Remote stereocontrol with azaarenes via enzymatic hydrogen atom transfer

Strategies for achieving asymmetric catalysis with azaarenes have traditionally fallen short of accomplishing remote stereocontrol, which would greatly enhance accessibility to distinct azaarenes with remote chiral centres. The primary obstacle to achieving superior enantioselectivity for remote stereocontrol has been the inherent rigidity of the azaarene ring structure. Here we introduce an ene-reductase system capable of modulating the enantioselectivity of remote carbon-centred radicals on azaarenes through a mechanism of chiral hydrogen atom transfer. This photoenzymatic process effectively directs prochiral radical centres located more than six chemical bonds, or over 6 angstrom, from the nitrogen atom in azaarenes, thereby enabling the production of a broad array of azaarenes possessing a remote gamma-stereocentre. Results from our integrated computational and experimental investigations underscore that the hydrogen bonding and steric effects of key amino acid residues are important for achieving such high stereoselectivities. The inherent rigidity of the azaarene ring structure has made it challenging to achieve remote stereocontrol through asymmetric catalysis on these substrates. Now, through a photoenzymatic process, an ene-reductase system facilitates the production of diverse azaarenes with distant gamma-stereocentres, highlighting the potential of biocatalysts for stereoselectivity at remote sites.

Automated summary

Strategies for achieving remote stereocontrol in asymmetric catalysis with azaarenes have been limited by the inherent rigidity of the azaarene ring structure. However, a photoenzymatic process using an ene-reductase system can modulate the enantioselectivity of remote carbon-centred radicals on azaarenes by chiral hydrogen atom transfer. This allows for the production of a wide range of azaarenes with remote gamma-stereocentres, showcasing the potential of biocatalysts for remote site stereoselectivity.