Memory of Chirality in Flow Electrochemistry: Fast Optimisation with DoE and Online 2D‐HPLC

Abstract

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

Memory of chirality in a room temperature flow electrochemical reactor

“…Preliminary screening of the reaction parameters were conducted in a batch electrochemical cell (results shown in Table S1 ) 39 , 40 . To begin with, the charge passing through the system was investigated.…”

“…A yellow solution was formed and purification by TLC preparative (silica gel, n -hexane/EtOAc 1:2) produced a clear colourless solution. The MeOH was then evaporated under vacuum to give white crystals 37 , 39 , 40 .…”

“…Flow rate and current were set and reaction proceeded at room temperature. Product was collected as a colourless liquid of mixed rotamers 39 . 1 H NMR (500 MHz, CDCl 3 ): δ 7.46–7.25 (m, 9H), 5.38 (br s, 0.2H, minor), 4.23 (d, J = 4.2 Hz, 0.8H, major), 3.47–3.42 (m, 1.7H), 3.28–3.22 (m, 1H), 2.70 (s, 2.3H, major), 1.79–1.35 (m, 4H).…”

Continuous‐Flow Dynamic Kinetic Resolution of Racemic Alcohols by Lipase–Oxovanadium Cocatalysis

“…Due to these improvements, the flow DKR could be conducted for continuous 3 days to produce the desired esters in high yield and with 99% ee by using smaller amounts of CALB and VMPS4 compared to the corresponding batch reactions. Considering the increasing need and importance of continuous‐flow reactions,, [9b], , this study should provide useful information for continuous‐flow systems using a column reactor packed with multiple catalysts where several different reactions proceed simultaneously.…”

“…Additionally, the continuous‐flow processes generally present advantages over batch procedures, such as better mass and heat transfer, improved safety profiles, easier work‐up and as well as the accurate control of temperature, pressure and reaction time. Thus, continuous‐flow processes have higher productivity and reproducibility than the batch reactions, and are also favorable for automation and scale‐up …”