Biocatalysts represent an efficient, highly selective and greener alternative to metal catalysts in both industry and academia. In the last two decades, the interest in biocatalytic transformations has increased due to an urgent need for more sustainable industrial processes that comply with the principles of green chemistry. Thanks to the recent advances in biotechnologies, protein engineering and the Nobel prize awarded concept of direct enzymatic evolution, the synthetic enzymatic toolbox has expanded significantly. In particular, the implementation of biocatalysts in continuous flow systems has attracted much attention, especially from industry. The advantages of flow chemistry enable biosynthesis to overcome well-known limitations of “classic” enzymatic catalysis, such as time-consuming work-ups and enzyme inhibition, as well as difficult scale-up and process intensifications. Moreover, continuous flow biocatalysis provides access to practical, economical and more sustainable synthetic pathways, an important aspect for the future of pharmaceutical companies if they want to compete in the market while complying with European Medicines Agency (EMA), Food and Drug Administration (FDA) and green chemistry requirements. This review focuses on the most recent advances in the use of flow biocatalysis for the synthesis of active pharmaceutical ingredients (APIs), pharmaceuticals and natural products, and the advantages and limitations are discussed.

An ovel metal-free synthesis of 3,3-disubstituted benzofuran-2-(3H)-ones through reacting a-aryl-a-diazoacetates with triarylboranes is presented. Initially,t riarylboranes were successfully investigated in a-arylations of a-diazoacetates,h owever in the presence of ah eteroatom in the ortho position, the boron enolate intermediate undergoes an intramolecular rearrangement to form aq uaternary center.T he intermediate cyclizes to affordv aluable 3,3-disubstituted benzofuranones in good yields.

Amino acid derivatives undergon on-Kolbe electrolysis to afford enantiomerically enriched a-alkoxyamino derivatives through intermediate chiralc arbenium ions. The products contain N,O-acetals which are important structural motifs foundi nb ioactive natural products.T he reactioni sp erformedi nacontinuous flow electrochemical reactor coupled to a2 D-HPLC for immediate online analysis. This allowed af ast screening of temperature, electrode material, current, flow-rate andc oncentration in aD oE approach. The combination with online HPLC demonstrates that also stereoselective reactions can benefit from ah ugely acceleratedo ptimisation by combining flow electrochemistry with multidimensional analysis.Scheme1.Electrochemical oxidation of N-arylcarbonylated amino acid derivativest oc hiral alkoxylated amides in aflow electro-microreactor.Scheme2.First example of 'memory of chirality' on N-aryl serine derivatives 1 reported by Matsumuraetal. [19] [a

A stereoselective synthesis of 2,3-dihydro-1H-indoles with a Rh(II) catalyzed C-H insertion is reported. The α-diazo carbonyl intermediates are obtained via a diazo-transfer reaction on 2-aminophenylacetic acids. Optimizations and kinetic studies were performed leading to increased yields of the diazo-transfer after mechanistic evaluation of the side product formation. trans-2,3-Dihydro-1H-indoles were obtained in high diasteromeric excesses (up to 94% de) and enantioselectivites (up to 94% ee).

The synthesis of a series of α-aryl or α-alkyl functionalised β-hydroxy and β-keto esters has been achieved by reacting α-diazoesters with boranes, and aldehydes, ketones, anhydrides, nitriles, esters or isocyanates....