CC BY-ND-NC 4.0 · Synthesis 2019; 51(01): 276-284
DOI: 10.1055/s-0037-1610373
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Enantioselective Electrochemical Lactonization Using Chiral Iodoarenes as Mediators

Wen-Chao Gao
,
Zi-Yue Xiong
,
Shafigh Pirhaghani
,
School of Chemistry, Cardiff University, Park Place, Cardiff, CF10 3AT, UK   Email: wirth@cf.ac.uk
› Author Affiliations
This work was supported by the China Scholarship Council (No. 201608140185). Support from Cardiff University and Taiyuan University of Technology is gratefully acknowledged.
Further Information

Publication History

Received: 07 September 2018

Accepted after revision: 04 October 2018

Publication Date:
25 October 2018 (eFirst)

 

Published as part of the 50 Years SYNTHESISGolden Anniversary Issue

Abstract

The enantioselective electrochemical lactonization of diketo acid derivatives using chiral iodoarenes as redox mediators is reported for the first time. Good to high stereoselectivities are observed in the lactonization and also in intermolecular α-alkoxylations of diketo ester derivatives. This enantioselective process was then adapted to an electrochemical flow microreactor where only small amounts of supporting electrolyte were necessary.


#

The utility of chiral hypervalent iodine compounds for enantioselective oxidative reactions represents an important and interesting area in organic chemistry.[2] Specifically, as a versatile and general oxidation system, the combination of mCPBA as the stoichiometric oxidant and chiral iodoarenes as catalysts has been successfully applied to various transformations, including the asymmetric difunctionalization of alkenes,[3] the stereoselective dearomatization of phenol or naphthol derivatives,[4] enantioselective oxidative rearrangement[5] and the enantioselective synthesis of spirooxindole derivatives.[6] Nevertheless, although enantioselective oxidative lactonization has been well developed via the dearomatization of phenol or naphthol derivatives using chiral iodoarenes in combination with mCPBA, direct lactone synthesis through oxidative cyclization of keto acids is underdeveloped, and only moderate enantioselectivities (<51% ee) were achieved (Scheme [1], eq. 1).[7]

As an efficient and environmentally friendly protocol for organic synthesis, electrochemical conversions have recently gained more attention as often an excess amount of conventional chemical oxidants and reducing reagents can be avoided.[8] Although the electrochemical oxidative α-lactonization of γ-keto acids has been reported using n-Bu4NI as the mediator (Scheme [1], eq. 2),[9] the enantioselective electrosynthesis of lactones is still unexplored.[10] In organic electrochemistry, iodoarenes represent a versatile class of redox mediators, which can generate hypervalent iodine(III) reagents via anodic oxidation to accomplish various transformations without use of a stoichiometric oxidant such as mCPBA. The first electrolysis of iodoarenes described the synthesis of (difluoroiodo)benzene, by Schmidt and Meinert in 1960,[11] and subsequently Fuchigami has contributed to the development of different fluorination reactions in electrochemistry.[12] Recently, the anodic oxidation of iodoarenes in trifluoroethanol and hexafluoroisopropanol (HFIP) has been reported by Nishiyama and Francke and their co-workers, who accomplished C–N and C–O bond formations.[13] Some reviews in this area have recently been published.[14]

Zoom Image
Scheme 1 Different methods for oxidative lactonization

The anodic oxidation of chiral iodoarenes and subsequent enantioselective synthesis has never been reported, although there are many reported works on stereoselective oxidative functionalizations using hypervalent iodine reagents.[15] Herein, we report the enantioselective electrochemical α-lactonization and α-alkoxylation of diketo acid derivatives with chiral iodoarenes as electron-transfer mediators.[16] These asymmetric reactions have been performed in batch chemistry but can also proceed using an electrochemical flow reactor[17] with lower amounts of electrolyte (Scheme [1], eq. 3).

Initial reactions were performed using diketo acid 1a as a model substrate for the enantioselective lactonization with chiral iodoarene 2b as redox mediator, and platinum as anode and cathode material, under galvanostatic conditions at 7 mA (Scheme [2]). Since fluorinated solvents are known to stabilize iodine(III) reagents by the anodic oxidation of iodoarenes,[14] 2,2,2-trifluoroethanol (TFE) was initially chosen as the solvent.

Zoom Image
Scheme 2 Sample reaction for the development of electrochemical reaction conditions and X-ray structure of (S)-3a

Several commonly used electrolytes were investigated in the electrochemical reaction shown in Scheme [2] (Table [1], entries 1–3); the use of n-Bu4NBF4 as the electrolyte gave lactone 3a in good yield (70%) and enantioselectivity (71% ee) (entry 3). Although the reaction does proceed in the absence of trifluoroacetic acid (TFA), both the efficiency and enantioselectivity were decreased (Table [1], entry 4). For this electrochemical process, the solvent HFIP is not a good choice and only results in moderate yield and lower enantioselectivity (Table [1], entry 5); no product was detected using acetonitrile as the solvent. There is also no product formed in the absence of either electrolyte or chiral iodoarene, and with catalytic amounts of 2b only traces of the product were observed (Table [1], entries 6–8). A decrease in the reaction temperature to –10 °C did not improve the enantioselectivity, but only resulted in a lower yield of 3a (Table [1], entry 9).

Table 1 Enantioselective Electrochemical Lactonization of 1a to 3a Using­ Chiral Iodoarenesa

Entry

Electrolyte

3a

Yield (%)

eeb (%)

 1

2b (1.2 eq), LiClO4

30

67

 2

2b (1.2 eq), 0.05 M n-Bu4NClO4

61

65

 3

2b (1.2 eq), 0.05 M n-Bu4NBF4

70

71

 4

2b (1.2 eq), 0.05 M n-Bu4NBF4, no TFA added

51

61

 5

2b (1.2 eq), 0.05 M n-Bu4NBF4, HFIP instead of TFE

50

29

 6

2b (1.2 eq)

 0

 7

no iodoarene, 0.05 M LiClO4

 0

 8

2b (0.2 eq), 0.05 M n-Bu4NBF4

<5

 9c

2b (1.2 eq), 0.05 M n-Bu4NBF4

41

70

10

2a (1.2 eq), 0.05 M n-Bu4NBF4

54

67

11

2c (1.2 eq), 0.05 M n-Bu4NBF4

15

68

a Reaction conditions: Pt cathode, Pt anode, 1a (0.025 M), 2 (0.03 M), electrolyte­ (0.05 M), TFA (0.075 M), solvent (4 mL), undivided cell (charge passed: 2.6 F).

b Determined by HPLC.

c The reaction was performed at –10 °C.

The absolute configuration of the major isomer of 3a was shown to be (S) via X-ray crystallographic analysis (Scheme [2]).[18] Other lactate-based 2-iodoresorcinol derivatives were also employed as potential electron-transfer mediators, including iodoarenes that have previously found applications in the enantioselective oxidative dearomatization of naphthols.[4] Neither 2a nor 2c gave better results than 2b (Table [1], entries 10 and 11) while the chiral iodoarenes 2d and 2e containing benzyl ester and amide functionalities decomposed after several minutes under the electrochemical reaction conditions.[19]

To explore the generality and the substrate scope of this electrochemical reaction, some diketo acid derivatives 1 were subjected to the electrolysis conditions (Scheme [3]). The electrolysis of substrates bearing electron-rich or -poor groups on the indanone moiety gave the corresponding lactones 3b3d in moderate yields with reasonable enantioselectivities. For the naphthyl-substituted substrate 1e, the reaction proceeded in high yield leading to the product 3e in 63% ee. Also, tetralone derivatives such as 1f led to the cyclized product 3f in 58% yield and 47% ee, while lactone 3g without an aryl moiety was only formed in 36% yield as a racemate.

When the carbonyl group and carboxylic acid were both fixed to an aromatic ring as 3h, the reaction proceeded well with good selectivity. Unfortunately, the attempted cyclization of the monocarbonyl substrate 5-oxo-5-phenylpentanoic acid (1i) failed to give any desired product 3i, which was previously reported in high yield under electrochemical conditions with n-Bu4NI as the mediator.[9]

Zoom Image
Scheme 3 Scope and limitations for enantioselective electrochemical spirolactonization using 2b. Reagents and conditions: Pt cathode, Pt anode, 1 (0.025 M), 2b (0.03 M), n-Bu4NBF4 (0.05 M), TFA (0.075 M), TFE (4 mL), undivided cell (charge passed: 2.6 F). [a] Current efficiency: 54%. [b] Reagents and conditions: mCPBA (1.5 eq), 2b (15 mol%), TFA (3 eq), TFE (2 mL), rt, 24 h.

It has been reported that oxidative lactonization can be achieved with a combination of chiral iodoarenes and mCPBA­ as stoichiometric oxidant.[7] Therefore, the combination of 2b and mCPBA was compared to the electrochemical reaction conditions, leading to products 3a, 3g and 3i. Compounds 3a and 3g were obtained with similar yields and selectivities, while 3i could be isolated in moderate yield and low enantioselectivity only using the combination of 2b and mCPBA (Scheme [3]).

With chiral iodoarene 2b, intermolecular C–O bond functionalization was also investigated using ester 4 as a substrate under the standard electrochemical conditions (Scheme [4]). Protic solvents such as water, alcohols and acetic acid were chosen, together with TFE, due to their conductivity and nucleophilicity.

Pleasingly, the electrochemical reaction of ester 4 in a mixture of TFE/H2O (3:1) with 2b as the chiral mediator gave the desired α-hydroxy product 5a in moderate yield with 31% ee. Although the reaction efficiency was reduced in solvent mixtures of TFE with methanol or ethanol, high enantioselectivities (up to 79% ee) were observed (5b and 5c). However, when the electrolysis was attempted in the solvent TFE/AcOH (3:1), the desired α-acetoxy product 5d was not detected. The absolute configuration of compounds 5 was assigned by analogy to compound 3a.

Zoom Image
Scheme 4 Intermolecular enantioselective electrosynthesis. Reagents and conditions: Pt cathode, Pt anode, 4 (0.1 mmol), 2b (0.12 mmol), n-Bu4NBF4 (0.05 M), TFA (0.075 M), TFE/ROH (3:1 v/v, 4 mL), undivided cell (charge passed: 2.6 F).

Compared with batch processes for electrochemical reactions, continuous flow reactors can reduce the amount or avoid the use of electrolytes because of the close distance of the electrodes.[20] We have reported electrochemical flow microreactors for several oxidative transformations.[17] Pleasingly, the present enantioselective lactonization could also be successfully accomplished using an electrochemical flow microreactor with a lower concentration of n-Bu4NBF4 (5 mM) (Scheme [5]), despite a slight decrease in the efficiency and enantioselectivity. There is no conversion without catalytic amounts of electrolyte and the conversion decreases when the platinum cathode is replaced by graphite. To the best of our knowledge, this is the first enantioselective reaction with iodine(III) reagents generated in an electrochemical flow microreactor.

Zoom Image
Scheme 5 Enantioselective electrochemical lactonization of 1a to 3a in a flow microreactor

Additional experiments were carried out to further explore the mechanism of this enantioselective electrolytic lactonization. Initially, a stepwise batch process was performed. After the anodic oxidation of mediator 2b, substrate 1a was added to the reaction mixture. However, this stepwise protocol only led to the desired product 3a in 9% yield (65% ee) (Scheme [6]). In the 1H NMR spectra of the electrolyzed 2b in TFE, a downfield peak at around 7.24 ppm was observed indicating the formation of an iodine(III) species, but this peak disappeared after several hours or after removal of the solvent (see the Supporting Information). This indicates the formation of an unstable iodine(III) species Ar*–IL2 by electrolysis of iodoarene 2b. In addition, cyclic voltammetry in TFE showed a lower potential (1.83 V, vs Ag/AgCl) for 2b than for 1a (2.07 V, vs Ag/AgCl) indicating that 2b is easier oxidized than 1a in the one-pot electrolysis (Figure [1]).[8c]

Zoom Image
Scheme 6 Electrolysis of 2b and reaction with 1a in a stepwise process
Zoom Image
Figure 1 Cyclic voltammograms using n-Bu4NBF4 (0.1 M) as electrolyte in TFE at 20 mV s–1, under N2. Working electrode: glass carbon; reference electrode: Ag/AgCl in 3 M NaCl; auxiliary electrode: Pt wire. Blank (dots); 1a with 3 eq of TFA (gray); 2b with 3 eq of TFA (black).

Based on the investigations from Muñiz, Ishihara and co-workers,[3e] two structures for a possible explanation of the observed stereoselectivities are shown in Figure [2]. These structures show the intermediates after the reaction of the substrate enolates with the iodine(III) reagent. Due to the steric hindrance between the indanone moiety and the lactate ester, intramolecular cyclization favorably proceeds through intermediate 6 rather than through intermediate 7.

Zoom Image
Figure 2 Proposed intermediates in the stereoselective lactonization of 3a

In summary, we have developed an electrochemical method for enantioselective lactonization using chiral lactate-based iodoarenes as redox mediators. This protocol was also applied to the intermolecular α-alkoxylation of diketo esters with good enantioselectivities. Furthermore, it was demonstrated that this enantioselective transformation could be adapted to an electrochemical flow microreactor with lower supporting electrolyte concentration. Further studies on stereoselective electrosynthesis using chiral iodoarenes are currently in progress.

All reactions were carried out in oven-dried glassware under an atmosphere of nitrogen/argon using anhydrous solvents. All commercial reagents were used as received. 1H NMR spectra were recorded at 400 or 500 MHz on Bruker DPX 400 or DPX 500 spectrometers. Chemical shifts are reported in parts per million (ppm, δ) relative to TMS (δ 0.00). 1H NMR splitting patterns are designated as singlet (s), doublet (d), doublet of doublet (dd), triplet (t), quartet (q), multiplet (m). 13C NMR spectra were recorded at 100 or 125 MHz. Mass spectra were obtained using a Waters Xevo G2-S ESI mass spectrometers. IR spectra were recorded as neat on a Shimadzu FTIR Affinity-1S spectrophotometer. Melting points were determined using a Gallenkamp hot-stage apparatus and are uncorrected. Optical rotations were measured using a 10.0 mL cell with a 1.0 dm path length on a SCHMIDT + HAENSCH UniPol L polarimeter apparatus and are reported as [α] (c in g per 100 mL, solvent) at 20 °C.


#

Methyl 4-Oxo-4-(1-oxo-2,3-dihydro-1H-inden-2-yl)butanoate (4)

To a solution of diisopropylamine (1.6 g, 15.8 mmol) in THF (40 mL) was added 2.5 M n-BuLi in hexane (6.9 mL, 17.4 mmol) at –78 °C. The resulting solution was stirred at –78 °C for 30 min and then at room temperature for an additional 30 min. The solution was cooled to –78 °C, and to this solution was added dropwise a solution of 1-indanone (1 g, 8 mmol) in THF (10 mL). After 1 h at –78 °C, to the solution was added dropwise methyl-4-chloro-4-oxobutyrate (1.36 mL, 11 mmol) in THF (5 mL). The resulting solution was warmed to room temperature over 2 h, and then quenched with saturated NH4Cl solution. The organic phase was separated, and the water phase was extracted with Et2O (3 × 20 mL). The combined organic layers were dried, concentrated and purified by chromatography (petroleum ether/EtOAc, 5:1) to give 4 as a colorless solid; yield: 1.01 g (51%); mp 57–59 °C.

IR (neat): 3025, 1734, 1628, 1545, 1221, 1167, 1038, 779, 731 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.78 (d, J = 8.0 Hz, 1 H), 7.55–7.48 (m, 2 H), 7.41 (t, J = 7.5 Hz, 1 H), 3.70 (s, 3 H), 3.64 (s, 2 H), 2.82 (t, J = 6.0 Hz, 2 H), 2.75 (t, J = 6.0 Hz, 2 H).

13C NMR (125 MHz, CDCl3): δ = 187.5, 182.4, 173.0, 146.8, 137.7, 132.4, 127.3, 125.6, 122.8, 110.6, 51.9, 30.5, 30.4, 28.9.

HRMS (ESI): m/z calcd for C14H15O4 [M + H]+: 247.0965; found: 247.0968.


#

4-Oxo-4-(1-oxo-2,3-dihydro-1H-inden-2-yl)butanoic Acid (1a)

Compound 4 (1.2 g, 5 mmol) was dissolved in THF/MeOH/water (3:1:1 v/v/v, 20 mL). To this mixture 1 M LiOH in water (10 mL) was added and the resulting solution stirred overnight. After removal of organic solvent in vacuo, the aqueous phase was acidified with HCl until pH 3. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic fractions were dried with sodium sulfate and concentrated in vacuo to give the crude acid 1a, which was recrystallized from EtOAc to give 1a as a white solid; yield: 1.03 g (89%); mp 119–121 °C.

IR (neat): 3025, 1699, 1624, 1549, 1404, 1067, 972, 775 cm–1.

1H NMR (500 MHz, CD3OD): δ (two isomers) = 7.70 (d, J = 7.5 Hz, 0.77 H) (major), 7.68–7.60 (m, 1 H), 7.57–7.52 (m, 2 H), 7.44–7.35 (m, 1.23 H), 3.66 (s, 1.54 H) (major), 3.60 (d, J = 16.5 Hz, 0.46 H), 3.28–3.25 (m, 0.23 H), 3.19 (d, J = 16.5 Hz, 0.46 H), 2.98–2.90 (m, 0.46 H), 2.83 (t, J = 6.5 Hz, 1.54 H) (major), 2.70 (t, J = 6.5 Hz, 1.63 H) (major), 2.63–2.50 (m, 0.77 H).

13C NMR (125 MHz, CD3OD): δ = 204.4, 202.1, 176.3, 156.2, 148.7, 139.1, 136.8, 136.5, 133.7, 128.9, 128.5, 128.0, 127.0, 125.3, 123.6, 112.3, 38.6, 31.6, 31.5, 29.9, 29.3, 28.8.

HRMS (ESI): m/z calcd for C13H11O4 [M – H]: 231.0663; found: 231.0665.


#

4-(6-Methoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)-4-oxobutanoic Acid (1b)

Yield: 406 mg (31%); white solid; mp 132–134 °C.

IR (neat): 3003, 1718, 1647, 1576, 1492, 1375, 1024, 877, 786 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ (two isomers) = 12.2 (br s, 1 H), 7.52 (d, J = 8.4 Hz, 0.40 H), 7.48 (d, J = 8.4 Hz, 0.60 H) (major), 7.29 (dd, J = 8.4, 2.8 Hz, 0.40 H), 7.25–7.20 (m, 0.60 H) (major), 7.15 (dd, J = 8.4, 2.8 Hz, 0.60 H) (major), 7.09 (d, J = 2.8 Hz, 0.40 H), 4.25 (dd, J = 8.0, 2.8 Hz, 0.60 H) (major), 3.81 (s, 2 H), 3.79 (s, 1 H), 3.56 (br s, 1.40 H), 3.37 (dd, J = 13.2, 2.8 Hz, 0.60 H) (major), 3.20–3.07 (m, 1 H), 2.92–2.80 (m, 1.60 H) (major), 2.56 (t, J = 2.8 Hz, 1.40 H), 2.43 (t, J = 6.8 Hz, 0.60 H) (major).

13C NMR (100 MHz, DMSO-d 6): δ = 202.8, 199.8, 173.7, 173.6, 159.2, 158.9, 147.0, 136.1, 127.7, 126.6, 124.3, 119.6, 112.5, 105.4, 105.1, 61.4, 55.6, 55.4, 37.1, 31.6, 30.1, 28.4, 27.6, 27.4.

HRMS (ESI): m/z calcd for C14H13O5 [M – H]: 261.0768; found: 261.0770.


#

4-(6-Methyl-1-oxo-2,3-dihydro-1H-inden-2-yl)-4-oxobutanoic Acid (1c)

Yield: 677 mg (55%); white solid; mp 138–140 °C.

IR (neat): 2950, 1703, 1614, 1544, 1207, 1165, 1111, 1031 cm–1.

1H NMR (400 MHz, DMSO-d 6): δ (two isomers) = 12.1 (br s, 1 H), 7.57–7.37 (m, 3 H), 4.23 (dd, J = 8.0, 3.2 Hz, 0.40 H), 3.60 (s, 1.3 H) (major), 3.43 (dd, J = 17.6, 3.2 Hz, 0.40 H), 3.24–3.10 (m, 1 H), 2.95–2.75 (m, 1.60 H) (major), 2.57 (t, J = 6.4 Hz, 1.40 H), 2.44 (t, J = 6.4 Hz, 1 H), 2.39 (m, 3 H).

13C NMR (100 MHz, DMSO-d 6): δ = 202.9, 199.9, 173.7, 173.6, 151.7, 137.3, 136.6, 135.0, 126.5, 125.5, 123.6, 122.0, 61.0, 37.1, 31.5, 30.4, 27.7, 27.6, 20.9, 20.5.

HRMS (ESI): m/z calcd for C14H13O4 [M – H]: 245.0819; found: 245.0822.


#

4-(6-Chloro-1-oxo-2,3-dihydro-1H-inden-2-yl)-4-oxobutanoic Acid (1d)

Yield: 373 mg (28%); white solid; mp 134–136 °C.

IR (neat): 2950, 1701, 1626, 1541, 1217, 1078, 813, 748 cm–1.

1H NMR (500 MHz, CD3OD): δ (two isomers) = 7.70–7.63 (m, 3 H), 3.67 (s, 1.50 H) (major), 3.60 (d, J = 18.0 Hz, 0.30 H), 3.30–3.24 (m, 0.30 H), 3.18 (d, J = 18 Hz, 0.30 H), 3.00–2.90 (m, 0.30 H), 2.90–2.82 (m, 1.50 H) (major), 2.71 (t, J = 7.0 Hz, 1.50 H) (major), 2.60–2.54 (m, 0.30 H).

13C NMR (125 MHz, CD3OD): δ = 203.9, 200.7, 176.4, 176.3, 154.4, 146.4, 140.8, 138.2, 136.5, 134.7, 133.2, 129.5, 128.4, 124.7, 123.1, 113.3, 38.5, 32.3, 31.6, 29.7, 28.9, 28.8.

HRMS (ESI): m/z calcd for C13H10ClO4 [M – H]: 265.0273, 267.0243; found: 265.0273, 267.0244.


#

4-Oxo-4-(1-oxo-2,3-dihydro-1H-cyclopenta[a]naphthalen-2-yl)butanoic Acid (1e)

Yield: 1.01 g (71%); white solid; mp 164–166 °C.

IR (neat): 3010, 1710, 1591, 1541, 1340, 1219, 1062, 870, 783 cm–1.

1H NMR (500 MHz, DMSO-d 6): δ (two isomers) = 12.2 (br s, 1 H), 8.97 (d, J = 8.5 Hz, 0.45 H), 8.92 (d, J = 8.5 Hz, 0.55 H) (major), 8.27 (d, J = 7.0 Hz, 0.55 H) (major), 8.20 (d, J = 7.5 Hz, 0.45 H), 8.08 (d, J = 8.0 Hz, 1 H), 7.77–7.67 (m, 2 H), 7.63 (t, J = 7.5 Hz, 1 H), 4.34 (tt, J = 7.5, 2.5 Hz, 0.45 H), 3.59–3.52 (m, 0.55 H) (major), 3.35–3.16 (m, 1.45 H), 3.00–2.90 (m, 0.55 H) (major), 2.78 (t, J = 7.5 Hz, 1 H), 2.48–2.44 (m, 2 H).

13C NMR (125 MHz, DMSO-d 6): δ = 203.1, 200.4, 190.6, 173.5, 173.4, 158.4, 149.7, 136.5, 133.8, 132.3, 131.2, 128.7, 128.2, 126.5, 124.3, 123.8, 123.2, 122.7, 111.0, 61.1, 37.1, 30.3, 29.6, 29.0, 28.6, 27.6.

HRMS (ESI): m/z calcd for C17H13O4 [M – H]: 281.0819; found: 281.0820.


#

4-Oxo-4-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoic Acid (1f)

Yield: 627 mg (51%); white solid; mp 102–104 °C.

IR (neat): 2934, 1697, 1614, 1558, 1410, 1153, 935, 781, 737 cm–1.

1H NMR (500 MHz, CDCl3): δ (two isomers) = 8.02 (dd, J = 8.0, 1.0 Hz, 0.10 H), 7.90 (dd, J = 8.0, 1.0 Hz, 0.90 H) (major), 7.49 (td, J = 9.0, 1.5 Hz, 0.10 H), 7.38 (td, J = 7.5, 1.5 Hz, 0.90 H) (major), 7.34–7.28 (m, 1 H), 7.25 (d, J = 7.5 Hz, 0.10 H), 7.19 (d, J = 7.5 Hz, 0.90 H) (major), 2.92–2.84 (m, 4 H), 2.75 (t, J = 6.5 Hz, 2 H), 2.67–2.62 (m, 2 H).

13C NMR (125 MHz, CDCl3): δ = 197.4, 178.3, 173.0, 140.3, 131.7, 130.4, 127.5, 126.8, 125.6, 105.5, 31.9, 28.2, 28.0, 21.8.

HRMS (ESI): m/z calcd for C14H13O4 [M – H]: 245.0819; found: 245.0821.


#

2-(1-Oxo-2,3-dihydro-1H-inden-2-ylcarbonyl)benzoic Acid (1h)

Yield: 1.08 g (77%); white solid; mp 142–144 °C.

IR (neat): 2893, 1699, 1647, 1568, 1361, 1205, 1091, 999, 849, 781 cm–1.

1H NMR (500 MHz, CD3OD): δ (two isomers) = 8.00 (dd, J = 7.5, 1.0 Hz, 0.5 H), 7.82 (br s, 0.5 H), 7.76 (d, J = 8.0 Hz, 0.55 H) (major), 7.74–7.52 (m, 5 H), 7.48 (d, J = 7.5 Hz, 0.55 H) (major), 7.43 (t, J = 7.5 Hz, 0.55 H) (major), 7.36 (t, J = 8.0 Hz, 0.55 H) (major), 3.46–3.15 (m, 2 H).

13C NMR (125 MHz, CD3OD): δ = 189.7, 169.8, 155.4, 139.1, 138.7, 136.7, 134.0, 133.4, 131.1, 129.8, 128.6, 127.9, 127.0, 124.8, 123.7, 112.8, 32.4, 30.5.

HRMS (ESI): m/z calcd for C17H11O4 [M – H]: 279.0663; found: 279.0665.


#

4-Oxo-4-(2-oxocyclopentyl)butanoic Acid (1g)

A mixture of cyclopentanone (2.6 mL, 30 mmol) and pyrrolidine (3.0 mL, 36 mmol) in benzene (12 mL) was refluxed using a Dean–Stark apparatus overnight. The solvents and excess pyrrolidine were removed in vacuo. The crude enamine and dry triethylamine (4.6 mL, 33 mmol) were dissolved in benzene (10 mL), and to this solution was added dropwise methyl-4-chloro-4-oxobutyrate (3 mL, 33 mmol). The reaction mixture was then heated at reflux for 8 h, cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo to give the acylated enamine which was used without further purification. The acylated enamine was dissolved in water (7.5 mL), acetic acid (7.5 mL) and THF (15 mL), and the resultant dark-brown solution stirred at room temperature for 24 h. The reaction mixture was then added to water (20 mL) and chloroform (50 mL), the phases were separated, and the aqueous phase was extracted with chloroform. The combined organic extracts were dried, the solvent was removed and the remainder was purified by chromatography using petroleum ether/ethyl acetate 4:1 as eluent to give 1g as a yellow oil; yield: 2.85 g (48%).

IR (neat): 2981, 2864, 1697, 1631, 1589, 1240, 928 cm–1.

1H NMR (500 MHz, CDCl3): δ (two isomers) = 3.40 (t, J = 8.0 Hz, 1 H), 3.18 (dd, J = 7.0, 5.5 Hz, 0.44 H), 3.14 (dd, J = 7.0, 5.5 Hz, 0.55 H) (major), 2.84–2.75 (m, 1 H), 2.73–2.65 (m, 2.7 H) (major), 2.63–2.54 (m, 4 H), 2.50–2.39 (m, 2.7 H) (major), 2.37–2.20 (m, 2.44 H), 2.12–2.00 (m, 2 H), 1.96–1.80 (m, 2.55 H) (major).

13C NMR (125 MHz, CDCl3): δ = 212.8, 202.5, 199.5, 181.5, 178.0, 109.8, 61.9, 38.7, 37.2, 35.8, 30.1, 28.6, 27.7, 25.8, 25.1, 20.7, 20.1.

HRMS (ESI): m/z calcd for C9H11O4 [M – H]: 183.0663; found: 183.0666.


#

Dimethyl (2R,2′R)-2,2′-((2-Iodo-5-(methoxycarbonyl)-1,3-phenylene)bis(oxy))dipropionate (2b)

Diisopropyl azodicarboxylate (10 mL, 50 mmol, 2.5 eq) was added dropwise via syringe over 30 min to a stirred suspension of methyl 3,5-dihydroxy-4-iodobenzoate (5.9 g, 20.0 mmol), triphenylphosphine (13 g, 50 mmol, 2.5 eq) and methyl (S)-(–)-lactate (4.85 mL, 50 mmol, 2.5 eq) in THF (100 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred overnight. The resultant residue was purified by column chromatography (petroleum ether/EtOAc, 3:1) to give 2b as a white solid; yield: 6.62 g (71%); mp 92–94 °C.

[α]D 20 +11 (c 0.73, CHCl3).

IR (neat): 2949, 1743, 1712, 1573, 1417, 1240, 1132, 1072, 1008, 966, 854 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.01 (s, 2 H), 4.88 (q, J = 7.0 Hz, 2 H), 3.88 (s, 3 H), 3.76 (s, 6 H), 1.71 (d, J = 7.0 Hz, 6 H).

13C NMR (125 MHz, CDCl3): δ = 171.6, 166.1, 158.2, 131.7, 107.2, 87.3, 74.1, 55.4, 18.5.

HRMS (ESI): m/z calcd for C16H20IO8 [M + H]+: 467.0197; found: 467.0194.


#

(S)-4′,5′-Dihydrospiro[indene-2,2′-pyran]-1,3′,6′(3H)-trione (3a); Typical Procedure for the Electrochemical Lactonization of 1

A 10-mL three-necked round-bottomed flask was equipped with a magnetic stirrer, and platinum plate (1 cm2) electrode as the working electrode and counter electrode. The substrate 1a (23 mg, 0.1 mmol), chiral iodobenzene 2b (56 mg, 0.12 mmol), TFA (34 mg, 0.3 mmol) and supporting electrolyte n-Bu4NBF4 (66 mg, 0.2 mmol) were added to the solvent TFE (4 mL). The resulting mixture was stirred and electrolyzed under galvanostatic conditions (7 mA/cm2) at room temperature for 1 h. The solvent was removed in vacuo and the residue purified by column chromatography (petroleum ether/EtOAc, 3:1) to give 3a as a white solid; yield: 16 mg (70%); mp 162–164 °C; 71% ee (determined by HPLC).

[α]D 20 +27 (c 0.4, CHCl3).

IR (neat): 2922, 1749, 1707, 1606, 1411, 1271, 1215, 1090, 972, 768 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.75 (d, J = 7.5 Hz, 1 H), 7.70 (t, J = 6.0 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 1 H), 7.44 (t, J = 7.0 Hz, 1 H), 3.77 (d, J = 17.0 Hz, 1 H), 3.73–3.63 (m, 1 H), 3.32 (d, J = 17.0 Hz, 1 H), 3.01 (dt, J = 17.5, 4.0 Hz, 1 H), 2.83 (dt, J = 10.0, 2.5 Hz, 2 H).

13C NMR (125 MHz, CDCl3): δ = 201.8, 197.3, 169.0, 151.9, 137.0, 132.4, 128.6, 126.2, 125.7, 92.7, 38.6, 33.4, 27.1.

HRMS (ESI): m/z calcd for C13H11O4 [M + H]+: 231.0652; found: 231.0653.

HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10, 0.8 mL/min, 20 °C, 254 nm): t R (minor) = 34.5 min, t R (major) = 39.8 min.


#

(S)-6-Methoxy-4′,5′-dihydrospiro[indene-2,2′-pyran]-1,3′,6′(3H)-trione (3b)

Yield: 13 mg (51%); white solid; mp 109–111 °C; 50% ee (determined by HPLC).

[α]D 20 +30 (c 0.28, CHCl3).

IR (neat): 1743, 1734, 1701, 1275, 1028, 983, 748 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.39 (d, J = 8.5 Hz, 1 H), 7.29 (dd, J = 8.5, 2.5 Hz, 1 H), 7.13 (d, J = 3.0 Hz, 1 H), 3.83 (s, 3 H), 3.71–3.61 (m, 2 H), 3.23 (d, J = 16.5 Hz, 1 H), 3.03–2.96 (m, 1 H), 2.85–2.81 (m, 2 H).

13C NMR (125 MHz, CDCl3): δ = 201.8, 197.2, 169.0, 160.1, 145.0, 133.5, 126.9, 126.5, 106.5, 93.3, 55.7, 38.3, 33.4, 27.1.

HRMS (ESI): m/z calcd for C14H13O5 [M + H]+: 261.0757; found: 261.0761.

HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10, 0.8 mL/min, 10 °C, 254 nm): t R (minor) = 65.4 min, t R (major) = 70.4 min.


#

(S)-6-Methyl-4′,5′-dihydrospiro[indene-2,2′-pyran]-1,3′,6′(3H)-trione (3c)

Yield: 13 mg (54%); white solid; mp 166–168 °C; 61% ee (determined by HPLC).

[α]D 20 +18 (c 0.21, CHCl3).

IR (neat): 2924, 1701, 1616, 1575, 1494, 1220, 1097, 831, 748 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.54 (s, 1 H), 7.52 (d, J = 7.5 Hz, 1 H), 7.39 (d, J = 7.5 Hz, 1 H), 3.74–3.64 (m, 2 H), 3.25 (d, J = 16.5 Hz, 1 H), 3.03–2.96 (m, 1 H), 2.85–2.80 (m, 2 H), 2.41 (s, 3 H).

13C NMR (125 MHz, CDCl3): δ = 201.9, 197.3, 169.1, 149.4, 138.8, 138.3, 132.6, 125.9, 125.5, 93.1, 38.6, 33.4, 27.1, 21.1.

HRMS (ESI): m/z calcd for C14H13O4 [M + H]+: 245.0808; found: 245.0811.

HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 85:15, 0.8 mL/min, 20 °C, 254 nm): t R (minor) = 33.5 min, t R (major) = 37.1 min.


#

(S)-6-Chloro-4′,5′-dihydrospiro[indene-2,2′-pyran]-1,3′,6′(3H)-trione (3d)

Yield: 10 mg (40%); white solid; mp 172–174 °C; 68% ee (determined by HPLC).

[α]D 20 +14 (c 0.24, CHCl3).

IR (neat): 2924, 2360, 1763, 1715, 1425, 1254, 1105, 982, 752 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.71 (d, J = 2.0 Hz, 1 H), 7.66 (dd, J = 8.5, 2.0 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 3.73 (d, J = 16.5 Hz, 1 H), 3.69–3.62 (m, 1 H), 3.27 (d, J = 17.0 Hz, 1 H), 3.01 (dt, J = 17.0, 4.5 Hz, 1 H), 2.86–2.82 (m, 2 H).

13C NMR (125 MHz, CDCl3): δ = 201.4, 196.2, 168.6, 145.0, 137.0, 135.1, 133.6, 127.4, 125.3, 92.8, 38.4, 33.3, 27.0.

HRMS (ESI): m/z calcd for C13H10ClO4 [M + H]+: 265.0262, 267.0233; found: 265.0266, 267.0237.

HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10, 1.0 mL/min, 20 °C, 254 nm): t R (minor) = 28.8 min, t R (major) = 38.1 min.


#

(S)-4′,5′-Dihydrospiro[cyclopenta[a]naphthalene-2,2′-pyran]-1,3′,6′(3H)-trione (3e)

Yield: 24 mg (87%); white solid; mp 200–202 °C; 63% ee (determined by HPLC).

[α]D 20 –26 (c 0.14, CHCl3).

IR (neat): 2920, 1699, 1573, 1517, 1417, 1312, 1180, 1155, 989, 826 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.85 (d, J = 8.5 Hz, 1 H), 8.16 (d, J = 8.5 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 7.70 (td, J = 8.0, 1.0 Hz, 1 H), 7.60 (td, J = 8.0, 1.0 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 1 H), 3.85 (d, J = 17.0 Hz, 1 H), 3.84–3.76 (m, 1 H), 3.42 (d, J = 17.0 Hz, 1 H), 3.07–3.01 (m, 1 H), 2.89–2.85 (m, 2 H).

13C NMR (125 MHz, CDCl3): δ = 201.9, 197.1, 169.2, 155.9, 138.4, 133.0, 129.9, 129.5, 128.6, 127.4, 126.9, 123.8, 123.0, 92.9, 39.1, 33.5, 27.2.

HRMS (ESI): m/z calcd for C17H13O4 [M + H]+: 281.0808; found: 281.0812.

HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10, 1.0 mL/min, 20 °C, 254 nm): t R (minor) = 28.8 min, t R (major) = 38.1 min.


#

(S)-3,4,4′,5′-Tetrahydro-1H-spiro[naphthalene-2,2′-pyran]-1,3′,6′-trione (3f)

Yield: 14 mg (58%); white solid; mp 96–98 °C; 47% ee (determined by HPLC).

[α]D 20 +11 (c 0.17, CHCl3).

1H NMR (400 MHz, CDCl3): δ = 7.98 (dd, J = 7.6, 1.2 Hz, 1 H), 7.57 (td, J = 7.6, 1.2 Hz, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 7.29 (d, J = 8.0 Hz, 1 H), 3.40–3.32 (m, 1 H), 3.28–3.14 (m, 2 H), 3.00–2.83 (m, 2 H), 2.75–2.63 (m, 2 H), 2.49–2.41 (m, 1 H).

13C NMR (100 MHz, CDCl3): δ = 203.5, 191.1, 169.3, 144.1, 135.1, 129.4, 128.9, 128.7, 127.2, 88.2, 34.1, 31.6, 27.7, 24.7.

HRMS (ESI): m/z calcd for C14H13O4 [M + H]+: 245.0808; found: 245.0811.

HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10, 0.8 mL/min, 20 °C, 254 nm): t R (major) = 34.2 min, t R (minor) = 41.4 min.


#

6-Oxaspiro[4.5]decane-1,7,10-trione (3g)

Yield: 7 mg (36%); yellow oil; 0% ee (determined by HPLC).

IR (neat): 2924, 1743, 1713, 1456, 1265, 1142, 1103, 1051, 1009, 970, 872 cm–1.

1H NMR (500 MHz, CDCl3): δ = 3.34–3.25 (m, 1 H), 2.94–2.87 (m, 1 H), 2.80–2.68 (m, 2 H), 2.65–2.57 (m, 1 H), 2.55–2.40 (m, 2H), 2.30–2.07 (m, 3 H).

13C NMR (125 MHz, CDCl3): δ = 209.9, 203.2, 168.9, 91.7, 35.8, 34.3, 33.8, 27.0, 18.2.

HRMS (ESI): m/z calcd for C9H11O4 [M + H]+: 183.0652; found: 183.0651.

HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10, 1.0 mL/min, 20 °C, 221 nm): t R (1) = 14.2 min, t R (2) = 21.3 min.


#

(R)-Spiro[indene-2,3′-isochroman]-1,1′,4′(3H)-trione (3h)

Yield: 18 mg (64%); white solid; mp 140–142 °C; 67% ee (determined by HPLC).

[α]D 20 –34 (c 0.51, CHCl3).

IR (neat): 1738, 1690, 1595, 1421, 1263, 1213, 1101, 1006, 935, 851 cm–1.

1H NMR (500 MHz, CDCl3): δ = 8.38 (dd, J = 8.0, 1.0 Hz, 1 H), 8.00 (dd, J = 7.5, 1.0 Hz, 1 H), 7.91 (td, J = 7.5, 1.0 Hz, 1 H), 7.80 (td, J = 8.0, 1.0 Hz, 1 H), 7.75–7.69 (m, 2 H), 7.59 (dt, J = 8.0, 1.0 Hz, 1 H), 7.44 (t, J = 8.0 Hz, 1 H), 4.20 (d, J = 16.5 Hz, 1 H), 3.47 (d, J = 16.5 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 195.5, 187.9, 161.6, 152.2, 137.0, 135.9, 134.2, 131.5, 130.9, 130.5, 129.5, 128.6, 126.6, 126.4, 126.0, 94.0, 37.4.

HRMS (ESI): m/z calcd for C17H11O4 [M + H]+: 279.0652; found: 279.0655.

HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10, 0.8 mL/min, 20 °C, 254 nm): t R (major) = 32.2 min, t R (minor) = 35.3 min.


#

(S)-Methyl 4-(2-Hydroxy-1-oxo-2,3-dihydro-1H-inden-2-yl)-4-oxobutanoate (5a)

Yield: 17 mg (66%); colorless oil; 31% ee (determined by HPLC).

[α]D 20 +19 (c 0.32, CHCl3).

IR (neat): 1726, 1705, 1609, 1211, 1092, 733 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.82 (d, J = 9.0 Hz, 1 H), 7.70 (t, J = 7.5 Hz, 1 H), 7.55 (d, J = 7.5 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H), 4.42 (s, 1 H), 3.82 (d, J = 17.5 Hz, 1 H), 3.65 (s, 3 H), 3.24 (d, J = 17.5 Hz, 1 H), 2.82–2.66 (m, 2 H), 2.54–2.43 (m, 2 H).

13C NMR (125 MHz, CDCl3): δ = 205.1, 201.5, 172.7, 152.2, 136.5, 134.3, 128.5, 126.8, 125.3, 87.1, 52.0, 38.9, 31.3, 27.5.

HRMS (ESI): m/z calcd for C14H15O5 [M + H]+: 263.0914; found: 263.0916.

HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10, 0.8 mL/min, 20 °C, 254 nm): t R (minor) = 22.6 min, t R (major) = 27.3 min.


#

(S)-Methyl 4-(2-Methoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)-4-oxobutanoate (5b)

Yield: 10 mg (38%); colorless oil; 77% ee (determined by HPLC).

[α]D 20 +26 (c 0.45, CHCl3).

IR (neat): 2953, 2926, 1730, 1707, 1609, 1458, 1209, 1132, 1101, 1020, 771 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.73 (d, J = 7.5 Hz, 1 H), 7.64 (t, J = 7.5 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.39 (t, J = 7.5 Hz, 1 H), 3.68 (d, J = 17.0 Hz, 1 H), 3.64 (s, 3 H), 3.41 (s, 3 H), 3.23–3.08 (m, 3 H), 2.62–2.46 (m, 2 H).

13C NMR (125 MHz, CDCl3): δ = 205.8, 199.5, 173.0, 152.5, 136.2, 134.1, 128.0, 126.5, 124.8, 93.7, 53.6, 51.7, 33.6, 32.6, 27.5.

HRMS (ESI): m/z calcd for C15H17O5 [M + H]+: 277.1071; found: 277.1075.

HPLC (Daicel Chiralcel OD-H column (25 cm), hexane/i-PrOH, 95:5, 1.0 mL/min, 20 °C, 254 nm): t R (minor) = 20.3 min, t R (major) = 24.1 min.


#

(S)-Methyl 4-(2-Ethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)-4-oxobutanoate (5c)

Yield: 12 mg (40%); colorless oil; 79% ee (determined by HPLC).

[α]D 20 +31 (c 0.70, CHCl3).

IR (neat): 2924, 1728, 1707, 1609, 1437, 1213, 1161, 1105, 1038, 772 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.72 (d, J = 7.6 Hz, 1 H), 7.63 (t, J = 8.0 Hz, 1 H), 7.48 (d, J = 7.6 Hz, 1 H), 7.38 (t, J = 7.6 Hz, 1 H), 3.70 (d, J = 17.2 Hz, 1 H), 3.64 (s, 3 H), 3.60–3.45 (m, 2 H), 3.24–3.10 (m, 3 H), 2.62–2.45 (m, 2 H), 1.30 (t, J = 6.8 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 206.1, 199.7, 173.1, 152.6, 136.1, 134.0, 128.0, 126.4, 124.8, 93.4, 61.7, 51.7, 34.3, 32.6, 27.5, 15.6.

HRMS (ESI): m/z calcd for C16H18O5Na [M + Na]+: 313.1052; found: 313.1061.

HPLC (Daicel Chiralcel OB-H column (25 cm), hexane/i-PrOH, 90:10, 1.0 mL/min, 20 °C, 254 nm): t R (major) = 22.2 min, t R (minor) = 36.8 min.


#
#

Acknowledgment

We thank the EPSRC National Mass Spectrometry Facility, Swansea, for mass spectrometric analysis.

Supporting Information

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    • For molecules containing chiral keto lactones, see:
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    • 10b Aramaki Y, Chiba K, Tada M. Phytochemistry 1995; 38: 1419
    • 10c Yan B.-F, Fang S.-T, Li W.-Z, Liu S.-J, Wang J.-H, Xia C.-H. Nat. Prod. Res. 2015; 29: 2013
  • 11 Schmidt H, Meinert H. Angew. Chem. 1960; 72: 109
    • 12a Fuchigami T, Fujita T. J. Org. Chem. 1994; 59: 7190
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    • 15d Brown M, Kumar R, Rehbein J, Wirth T. Chem. Eur. J. 2016; 22: 4030
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      For selected enantioselective electrochemical processes, see:
    • 16a Fu N, Li L, Yang Q, Luo S. Org. Lett. 2017; 19: 2122
    • 16b Jensen KL, Franke PT, Nielsen LT, Daasbjerg K, Jørgensen KA. Angew. Chem. Int. Ed. 2010; 49: 129
    • 16c Nguyen BH, Redden A, Moeller KD. Green Chem. 2014; 16: 69
    • 17a Folgueiras-Amador AA, Qian X.-Y, Xu H.-C, Wirth T. Chem. Eur. J. 2018; 24: 487
    • 17b Folgueiras-Amador AA, Philipps K, Guilbaud S, Poelakker J, Wirth T. Angew. Chem. Int. Ed. 2017; 56: 15446
    • 17c Arai K, Wirth T. Org. Process Res. Dev. 2014; 18: 1377
  • 18 CCDC 1834441 (3a) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

    • For recent electrochemical oxidations of amides and benzyl ethers, see:
    • 19a Xu F, Qian X.-Y, Li Y.-J, Xu H.-C. Org. Lett. 2017; 19: 6332
    • 19b Gieshoff T, Kehl A, Schollmeyer D, Moeller KD, Waldvogel SR. J. Am. Chem. Soc. 2017; 139: 12317
    • 19c Xiong P, Xu H.-H, Xu H.-C. J. Am. Chem. Soc. 2017; 139: 2956
    • 19d Rafiee M, Wang F, Hruszkewycz DP, Stahl SS. J. Am. Chem. Soc. 2018; 140: 22

      For reviews on flow electrolysis, see:
    • 20a Watts K, Baker A, Wirth T. J. Flow Chem. 2014; 4: 2
    • 20b Folgueiras-Amador AA, Wirth T. In Science of Synthesis: Flow Chemistry in Organic Synthesis . Jamison TF, Koch G. Georg Thieme Verlag KG; Stuttgart: 2018
    • 20c Pletcher D, Green RA, Brown RC. D. Chem. Rev. 2018; 118: 4573
    • 20d Atobe M, Tateno H, Matsumura Y. Chem. Rev. 2018; 118: 4541

    • For selected publications, see:
    • 20e Gütz C, Stenglein A, Waldvogel SR. Org. Process Res. Dev. 2017; 21: 771
    • 20f Green RA, Brown RC. D, Pletcher D, Harji B. Org. Process Res. Dev. 2015; 19: 1424
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    • 20h Green RA, Pletcher D, Leach SG, Brown RC. D. Org. Lett. 2016; 18: 1198
    • 20i Arai T, Tateno H, Nakabayashi K, Kashiwagi T, Atobe M. Chem. Commun. 2015; 51: 4891

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  • 9 Zhang S, Lian F, Xue M, Qin T, Li L, Zhang X, Xu K. Org. Lett. 2017; 19: 6622

    • For molecules containing chiral keto lactones, see:
    • 10a Nakayama M, Fukuoka Y, Nozaki H, Matsuo A, Hayashi S. Chem. Lett. 1980; 1243
    • 10b Aramaki Y, Chiba K, Tada M. Phytochemistry 1995; 38: 1419
    • 10c Yan B.-F, Fang S.-T, Li W.-Z, Liu S.-J, Wang J.-H, Xia C.-H. Nat. Prod. Res. 2015; 29: 2013
  • 11 Schmidt H, Meinert H. Angew. Chem. 1960; 72: 109
    • 12a Fuchigami T, Fujita T. J. Org. Chem. 1994; 59: 7190
    • 12b Sawamura T, Kuribayashi S, Inagi S, Fuchigami T. Org. Lett. 2010; 12: 644
    • 12c Sawamura T, Kuribayashi S, Inagi S, Fuchigami T. Adv. Synth. Catal. 2010; 352: 2757
    • 13a Inoue K, Ishikawa Y, Nishiyama S. Org. Lett. 2010; 12: 436
    • 13b Kajiyama D, Inoue K, Ishikawa Y, Nishiyama S. Tetrahedron 2010; 66: 9779
    • 13c Broese T, Francke R. Org. Lett. 2016; 18: 5896
    • 13d Koleda O, Broese T, Noetzel J, Roemelt M, Suna E, Francke R. J. Org. Chem. 2017; 82: 11669
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    • 15b Malmedy F, Wirth T. Chem. Eur. J. 2016; 22: 16072
    • 15c Mizar P, Niebuhr R, Hutchings M, Farooq U, Wirth T. Chem. Eur. J. 2016; 22: 1614
    • 15d Brown M, Kumar R, Rehbein J, Wirth T. Chem. Eur. J. 2016; 22: 4030
    • 15e Mizar P, Wirth T. Angew. Chem. Int. Ed. 2014; 53: 5993
    • 15f Farid U, Malmedy F, Claveau R, Albers L, Wirth T. Angew. Chem. Int. Ed. 2013; 52: 7018
    • 15g Farid U, Wirth T. Angew. Chem. Int. Ed. 2012; 51: 3462

      For selected enantioselective electrochemical processes, see:
    • 16a Fu N, Li L, Yang Q, Luo S. Org. Lett. 2017; 19: 2122
    • 16b Jensen KL, Franke PT, Nielsen LT, Daasbjerg K, Jørgensen KA. Angew. Chem. Int. Ed. 2010; 49: 129
    • 16c Nguyen BH, Redden A, Moeller KD. Green Chem. 2014; 16: 69
    • 17a Folgueiras-Amador AA, Qian X.-Y, Xu H.-C, Wirth T. Chem. Eur. J. 2018; 24: 487
    • 17b Folgueiras-Amador AA, Philipps K, Guilbaud S, Poelakker J, Wirth T. Angew. Chem. Int. Ed. 2017; 56: 15446
    • 17c Arai K, Wirth T. Org. Process Res. Dev. 2014; 18: 1377
  • 18 CCDC 1834441 (3a) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

    • For recent electrochemical oxidations of amides and benzyl ethers, see:
    • 19a Xu F, Qian X.-Y, Li Y.-J, Xu H.-C. Org. Lett. 2017; 19: 6332
    • 19b Gieshoff T, Kehl A, Schollmeyer D, Moeller KD, Waldvogel SR. J. Am. Chem. Soc. 2017; 139: 12317
    • 19c Xiong P, Xu H.-H, Xu H.-C. J. Am. Chem. Soc. 2017; 139: 2956
    • 19d Rafiee M, Wang F, Hruszkewycz DP, Stahl SS. J. Am. Chem. Soc. 2018; 140: 22

      For reviews on flow electrolysis, see:
    • 20a Watts K, Baker A, Wirth T. J. Flow Chem. 2014; 4: 2
    • 20b Folgueiras-Amador AA, Wirth T. In Science of Synthesis: Flow Chemistry in Organic Synthesis . Jamison TF, Koch G. Georg Thieme Verlag KG; Stuttgart: 2018
    • 20c Pletcher D, Green RA, Brown RC. D. Chem. Rev. 2018; 118: 4573
    • 20d Atobe M, Tateno H, Matsumura Y. Chem. Rev. 2018; 118: 4541

    • For selected publications, see:
    • 20e Gütz C, Stenglein A, Waldvogel SR. Org. Process Res. Dev. 2017; 21: 771
    • 20f Green RA, Brown RC. D, Pletcher D, Harji B. Org. Process Res. Dev. 2015; 19: 1424
    • 20g Kabeshov MA, Musio B, Murray PR. D, Browne DL, Ley SV. Org. Lett. 2014; 16: 4618
    • 20h Green RA, Pletcher D, Leach SG, Brown RC. D. Org. Lett. 2016; 18: 1198
    • 20i Arai T, Tateno H, Nakabayashi K, Kashiwagi T, Atobe M. Chem. Commun. 2015; 51: 4891

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Scheme 1 Different methods for oxidative lactonization
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Scheme 2 Sample reaction for the development of electrochemical reaction conditions and X-ray structure of (S)-3a
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Scheme 3 Scope and limitations for enantioselective electrochemical spirolactonization using 2b. Reagents and conditions: Pt cathode, Pt anode, 1 (0.025 M), 2b (0.03 M), n-Bu4NBF4 (0.05 M), TFA (0.075 M), TFE (4 mL), undivided cell (charge passed: 2.6 F). [a] Current efficiency: 54%. [b] Reagents and conditions: mCPBA (1.5 eq), 2b (15 mol%), TFA (3 eq), TFE (2 mL), rt, 24 h.
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Scheme 4 Intermolecular enantioselective electrosynthesis. Reagents and conditions: Pt cathode, Pt anode, 4 (0.1 mmol), 2b (0.12 mmol), n-Bu4NBF4 (0.05 M), TFA (0.075 M), TFE/ROH (3:1 v/v, 4 mL), undivided cell (charge passed: 2.6 F).
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Scheme 5 Enantioselective electrochemical lactonization of 1a to 3a in a flow microreactor
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Scheme 6 Electrolysis of 2b and reaction with 1a in a stepwise process
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Figure 1 Cyclic voltammograms using n-Bu4NBF4 (0.1 M) as electrolyte in TFE at 20 mV s–1, under N2. Working electrode: glass carbon; reference electrode: Ag/AgCl in 3 M NaCl; auxiliary electrode: Pt wire. Blank (dots); 1a with 3 eq of TFA (gray); 2b with 3 eq of TFA (black).
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Figure 2 Proposed intermediates in the stereoselective lactonization of 3a