Chemoenzymatic synthesis of (S)-duloxetine using carbonyl reductase from Rhodosporidium toruloides

• An effective chemoenzymatic strategy was developed for (S)-duloxetine production.
• Carbonyl reductase from Rhodosporidium toruloides was employed in the key step.
• Cofactor regeneration was accomplished using RtSCR9 coupled glucose dehydrogenase.
• Production of chiral intermediate (S)-3a with so far the highest substrate loading.
• (S)-duloxetine was prepared in 60.2% yield from 2-acethylthiophene with >98.5% ee.

A chemoenzymatic strategy was developed for (S)-duloxetine production employing carbonyl reductases from newly isolated Rhodosporidium toruloides into the enantiodetermining step. Amongst the ten most permissive enzymes identified, cloned, and overexpressed in Escherichia coli, RtSCR9 exhibited excellent activity and enantioselectivity. Using co-expressed E. coli harboring both RtSCR9 and glucose dehydrogenase, (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol 3a was fabricated with so far the highest substrate loading (1000 mM) in a space-time yield per gram of biomass (DCW) of 22.9 mmol L−1 h−1 g DCW−1 at a 200-g scale. The subsequent synthetic steps from RtSCR9-catalyzed (S)-3a were further performed, affording (S)-duloxetine with 60.2% overall yield from 2-acethylthiophene in >98.5% ee.

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