Selective Metalation–Substitution alpha to a Chiral Nitrile

Iain Coldham presents a highly enantioselective metalation–substitution alpha to a chiral nitrile.

Carbanion chemistry is extremely important in synthesis, since carbanions act as nucleophiles for efficient carbon–carbon bond formation. Arguably the most-used type of carbanion is an enolate, and enolate alkylation and the aldol reaction play a key role in many synthetic endeavors. As the anion in enolates is delocalized, they adopt a planar structure. Therefore, any stereocenter that was present alpha to the carbonyl is lost on formation of the enolate and it is necessary to use a chiral auxiliary, a chiral electrophile, or a chiral catalyst that is associated with the transition state to induce asymmetry in the resulting alkylated product.

The similarity of nitriles to carbonyls has led the scientific community to consider their reactivity to be related. Indeed, deprotonation of a nitrile to form a carbanion using a base such as LDA provides a carbanion where the lithium ion resides on the nitrogen atom in a dimeric structure. Such a ketenimine, like an enolate, reacts with alkyl halides and carbonyl compounds through the carbon atom thereby leading to C-alkylated products. Therefore, it might be expected that starting from an alpha chiral nitrile the reaction would give, after deprotonation, an achiral metalated intermediate and hence racemic products. Indeed, Iain Coldham and his group at the University of Sheffield (UK) found that treating an chiral N-Boc-substituted piperidine-2-carbonitrile with LDA followed by addition of electrophiles gives racemic products substituted alpha to the chiral nitrile group.

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