Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Key words
electrolysis - flow microreactors - hypervalent iodine - lactonization - stereoselective
synthesis
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]
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.
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 3b–3d 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]
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.
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.
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]
Scheme 6 Electrolysis of 2b and reaction with 1a in a stepwise process
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.
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
(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)
(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)
(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)
(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)
(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)
(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)
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)
(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)
(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)
(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)
(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.
