Combining biocatalytic oxyfunctionalisation and organocatalytic aldol reaction to access chiral β-hydroxy ketones

• A chemoenzymatic cascade combining peroxygenases and proline-derived organocatalysts is presented. • Mutual inactivation of both catalysts can be overcome by increasing the steric demand of the organocatalyst. • A one-pot tandem cascade reaction to generate chiral β-hydroxy ketones is presented. This study explores a chemoenzymatic cascade to synthesise chiral β-hydroxy ketones by integrating the selective oxyfunctionalisation capabilities of peroxygenases with the carbon-carbon bond-forming progress of organocatalysts. Initial results with simple organocatalysts demonstrated poor performance due to mutual inactivation of the biocatalyst and organocatalyst. However, the use of more complex prolinamide derivatives improved the reaction efficiency and enantioselectivity, enabling a one-pot, one-step synthesis process. This methodology was further optimised to produce high yields of enantiomerically pure aldol products and was shown to be extendable to other substituted toluenes and aldol donors.