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.
Fleming
Fraser F
FF
Department of Chemistry and Biochemistry, Duquesne University, Pittsburgh, PA 15282-1530, USA. flemingf@duq.edu
Liu
Wang
W
Ghosh
Somraj
S
Steward
Omar W
OW
D000478:Alkylation; D008670:Metals / Q000737:chemistry*; D015394:Molecular Structure; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013237:Stereoisomerism
D008670:Metals; D009570:Nitriles; D009942:Organometallic Compounds