The identification of enzyme pairs with overlapping substrate specificity and enantiocomplementary transformations is a key challenge in biocatalysis. Enantio‐ and regiodivergent Baeyer–Villiger oxidations were successfully carried out by using a small library of recombinant Escherichia coli strains expressing monooxygenases of various microbial origin (see picture). The clustering of enzymes based on stereopreference is in good agreement with phylogenetic similarity.

Recombinant Escherichia coli cells expressing monooxygenases of different bacterial origin were evaluated in microbial Baeyer-Villiger oxidations of racemic fused ketones. During the enzymatic oxidation process, both the "normal" lactone generated by migration of the more-substituted carbon atom and/or the "abnormal" lactone resulting from migration of the less-substituted carbon atom can be formed. Depending on the nature of the Baeyer-Villiger monooxygenase, either a regiodivergent biooxygenation to both lactones in high optical purities was observed or essentially racemic "normal" rearrangement product was formed. The complementary behavior of enzymes was found to correlate with our previous observation of clustering of cycloketone-oxidizing proteins into two distinct clusters based on phylogenetic relationship and biocatalyst performance.

Several methods are presented for the enantioselective synthesis of the tetrahydroisoquinoline core of almorexant (ACT-078573A), a dual orexin receptor antagonist. Initial clinical supplies were secured by the Noyori Ru-catalyzed asymmetric transfer hydrogenation (Ru-Noyori ATH) of the dihydroisoquinoline precursor. Both the yield and enantioselectivity eroded upon scale-up. A broad screening exercise identified TaniaPhos as ligand for the iridium-catalyzed asymmetric hydrogenation with a dedicated catalyst pretreatment protocol, culminating in the manufacture of more than 6 t of the acetate salt of the tetrahydroisoquinoline. The major cost contributor was TaniaPhos. By switching the dihydroisoquinoline substrate of the Ru-Noyori ATH to its methanesulfonate salt, the ATH was later successfully reduced to practice, delivering several hundreds of kilograms of the tetrahydroisoquinoline, thereby reducing the catalyst cost contribution significantly. The two methods are compared with regard to green and efficiency metrics.

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Die Identifizierung von Enzympaaren mit überlappender Substratspezifität und enantiokomplementären Transformationen ist eine zentrale Herausforderung der Biokatalyse. Enantio‐ und regiodivergente Baeyer‐Villiger‐Oxidationen gelangen mit einer kleinen Bibliothek rekombinanter Escherichia‐coli‐Stämme, die Monooxygenasen unterschiedlichen mikrobiellen Ursprungs exprimieren (siehe Bild). Die auf der Stereopräferenz basierende Gruppenbildung von Enzymen stimmt gut mit der phylogenetischen Nähe überein.