Coaxing chiral products from an S_N1 reaction

One of the first reactions organic chemistry students learn is the unimolecular nucleophilic substitution, or S_N1. Yet S_N1 reactions are unpopular among chemists, largely because chiral molecules made in this manner wind up as a racemic mixture of both enantiomers. But now, Harvard University chemists Eric N. Jacobsen, Alison E. Wendlandt, and Prithvi Vangal report a method to produce quaternary stereocenters via the S_N1 reaction (Nature 2018, DOI: 10.1038/s41586-018-0042-1). The chemists use a chiral squaramide catalyst, which acts as a dual hydrogen-bond donor, in combination with the strong Lewis acid trimethylsilyl trifluoromethanesulfonate. This catalyst system promotes formation of a planar carbocation, as happens normally in S_N1 reactions. However, it sidesteps elimination reactions that plague typical S_N1 chemistry, and guides the nucleophile’s approach to just one face of the carbocat­ion, so that the chemists could transform racemic tertiary propargyl acetates into compounds with quaternary stereocenters (example shown). Although similar strategies have been deployed to make chiral products from cationic intermediates, such examples have been limited to heteroatom-stabilized carbocations, which are less likely to rearrange or generate elimination products.