Catalytic Asymmetric Ketene [2 + 2] and [4 + 2] Cycloadditions

Nelson, S. G.; Dura, R. D.; Peelen, T. J.


Ketenes are among the few synthetic building blocks that undergo facile thermal [2 + 2] and [4 + 2] cycloadditions, yielding cyclobutanes, β-lactones, β-lactams, dioxins, quinoxalines, thiazinones, pyranones, and other useful carbo- and heterocycles. In addition to substrate structure, the presence of Lewis acids and bases can have a decisive effect on product outcome by diverting ketene reactivity to different cycloaddition manifolds.

This comprehensive review focuses on catalyzed enantioselective ketene [2 + 2] and [4 + 2] cycloadditions in which the asymmetric induction is derived solely from the catalyst complex. Accordingly, diastereoselective cycloadditions are described only when they are relevant to a catalytic asymmetric reaction variant. Molecular orbital interactions are correlated to the electronic structure of ketenes and used to explain ketene reaction pathways.

Cinchona alkaloids play an important role in Lewis base catalyzed asymmetric carbonyl and imine cycloadditions, whereas Al(III)-, Fe(II)-, Ti(IV)-, and Cu(II)-complexes are mainly responsible for Lewis acid catalyzed asymmetric transformations. Carbene catalysts are also significant for both ketene–carbonyl and ketene–imine cycloadditions.

The subject cycloaddition protocol is also compared with other methods, including Mannich- and aldol-based approaches to β-lactams and β-lactones, nitrone–alkyne and hetero Diels–Alder reactions, and the catalytic asymmetric allylation–lactonization.