Biocatalytic Formal Asymmetric para-Aminoethylation of Unprotected Phenols to Chiral Amines

Enantiomerically pure amines are vital for the development of biologically active compounds in medicine and agriculture. While aminoalkylation of phenols is well-established for creating nitrogen-containing frameworks, the regio- and stereoselective para-aminoethylation of unprotected phenols is underexplored. To fill this gap, we propose a one-pot cascade biocatalysis system for the asymmetric para-aminoethylation of unprotected phenols into chiral amines, using simple pyruvate, NH4Cl, and D/l-alanine as starting materials. Utilizing a modular cascade approach, we successfully performed asymmetric para-aminoethylation of unprotected phenols through a sequential process of vinylation and hydroamination, achieving good conversions (51.0-72.0%) and >99% ee for both enantiomers of amines. Additionally, biobased p-hydroxycinnamic acid and l-tyrosine and their derivatives were converted into chiral amines with moderate to good conversions (39.4-87%) and >99% ee through integrating decarboxylation/hydroamination and deamination-decarboxylation/hydroamination. This cascade marks a successful de novo biosynthesis method for the formal asymmetric para-aminoethylation of unprotected phenols.