Nature 508, 340–344 (2014)

Enantioselectivity is an important consideration for synthetic chemists because two stereoisomers can have marked differences in terms of their chemical and physical properties. The specificity of binding sites within enzymes and cell receptors, for example, means that enantiomers can have very different biological effects. There are classic examples of enantiomers displaying different scents or tastes, and where one isomer might be therapeutically beneficial, its mirror image may be inactive or possibly toxic.

Asymmetric catalysis can be used to promote various enantioselective transformations; however, its application in the synthesis of quaternary stereocentres is challenging. This is due to the difficulty of adding an additional carbon to an already crowded tertiary centre, while also requiring a suitable catalyst able to produce an enantiomerically pure product. Previous approaches have involved the use of neighbouring functional groups to install this final C–C bond, such as α- and β-carbonyls. However, subsequent carbonyl deprotection may be necessary and these strategies are not applicable to the synthesis of quaternary centres at remote sites.

To get around these limitations, a team of researchers led by Matthew Sigman from The University of Utah have developed a catalytic and enantioselective reaction for the installation of more-isolated quaternary centres. They found that by using a palladium catalyst in an intermolecular Heck-type reaction of aryl boronic acids with trisubstituted alkenyl alcohols, incorporation of the aryl group was promoted at the more substituted alkene carbon with very good enantioselectivity. This bond formation led to the migration of unsaturation along the alkyl chain to the alcohol, which was then converted to a carbonyl. Importantly, they found that this migration was preserved over long chain lengths, thus allowing the enantioselective synthesis of quaternary β-, γ-, δ-, ɛ- or ζ-aryl carbonyl compounds. They also found that pre-existing stereocentres along the alkyl chain are preserved during alkene relay to the alcohol. Although currently limited to aryl groups, it is possible that various other groups may be reacted with the tertiary alkene, furthering the synthetic possibilities of the technique.