A unique chemoenzymatic synthesis route toward (S)-baclofen is presented, which highlights a hydroformylation and biocatalysis step toward the synthesis of such a challenging β-chiral amino acid. The shown methodology exhibits high conversions and enantiomeric excess and is transferable to other β-chiral amines and amino acids.

This study explores the chemoenzymatic synthesis of (S)-baclofen, which involves a sequential combination of transition metal catalysis and biocatalysis. The synthesis approach starts from a readily accessible cinnamic acid ester that is converted using a rhodium-based hydroformylation catalyst toward the corresponding chiral aldehyde. This compound is subsequently converted via a transaminase-catalyzed reaction system that yields the desired β-chiral amino acid ester and the final free β-chiral amino acid ( S )-baclofen after a simple hydrolysis reaction. This synthesis concept does provide high atom efficiency and does not require an additional chiral resolution step of a racemic product.