*2.2. Alkene Functionalization*

The prochiral nature of alkenes makes them excellent starting materials for asymmetric synthesis. A classic asymmetric oxidative transformation of alkenes is the Sharpless dihydroxylation using osmium catalysis in conjunction with chiral amine ligands and a stoichiometric oxidant [61–63]. As reported by Tsuji and Sharpless in the early 1990s, potassium ferricyanide [K3Fe(CN)6] can efficiently reoxidize an Os catalyst back to the active +8 state [64–66]. In the original Sharpless procedure, 3 equivalents of the ferricyanide salt were added to enable good turnover for the asymmetric dihydroxylation with excellent *ee*'s. Making use of anodic regeneration, Amundsen and Balko were able to reduce the stoichiometry to 0.4 equivalents using coupled redox cycles (Figure 3) in a divided cell with Pt electrodes at constant potential [67]. Similar to the Sharpless protocol, the authors used a biphasic mixture with the Fe salt in the aqueous phase and the organic transformation occurring in the organic phase, with re-oxidation of the Os catalyst taking place at the solvent interface. With an analogous approach, Torii et al. were able to further reduce the loading of both Os and K3Fe(CN)6 using an undivided cell with Pt electrodes at constant current conditions at 0 ◦C [68]. In addition, Torii et al. developed an electrochemical iodine-assisted asymmetric dihydroxylation under similar electrochemical conditions, replacing ferricyanide with substoichiometric I2 as co-oxidant. As pointed out by the authors, although the OsIV complex could be directly oxidized at the anode, mediated electrolysis in solution is preferred as direct oxidation can lead to catalyst adsorption on the electrode surface that may inhibit catalysis [69].

**Figure 3.** Principle for indirect oxidative electrolysis using coupled redox cycles.

Using the same principle of electrochemically driven coupled redox cycles, Torii and co-workers developed a protocol using anodically generated chloronium oxidants for olefin epoxidation [70], inspired by the Katsuki-Jacobsen epoxidation [71–73]. With an optically active Mn-salen complex (5 mol%) in an undivided cell and Pt electrodes at 0 ◦C under constant current conditions in biphasic media, a handful of substrates were converted to the corresponding epoxides in up to 93% yield and 87% *ee*. According to the authors, chloride ions were oxidized in the aqueous phase to chloronium species that subsequently entered the organic phase to oxidize the Mn catalyst, thereby driving the oxidation process forward. Along the same lines, Bethell and co-workers utilized electrogenerated percarbonate and persulfate oxidants for iminium catalyzed epoxidation of alkenes with moderate enantiomeric excess (up to 64% *ee*), using a boron-doped diamond anode and Pt wire cathode in an undivided cell under constant current conditions [74]. In recent years, asymmetric electrochemical Os-catalyzed dihydroxylation and Mn-catalyzed epoxidation have been demonstrated to work well on a photovoltaic platform for improved process sustainability (Scheme 10) [75,76].

**Scheme 10.** Indirect electrooxidation of alkenes using coupled redox cycles in a photovoltaic system.

Lin and co-workers described enantioselective cyanophosphinoylation and cyanosulfinylation of alkenes in an anodically driven electrochemical process, using a copper catalyst with a newly developed serine-derived bisoxazoline ligand (Scheme 11) [77]. With a carbon felt anode and Pt cathode in an undivided cell under constant current conditions at 0 ◦C, a variety of styrene derivatives were functionalized in moderate to good yields with *ee*'s up to 95% (cyanophosphinoylation) and 98% (cyanosulfinylation), including heterocyclic substrates and substrates with functional groups sensitive to oxidation such as aldehyde and sulfide. The authors proposed that the electric current is required to oxidize the Cu catalyst from oxidation state +1 to its catalytically active +2 state. In its activated state, the copper catalyst was claimed to have a dual role (Scheme 11). Initially, the CuII catalyst was envisioned to oxidize a secondary phosphine oxide to its corresponding radical. This would in turn attack the alkene substrate to form an intermediate with the resulting radical situated in the stabilized benzylic position. Secondly, the reduced Cu catalyst would undergo another anodic oxidation event to form once more the active CuII complex. The active complex would thereafter accommodate the benzylic radical intermediate and form the enantiomerically enriched product upon reductive elimination. As such, the Cu catalyst is envisioned to act as a redox mediator in the first step in accordance with the general principle in Figure 1b, whereas it acts as an enantioselective cross-coupling catalyst in an electrochemically driven redox cycle in the second step (Figure 1c). Based on the assumption of a CuIII intermediate, optimization of the ligand structure was carried out by adding ancillary ester groups to the bisoxazoline (BOX) sca ffold to stabilize the high-valent intermediate prior to reductive elimination. In addition, it was hypothesized that this modification would allow for a more rigid structure that could improve selectivity in the enantio-determining step, as well as prevent cathodic demetalation of the catalyst. With the new ligand, an increase in *ee* from 84% to 95% was observed for the benchmark substrate.

**Scheme 11.** Copper-catalyzed asymmetric oxidative difunctionalization of alkenes.

Along the same lines, the Lin group published a second anodically driven enantioselective functionalization of alkenes [78]. In conjunction with a cobalt(salen) complex, the use of the same type of asymmetric Cu catalyst as in their prior work enabled hydrocyanation of differently substituted olefins using PhSiH3 and TMSCN in an undivided cell at 0 ◦C and constant potential, equipped with a carbon anode and Pt cathode (Scheme 12). A range of terminal and internal alkenes were transformed into their corresponding hydrocyanated products with high enantioselectivity (80–95% *ee*). Dienes, enynes and allenes were also compatible substrates, with terminal bonds being favored sites for hydrocyanation. In the case of allenes, excess reagents allowed for dicyanation. A comparison between the developed electrochemical protocol and the use of several chemical oxidants indicated that anodic oxidation resulted in the best yields and enantioselectivities under the examined conditions. Acetic acid was used as an additive in the transformation, rationalized as preventing undesired cathodic reduction of the Cu catalyst.

The suggested mechanism for the transformation resembles that proposed for the Lin group's preceding work on Cu-catalyzed alkene functionalization in Scheme 11 [77]. The first anodic event leads to the formation of a C-centered radical and the second anodic event produces the active asymmetric CuII cross-coupling catalyst that reacts with the C-centered radical and forms product upon reductive elimination. For the hydrocyanation reaction, the initial anodic oxidation step was proposed to involve electrochemical oxidation of the CoII catalyst, followed by the formation of a cobalt hydride species upon reaction with the hydrosilane reagent. Hydrogen atom transfer of this metal hydride to the alkene would result in a C-centered radical that in turn reacts with the asymmetric Cu-catalyst and eventually forms product. As such, both electrochemical processes appear to follow the general principle of Figure 1c. A radical rearrangemen<sup>t</sup> experiment provided support for the notion of intermediate radicals, whereas DFT calculations suggested that the enantio-determining C–CN bond formation was the turnover-limiting step of the process.

**Scheme 12.** Anodically driven asymmetric hydrocyanation of alkenes by Co/Cu catalysis.
