Heck reaction is an excellent method to introduce an aromatic group to one end of a double bond using palladium(0) catalysis. The asymmetric variant of the Heck reaction has received great attention as it generates chiral centers when forming new carbon-carbon bonds, of vast importance in natural product and pharmaceutical syntheses. Among most of the asymmetric Heck reactions, however, there are still limitations of achieving high site- and enantioselectivity. Recently, Sigman’s group reported a highly regioselective and enantioselective Heck reactions of electronically nonbiased alkenes without chelating groups. This type of reaction is very attractive for two reasons: first is the high site selectivity and enantioselectivity with unbiased achiral substrates; and second is the simultaneously functionalization of multiple carbons through a presumably iterative -hydride elimination/migratory insertion process.
To understand the effects that control the site- and enantioselectivity, and the ligand effect on the relay strategy, Professor Wu’s group conducted detailed computational studies on this Pd-catalyzed redox-relay Heck arylations of alkenyl alcohols. The calculations showed that the regiochemistry is controlled by a remote electronic effect, where the developing polarization of the alkene in the migratory insertion transition state is stabilized by the C–O dipole of the alcohol moiety. The enantioselectivity, on the other hand, is controlled by steric repulsion between the oxazoline substituent and the alcohol-bearing alkene substituent. The relay efficiency is due to an unusually smooth potential energy surface without high barriers, where the hydroxyalkyl-palladium species acts as a thermodynamic sink, driving the reaction towards the carbonyl product. At last, the computational predictions of the relative reactivity and selectivity are valided experimentally. These results provide detailed mechanistic insights into this novel reaction and will allow further improvements for cases where the selectivity of the reaction needs to be enhanced. This work has been published recently at J. Am. Chem. Soc., 2014, 136, 1960-1967.

This article can be accessed at: http://pubs.acs.org/doi/abs/10.1021/ja4109616