ChirPyr · Access to chiral pyridine derivatives via catalytic asymmetric synthesis

Access to chiral pyridine derivatives via catalytic asymmetric synthesis

The pyridine ring is one of the most important N-containing aromatic heterocycles in drug discovery. Playing a vital role in the field of heterocyclic chemistry, pyridine and its derivatives abundantly exist in nature and are widely used for many applications in medicinal science. The ability of the C=N moiety of a pyridine ring to activate the adjacent alkenyl towards nucleophilic attack (in analogy to carbonyl compounds), offers an attractive opportunity to carry out conjugate nucleophilic additions using carbon-nucleophiles. This concept has been broadly implemented for additions of a variety of nucleophiles to vinyl-substituted pyridines as well as other types of heteroarenes. Catalytic enantioselective addition of carbon-nucleophiles to β-substituted alkenyl pyridines represents a conceptually simple and atom economical method for the preparation of chiral pyridine scaffolds. However, compared to vinyl-pyridines, nucleophilic additions to β-substituted alkenyl pyridines (AP) are much less explored due to the lower reactivity caused by the steric hindrance derived from the β-substituent. As a result of this low reactivity, only few literature examples exists, and they deal with racemic addition of carbon-nucleophiles to β-substituted AP. When catalytic enantioselective synthesis is in consideration, the only two literature reports are restricted to arylation reactions using β-substituted AP with strong electron-withdrawing groups in the aromatic ring under microwave irradiations or at elevated temperature. The shortage of methodologies clearly indicates a need for novel strategies to activate β-substituted AP towards nucleophilic additions. Recently, the Harutyunyan group reported, in Science magazine, a breakthrough in a closely related field: synthesis of chiral heteroarenes via catalytic asymmetric addition of various alkyl, as well as phenyl, Grignard reagents to alkenyl-substituted aromatic N-heterocycles using Cu(I)-catalyst. The scope of explored heteroaromatic substrates included benzoxazoles, benzothiazoles, thiazoles, oxazoles, pyrimidines and triazines. The key strategy was the enhancing of the reactivity of alkenyl-heteroarenes via Lewis acid (L.A.) activation combined with the use of highly reactive carbon-nucleophiles such as Grignard reagents.

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