Fungal enzymatic systems in the efficient synthesis of (R)-4-phenyl-4,5,6,7-tetrahydrothiene[3,2-c]pyridine

A highly efficient and enantioselective bioreduction of 4-phenyl-6,7-dihydrothieno[3,2-c]pyridine has been developed, marking the first successful access to its optically pure (R)-tetrahydrothienopyridine derivative. Given that (R)-enantiomers in this class exhibit superior antibacterial activity compared to their (S)-counterparts, providing a scalable route to these compounds is of paramount importance in the global effort to combat escalating multidrug resistance. While conventional asymmetric chemical reductions using chiral reagents have proven inadequate for this transformation, whole-cell biocatalysis utilizing Aspergillus japonicus DSM 104286 offers a robust and highly selective alternative. Under optimized conditions, this enzymatic system achieves conversion rates of 72%-74% within 72 hours, yielding the target (R)-isomer with excellent enantiopurity. The catalytic performance is intricately linked to the metabolic state of the biomass, dictated by the media composition and cultivation kinetics. We demonstrate that a synergy between nitrogen metabolite repression (NMR) and a maltose-induced metabolic shift-promoted by a specific maltose/organic nitrogen ratio-is essential for modulating the intracellular redox state. This study not only provides a high-value synthetic tool for medicinal chemistry but also elucidates the metabolic regulation necessary for efficient whole-cell redox transformations in Aspergillus species.