Metalated Nitriles: Internal 1,2-Asymmetric Induction

Alkylations of conformationally constrained acyclic nitriles containing vicinal dimethyl groups and an
adjacent phenyl group or trisubstituted alkene are exceptionally diastereoselective. Probing the alkylation
stereoselectivity with a series of C- and N-metalated nitriles implicates a reactive conformation in which
an sp2-hybridized substituent projects over the metalated nitrile to avoid allylic strain. Steric screening
thereby directs the electrophilic attack to the face of the metalated nitrile opposite the projecting substituent.
Excellent stereoselectively is maintained in a diverse range of alkylations that efficiently install quaternary
centers, even with isopropyliodide in which a contiguous array of tertiary−quaternary−tertiary stereocenters
is created! Screening the conformational requirements with a series of acyclic nitriles and esters reveals
the key structural requirements for high selectivity while providing a robust, predictive model that accounts
for comparable ester alkylations affording the opposite diastereomer! The intensive survey of metalated
nitrile alkylations identifies the key structural features required for high 1,2-asymmetric induction, addresses
the long-standing challenge of asymmetric alkylations with acylic metalated nitriles, and provides a versatile
method for installing hindered quaternary centers with excellent stereocontrol.