Asymmetric synthesis of new γ-butenolides: Via organocatalyzed epoxidation of chalcones

Article abstract of DOI:10.1039/c7ob00165g

γ-Butenolides have been recognized as an important structural framework in a number of natural products and medicinally important agents. In this work we describe a new metal-free sequential strategy for the asymmetric synthesis of substituted γ-butenolides having epoxychalcones as the advanced intermediate. Using the optimized reaction conditions, we were able to carry out the three-step sequence, epoxidation, olefination and hydrolysis, with only one single chromatographic purification of the final product, furnishing new enantiomerically enriched γ-butenolides in moderate overall yield and good enantiomeric excess.

Full text of DOI:10.1039/c7ob00165g

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C. Vieira, B. T. Matsuo, M. Gall , M. W. Paixao and L. S. R. Martelli , Org. Biomol. Chem., 2017, DOI:
10.1039/C7OB00165G.
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DOI: 10.1039/C7OB00165G
Asymmetric synthesis of new γ-butenolides via
organocatalyzed epoxidation of chalcones†
Lucas C. C. Vieira,a,b Bianca T. Matsuo,a Lorena S. R. Martelli,a Mayara Gall,a
Marcio W. Paixãoa and Arlene G. Corrêaa*
Abstract: γ-Butenolides have been recognized as an important structural framework in a
number of natural products and medicinally important agents. In this work we describe a new
metal-free sequential strategy for the asymmetric synthesis of substituted γ-butenolides having
epoxychalcones as advanced intermediate. Using the optimized reaction conditions, we were
able to carry out the three-step sequence, epoxidation, olefination and hydrolysis, with only one
single chromatographic purification of the final product, furnishing new enantiomerically
enriched γ-butenolides in moderate overall yield and good enantiomeric excess.
Keywords: epoxychalcones, organocatalysis, olefination, microwaves, green synthesis
γ-Butenolides have been recognized as an important structural
framework in a number of natural products and medicinally important agents,
e.g. ascorbic acid, (-)-iso-cladospolide B, isolated from Cladosporium sp,1 and
saxorumamide, an alkaloid obtained from Stemona saxorum.2 Miao and
Andersen reported the isolation of metabolites of the colonial tunicate Ritterella
rubra, named rubrolides A-H which showed antibacterial activity.3 More
recently, Kang et al. have synthesized rubrolide analogues with antibiotic and
immunosuppressant properties (Figure 1).4
aCentre of Excellence for Research in Sustainable Chemistry, Department of Chemistry,
Federal University of São Carlos, 13565-905, São Carlos, SP, Brazil Tel.:+55-16-33518281; fax:
+55-16-33518350. e-mail: agcorrea@ufscar.br
b Instituto de Engenharia, Universidade Federal de Mato Grosso, 78060-900, Cuiabá, MT, Brazil
† Electronic supplementary information (ESI) available: Experimental details and NMR spectra.
See DOI: 10.1039/

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DOI: 10.1039/C7OB00165G
O
O
Br
Br
HO
OH
HO
Br
R1
Br
rubrolide G
O
O
O
O
R1
O
O
R3
R3
HO
R2
rubrolide
R2
analogues
Figure 1 Examples of biologically active γ-butenolides.
Due to their biological importance, several strategies towards the
synthesis of γ-butenolides has been explored.5 In this regard, the catalytic
asymmetric vinylogous-type reactions of γ-butenolides have received growing
attention, because the resulting enantiomerically pure γ-substituted butenolides
are versatile building blocks for various natural products and biologically active
compounds. Among which, the vinylogous aldol reaction,6 vinylogous Mannich
reaction,7 vinylogous Michael reactions,8 as well as allylic alkylation reaction
have been well developed in the past two decades, by using either chiral Lewis
acid catalysis or organocatalysts. Among the plethora of catalytic systems
developed so far, vinylogous Mukaiyama-type reactions using 2-silyloxyfurans
as the nucleophiles are popular for the synthesis of γ-substituted butenolides.9
Devalankar et al. reported a sequential strategy that involves an
organocatalytic α-aminoxylation followed by Wittig olefination to afford γ-
butenolides as the major product in good yields and excellent enantiomeric
excess.10 A gold(I)-catalyzed cascade cyclization−oxidative cross-coupling
process has been applied to prepare β-alkynyl-γ-butenolides directly from
allenoates and various terminal alkynes.11
Furthermore, Patil et al. described a catalytic cross-coupling reaction of
tert-butyl allenoates with diazonium salts under a cooperative catalysis
(photoredox and gold (I)) in which the corresponding butenolides were delivered
in good to excellent yields (Scheme 1a).12 Dénès and co-authors reported the

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synthesis of polysubstituted butenolides from α-bromoesters derivDeOdI: 10f.1r0o3Vm9i/eCw7AOrtBic0le0O16nl5inGe
propargyl alcohols by a one-pot reaction involving the radical cyclization of α-
bromo-aluminium acetals, followed by the oxidation of the resulting cyclic
aluminium acetals in an Oppenauer-type process and migration of the exocyclic
C=C bond into the α,β-position. Using this procedure, the total synthesis of
maculalactone A was accomplished (Scheme 1b). The configuration of the
chiral centre was set using asymmetric reduction of ynone using Noyori’s
ruthenium-based catalyst.13
Scheme 1 Synthesis of γ-butenolides.
We describe in this work a new metal-free sequential strategy for the
asymmetric synthesis of substituted γ-butenolides having epoxychalcones as
intermediate (Scheme 1c). Optically active epoxyketones are versatile building
blocks for the synthesis of several natural products and pharmaceuticals.14 In
this context, the development of efficient methods for the asymmetric
epoxidation of α,β-enones is an interesting goal in organic synthesis. Therefore,

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a number of organocatalyzed15 and metal-catalyzed16 protocols haDvOeI: 10b.1e0e39n/C7OB00165G
developed for the epoxidation of electron-deficient olefins in a stereoselective
manner.
View Article Online
In this way, independently, Lygo and Corey have shown that N-
anthracenylmethyl-substituted ammonium salts with the C-9 hydroxyl groups
being protected as benzyl ethers are effective catalysts for epoxidation of α,β-
unsaturated ketones using NaOCl or KOCl as oxidant.17,18 Motivated by these
previous results, new types of bis-quaternary ammonium bromide as chiral
multisite phase transfer catalysts have been developed and evaluated for the
enantioselective epoxidation of chalcones in the presence of lower
concentrations of various oxidants, bases and ultrasonic irradiation conditions.19
In order to obtain the epoxychalcones, different catalysts and oxidants
were first evaluated in the epoxidation reaction (Table 1). The organocatalysts
1-6 were synthesized as previously described (Figure 2).20
Figure 2 Organocatalysts evaluated on the epoxidation of chalcone.

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DOI: 10.1039/C7OB00165G
Table 1 Optimization of the epoxidation reaction of chalcone 7a.
O
O
O
Catalyst,
Oxidant
Solvent, Time,
Temperature
7a
(+)-8a
Time
T
(°C)
rt
Yield
(%)h (%)i
ee
Entry Catalyst Oxidant Solvent
Additive
(h)
48
48
48
48
48
48
48
12
12
12
12
12
12
48
48
24
24
72
24
48
1
2
1a
1b
1c
1d
2a
2b
2c
2c
2c
2c
2c
2c
2c
2d
3
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
NaOCl
H2O2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Ph2O
-
78
7
44
75
ndk
46
64
34
85
80
60
25
-
-
rt
3
-
rt
3
4
-
rt
63
64
67
64
86
66
34
5
-
rt
6
-
rt
7
-
-20
rt
8
-
9
DCM
-
rt
10
11
12
13
14
15
16c
17c
18c
19c
20d
Hexane
THF
-
rt
j
-
rt
-
Xylene
Tol:DCM
Toluene
Toluene
THF
-
rt
81
95
63
60
80
80
66
26
-
-
rt
-
rt
-
-
rt
j
4
rt
-
4
5a
5a
5a
H2O2
Dioxane
Dioxane
Dioxane
-
50
rt
4
0
j
H2O2
TFAb
TFAb
TFA
-
-
H2O2
50
50
5
14
8
80
72
t-BuO2H Dioxane
m-CPBA Dioxane
21d
22e
23e
24f
TFA
TFA
TFA
TFA
TFA
48
48
48
48
48
48
50
60
60
50
50
50
10
-
5a
5a
5a
5a
5a
5a
j
H2O2
H2O2
H2O2
H2O2
H2O2
Toluene
Hexane
EtOH
-
j
-
-
j
-
-
j
25f
MeOH
-
-
j
26g
Dioxane
CH3SO3H
p-
-
-
27g
28g
H2O2
H2O2
Dioxane
Dioxane
48
48
50
50
6
6
74
70
5a
5a
NO2C6H4CO2H
C6H5CO2H

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o-
Dioxane
29g
H2O2
48
50
D6OI: 10.1039/C7OB00165G
82
5a
NO2C6H4CO2H
30
31
6a
6b
NaOCl
NaOCl
Toluene
Toluene
-
-
48
48
rt
rt
11
8
0
0
Unless otherwise noted, all reactions were carried out with chalcone 7a (0.144 mmol) using 1
a
mL of solvent, 2 equiv. of oxidant, 10 mol% of catalyst and 40 mol% of additive. 20 mol% of
c
f
catalyst. b 20 mol% of additive. 0.245 mmol of 7a. d 0.315 mmol of 7a. e 0.289 mmol of 7a.
0.37 mmol of 7a. g 0.176 mmol of 7a. h Isolated yields after column chromatography. i Measured
by HPLC with chiral column. j Starting material recovered. k nd = not determined.
Using the optimized conditions (entry 7), the epoxychalcones 8 were
obtained from chalcones 7 employing the N-anthracenylmethyl-substituted
ammonium salt 2c as described by Corey et al. (Table 2).18 The stereochemical
course of the epoxidation reaction employing catalyst 2c provided the desired
products 8a-f in a good yields and high enantiomeric excess.
Table 2 Asymmetric epoxidation using phase-transfer organocatalyst 2c.
O
O
Cat. 2c
O
(10 mol.%)
NaOCl
R1
R2
R1
R2
Br
O
N
Toluene, 48h,
-20oC
R3
H
R3
7
(+)-8
2c
N
Epoxychalcone R1
R2
H
R3
H
Yield (%)a ee (%)b
8a
8b
8c
8d
8e
8f
H
H
64
83
68
68
72
90
85
87
96
81
91
92
H
Cl
Br
H
O-CH2-O
H
H
H
Br
OCH3
H
H
NO2
Unless otherwise noted, all reactions were carried out with chalcone 7 (0.144 mmol) using 1 mL
of solvent, 2 equiv. of oxidant, 10 mol% of catalyst. aIsolated yields after column
chromatography. b Measured by HPLC with chiral column.
We then turned our attention to the γ-butenolides synthesis. In this
regard, the epoxyester (±)-9a was synthesized as described by Tarver et al.

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21
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DOI: 10.1039/C7OB00165G
starting from the corresponding epoxychalcone. The racemic epoxychalcone
8a was obtained employing H2O2 as oxidant and NaOH in MeOH22 and then
submitted to the Horner–Wadsworth–Emmons (HWE) reaction, with triethyl
phosphonoacetate and sodium hydride in dry THF under reflux for 3h.21 Under
these standard conditions, the corresponding racemic epoxyester 9a was
obtained in 71% yield. Finally, the hydrolysis of epoxyester 9a followed by
intramolecular esterification was investigated with different catalysts23 as well as
conventional and biobased solvents24 (Table 3).
The best result and using a greener condition was achieved with 15%
w/w of montmorillonite K10 (MK-10) clay, ethanol as solvent, for 7 hours at
room temperature in which delivered the desired γ-butenolide 10a in 96%
isolated yield (entry 16). The selective formation of 10a instead of the δ-
pentenolide 11 was confirmed by NMR experiments. The HMBC spectrum
4
showed a JC-H correlation between the C5 (δ 84.0) with the hydrogen at ortho
position of B ring and, in the NOESY, H5 correlates with both H6 and the OH
suggesting free rotation of the C5-C6 bond (Figure 3).
Figure 3 γ-Butenolide 10a vs δ-pentenolide 11.

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Table 3 Optimization studies for hydrolysis and cyclization.
O
O
O
OEt
O
catalyst
solvent
rt
HO
time,
(±)-9a
(±)-10a
Entry
Catalyst
Solvent
Yield (%)k
Time (h)
14
1
2
PTSAa
TFAa
Amberlyst 15b
Benzoic acida
MK 10a
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
DCM
50i
55
58
42
84
41
--- j
68
67
83
74
90
91
81
86
96
58
78
75
72
34
11
14
3
14
4
14
5
14
a
6
AlCl3
14
7
BF3 . Et2Oa
TFAa
Amberlyst 15g
Benzoic acida
14
8
0.5h
0.5h
0.5h
0.5h
14
9
10
11
12
13
14
15
16
17
18
19
20
21
22
a
AlCl3
MK 10c
MK 10d
MK 10f
MK 10e
MK 10d
MK 10c
MK 10c
MK 10a
MK 10a
MK 10c
----
14
14
14
7
14
Toluene
THF
14
14
Et2O
14
PEG 400
EtOH
14
14
Unless otherwise noted, all reactions were carried out with 0.170 mmol (1 equiv) of 9a and 1 mL
a
b
c
d
e
f
of solvent. 0.25 equivalent. 30% weight. 25% weight. 15% weight. 10% weight. 5%
weight. g 13% weight. h microwave irradiation at 100 °C and 300 W, 0.150 mmol of 9a and 1 mL
of solvent. i 0.340 mmol of 9a and 2 mL of solvent. Complex mixture. k After chromatographic
j
purification.
We then evaluated the olefination and hydrolysis reactions in a one-pot
fashion, only changing the solvent between the two steps. To our delight, the
desired γ-butenolide (±)-10a was obtained from epoxyketone (±)-8a in 68% yield

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DOI: 10.1039/C7OB00165G
over two steps (Scheme 2). The scope and limitations of this method was
further explored with electron withdrawing and donating groups on both A and B
rings of the chalcone, affording γ-butenolides (±)-10b-j in good overall yields. It
is worth to note that no steric hindrance effects were observed since this
method could be applied to chalcone (±)-7g containing a methoxy group at the
orto position of the A ring, leading to (±)-10g in good overall yield.
Furthermore, chalcones possessing heterocyclic aromatic rings were
also evaluated and successfully afforded the corresponding furan and thiophen
derivatives (±)-10k and (±)-10l, respectively. However, N-heterocyclic
chalcones did not furnished the desired products. For example, the epoxidation
of 3-(1H-indol-2-yl)-1-phenyl-2-propen-1-one25 failed whereas for the pyridine
derivative,26 no formation of the desired product (±)-10m was observed, with
recovery of either the corresponding unreacted epoxyketone (±)-7m or the
Wittig adduct (±)-9m from the olefination step.
Aiming to provide a greener reaction condition for this novel protocol, we
performed additional experiments using microwave irradiation.27 After short
optimization, the olefination reaction of epoxyketone (±)-8a was carried out at
90ºC (300 W) for 30 min then the solvent (THF) was evaporated and EtOH and
MK-10 were added. This mixture was again submitted to microwave irradiation
at 100ºC (300 W) for 30 min furnishing the γ-butenolide (±)-10a in 66% yield
(Table 4, entry 1). In order to demonstrate the applicability of this reaction, this
procedure was also successfully applied to epoxyketones (±)-8b-d leading to
the corresponding γ-butenolides (±)-10b-d (Table 4, entries 2-4) and in all cases
the reaction yields under microwave irradiation were similar or even higher than
the conventional procedure.

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10
O
O
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DOI: 10.1039/C7OB00165G
O
POCH CO Et
1) (EtO)2
NaH
(1.6 eq)
2
2
O
3h
THF, reflux,
(1.6 eq),
R1
R1
R2
MK-10
EtOH,
2)
(15% w/w)
rt,
R2
(±)-8a-m
HO
(±)-10a-m
7h
O
O
O
O
O
O
O
O
O
O
Br
HO
HO
HO
HO
10d:
Br
Cl
10a:
10b:
10c:
68%
65%
54%
63%
O
O
O
O
O
O
H
3CO
HO
HO
OMe
HO
NO2
10e:
72%
64%
10f: 40%
O
10g:
O
O
O
O
O
N
O2
I
Br
HO
10h:
HO
HO
F
Cl
18%
O
10i:
55%
46%
10j:
O
O
O
O
O
O
S
HO
HO
HO
N
10k:
10l:
10m:
0%
52%
53%
Scheme 2 Scope and limitation on the synthesis of γ-butenolides.
Table 4 Synthesis of γ-butenolides under microwave irradiation.
O
R3
O
CO
2Et, NaH,
30 min
W, 90ºC,
(EtO2)POCH2
THF,
O
R1
R2
O
300
then MK10
300
W,
,
EtOH,
30 min
R3
R4
R2
HO
100ºC,
R4
R1
(±)-8
Compound
10a
(±)-10
Yield (%)a
R1
H
R2
R3
H
H
H
Cl
Br
H
66
64
67
80
10b
H
10c
O-CH2-O
10d
H
Br
a Overall yield after chromatographic purification.

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Moreover, we were also able to carry out the three-step sequence, in its
asymmetric version to this end, the epoxidation, olefination and hydrolysis
required only a single chromatographic purification of the final product. Thus,
employing the optimized conditions described above, the enantiomerically
enriched γ-butenolides (-)-10a and (-)-10b were obtained in moderate overall
yield and good enantiomeric excess (Scheme 3).
2c
NaOCl
-20ºC
1)
(10 mol%),
toluene, 48h,
O
O
POCH2CO2Et
O
2) (EtO)2
NaH, THF, reflux,
3h
R
R
MK10
EtOH,
3)
(15%w/w)
rt,
HO
7h
7
ee
R=
R=
97%
H, 44%,
(-)-10a,
(-)-10b,
ee
89%
Cl, 30%,
Scheme 3 Asymmetric synthesis of γ-butenolides (-)-10a and (-)-10b.
In conclusion, we have developed a new methodology for the synthesis
of γ-butenolides from chalcones in a short reaction sequence. Furthermore, the
epoxychalcones were converted to γ-butenolides in greener conditions,
reducing several chromatographic purifications,28 minimizing the waste
chemicals generation and saving time.
We gratefully acknowledge FAPESP (grants 2013/07600-3, 2014/50249-
8 and 2015/17141-1), CAPES, CNPq and GSK for financial support and
fellowships.
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DOI: 10.1039/C7OB00165G
A greener three-step sequence, with only one single chromatographic purification, afforded γ-
butenolides in moderate overall yield and high enantiomeric excess.
O
O
1) cat., NaOCl
2) HWE
R1
R2
O
R1
R2
R3
3) MK10
HO
R3
10 examples
Transition metal-free
Functional group tolerance
Br
O
N
H
cat.
N