The ability to marshal existing stereochemical elements for the generation of new stereocenters (i.e., diastereoselectivity) is of central importance in complex molecule synthesis. Several general models have been advanced that allow researchers to predict the major diastereomer that will be formed for a particular reaction. However, as the substrate and reaction under consideration begin to more closely resemble a specific target molecule, researchers often resort to simple “steric effects” for predicting the stereochemcial outcome. This is especially true with substrates or reactions for which a more precise model has not been proposed, or which do not have a close analog in the literature. Previous work from our laboratory has shown that torsional effects can be used to rationalize malonate alkylation reactions that proceed contrary to a traditional steric argument (J. Org. Chem. 2013, 78, 7554). More recently, we have examined other stereoselective enolate alkylations that are commonly rationalized with steric effects and those that lack a suitable literature counterpart. For example, the alkylation of enolate 1 to give ketone 2, and the alkylation of diastereomeric malonates 3 to give β-ketoesters 4 and 5. Using DFT calculations we have found that torsional effects in the transition state, rather than steric effects, are the dominant influence in these reactions. Unexpectedly, our calculations also reveal that Curtin–Hammett kinetics may also play a role in influencing which stereoisomer is formed. Transition state analysis for the alkylation of enolates 1 and 3 will be presented.

Computational investigations into stereoselective alkylation reactions: Evidence for torsional and Curtin–Hammett control

249th National Meeting (2015)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.