2.14 Selected Diastereoselective Reactions: Enolate Alkylation

Catalytic Enantioselective α-Alkylation of Amides by Unactivated Alkyl Electrophiles

“…Furthermore, since I cyclizes with a rate constant of ∼1 × 10 5 s –1 at 25 °C, much slower than the rate of diffusion (generally ∼10 8 –10 9 s –1 at 25 °C), our observation of cyclized product is consistent with out-of-cage coupling of R • , as required by the mechanism illustrated in Figure A. Taken together, our various studies are fully congruent with the catalytic enantioselective radical-based pathway outlined in Figure A, which complements classic approaches to stereoselective α-alkylation that have relied on polar reactions and stoichiometric chiral auxiliaries. − …”

“…Because carbonyl groups that bear an α stereocenter are a common motif in biologically active molecules, the development of efficient methods for generating this subunit has been a long-standing objective in organic synthesis (Figure A). − One straightforward approach to accessing such structures is through the α-alkylation of enolates, a process that accounted for 11% of all carbon–carbon bond-forming reactions run in bulk in a Pfizer research facility between 1985 and 2002 . The development of methods by Evans, Myers, and others that achieve the stereoselective α-alkylation of carbonyl derivatives through the use of a covalently bound chiral auxiliary represents one of the landmark advances in the field of asymmetric synthesis (Figure B); − such methods have been widely applied throughout academia and industry, including syntheses on a metric-ton scale …”

Ni-Electrocatalytic Enantioselective Doubly Decarboxylative C(sp3)–C(sp3) Cross Coupling

“…The enantioselective α-alkylation of carbonyl compounds is a staple transformation in organic synthesis that has been widely studied . With regard to ester and amide alkylation, the use of chiral auxiliaries is still commonplace due to the predictable outcomes and practical ease with which diastereomers can be separated . Such an approach is also intuitive, as it takes advantage of polar-bond analysis, resulting in an enolate nucleophile reacting with an alkyl halide electrophile.…”