A strategy for the catalytic, asymmetric alkylation of silyl enol ethers and silyl ketene acetals via chiral nucleophilic catalysis is presented. Peptide-based catalysts containing a nucleophilic residue are predicted to both activate primary alkyl electrophiles toward attack by the silyl enol nucleophiles and provide a chiral environment (by way of the peptide's secondary structure) to induce enantioselectivity in the alkylation event. Specifically, i-butylhistidine is anticipated to be an effective nucleophilic amino acid upon which to build such peptide catalysts. Strategies for optimizing both reactivity and selectivity in the alkylation process are discussed, including catalyst design, the possible benefit of additives, slow addition of reaction components, and the judicious choice of substrates. Development of this method to encompass the use of other nucleophiles including substituted allylstannanes and silanes is proposed. Additionally, the use of alternative electrophiles such as oxygen and halogen sources is discussed.
