Prized for their ability to rapidly generate chemical complexity by building new ring systems and stereocentres, cycloaddition reactions have featured in numerous total syntheses and are a key component in the education of chemistry students. Similarly, carbon-carbon (C-C) cross-coupling methods are integral to synthesis because of their programmability, modularity and reliability. Within the area of drug discovery, an overreliance on cross-coupling has led to a disproportionate representation of flat architectures that are rich in carbon atoms with orbitals hybridized in an sp manner. Despite the ability of cycloadditions to introduce multiple carbon sp centres in a single step, they are less used. This is probably because of their lack of modularity, stemming from the idiosyncratic steric and electronic rules for each specific type of cycloaddition. Here we demonstrate a strategy for combining the optimal features of these two chemical transformations into one simple sequence, to enable the modular, enantioselective, scalable and programmable preparation of useful building blocks, natural products and lead scaffolds for drug discovery.
A simple, new strategy for the direct asymmetric α-functionalization of 2-alkyl azaarenes is described. Specifically, a Brønsted base catalyzed conjugate addition of substituted 2-cyanomethylpyridine (and pyrazine) N-oxides to acrylate equivalents to afford hitherto elusive 2-tert-alkyl azaaryl adducts with high enantioselectivity (up to 94% ee) is realized. Extension of the method to the α-amination reaction by using azodicarboxylate esters as electrophiles is also demonstrated. Key for success is the N-oxide functionality of substrates that acts as a removable activating and stereodirecting group. A bifunctional Brønsted base catalyst bearing a squaramide with an attached bulky silyl group is also disclosed.
We report the first diastereo- and enantioselective formal Mannich reaction of 2-pyridyl acetates which gives rise to α- and β-functionalized 2-substituted pyridines. Key for success is the previous azaarene N-oxide formation enabling α-carbon deprotonation by a mild bifunctional Brønsted base and subsequent reaction with N-Boc imines under almost perfect stereocontrol.
The potential of β-alkoxy α-keto amides as pronucleophiles in the enantioselective Mannich type reaction with p-nosyl imines is presented. The proper combination of β-alkoxy α-keto amides and a squaramide-based Brønsted base catalyst produced highly enantioenriched Mannich adducts, which may be transformed into functionalized amino diols.
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