Stereochemical Editing at sp3-Hybridized Carbon Centers by Reversible, Photochemically Triggered Hydrogen Atom Transfer

Millions of chiral compounds contain a stereogenic sp³-hybridized carbon center with a hydrogen atom as one of the four different substituents. The stereogenic center can be edited in an increasing number of cases by selective hydrogen atom transfer (HAT) to and from a photocatalyst. This Account describes the development of photochemical deracemization reactions using chiral oxazole-annulated benzophenones with a bonding motif that allows them to recognize chiral lactam substrates by two-point hydrogen bonding. The backbone of the catalysts consists of a chiral azabicyclo[3.3.1]nonan-2-one with a U-shaped geometry, which enables substrate recognition to occur parallel to the benzoxazole part of the aromatic ketones. The photocatalysts facilitate a catalytic photochemical deracemization of several compound classes including hydantoins, N-carboxyanhydrides, oxindoles, 2,5-diketopiperazines, and 4,7-diaza-1-isoindolinones. In addition, if more than one stereogenic center is present, the editing delivers a distinct diastereoisomer upon the appropriate selection of the respective photocatalyst enantiomer. The chiral photocatalysts operate via the benzophenone triplet that selectively abstracts a properly positioned hydrogen atom in exclusively one of the two substrate enantiomers. The photochemical step creates a planar carbon-centered radical and erases the absolute configuration at this position. While returning HAT to the same position would likely recreate the stereogenic center with the same absolute configuration, spectroscopic and quantum chemical studies suggest that the hydrogen atom is delivered from the photocatalyst to a heteroatom that is in conjugation to the radical center. Two scenarios can be distinguished for the hydrogen atom shuttling process. For hydantoins, N-carboxyanhydrides, and 4,7-diaza-1-isoindolinones, the back HAT occurs to a carbonyl oxygen atom or an imine-type nitrogen atom which is not involved in binding to the catalyst. For oxindoles and 2,5-diketopiperazines, a single lactam carbonyl group in the substrate is available to accept the hydrogen atom. It is currently assumed that back HAT occurs to this group, although the carbonyl oxygen atom is involved in hydrogen bonding to the catalyst. In comparison to the former reaction pathway, the latter process appears to be less efficient and more prone to side reactions. For both cases, an achiral enol or enamine is formed, which delivers upon dissociation from the catalyst statistically either one of the two stereoisomers of the substrate. Since only one substrate enantiomer (or diastereoisomer) is processed, a high enantioselectivity (or diastereoselectivity) results. Even though the editing is a contra-thermodynamic process, the described decoupling of a photochemical and a thermal step allows the usage of a single catalyst in loadings that vary between 2.5 and 10 mol % depending on the specific mode of action.