-tertiary amines in good yields and excellent stereospecificity. We also investigated migrations of vinyl groups instead of aryl groups in the ureas, which creates new possibilities of functionalisation at the 2-position of the azepane ring. We extended our aryl migration methodology to acyclic systems and rearrangements of ureas with a pyridine ring at the benzylic position. We developed a method for generating stereogenic centers bearing pyridine rings by means of stereospecific intramolecular arylation alpha to 2- or 3-pyridyl susbtituents. The reaction is mediated by pyridine-stabilized organolithiums that exhibit remarkable configurational stability, given the account the anion-stabilizing and electron-withdrawing of the pyridyl substituents.

Biocatalysis meets organolithiums: Asymmetric synthesis of heterocyclic α-tertiary amines

254th National Meeting (2017)

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