Bioorg Chem. 2026 Jul 19;181:110260. doi: 10.1016/j.bioorg.2026.110260. Online ahead of print.

ABSTRACT

Adrenergic agonists with (R)-configuration are active pharmaceutical ingredients, whereas the (S)-enantiomers exhibit reduced activity or even toxicity. However, the asymmetric synthesis of adrenergic agonist precursors is highly challenging due to the instability of the characteristic catechol/phenolic hydroxyl groups and the poor reactivity of their starting materials in adol condensation reactions. In this work, by application of the highly stereoselective L-threonine aldolase (LTA) variant LTA-LN and efficient tyrosine decarboxylase from Enterococcus faecalis (EfaTDC), a bienzymatic cascade system for the asymmetric synthesis of (R)-configured adrenergic agonist precursors was developed. The versatile precursors for most adrenergic agonists were achieved as (R)-enantiomers (88-98% yield; 77-93% enantiomeric excess (ee)), with innocuous CO₂ as the sole byproduct. Significantly, the clinical first-line emergency medication (R)-norepinephrine (98% yield, 84% ee) and the precursor for the natural adrenergic agonist (R)-synephrine (95% yield, 93% ee) were synthesized efficiently. Further mechanistic studies revealed that the high stereoselectivity and robust stereochemical control of LTA-LN, coupled with the efficient catalysis by EfaTDC, critically governed reaction outcomes. This bienzymatic system synergistically leverages the strengths of LTA-LN and EfaTDC while compensating for their individual limitations, representing an efficient LTA-mediated catalytic strategy for adrenergic agonist precursors with pharmacologically active (R)-configuration.

PMID:42485706 | DOI:10.1016/j.bioorg.2026.110260