Enantioselective Electrochemical Lactonization Using Chiral Iodoarenes as Mediators

Article abstract of DOI:10.1055/s-0037-1610373

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.

Full text of DOI:10.1055/s-0037-1610373

SYNTHESIS
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Georg Thieme Verlag Stuttgart · New York
2018, 50, A–I
paper
A
en
Synthesis
W.-C. Gao et al.
Paper
Enantioselective Electrochemical Lactonization Using Chiral
Iodoarenes as Mediators
Wen-Chao Gao1
Electrolysis in Batch
O
O
O
R
OMe
Zi-Yue Xiong
O
R
*
Shafigh Pirhaghani
OR’’
R’
Ar*–I
Chiral Mediator
CO2R’’
O
Thomas Wirth*
0
0
0
0-
0
0
0
2-8
9
9
0-0
6
6
7
R’
up to 87% yield
up to 79% ee
O
or
R’’ = H, Me
School of Chemistry, Cardiff University, Park Place, Cardiff,
O
*
O
O
CF10 3AT, UK
wirth@cf.ac.uk
R’
Electrolysis in Flow
R
Published as part of the 50 Years SYNTHESIS – Golden Anniversary
Issue
Received: 07.09.2018
Accepted after revision: 04.10.2018
Published online: 25.10.2018
tonization of γ-keto acids has been reported using n-Bu NI
as the mediator (Scheme 1, eq. 2), the enantioselective
4
9
electrosynthesis of lactones is still unexplored.10 In organic
electrochemistry, iodoarenes represent a versatile class of
redox mediators, which can generate hypervalent io-
dine(III) reagents via anodic oxidation to accomplish vari-
ous transformations without use of a stoichiometric oxi-
dant such as mCPBA. The first electrolysis of iodoarenes de-
scribed the synthesis of (difluoroiodo)benzene, by Schmidt
and Meinert in 1960,11 and subsequently Fuchigami has
contributed to the development of different fluorination re-
actions in electrochemistry.12 Recently, the anodic oxida-
tion of iodoarenes in trifluoroethanol and hexafluoroiso-
propanol (HFIP) has been reported by Nishiyama and
Francke and their co-workers, who accomplished C–N and
C–O bond formations.1 Some reviews in this area have re-
cently been published.14
DOI: 10.1055/s-0037-1610373; Art ID: ss-2018-z0601-op
License terms:
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 elec-
trochemical flow microreactor where only small amounts of supporting
electrolyte were necessary.
Key words electrolysis, flow microreactors, hypervalent iodine, lac-
tonization, stereoselective synthesis
3
The utility of chiral hypervalent iodine compounds for
enantioselective oxidative reactions represents an import-
ant and interesting area in organic chemistry. Specifically,
2
Previous work
as a versatile and general oxidation system, the combina-
tion of mCPBA as the stoichiometric oxidant and chiral io-
doarenes as catalysts has been successfully applied to vari-
ous transformations, including the asymmetric difunction-
O
Ar*I (10 mol%)
p-TsOH (3 eq)
O
O
O
Ph
4
*
(1)
(2)
O
O
Ph
Ph
OH
OH
mCPBA
CH Cl , rt
2
2
7%, 51% ee
3
alization of alkenes, the stereoselective dearomatization of
4
phenol or naphthol derivatives, enantioselective oxidative
O
TBAI (15 mol%)
5
rearrangement and the enantioselective synthesis of spiro-
O
O
n-Bu NOAc (2 eq)
4
O
6
Ph
oxindole derivatives. Nevertheless, although enantioselec-
CH3CN/TFE, 40 °C
Pt(+)/Pt(–), 15 mA
tive oxidative lactonization has been well developed via the
dearomatization of phenol or naphthol derivatives using
chiral iodoarenes in combination with mCPBA, direct lac-
tone synthesis through oxidative cyclization of keto acids is
underdeveloped, and only moderate enantioselectivities
81%
This work
Electrolysis
O
O
in Batch
O
R2
OH
O
(
<51% ee) were achieved (Scheme 1, eq. 1).7
O
(3)
*
O
R1
R2
+
O
R1
As an efficient and environmentally friendly protocol
for organic synthesis, electrochemical conversions have re-
cently gained more attention as often an excess amount of
conventional chemical oxidants and reducing reagents can
Electrolysis
in Flow
up to 86%
up to 71% ee
Ar*I
Scheme 1 Different methods for oxidative lactonization
8
be avoided. Although the electrochemical oxidative α-lac-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

B
Synthesis
W.-C. Gao et al.
Paper
The anodic oxidation of chiral iodoarenes and subse-
quent enantioselective synthesis has never been reported,
although there are many reported works on stereoselective
oxidative functionalizations using hypervalent iodine re-
Table 1 Enantioselective Electrochemical Lactonization of 1a to 3a
Using Chiral Iodoarenesa
Entry Electrolyte
3a
Yield (%) ee (%)
15
b
agents. Herein, we report the enantioselective electro-
chemical α-lactonization and α-alkoxylation of diketo acid
derivatives with chiral iodoarenes as electron-transfer me-
1
2
3
4
5
6
7
8
2b (1.2 eq), LiClO
4
30
67
65
71
61
29
–
16
2b (1.2 eq), 0.05 M n-Bu
2b (1.2 eq), 0.05 M n-Bu
4
NClO
NBF
4
61
diators. These asymmetric reactions have been performed
in batch chemistry but can also proceed using an electro-
4
4
70
17
chemical flow reactor with lower amounts of electrolyte
2b (1.2 eq), 0.05 M n-Bu NBF , no TFA added
51
4
4
(Scheme 1, eq. 3).
2b (1.2 eq), 0.05 M n-Bu
2b (1.2 eq)
4
NBF
4
, HFIP instead of TFE 50
Initial reactions were performed using diketo acid 1a as
0
0
a model substrate for the enantioselective lactonization
with chiral iodoarene 2b as redox mediator, and platinum
as anode and cathode material, under galvanostatic condi-
tions at 7 mA (Scheme 2). Since fluorinated solvents are
known to stabilize iodine(III) reagents by the anodic oxida-
no iodoarene, 0.05 M LiClO
4
–
2b (0.2 eq), 0.05 M n-Bu
4
NBF
4
4
4
<5
41
54
–
9c 2b (1.2 eq), 0.05 M n-Bu
10
NBF
70
67
68
4
2a (1.2 eq), 0.05 M n-Bu NBF
4
14
tion of iodoarenes, 2,2,2-trifluoroethanol (TFE) was ini-
tially chosen as the solvent.
11
2c (1.2 eq), 0.05 M n-Bu
4
NBF
4
15
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.
The reaction was performed at –10 °C.
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 deriva-
tives were also employed as potential electron-transfer me-
diators, including iodoarenes that have previously found
applications in the enantioselective oxidative dearomatiza-
tion of naphthols.4 Neither 2a nor 2c gave better results
than 2b (Table 1, entries 10 and 11) while the chiral iodo-
arenes 2d and 2e containing benzyl ester and amide func-
tionalities decomposed after several minutes under the
electrochemical reaction conditions.19
Scheme 2 Sample reaction for the development of electrochemical re-
action conditions and X-ray structure of (S)-3a
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 lac-
tones 3b–3d in moderate yields with reasonable enantiose-
lectivities. 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 cycliza-
tion of the monocarbonyl substrate 5-oxo-5-phenylpenta-
noic acid (1i) failed to give any desired product 3i, which
Several commonly used electrolytes were investigated
in the electrochemical reaction shown in Scheme 2 (Table 1,
entries 1–3); the use of n-Bu NBF as the electrolyte gave
4
4
lactone 3a in good yield (70%) and enantioselectivity (71%
ee) (entry 3). Although the reaction does proceed in the ab-
sence 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 enanti-
oselectivity (Table 1, entry 5); no product was detected us-
ing acetonitrile as the solvent. There is also no product
formed in the absence of either electrolyte or chiral iodo-
arene, 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 en-
antioselectivity, but only resulted in a lower yield of 3a (Ta-
ble 1, entry 9).
was previously reported in high yield under electrochemi-
9
cal conditions with n-Bu NI as the mediator.
4
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

C
Synthesis
W.-C. Gao et al.
Paper
R2
O
O
O
O
O
O
Pt cathode, Pt anode
b (1.2 eq), TFA (3 eq)
CO Me n-Bu4NBF4 (0.05 M)
O
O
2
O
OH Pt cathode, Pt anode
b (1.2 eq), TFA (3 eq) R1
R2
2
2
CO Me
2
OR
R1
R2
n-Bu4NBF4 (0.05 M)
O
n
n
O
TFE/ROH (3:1)
rt, 2.6 F
R2
TFE, rt, 2.6 F
1
3
5
a R = H: 66%, 31% ee
O
O
O
O
O
O
5b R = Me: 38%, 77% ee
5c R = Et: 40%, 79% ee
4
O
MeO
O
Me
O
5d R = Ac: 0%
Scheme 4 Intermolecular enantioselective electrosynthesis. Reagents
and conditions: Pt cathode, Pt anode, 4 (0.1 mmol), 2b (0.12 mmol),
n-Bu NBF (0.05 M), TFA (0.075 M), TFE/ROH (3:1 v/v, 4 mL), undivided
O
O
O
3a
7
0%, 71% ee
5%, 68% ee[a,b]
3b 51%, 50% ee
3c 54%, 61% ee
4
4
6
cell (charge passed: 2.6 F).
O
O
O
O
O
Cl
O
O
O
O
Compared with batch processes for electrochemical re-
actions, 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
O
O
3e 87%, 63% ee
O
O
3
d 40%, 68% ee
3f 58%, 47% ee
O
17
microreactors for several oxidative transformations.
O
O
O
O
O
O
Pleasingly, the present enantioselective lactonization could
also be successfully accomplished using an electrochemical
flow microreactor with a lower concentration of n-Bu NBF
O
O
O
4
4
3
g
(5 mM) (Scheme 5), despite a slight decrease in the efficien-
cy and enantioselectivity. There is no conversion without
catalytic amounts of electrolyte and the conversion de-
creases when the platinum cathode is replaced by graphite.
To the best of our knowledge, this is the first enantioselec-
tive reaction with iodine(III) reagents generated in an elec-
trochemical flow microreactor.
3
i
3
6%, 0% ee
7%, 0% ee[b]
3
h 64%, 67% ee
0% (15 F)
6%, 27% ee[b]
4
5
Scheme 3 Scope and limitations for enantioselective electrochemical
spirolactonization using 2b. Reagents and conditions: Pt cathode, Pt an-
ode, 1 (0.025 M), 2b (0.03 M), n-Bu NBF (0.05 M), TFA (0.075 M), TFE
4 mL), undivided cell (charge passed: 2.6 F). [a] Current efficiency:
4%. [b] Reagents and conditions: mCPBA (1.5 eq), 2b (15 mol%), TFA (3
4
4
(
5
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. Therefore, the combina-
1
a (0.05 M in TFE)
+
2b (1.2 eq)
7
+
3
2 mA
tion of 2b and mCPBA was compared to the electrochemical
reaction conditions, leading to products 3a, 3g and 3i. Com-
pounds 3a and 3g were obtained with similar yields and se-
lectivities, 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
n-Bu4NBF4 (0.1 eq, 0.005 M)
O
O
0.1 mL/min
O
O
Syringe pump
3
a 56%, 55% ee
Scheme 5 Enantioselective electrochemical lactonization of 1a to 3a
in a flow microreactor
(
Scheme 4). Protic solvents such as water, alcohols and ace-
Additional experiments were carried out to further ex-
plore the mechanism of this enantioselective electrolytic
lactonization. Initially, a stepwise batch process was per-
formed. After the anodic oxidation of mediator 2b, sub-
strate 1a was added to the reaction mixture. However, this
stepwise protocol only led to the desired product 3a in 9%
tic acid were chosen, together with TFE, due to their con-
ductivity and nucleophilicity.
Pleasingly, the electrochemical reaction of ester 4 in a
mixture of TFE/H O (3:1) with 2b as the chiral mediator
2
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
1
yield (65% ee) (Scheme 6). In the H 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 af-
ter removal of the solvent (see the Supporting Information).
This indicates the formation of an unstable iodine(III) spe-
5
c). 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.
cies Ar*–IL by electrolysis of iodoarene 2b. In addition, cy-
2
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

D
Synthesis
W.-C. Gao et al.
Paper
clic voltammetry in TFE showed a lower potential (1.83 V,
vs Ag/AgCl) for 2b than for 1a (2.07 V, vs Ag/AgCl) indicat-
ing that 2b is easier oxidized than 1a in the one-pot elec-
In summary, we have developed an electrochemical
method for enantioselective lactonization using chiral lac-
tate-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 transforma-
tion could be adapted to an electrochemical flow microre-
actor with lower supporting electrolyte concentration. Fur-
ther studies on stereoselective electrosynthesis using chiral
iodoarenes are currently in progress.
8c
trolysis (Figure 1).
Pt cathode, Pt anode
TFA (3 eq)
n-Bu4NBF4 (0.05 M)
1a
*
*
Ar-I
Ar-IL
3a
2
TFE
rt, 1 h
9%, 65% ee
2b
rt, 2.6 F
Scheme 6 Electrolysis of 2b and reaction with 1a in a stepwise process
All reactions were carried out in oven-dried glassware under an at-
mosphere of nitrogen/argon using anhydrous solvents. All commer-
1
cial reagents were used as received. H 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
1
TMS (δ 0.00). H NMR splitting patterns are designated as singlet (s),
doublet (d), doublet of doublet (dd), triplet (t), quartet (q), multiplet
13
(
m). C 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 spec-
trophotometer. Melting points were determined using a Gallenkamp
hot-stage apparatus and are uncorrected. Optical rotations were mea-
sured 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.
Figure 1 Cyclic voltammograms using n-Bu NBF (0.1 M) as electrolyte
4
4
in TFE at 20 mV s–1, under N . Working electrode: glass carbon; refer-
Methyl 4-Oxo-4-(1-oxo-2,3-dihydro-1H-inden-2-yl)butanoate (4)
2
ence electrode: Ag/AgCl in 3 M NaCl; auxiliary electrode: Pt wire. Blank
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
(
dots); 1a with 3 eq of TFA (gray); 2b with 3 eq of TFA (black).
–
78 °C, and to this solution was added dropwise a solution of 1-inda-
Based on the investigations from Muñiz, Ishihara and
none (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 NH Cl solu-
tion. The organic phase was separated, and the water phase was ex-
tracted with Et O (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
3e
co-workers, 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.
4
2
57–59 °C.
IR (neat): 3025, 1734, 1628, 1545, 1221, 1167, 1038, 779, 731 cm–1
.
O
1
H NMR (500 MHz, CDCl ): δ = 7.78 (d, J = 8.0 Hz, 1 H), 7.55–7.48 (m, 2
3
HO
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).
OH
O
O
O
I
L
O
L
O
13
I
C NMR (125 MHz, CDCl ): δ = 187.5, 182.4, 173.0, 146.8, 137.7,
O
O
3
O
O
O
O
132.4, 127.3, 125.6, 122.8, 110.6, 51.9, 30.5, 30.4, 28.9.
O
O
OMe
OMe
+
HRMS (ESI): m/z calcd for C14H15O4 [M + H] : 247.0965; found:
MeO
MeO
247.0968.
CO2Me
CO2Me
6
7
4-Oxo-4-(1-oxo-2,3-dihydro-1H-inden-2-yl)butanoic Acid (1a)
Figure 2 Proposed intermediates in the stereoselective lactonization
of 3a
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 con-
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

E
Synthesis
W.-C. Gao et al.
Paper
1
centrated 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–
H NMR (500 MHz, CD OD): δ (two isomers) = 7.70–7.63 (m, 3 H),
3
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,
121 °C.
IR (neat): 3025, 1699, 1624, 1549, 1404, 1067, 972, 775 cm–1
.
0
.30 H).
1
H NMR (500 MHz, CD OD): δ (two isomers) = 7.70 (d, J = 7.5 Hz, 0.77
3
13
C NMR (125 MHz, CD OD): δ = 203.9, 200.7, 176.4, 176.3, 154.4,
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,
3
1
1
46.4, 140.8, 138.2, 136.5, 134.7, 133.2, 129.5, 128.4, 124.7, 123.1,
13.3, 38.5, 32.3, 31.6, 29.7, 28.9, 28.8.
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–
HRMS (ESI): m/z calcd for C13H10ClO4 [M – H] : 265.0273, 267.0243;
2.50 (m, 0.77 H).
found: 265.0273, 267.0244.
13
C NMR (125 MHz, CD OD): δ = 204.4, 202.1, 176.3, 156.2, 148.7,
3
139.1, 136.8, 136.5, 133.7, 128.9, 128.5, 128.0, 127.0, 125.3, 123.6,
4-Oxo-4-(1-oxo-2,3-dihydro-1H-cyclopenta[a]naphthalen-2-
112.3, 38.6, 31.6, 31.5, 29.9, 29.3, 28.8.
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
HRMS (ESI): m/z calcd for C13H11O4 [M – H] : 231.0663; found:
231.0665.
.
1
H NMR (500 MHz, DMSO-d ): δ (two isomers) = 12.2 (br s, 1 H), 8.97
6
4
-(6-Methoxy-1-oxo-2,3-dihydro-1H-inden-2-yl)-4-oxobutanoic
(
d, J = 8.5 Hz, 0.45 H), 8.92 (d, J = 8.5 Hz, 0.55 H) (major), 8.27 (d,
Acid (1b)
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
H).
Yield: 406 mg (31%); white solid; mp 132–134 °C.
IR (neat): 3003, 1718, 1647, 1576, 1492, 1375, 1024, 877, 786 cm–1
.
.00–2.90 (m, 0.55 H) (major), 2.78 (t, J = 7.5 Hz, 1 H), 2.48–2.44 (m, 2
1
H NMR (400 MHz, DMSO-d ): δ (two isomers) = 12.2 (br s, 1 H), 7.52
6
(d, J = 8.4 Hz, 0.40 H), 7.48 (d, J = 8.4 Hz, 0.60 H) (major), 7.29 (dd,
1
3
C NMR (125 MHz, DMSO-d ): δ = 203.1, 200.4, 190.6, 173.5, 173.4,
J = 8.4, 2.8 Hz, 0.40 H), 7.25–7.20 (m, 0.60 H) (major), 7.15 (dd, J = 8.4,
.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,
.60 H) (major), 2.56 (t, J = 2.8 Hz, 1.40 H), 2.43 (t, J = 6.8 Hz, 0.60 H)
6
1
1
58.4, 149.7, 136.5, 133.8, 132.3, 131.2, 128.7, 128.2, 126.5, 124.3,
23.8, 123.2, 122.7, 111.0, 61.1, 37.1, 30.3, 29.6, 29.0, 28.6, 27.6.
2
–
(
1
HRMS (ESI): m/z calcd for C17H13O4 [M – H] : 281.0819; found:
281.0820.
(major).
1
3
C NMR (100 MHz, DMSO-d ): δ = 202.8, 199.8, 173.7, 173.6, 159.2,
4-Oxo-4-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)butanoic Acid
(1f)
6
1
58.9, 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.
Yield: 627 mg (51%); white solid; mp 102–104 °C.
–
IR (neat): 2934, 1697, 1614, 1558, 1410, 1153, 935, 781, 737 cm–1
HRMS (ESI): m/z calcd for C14H13O5 [M – H] : 261.0768; found:
.
261.0770.
1
H NMR (500 MHz, CDCl ): δ (two isomers) = 8.02 (dd, J = 8.0, 1.0 Hz,
3
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).
13
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
.
C NMR (125 MHz, CDCl ): δ = 197.4, 178.3, 173.0, 140.3, 131.7,
3
1
130.4, 127.5, 126.8, 125.6, 105.5, 31.9, 28.2, 28.0, 21.8.
H NMR (400 MHz, DMSO-d ): δ (two isomers) = 12.1 (br s, 1 H),
.57–7.37 (m, 3 H), 4.23 (dd, J = 8.0, 3.2 Hz, 0.40 H), 3.60 (s, 1.3 H)
6
–
7
HRMS (ESI): m/z calcd for C14H13O4 [M – H] : 245.0819; found:
(major), 3.43 (dd, J = 17.6, 3.2 Hz, 0.40 H), 3.24–3.10 (m, 1 H), 2.95–
245.0821.
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).
2
-(1-Oxo-2,3-dihydro-1H-inden-2-ylcarbonyl)benzoic Acid (1h)
13
C NMR (100 MHz, DMSO-d ): δ = 202.9, 199.9, 173.7, 173.6, 151.7,
Yield: 1.08 g (77%); white solid; mp 142–144 °C.
6
1
37.3, 136.6, 135.0, 126.5, 125.5, 123.6, 122.0, 61.0, 37.1, 31.5, 30.4,
IR (neat): 2893, 1699, 1647, 1568, 1361, 1205, 1091, 999, 849, 781
27.7, 27.6, 20.9, 20.5.
–1
cm
.
–
HRMS (ESI): m/z calcd for C14H13O4 [M – H] : 245.0819; found:
1
H NMR (500 MHz, CD OD): δ (two isomers) = 8.00 (dd, J = 7.5, 1.0 Hz,
3
245.0822.
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).
3
(
(
1
4
-(6-Chloro-1-oxo-2,3-dihydro-1H-inden-2-yl)-4-oxobutanoic
Acid (1d)
C NMR (125 MHz, CD OD): δ = 189.7, 169.8, 155.4, 139.1, 138.7,
3
Yield: 373 mg (28%); white solid; mp 134–136 °C.
IR (neat): 2950, 1701, 1626, 1541, 1217, 1078, 813, 748 cm–1
1
36.7, 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:
79.0665.
.
–
2
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

F
Synthesis
W.-C. Gao et al.
Paper
4
-Oxo-4-(2-oxocyclopentyl)butanoic Acid (1g)
to the solvent TFE (4 mL). The resulting mixture was stirred and elec-
trolyzed under galvanostatic conditions (7 mA/cm ) at room tem-
perature 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
2
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 re-
moved in vacuo. The crude enamine and dry triethylamine (4.6 mL,
(determined by HPLC).
33 mmol) were dissolved in benzene (10 mL), and to this solution was
[α]D20 +27 (c 0.4, CHCl3).
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 con-
centrated 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 reac-
tion 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 sol-
vent was removed and the remainder was purified by chromatogra-
phy using petroleum ether/ethyl acetate 4:1 as eluent to give 1g as a
yellow oil; yield: 2.85 g (48%).
IR (neat): 2922, 1749, 1707, 1606, 1411, 1271, 1215, 1090, 972, 768
–1
cm
.
1
H NMR (500 MHz, CDCl ): δ = 7.75 (d, J = 7.5 Hz, 1 H), 7.70 (t, J = 6.0
3
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).
13
C NMR (125 MHz, CDCl ): δ = 201.8, 197.3, 169.0, 151.9, 137.0,
3
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:
31.0653.
HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10,
.8 mL/min, 20 °C, 254 nm): tR (minor) = 34.5 min, tR (major) = 39.8
min.
2
IR (neat): 2981, 2864, 1697, 1631, 1589, 1240, 928 cm–1
.
0
1
H NMR (500 MHz, CDCl ): δ (two isomers) = 3.40 (t, J = 8.0 Hz, 1 H),
3
3
.18 (dd, J = 7.0, 5.5 Hz, 0.44 H), 3.14 (dd, J = 7.0, 5.5 Hz, 0.55 H) (ma-
jor), 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,
(
S)-6-Methoxy-4′,5′-dihydrospiro[indene-2,2′-pyran]-1,3′,6′(3H)-
trione (3b)
2
H), 1.96–1.80 (m, 2.55 H) (major).
Yield: 13 mg (51%); white solid; mp 109–111 °C; 50% ee (determined
by HPLC).
13
C NMR (125 MHz, CDCl ): δ = 212.8, 202.5, 199.5, 181.5, 178.0,
3
1
09.8, 61.9, 38.7, 37.2, 35.8, 30.1, 28.6, 27.7, 25.8, 25.1, 20.7, 20.1.
α]D20 +30 (c 0.28, CHCl3).
[
–
HRMS (ESI): m/z calcd for C H11O4 [M – H] : 183.0663; found:
IR (neat): 1743, 1734, 1701, 1275, 1028, 983, 748 cm–1
1
9
.
183.0666.
H NMR (500 MHz, CDCl ): δ = 7.39 (d, J = 8.5 Hz, 1 H), 7.29 (dd,
3
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,
Dimethyl (2R,2′R)-2,2′-((2-Iodo-5-(methoxycarbonyl)-1,3-phenyl-
ene)bis(oxy))dipropionate (2b)
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).
13
C NMR (125 MHz, CDCl ): δ = 201.8, 197.2, 169.0, 160.1, 145.0,
3
Diisopropyl azodicarboxylate (10 mL, 50 mmol, 2.5 eq) was added
dropwise via syringe over 30 min to a stirred suspension of methyl
133.5, 126.9, 126.5, 106.5, 93.3, 55.7, 38.3, 33.4, 27.1.
+
3,5-dihydroxy-4-iodobenzoate (5.9 g, 20.0 mmol), triphenylphos-
HRMS (ESI): m/z calcd for C14
261.0761.
HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10,
.8 mL/min, 10 °C, 254 nm): tR (minor) = 65.4 min, tR (major) = 70.4
min.
H
13
O
5
[M + H] : 261.0757; found:
phine (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
0
9
2–94 °C.
α]D20 +11 (c 0.73, CHCl3).
IR (neat): 2949, 1743, 1712, 1573, 1417, 1240, 1132, 1072, 1008, 966,
(
S)-6-Methyl-4′,5′-dihydrospiro[indene-2,2′-pyran]-1,3′,6′(3H)-tri-
[
one (3c)
Yield: 13 mg (54%); white solid; mp 166–168 °C; 61% ee (determined
by HPLC).
–1
854 cm .
1
[α]D20 +18 (c 0.21, CHCl3).
H NMR (500 MHz, CDCl ): δ = 7.01 (s, 2 H), 4.88 (q, J = 7.0 Hz, 2 H),
3
3
.88 (s, 3 H), 3.76 (s, 6 H), 1.71 (d, J = 7.0 Hz, 6 H).
IR (neat): 2924, 1701, 1616, 1575, 1494, 1220, 1097, 831, 748 cm–1
.
13
C NMR (125 MHz, CDCl ): δ = 171.6, 166.1, 158.2, 131.7, 107.2, 87.3,
1
3
H NMR (500 MHz, CDCl ): δ = 7.54 (s, 1 H), 7.52 (d, J = 7.5 Hz, 1 H),
3
74.1, 55.4, 18.5.
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),
+
HRMS (ESI): m/z calcd for C16H20IO8 [M + H] : 467.0197; found:
3.03–2.96 (m, 1 H), 2.85–2.80 (m, 2 H), 2.41 (s, 3 H).
467.0194.
13
C NMR (125 MHz, CDCl ): δ = 201.9, 197.3, 169.1, 149.4, 138.8,
3
1
38.3, 132.6, 125.9, 125.5, 93.1, 38.6, 33.4, 27.1, 21.1.
(
S)-4′,5′-Dihydrospiro[indene-2,2′-pyran]-1,3′,6′(3H)-trione (3a);
+
HRMS (ESI): m/z calcd for C14H13O4 [M + H] : 245.0808; found:
Typical Procedure for the Electrochemical Lactonization of 1
2
45.0811.
HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 85:15,
.8 mL/min, 20 °C, 254 nm): tR (minor) = 33.5 min, tR (major) = 37.1
min.
A 10-mL three-necked round-bottomed flask was equipped with a
magnetic stirrer, and platinum plate (1 cm ) 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-Bu NBF (66 mg, 0.2 mmol) were added
2
0
4
4
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

G
Synthesis
W.-C. Gao et al.
Paper
(S)-6-Chloro-4′,5′-dihydrospiro[indene-2,2′-pyran]-1,3′,6′(3H)-tri-
6-Oxaspiro[4.5]decane-1,7,10-trione (3g)
one (3d)
Yield: 7 mg (36%); yellow oil; 0% ee (determined by HPLC).
Yield: 10 mg (40%); white solid; mp 172–174 °C; 68% ee (determined
by HPLC).
IR (neat): 2924, 1743, 1713, 1456, 1265, 1142, 1103, 1051, 1009, 970,
–1
872 cm
.
[
α
]
2
0
+
1
4
(
c
0
.
2
4
,
C
H
C
l
)
.
1
D
3
H NMR (500 MHz, CDCl ): δ = 3.34–3.25 (m, 1 H), 2.94–2.87 (m, 1 H),
3
IR (neat): 2924, 2360, 1763, 1715, 1425, 1254, 1105, 982, 752 cm–1
.
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).
1
H NMR (500 MHz, CDCl ): δ = 7.71 (d, J = 2.0 Hz, 1 H), 7.66 (dd,
3
13
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),
C NMR (125 MHz, CDCl ): δ = 209.9, 203.2, 168.9, 91.7, 35.8, 34.3,
3
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,
33.8, 27.0, 18.2.
1
H), 2.86–2.82 (m, 2 H).
HRMS (ESI): m/z calcd for C9H11O4 [M + H]+: 183.0652; found:
183.0651.
13
C NMR (125 MHz, CDCl ): δ = 201.4, 196.2, 168.6, 145.0, 137.0,
3
1
35.1, 133.6, 127.4, 125.3, 92.8, 38.4, 33.3, 27.0.
HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10,
1.0 mL/min, 20 °C, 221 nm): t (1) = 14.2 min, t (2) = 21.3 min.
+
HRMS (ESI): m/z calcd for C13H10ClO4 [M + H] : 265.0262, 267.0233;
R
R
found: 265.0266, 267.0237.
HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10,
(R)-Spiro[indene-2,3′-isochroman]-1,1′,4′(3H)-trione (3h)
1
min.
.0 mL/min, 20 °C, 254 nm): tR (minor) = 28.8 min, tR (major) = 38.1
Yield: 18 mg (64%); white solid; mp 140–142 °C; 67% ee (determined
by HPLC).
[
α]D20 –34 (c 0.51, CHCl3).
(
1
S)-4′,5′-Dihydrospiro[cyclopenta[a]naphthalene-2,2′-pyran]-
,3′,6′(3H)-trione (3e)
IR (neat): 1738, 1690, 1595, 1421, 1263, 1213, 1101, 1006, 935, 851
cm
–1
.
Yield: 24 mg (87%); white solid; mp 200–202 °C; 63% ee (determined
by HPLC).
1
H NMR (500 MHz, CDCl ): δ = 8.38 (dd, J = 8.0, 1.0 Hz, 1 H), 8.00 (dd,
3
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).
13
[
α
]
2
0
–
2
6
(
c
0
.
1
4
,
C
H
C
l
)
.
D
3
IR (neat): 2920, 1699, 1573, 1517, 1417, 1312, 1180, 1155, 989, 826
cm
–1
.
C NMR (125 MHz, CDCl ): δ = 195.5, 187.9, 161.6, 152.2, 137.0,
3
1
H NMR (500 MHz, CDCl ): δ = 8.85 (d, J = 8.5 Hz, 1 H), 8.16 (d, J = 8.5
135.9, 134.2, 131.5, 130.9, 130.5, 129.5, 128.6, 126.6, 126.4, 126.0,
94.0, 37.4.
3
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
2
1
+
HRMS (ESI): m/z calcd for C17H11O4 [M + H] : 279.0652; found:
2
.84–3.76 (m, 1 H), 3.42 (d, J = 17.0 Hz, 1 H), 3.07–3.01 (m, 1 H), 2.89–
.85 (m, 2 H).
79.0655.
HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10,
0.8 mL/min, 20 °C, 254 nm): tR (major) = 32.2 min, tR (minor) = 35.3
min.
3
C NMR (125 MHz, CDCl ): δ = 201.9, 197.1, 169.2, 155.9, 138.4,
3
1
2
33.0, 129.9, 129.5, 128.6, 127.4, 126.9, 123.8, 123.0, 92.9, 39.1, 33.5,
7.2.
+
HRMS (ESI): m/z calcd for C17H13O4 [M + H] : 281.0808; found:
2
(S)-Methyl 4-(2-Hydroxy-1-oxo-2,3-dihydro-1H-inden-2-yl)-4-
oxobutanoate (5a)
81.0812.
HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10,
.0 mL/min, 20 °C, 254 nm): tR (minor) = 28.8 min, tR (major) = 38.1
min.
Yield: 17 mg (66%); colorless oil; 31% ee (determined by HPLC).
1
α]D20 +19 (c 0.32, CHCl3).
[
IR (neat): 1726, 1705, 1609, 1211, 1092, 733 cm–1
.
1
H NMR (500 MHz, CDCl ): δ = 7.82 (d, J = 9.0 Hz, 1 H), 7.70 (t, J = 7.5
(
S)-3,4,4′,5′-Tetrahydro-1H-spiro[naphthalene-2,2′-pyran]-1,3′,6′-
3
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
2
trione (3f)
.82 (d, J = 17.5 Hz, 1 H), 3.65 (s, 3 H), 3.24 (d, J = 17.5 Hz, 1 H), 2.82–
.66 (m, 2 H), 2.54–2.43 (m, 2 H).
Yield: 14 mg (58%); white solid; mp 96–98 °C; 47% ee (determined by
HPLC).
13C NMR (125 MHz, CDCl
34.3, 128.5, 126.8, 125.3, 87.1, 52.0, 38.9, 31.3, 27.5.
): δ = 205.1, 201.5, 172.7, 152.2, 136.5,
[
α]D20 +11 (c 0.17, CHCl3).
3
1
1
H NMR (400 MHz, CDCl ): δ = 7.98 (dd, J = 7.6, 1.2 Hz, 1 H), 7.57 (td,
3
+
HRMS (ESI): m/z calcd for C14H15O5 [M + H] : 263.0914; found:
63.0916.
HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10,
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),
.40–3.32 (m, 1 H), 3.28–3.14 (m, 2 H), 3.00–2.83 (m, 2 H), 2.75–2.63
2
3
(m, 2 H), 2.49–2.41 (m, 1 H).
1
3
0.8 mL/min, 20 °C, 254 nm): t (minor) = 22.6 min, t (major) = 27.3
min.
R
R
C NMR (100 MHz, CDCl ): δ = 203.5, 191.1, 169.3, 144.1, 135.1,
3
1
29.4, 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:
(
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).
2
45.0811.
HPLC (YMC Chiral Amylose-C S-5 μm (25 cm), hexane/i-PrOH, 90:10,
.8 mL/min, 20 °C, 254 nm): tR (major) = 34.2 min, tR (minor) = 41.4
min.
0
[
α
]
2
0
+
2
6
(
c
0
.
4
5
,
C
H
C
l
)
.
D
3
IR (neat): 2953, 2926, 1730, 1707, 1609, 1458, 1209, 1132, 1101,
–1
1
020, 771 cm .
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I

H
Synthesis
W.-C. Gao et al.
Paper
1
H NMR (500 MHz, CDCl ): δ = 7.73 (d, J = 7.5 Hz, 1 H), 7.64 (t, J = 7.5
Chemistry; Berlin: Springer-Verlag, 2016. For recent publica-
tions on chiral iodine(III) reagents, see: (d) Companys, S.;
Peixoto, P. A.; Bosset, C.; Chassaing, S.; Miqueu, K.; Sotiropoulos,
J. M.; Pouységu, L.; Quideau, S. Chem. Eur. J. 2017, 23, 13309.
(e) Shimogaki, M.; Fujita, M.; Sugimura, T. Angew. Chem. Int. Ed.
3
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).
13
C NMR (125 MHz, CDCl ): δ = 205.8, 199.5, 173.0, 152.5, 136.2,
3
2016, 55, 15797. (f) Kong, W.; Feige, P.; Haro, T.; Nevado, C.
1
34.1, 128.0, 126.5, 124.8, 93.7, 53.6, 51.7, 33.6, 32.6, 27.5.
Angew. Chem. Int. Ed. 2013, 52, 2469.
+
HRMS (ESI): m/z calcd for C15H17O5 [M + H] : 277.1071; found:
(
3) (a) Fujita, M. Tetrahedron Lett. 2017, 58, 4409. (b) Woerly, E. M.;
Banik, S. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2016, 138, 13858.
(c) Muñiz, K.; Barreiro, L.; Romero, R. M.; Martínez, C. J. Am.
Chem. Soc. 2017, 139, 4354. (d) Suzuki, S.; Kamo, T.; Fukushi, K.;
Hiramatsu, T.; Tokunaga, E.; Dohi, T.; Kita, Y.; Shibata, N. Chem.
Sci. 2014, 5, 2754. (e) Haubenreisser, S.; Wöste, T. H.; Martínez,
C.; Ishihara, K.; Muñiz, K. Angew. Chem. Int. Ed. 2016, 55, 413.
(f) Gelis, C.; Dumoulin, A.; Bekkaye, M.; Neuville, L.; Masson, G.
Org. Lett. 2017, 19, 278.
4) (a) Dohi, T.; Maruyama, A.; Takenaga, N.; Senami, K.;
Minamitsuji, Y.; Fujioka, H.; Caemmerer, S. B.; Kita, Y. Angew.
Chem. Int. Ed. 2008, 47, 3787. (b) Uyanik, M.; Yasui, T.; Ishihara,
K. Angew. Chem. Int. Ed. 2010, 49, 2175. (c) Uyanik, M.; Yasui, T.;
Ishihara, K. Angew. Chem. Int. Ed. 2013, 52, 9215. (d) Uyanik, M.;
Sasakura, N.; Mizuno, M.; Ishihara, K. ACS Catal. 2017, 7, 872.
2
77.1075.
HPLC (Daicel Chiralcel OD-H column (25 cm), hexane/i-PrOH, 95:5,
.0 mL/min, 20 °C, 254 nm): tR (minor) = 20.3 min, tR (major) = 24.1
min.
1
(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]D20 +31 (c 0.70, CHCl3).
IR (neat): 2924, 1728, 1707, 1609, 1437, 1213, 1161, 1105, 1038, 772
cm
–1
.
1
H NMR (400 MHz, CDCl ): δ = 7.72 (d, J = 7.6 Hz, 1 H), 7.63 (t, J = 8.0
3
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
(e) Dohi, T.; Sasa, H.; Miyazaki, K.; Fujitake, M.; Takenaga, N.;
Kita, Y. J. Org. Chem. 2017, 82, 11954. (f) Uyanik, M.; Yasui, T.;
Ishihara, K. J. Org. Chem. 2017, 82, 11946.
.62–2.45 (m, 2 H), 1.30 (t, J = 6.8 Hz, 3 H).
13
C NMR (100 MHz, CDCl ): δ = 206.1, 199.7, 173.1, 152.6, 136.1,
3
(
(
5) Banik, S. M.; Medley, J. W.; Jacobsen, E. N. Science 2016, 353, 51.
6) (a) Wu, H.; He, Y.-P.; Xu, L.; Zhang, D.-Y.; Gong, L.-Z. Angew.
Chem. Int. Ed. 2014, 53, 3466. (b) Zhang, D.-Y.; Xu, L.; Wu, H.;
Gong, L.-Z. Chem. Eur. J. 2015, 21, 10314. (c) Cao, Y.; Zhang, X.;
Lin, G.; Negrerie, D. Z.; Du, Y. Org. Lett. 2016, 18, 5580. (d) Hu,
B.; Cao, Y.; Zhang, B.; Negrerie, D. Z.; Du, Y. Adv. Synth. Catal.
2017, 359, 2542.
1
34.0, 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 C16H18O Na [M + Na] : 313.1052; found:
5
3
13.1061.
HPLC (Daicel Chiralcel OB-H column (25 cm), hexane/i-PrOH, 90:10,
.0 mL/min, 20 °C, 254 nm): tR (major) = 22.2 min, tR (minor) = 36.8
1
min.
(
7) (a) Farooq, U.; Schäfer, S.; Shah, A.-H. A.; Freudendahl, D. M.;
Wirth, T. Synthesis 2010, 1023. (b) Rodríguez, A.; Moran, W. J.
Synthesis 2012, 44, 1178.
Funding Information
(
8) For reviews on electrochemistry, see: (a) Möhle, S.; Zirbes, M.;
Rodrigo, E.; Gieshoff, T.; Wiebe, A.; Waldvogel, S. R. Angew.
Chem. Int. Ed. 2018, 57, 6018. (b) Yan, M.; Kawamata, Y.; Baran,
P. S. Chem. Rev. 2017, 117, 13230. (c) Francke, R.; Little, R. D.
Chem. Soc. Rev. 2014, 43, 2492. (d) Yoshida, J.; Kataoka, K.;
Horcajada, R.; Nagaki, A. Chem. Rev. 2008, 108, 2265. (e) Sperry,
J. B.; Wright, D. L. Chem. Soc. Rev. 2006, 35, 605. (f) Moeller, K. D.
Tetrahedron 2000, 56, 9527. For selected recent publications on
electroorganic chemistry, see: (g) Kawamata, Y.; Yan, M.; Liu, Z.;
Bao, D.-H.; Chen, J.; Starr, J. T.; Baran, P. S. J. Am. Chem. Soc. 2017,
This work was supported by the China Scholarship Council (No.
201608140185). Support from Cardiff University and Taiyuan Univer-
sity of Technology is gratefully acknowledged.
C
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n
a
S
c
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o
l
arsh
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p
C
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n
c
i
l (2
0
1
6
0
8
1
4
0
1
8
5)
Acknowledgment
We thank the EPSRC National Mass Spectrometry Facility, Swansea,
for mass spectrometric analysis.
139, 7448. (h) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.;
Eastgate, M. D.; Baran, P. S. Nature 2016, 533, 77. (i) Wiebe, A.;
Lips, S.; Schollmeyer, D.; Franke, R.; Waldvogel, S. R. Angew.
Chem. Int. Ed. 2017, 56, 14727. (j) Schulz, L.; Enders, M.; Elsler,
B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R.
Angew. Chem. Int. Ed. 2017, 56, 4877. (k) Wu, Z.-J.; Xu, H.-C.
Angew. Chem. Int. Ed. 2017, 56, 4734. (l) Zhao, H.-B.; Liu, Z.-J.;
Song, J.; Xu, H.-C. Angew. Chem. Int. Ed. 2017, 56, 12732.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610373.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–I