Electrophile‐Directed Diastereoselective Oxonitrile Alkylations

Abstract

Diastereoselective alkylation of prochiral oxonitrile dianions with secondary alkyl halides efficiently installs two contiguous stereogenic centers. The confluence of nucleophilic trajectory and the electrophile chirality causes distinct steric differences that allow efficient discrimination for one of the six possible conformers. Numerous oxonitrile-derived dianions efficiently displace secondary alkyl halides propagating the electrophile chirality to efficiently install two contiguous tertiary centers. The prevalence of chiral, secondary electrophiles makes the interdigitated alkylation of chiral electrophiles a particularly attractive route because the resulting oxonitriles are readily transformed into bioactive heterocycles.

Diastereoselective Electrophile‐Directed Alkylations

“…A series of diastereoselective alkylations employing prochiral oxonitrile dianions derived from 19 displace secondary (1‐haloalkyl)arenes to install a new chiral center with the same stereochemical relationship as the diketone 16 (cf. Scheme with Scheme ) . Mechanistic experiments identified an extended Z‐ enolate geometry of the dianion 20 that attacks the electrophile through an S N 2 displacement.…”

“…Selective attack on one prochiral face of the enolate is dictated in part by the reaction trajectory of the electrophile. For methyl fluoride, attack on the naked acetaldehyde enolate occurs at an angle of 106° relative to the plane of the enolate, though recent calculations using a higher level of theory revise the attack angle upward to 116° (Figure ) . The 116° trajectory correlates with the Bürgi–Dunitz angle for attack in enolate alkylations, aldol reactions, and conjugate additions …”