Introduction

Organic electrochemistry owes its origins to Alessandro Volta's groundbreaking discovery of the electrochemical cell in 1800 [1]. This pivotal event paved the way for significant advancements in the field, such as the ones developed by Michael Faraday [2], Hermann Kolbe [3], and Fritz Haber [4], who applied electrochemical principles to organic reactions. These trailblazing contributions broadened the horizons of organic electrochemistry and opened new possibilities for employing electrochemical processes in the synthesis and manipulation of organic compounds.

Currently, organic electrochemistry [5,6,7,8,9,10] is regarded as an invaluable tool for enabling redox neutral, reductive, or oxidative reactions in a manner that is mild and environmentally friendly [11]. A key advantage of this approach is the replacement of toxic and potentially hazardous oxidants and reducing agents with controlled electricity. By harnessing the power of electricity, organic electrochemistry not only enhances the safety and sustainability of organic synthesis but also enables the development of efficient and selective transformations. This paradigm shift towards electrochemical methodologies provides researchers with innovative strategies to minimize waste production and promote greener chemical processes [12]. However, the use of electrochemistry does come with certain challenges [13]. For instance, a notable drawback is the requirement of significant quantities of electrolyte to achieve a conductive solution. Additionally, the intrinsic heterogeneous nature of the electrochemical process places great importance on mass transfer phenomena. In some cases, these phenomena can even become rate-determining factors and, if not carefully considered, may lead to electrode surface modification or degradation [14]. Nonetheless, many of these issues can be effectively addressed by integrating electrosynthesis with flow chemistry [15,16,17,18,19]. This does not come as a surprise since flow chemistry [20, 21] has always been associated with improved mass and heat transfer, as well as a more precise control over the reaction conditions, reduced reaction times and enhanced scalability. Additionally, the increased proximity of electrodes in flow reactors often reduces the necessary amount of electrolyte for achieving good conductivity, further mitigating the issue. The synergistic power of electrochemistry and flow chemistry is exemplified by its successful application in industrial settings [22,23,24,25,26], such as the development of the new Monsanto process for adiponitrile production (up to 300.000 tons/year). Recently, there has been a significant surge of interest in utilizing organic electrochemistry to drive asymmetric transformations [27,28,29,30]. For example, electrochemistry has been successfully integrated with other catalytic systems, including organocatalysis [31], transition metal catalysis [32,33,34], and biocatalysis [35,36,37,38,39,40]. Additionally, alternative approaches (outside of the scope of this perspective) utilizing chiral electrodes, chiral solvents, or chiral electrolytes have been reported, further expanding the scope and potential of organic electrochemistry in achieving asymmetric synthesis.

Despite all these advancements, the development of asymmetric electrochemical transformations in flow is far from ideal, with a multitude of contributing factors. First of all, electroorganic synthesis and especially its merger with catalytic manifold is still in its infancy. For a long time, electrochemistry has been considered mostly part of the domain of physical chemistry, therefore organic electrochemistry has remained a niche approach [41]. Furthermore, there is a low abundance of reactors capable of performing electrochemical reactions in flow [15], especially if we compare it to the ones available for photoredox catalysis. As a matter of fact, the majority of these devices are built in-house and might pose problems of reproducibility.

The objective of this perspective is to focus on the major contributions within the realm of asymmetric organic electrochemistry in flow, highlighting the positive aspects, challenges, and milestones of coupling flow chemistry with electrochemical asymmetric synthesis. By doing so, the aim is to ignite increased enthusiasm for this field and expedite its advancement. To facilitate the discussion, the selected examples are categorized into four classes, based on whether the process is mediated/catalyzed or not by an organic molecule, a metal catalyst, or a biocatalyst. Finally, the future prospects and the advancements required to fully unlock the potential of this young interdisciplinary field will be discussed.

Non-mediated and non-catalytic processes

Electrochemistry is a powerful technique that offers unconventional synthetic solutions for the synthesis of complex molecules [42]. Opatz and colleagues have recently reported a noteworthy achievement in the total synthesis of ( −)-Oxycodone, a semisynthetic opioid produced commercially on a multi-ton scale [43]. In their synthetic route, the initial step involved a diastereoselective anodic oxidation of a Laudanosine derivative 1 (Scheme 1), leading to the formation of morphinandienone compound 2. This process, which relies on the electrochemical oxidative aryl-aryl coupling developed by Waldvogel [44,45,46], consists of a first electrochemical oxidation on the more electron-rich aromatic system, affording radical cation I. The judicious choice of the substituents on the aromatic rings completely drives the regioselectivity of the intramolecular recombination, generating intermediate III. Subsequently, III undergoes a second oxidation step, followed by deprotonation, leading to the formation of V. Hydrolysis of the latter furnishes the desired compound 2.

Scheme 1.
scheme 1

Total synthesis of ( −)-Oxycodone via anodic aryl–aryl coupling by Opatz and co-workers. Adapted with permission from reference [43]; copyright 2019, American Chemical Society. BDD: Boron Doped Diamond. IED: Interelectrode Distance

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This protocol was carried out in an undivided electrochemical cell under galvanostatic conditions and could be performed either in batch (69% yield) or in flow (57% yield). Boron-doped diamond and platinum proved to be the optimal materials for the anode and cathode, respectively. Additionally, 4 equivalents of HBF4 were utilized as electrolyte and acid to prevent oxidation of the amine moiety, as well as proton source for the cathodic half-reaction, while a temperature of 0 °C and an interelectrode distance of 0.5 mm proved to be crucial to obtain the target molecule with good chemical efficiency.

Overall, this achievement showcases the successful application of electrochemistry in the total synthesis of ( −)-Oxycodone, demonstrating the potential of electrochemical methods for complex molecule construction in the pharmaceutical industry. The use of selective electrochemical transformations offers a promising strategy for the synthesis of valuable compounds with improved efficiency and sustainability.

The possibility to couple microfluidic reactors with inline techniques is an extremely advantageous feature of flow chemistry [47]. For instance, the reactor can be coupled with a sequential analysis to reduce the number of experiments needed for the optimization of the process and/or an analytical device, such as HPLC or NMR, to directly measure conversions and yields. This approach has also been applied within the field of asymmetric flow electrochemistry. The group of Wirth has detailed the development of a microfluidic electrochemical approach to yield enantioenriched N,O acetals by a “memory of chirality” approach (Scheme 2) [48]. In this strategy [49], pioneered by Seebach [50] and Fuji [51], the chirality of the starting material is translated to some extent to the corresponding product even though the reaction intermediate is planar, and no other permanently chiral element is present in the system. This electrochemical process relies on the oxidative decarboxylation of α-amino acid derivative 3, which leads to planar iminium ion intermediate VI that is ultimately trapped by methanol to yield compound 4. In this case, the presence of a sterically encumbering substituent at the nitrogen center is responsible for the facial discrimination of the iminium ion by the nucleophile, ultimately leading to the retention of the configuration of the stereocenter of the product as in the starting material. Notably, the authors coupled their microfluidic electrochemical setup, the commercially available Ion electrochemical reactor, with an online 2D-HPLC and used a Design of Experiment (DoE) [52] approach to carry on the optimization step. This combination enabled the intensive screening of several reaction parameters, such as electrode material, interelectrode distance, temperature, and flow rate, in a very short timeframe. Through this approach, product 4 was obtained in a 60% yield and 70% enantiomeric excess when employing glassy carbon as the anode, platinum as the cathode, NaOMe as base and electrolyte at -10 °C with an interelectrode distance of 0.5 mm in a galvanostatic approach.

Scheme 2.
scheme 2

Memory of chirality in flow electrochemistry: fast optimisation with DoE and online 2D HPLC by Wirth and co-workers. DoE: Design of Experiment. GC: Glassy Carbon. IED: Interelectrode Distance. τ: Residence Time

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Organo-mediated processes

Unlike biocatalysis and metal catalysis, enantioselective organocatalysis has not been extensively coupled with electrochemistry, despite this merger has been recognized as a possible prominent research area in this decade [53]. A significant obstacle in this endeavor might be represented by the inherent fragility of organic catalysts when compared to metallic counterparts, particularly in the challenging area of redox chemistry. As a testament to this issue, the only report where a chiral organic molecule is used to promote an enantioselective electrochemical transformation in flow makes use of hypervalent iodine [54], a class of compounds that closely emulates the behavior of transition-metal catalysts [55]. However, this process is not able to operate under a catalytic manifold. Indeed, the group of Wirth has reported the use of chiral iodoarene 5 (Scheme 3) to promote the enantioselective galvanostatic electrochemical lactonization of diketo acid derivative 6 [56]. Specifically, chiral iodoarene 5 is converted in situ into the pivotal iodine(III) intermediate VII by electrochemical oxidation at the anode of an undivided cell, replacing the use of stoichiometric oxidants like peroxycarboxylic acids. The hypervalent iodine compound is then responsible for driving the lactonization in an enantioselective fashion, affording compound 7. After an initial optimization in batch, platinum was selected as the best performing material as both anode and cathode, while nBu4NBF4 was selected as the optimal electrolyte and trifluoroacetic acid as a key additive to promote the lactonization in a satisfactory yield and selectivity. Furthermore, the authors used trifluoroethanol as solvent due to its ability to stabilize iodine(III) reagents under anodic environment [57]. Under these conditions, the scope of the process was evaluated in batch and subsequently translated into a microfluidic device, where the target lactone 7 was obtained with a 56% yield and 55% enantiomeric excess, with a tenfold decrease of the amount of the electrolyte required with respect to the batch setup but a decrease in terms of yield and enantioselectivity (70% yield and 71% enantiomeric excess under batch conditions). Unfortunately, when using the iodoarene in a catalytic amount, only traces of the product were observed.

Scheme 3.
scheme 3

Enantioselective electrochemical lactonization using chiral iodoarenes as mediators by Wirth and co-workers. IED: Interelectrode Distance. τ: Residence Time. TFA: Trifluoroacetic Acid. TFE: Trifluoroethanol

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Biocatalytic processes

Biocatalysis and electrochemistry have a long-standing history of integration, particularly within the domain of oxidoreductases [35,36,37,38,39,40, 58]. These remarkable enzymes play a crucial role in facilitating oxidation and reduction processes, involving the transfer of one or more electrons [59]. They are indispensable for numerous vital biological functions, including biosynthesis, energy production, and respiration, among others. To carry out their functions, these enzymes rely on a redox partner, such as cytochrome or flavoprotein, or a co-substrate like molecular oxygen or NAD(P)H, which helps balance the redox half-reaction. Electrochemistry has been employed either to substitute the electron-transfer partner or to provide a tool to replenish it, thereby enabling its use in a catalytic manner [60].

This approach has also been effectively implemented in flow systems [61]. In this context, utilizing an electrochemical flow cell for biocatalysis offers a dual advantage. Firstly, it expedites overall electrochemical cofactor regeneration. Secondly, it facilitates process scaling. Additionally, in the case of biocatalytic oxidations, it may even offer the opportunity to enhance the solubility of poorly soluble molecular oxygen by adjusting reactor pressure or increasing the interface between the liquid and gaseous phases.

The Schmid research group has introduced a microfluidic reactor comprising separate flow-through cathodic and anodic compartments, both constructed from reticulated vitreous carbon (RVC) [62]. This material provides a substantial active surface area for electrochemical reactions and a substantial void volume, making these electrodes ideal for scaling up processes without generating significant backpressure. This setup, operating in a recirculation mode, was employed for two distinct processes: the asymmetric reduction of 3-methylcyclohexanone [62] and the enantioselective epoxidation of styrene [63].

In the first process (Scheme 4a), the reaction is catalyzed by a thermophilic alcohol dehydrogenase from Thermus sp., which utilizes NADH as cofactor. The flow electrochemical setup was used to regenerate the cofactor, therefore enabling its use in a catalytic manner. However, NAD+ is known to undergo unspecific reduction at the electrode, leading to dimerization products and overall to an inactive cofactor species [64]. To tackle this issue, the authors used [Cp*Rh(bpy)(H2O)]2+, an efficient electrochemical mediator for the restoration of nicotinamide cofactors [65]. Under the optimized conditions, involving the use of a divided cell setup operating under potentiostatic conditions (-0.8 V vs Ag/AgCl), compound 8 was reacted in the cathodic compartment at 60 °C using a Bis–Tris buffer solution, 1 mol% of the redox mediator, 5 mol% of the cofactor and 0,002 mol% of the enzyme, yielding compound 9 in a 32% yield, full enantioselectivity and a diastereomeric excess of 96%. Furthermore, by increasing the concentration of 8, the authors were able to boost the productivity of the system from 0.06 to 0.13 g L−1 h−1.

Scheme 4.
scheme 4

a) Electroenzymatic asymmetric reduction of 3-methylcyclohexanone and b) asymmetric styrene epoxidation by Schmid and co-workers. RVC: Reticulated Vitreous Carbon. τ: Residence Time. TADH: Thermostable Alcohol Dehydrogenase

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The same reactor was then employed for the enantioselective epoxidation of styrene 10 (Scheme 4b) catalyzed by styrene monooxygenase (StyA), an enzyme reliant on molecular oxygen as oxidant and FADH2 to restore its catalytic activity. Previous findings from the group of Schmid had already outlined the potential use of FADH2 in catalytic amounts under an electrochemical regime [66]. However, such a system suffered from low cofactor regeneration rates compared to the native cycle, due to the inherent mass transfer issues related to the use of a batch-type electrochemical reactor and by the fast aerobic oxidation of the flavin. Nonetheless, by conducting this reaction in their flow-through electrochemical reactor, equipped with a RVC electrode serving also as a turbulence promoter, the authors were able to obtain the desired (S)-styrene oxide 11 with a 99.5% enantiomeric excess and 82% yield under the optimized reaction conditions in a potentiostatic regime (-0.75 V vs Ag/AgCl).

The group of Holtmann also devised a conceptually akin flow-through reactor to facilitate asymmetric biocatalytic reactions (Scheme 5) [67]. Specifically, this reactor is composed of a RVC packed bed anode, an iridium-based oxide plated titanium net as counter electrode separated by an ion exchange membrane and an Ag/AgCl reference electrode plugged into the catholyte chamber [68]. The authors developed a potentiostatic electrochemical approach to regenerate NADH within the asymmetric oxidation of meso-2,3-butanediol 12 to (R)-acetoin 13 catalyzed by an alcohol dehydrogenase (ADH-9). As previously discussed, NAD+ is not electrochemically stable, necessitating the use of a redox mediator to be restored to NADH. In this case, the authors used 2,2’-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) as mediator. However, a previous study already highlighted that, under batch conditions, the mass transport of the oxidized form of ABTS from the electrode surface into the bulk solution significantly hampered the reaction rate and efficiency [69]. Crucially, by opting for an electrochemical flow cell instead of a batch one, the authors were able to obtain the desired compound at a potential of -0.8 V vs Ag/AgCl in a 65% yield, complete enantioselectivity and an average productivity of 5.7 mM h−1.

Scheme 5.
scheme 5

Enantioselective enzymatic synthesis of (R)-acetoin by Holtmann and co-workers. Adapted with permission from reference [68]; copyright 2014, Elsevier. GC: Glassy Carbon. τ: Residence Time. ADH-9: Alcohol Dehydrogenase 9. ABTS: 2,2’-azino-bis-(3-ethylbenzothiazoline-6-sulphonic acid)

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Transition-metal catalyzed processes

Metal catalysis is an established tool in organic synthesis, encompassing an extremely rich and diverse reactivity, which is well understood and can be predicted [70]. Among the wide plethora of metal catalyzed processes, asymmetric hydrogenation [71, 72] is perhaps the most important from an industrial point of view [73, 74], superseding all other catalytic enantioselective methods for the manufacture of chiral compounds. As hydrogen can be easily obtained by electrochemical means (i.e. cathodic hydrogen evolution), it is not a surprise that transition-metal catalyzed hydrogenations and electrochemistry have been coupled [75]. Additionally, this strategy has been effectively performed under flow chemistry conditions. For instance, the group of Atobe has recently developed a galvanostatic electrochemical asymmetric hydrogenation of α,β-unsaturated carboxylic acids 14 (Scheme 6) in a microfluidic proton-exchange membrane (PEM) reactor [76]. This process relies on the cathodically in situ generation of hydrogen and the concomitant use of palladium as both cathode and catalyst of the reaction, while the enantioselectivity of the process originates from the use of cinchonidine 16 as chiral ligand. As detailed in Scheme 6, the PEM reactor consists of an ion-exchange membrane placed in between two catalyst/electrode layers composed of an ionomer, carbon black and platinum for the anode side and palladium for the cathode one. In their protocol, the authors introduced humidified hydrogen in the anodic chamber to be converted into protons on the Pt anode. It must be noted that the generation of H+ could also be achieved by other anodic reactions such as water oxidation. The electrochemically generated protons were transported through the membrane to the cathode to be reduced to monoatomic hydrogen species directly attached on the palladium catalyst surface and ultimately reacted with α,β-unsaturated carboxylic acids 14 to yield compounds 15. Furthermore, the authors have recently applied a similar reactor to promote the electrocatalytic diastereoselective hydrogenation of cyclic ketones [77].

Scheme 6.
scheme 6

Electrocatalytic asymmetric hydrogenation of α,β-unsaturated acids in a PEM reactor by Atobe and co-workers. Adapted with permission from reference [76]; copyright 2019, American Chemical Society. Yields refers to the current efficiencies

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One of the key features of a metal catalyst is the wide range of oxidation states within reach, which are usually necessary for each elementary step in a catalytic cycle. In this sense, its coupling with electrochemistry is logical, to modulate the oxidation state of the metal catalyst at will, opening new reactivity venues while accessing often air-sensitive oxidation states directly in situ [32, 78]. The group of Ackermann has very recently disclosed an atroposelective cobaltaelectro-catalyzed C − H [79] annulation with allenes in both batch and flow environments, employing graphite felt as the anodic material and platinum as the cathodic one (Scheme 7) [80]. Notably, this transformation is the first enantioselective electrochemical organometallic C−H activation in continuous flow. The reaction, as suggested by a combination of kinetic analyses, stoichiometric experiments and cyclovoltammetric studies, involves a Co(III/I/II) catalytic cycle, proving the crucial role of electrochemistry in mediating the redox state of the metal catalyst by anodic means, while hydrogen evolution is taking place on the cathode. Under these galvanostatic conditions, the desired annulated products were obtained with outstanding yields and enantioselectivities (up to 86% yield and 99% enantiomeric excess), with slightly lower chemical efficiency when moving from batch to flow, but constant enantioselectivity. Furthermore, the use of a flow setup, the commercially available IKA ElectraSyn Flow, avoided the addition of electrolytes to the reaction mixture as well as enabling a decagram scale up.

Scheme 7.
scheme 7

Cobaltaelectro-Catalyzed C−H Annulation with Allenes for Atropochiral Compounds by Ackermann and co-workers. GF: Graphite Felt. τ: Residence Time. TFE: Trifluoroethanol. DCE: Dichloroethane

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Conclusions

Over the past few years, asymmetric synthesis, flow chemistry and electrochemistry have been audaciously merged to produce added-value molecules under mild conditions and, in the majority of cases, in a continuous fashion. This perspective has outlined how this was achieved within a total synthesis or how flow could enable the implementation of in-line monitoring techniques. Furthermore, this approach has been effectively applied to transition metal and biocatalysis, offering innovative solutions to address significant synthetic challenges, such as the modulation of the redox state of metal catalysts or regenerating cofactors in biocatalysis. Despite these trailblazing examples, the fields of asymmetric flow and even batch electrochemistry are still in their early stages, and there is plenty of room for further advancements. From an engineering perspective, the development of more standardized and accessible flow electrochemical reactors is essential. Additionally, as exemplified by the lack of reports in the area of organocatalysis and by the often non-optimal enantioselectivities, a future goal for the continued expansion of this field is the design of new asymmetric catalysts, taking into consideration also their electrochemical stability. Finally, as this process operates under mild conditions and can offer unique selectivity, applications in the area of late-stage functionalization can be expected in the upcoming future.

Given the promising results achieved thus far and the vast potential that lies ahead, the future of asymmetric flow electrochemistry holds great promise, excitement, and is undoubtedly electrifying.