Oxiranyl remote anions from epoxy cinnamates and their application towards the synthesis of α,β-epoxy-γ-butyrolactones

Article abstract of DOI:10.1016/j.tetlet.2020.152609

A series of α,β-epoxy-γ-butyrolactones were synthesized in moderate yields via oxiranyl remote anions derived from epoxy cinnamate esters. The key synthetic step involved deprotonation of the β-position of α,β-epoxy cinnamate derivatives where the generated β-anion was stabilized by remote chelation from an ester group. The substitution reaction of the anion with a variety of ketones, followed by cyclization, readily furnished the desired substituted α,β-epoxy-γ-butyrolactones.

Full text of DOI:10.1016/j.tetlet.2020.152609

Journal Pre-proofs
Oxiranyl remote anions from epoxy cinnamates and their application towards
the synthesis of α,β-epoxy-γ-butyrolactones
Patpanat Sermmai, Nopporn Ruangsupapichat, Tienthong Thongpanchang
PII:
S0040-4039(20)31108-4
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152609
TETL 152609
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Tetrahedron Letters
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Revised Date:
Accepted Date:
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21 October 2020
26 October 2020
Please cite this article as: Sermmai, P., Ruangsupapichat, N., Thongpanchang, T., Oxiranyl remote anions from
epoxy cinnamates and their application towards the synthesis of α,β-epoxy-γ-butyrolactones, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.152609
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Tetrahedron Letters
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Oxiranyl remote anions from epoxy cinnamates and their application towards the
synthesis of ,-epoxy--butyrolactones
Patpanat Sermmai, Nopporn Ruangsupapichat, Tienthong Thongpanchang*
Department of Chemistry and Center of Excellence for Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of ,-epoxy--butyrolactones were synthesized in moderate yields via oxiranyl
remote anions derived from epoxy cinnamate esters. The key synthetic step involved
deprotonation of the -position of ,-epoxy cinnamate derivatives where the generated -
anion was stabilized by remote chelation from an ester group. The substitution reaction of the
anion with a variety of ketones, followed by cyclization, readily furnished the desired
substituted ,-epoxy--butyrolactones.
Available online
Keywords:
Oxiranyl remote anion
-deprotonation
,-Epoxy--butyrolactone
Due to its characteristic ring strain and polarized C-O bond,
epoxides are able to react with a large number of reagents
including nucleophiles, electrophiles, acids, and bases.1 The
reaction of an epoxide with a strong base typically generates an
oxiranyl anion which can further react with a variety of
electrophiles to provide polysubstituted epoxides. In certain
cases, deprotonation by a lithium base could occur at the -
position of an epoxide and the stability of the anion could be
enhanced by a chelating group, e.g. ester, oxazoline, ketone,
lactone, ether, or pyridine moieties (Fig.1).2-8
The synthesis of ,-epoxy--butyrolactones from epoxide
intermediates have been investigated.14 In 2017, Leiyang and co-
workers reported the synthesis and structural revision of an
antifungal agent, (±)-clavilactone D, via selective cyclization of
an ,-dicarbonyl peroxide using the three-component reaction
of benzaldehyde, an alkene, and TBHP.14 Thus, to extend the
scope of the chemistry of an oxiranyl remote anion, in this work
we wish to report the application of oxiranyl remote anions as an
alternative approach for the synthesis of ,-epoxy--
butyrolactones (Scheme 1).
OMe
Li
O
H
O
O
Li
H
O
H
O
Li
R
O
R
O
R
O
O
O
H3CO
H
CO2CH3
CH2OCH3
O
OMe
O
Li-base
ketone
O
Li
R2
H3CO
R1
,
-epoxy- -butyrolactone
 

Ester-chelation
Ether-stabilization
Ester-stabilization
Lactone-stabilization
Scheme 1. Synthesis of ,-epoxy--butyrolactones via oxiranyl
remote anions.
H
O
N
Li
O
N
O
O
O
Li
H3C
Ph
Li
H
Our work started with the preparation of epoxy cinnamates 5
and 6 via the epoxidation of the methyl ester derived from -
methyl cinnamic acid 1 and -phenyl cinnamic acid 2,
respectively (Scheme 2). Next, the epoxy cinnamates 5 and 6
were treated with lithium diisopropylamide (LDA) in the
presence of various electrophiles to generate a series of -
substituted epoxides.
Pyridyl-stabilization
Keto-stabilization
Oxazolinyl-stabilization
Figure 1. Representative stabilizing groups for the oxiranyl
“remote” anion.
Substituted epoxides exhibit numerous biological activities
such as anticancer,9,10 anti-inflammatory,11 antifungal,12 and
antibiotic agents.13 Among them, ,-epoxy--butyrolactones
which combine two versatile functional skeleta, i.e. epoxide and
butyrolactone, have been observed in naturally occurring
compounds14 or their intermediates.15-16
The model reaction of epoxide 5 and ethyl chloroformate was
used to optimize the reaction conditions, see Table 1. Treatment
of the mixture of epoxide 5 and 3 equivalents of ethyl
chloroformate in THF with
3
equivalents of lithium
o
diisopropylamide (LDA) at –78 C generated an anion in situ,
which was followed by reaction with an electrophile to furnish
the substituted product 7c in an optimal 42% yield (Entry 3).
*Corresponding author: Department of Chemistry and Center of Excellence for
Innovation in Chemistry (PERCH-CIC), Faculty of Science, Mahidol University, Rama
6 Road, Bangkok 10400, Thailand.
E-mail address: tienthong.tho@mahidol.ac.th (T. Thongpanchang).

2
Decreasing the amount of LDA to 1 equivalent failed to give the
desired product (Entry 1).
The stereochemistry of the substituted epoxides was
confirmed by selective NOE experiments.17 For example, in the
case of compound 8a, the methyl ester proton at 3.82 ppm was
enhanced upon irradiation at the trimethylsilyl proton at 0.10
ppm (H). This result evidently identified that -deprotonation and
reaction with TMSCl proceeded syn to the ester group.
The use of three equivalents of LDA was optimal since an
increase to 5 equivalents (Entry 5) did not increase the yield.
Increasing the amount of the electrophile to more than 3
equivalents did not benefit the reaction (Entry 4). Moreover, the
temperature played a key role in this reaction, i.e. the reaction at
In a separate experiment, the reaction of epoxide 5 with LDA
in the absence of an external electrophile gave methyl 2-methyl-
3-(2-methyl-3-phenyloxirane-2-carbonyl)-3-phenyl-oxirane-2-
o
0 C or at room temperature gave only trace amounts of the
product. In addition, the sequence of reagent addition was also
investigated. When epoxide 5 was treated with LDA followed by
the addition of ethyl chloroformate, both product 7c (41%) and
the self-condensation product 9 (18%) were obtained (Entry 8).
Since the sequence of the reagent addition did not affect the yield
of product 9, the protocol where all starting materials were mixed
prior to the addition of a lithium base was preferred.
carboxylate
(9)
and
3,6-dimethyl-1,4-diphenyl-7,8-
dioxatricyclo[2.1.1] octane-2,5-dione (10) in 37% and 30% yield,
respectively (Scheme 3). The formation of product 10 could be
rationalized by the subsequent -deprotonation of dimer 9
followed by intramolecular substitution of the new remote anion
with the ester group. This finding could lead to an alternative
pathway for the synthesis of other epoxide derivatives containing
a benzoquinone backbone. The formation of cyclization product
10 also suggested the possibility to apply this remote anion
strategy to the synthesis of ,-epoxy--butyrolactones. Thus the
reaction of epoxides 5 and 6 with LDA generated oxiranyl anions
which could further add to a carbonyl electrophile to form an
alkoxide intermediate. Subsequent intramolecular cyclization
then furnished the desired butyrolactones as shown in Scheme 4.
The reaction was compatible with a variety of ketones as
electrophiles and the product yields are summarized in Table 3.
O
O
R
R
Thionyl chloride
OH
OMe
MeOH
rt, 3 h
1 : R = Me
2 : R = Ph
3 : R = Me (quantitative yield)
4 : R = Ph (quantitative yield)
-CPBA
m
CCl4 / reflux
3 h
O
O
R
O
O
R
O
OMe LDA / electrophile (E+)
OMe
O
OMe
O
OMe
O
O
H
E
THF / - 78 o
C
LDA
OMe
O
O
H
H
THF, -78 o
C
Li
5 : R = Me (67%)
6 : R = Ph (72%)
O
Ph
9 (37%)
5
Scheme 2. Synthesis of ,-epoxy cinnamate methyl esters and
the reaction of their corresponding remote anions.
O
Subsequently, the reactions of the remote anion generated
from epoxy cinnamate derivatives 5 and 6 were investigated with
trimethylsilyl chloride, tributyltin chloride, ethyl chloroformate,
and phenyl chloroformate as electrophiles to extend the scope of
the reaction. The corresponding products were obtained in
moderate yields as shown in Table 2.
Ph
O
O
Ph
O
10 (30%)
Scheme 3. Oxiranyl remote anion reaction without an
electrophile.
Table 1. Optimization of the reaction conditions for the -
deprotonation of epoxy ester 5.
O
O
H
O
O
O
OMe
O
OMe
O

R
O
R
O
R
O
LDA
R1 R2
OMe
OMe
OLi
R2
OMe
OMe
OEt
O
LDA
Cl
OEt
O
O
O
THF, -78 o
C
THF, -78 o
5 h
C
H

Li
Li
THF, 5 h
O
R1
5
7c
5 : R = Me
6 : R = Ph
cyclization
O
Electrophile, THF
-78 oC, 5 h
Entry
LDA (eq.)
Ethyl chloroformate (eq.)
Temperature (oC)
Yield 7c (%)
O
R
O
1
2
3
4
5
6
7
8
1
3
3
3
5
3
3
3
1
2
3
5
5
3
3
3
-78
-78
-78
-78
-78
0
Not observed
R
O
OMe
E
O
22
42
R2
R1
31
26
Scheme 4. Reaction of oxiranyl remote anions from ,-epoxy
Trace
Trace
41
carbonyl compounds.
rt
When asymmetric ketones were used as the electrophile, a
pair of diastereomeric products, e.g. compound 7g, could be
expected. Unexpectedly, in the case of 7f, 8f, and 8g, only a
single diastereomer was isolated by preparative TLC purification.
*
-78
*
7c
In the case of the sequential method, the desired product
was observed along with methyl
9
2-methyl-3-(2-methyl)-3-phenyloxirane-2-(carbonyl)-3-phenyloxirane-2-carboxylate

3
Although it is possible that another diastereomer might also be
formed,
Table 2. Lithiation and substitution of epoxy cinnamates 5 and 6.
Table 3. Synthesis of ,-epoxy--butyrolactones 7 and 8.
O
H
O
E
O
OMe
LDA, THF
O
-78 o
C
R
O
R
O
R
O
R
O
R
O
OMe
OMe
OMe
LDA
O
E
O
Li
H
THF, -78 o
C
R2
E
R1
5 : R = Me
6 : R = Ph
7 : R = Me
8 : R = Ph
5 : R = Me
6 : R = Ph
7 : R = Me
8 : R = Ph
(R)
Entry
Electrophile (E)
Product
O
% Yield
% Recovery
% Recovery
Entry
Electrophile (E)
Product
% Yield
O
R
O
21
19
O
7e ; 41
8e ; 43
OMe
TMS
O
O
1
TMSCl
46
1
Me
Ph
Me
Ph
-
Ph
Ph
Ph
Ph
7a
O
O
R
O
O
15
21
7f ; 19
8f ; 23
OMe
O
2
3
4
TMSCl
54
42
48
2
O
-
Ph
TMS
Ph
8a
O
O
O
OMe
** 7g ; 53
12
O
O
O
Bu3SnCl
3
11
SnBu3
7b
Ph
Cl
Cl
O
O
OMe
SnBu3
O
O
O
Bu3SnCl
14
17
8g ; 42
Ph
8b
Cl
O
O
O
O
R
O
OMe
OEt
18
14
7h ; 30
8h ; 33
O
O
O
4
5
42
Me
5
Cl
OEt
7c
O
O
R
O
O
OMe
OEt
24
15
7i ; 29
8i ; 29
O
O
O
5
6
7
8
48
51
30
Ph
Me
Ph
12
18
24
Cl
OEt
O
8c
O
O
R
O
OMe
O
O
O
O
O
22
6
7
8
7j ; 29
Cl
Cl
O
O
O
7d
O
O
R
O
OMe
O
O
18
23
7k ; 28
8j ; 33
O
O
O
O
8d
O
R
O
Ph
O
O
-
7l ; 31
8k ; 8
*
18
* LTMP was used as a base in the lithiation step.
** The reaction gave the diastereomeric mixture.

4
naturally occurring core structure, by using diversified ketones
as electrophiles.
not observed
a)
b)
x
Ha
CH3
O
A
Acknowledgments
O
O
OCH3
Ha
O
Hb
Hc
Si CH3
Financial support from Mahidol University, the Thailand
Research Fund through the Royal Golden Jubilee Ph.D. Program
(Grant No. PHD/0115/2557) for P.S. and T.T. and the Center of
Excellence for Innovation in Chemistry (PERCH-CIC) are
gratefully acknowledged.
O
H3C CH3
8a
Hc
7f
Figure 2. Key NOE correlations of compounds a) 8a and b) 7f.
Supplementary data
it was unable to be isolated by this purification method. The
relative stereochemistry of 7f could be assigned by selective
NOE correlations as shown in Figure 2b. Irradiation of the
cyclopropyl proton at  1.69 ppm (Hb) enhanced the other
cyclopropyl protons at  0.50 ppm and 0.85 ppm, as well as the
phenyl protons at  6.80 ppm (Ha) and 7.10 ppm (Hc). However,
irradiation of Ha enhanced Hb, but not Hc. This result suggested
that the cyclopropyl group was located on the same side as the
phenyl ring A.18
Synthetic procedures and supplementary data (1H and 13C
NMR spectra of compounds 7a-l, 8a-k, 9 and 10) associated with
this article can be found, in the online version, at
doi:XXXXXXXXX.
References
1.
2.
Hodgson, D. M.; Gras, E., Synthesis 2002, 12, 1625-1642.
Lertvorachon, J; Thebtaranonth, Y.; Thongpanchang, T.;
Thongyoo, P. J. Org. Chem. 2001, 66,4692-4694.
Unfortunately, the reaction of epoxides 5 and 6 with
fluorenone as an electrophile in the presence of LDA provided
only the reduced product fluorenol 11, without any of the desired
product (Scheme 5).19 To avoid the reduction, lithium 2,2,6,6-
tetramethylpiperidide (LTMP) was applied to generate the
lithiated anion and further reacted with fluorenone to afford the
desired products 7l and 8k. Surprisingly, keto-alcohol 12 was
also observed due to the ortho-lithiation of fluorenone (Scheme
5).20
3.
(a) Capriati, V.; Degennaro, L.; Flavia, R.; Florio, S.; Luisi, R.
Org. Lett. 2002, 4, 1551–1554. (b) Capriati, V.; Degennaro, L.;
Florio, S.; Luisi, R.; Punzi, P. Org. Lett. 2006, 8, 4803–4806. (c)
Florio, S.; Perna, F. M.; Luisi, R.; Barluenga, J.; Fananas, F. J.;
Rodriguez, F. J. Org. Chem. 2004, 69, 9204–9207.
4.
5.
Baramee, A.; Clardy, J.; Kongsaeree, P.; Rajviroongit, S.;
Suteerachanon, C.; Thebtaranonth, Y. Chem. Commun. 1996,
1511–1512.
Chaiyanurakkul, A.; Jitchati, R.; Kaewpet, M.; Rajviroongit, S.;
Thebtaranonth, Y.; Thongyoo, P.; Watcharin, W. Tetrahedron
2003, 59, 9825–9837.
O
O
O
Li
R
O
OMe
LTMP, THF
-78 o
6.
7.
Saisaha, P.; Nerungsi, C.; Iamsaard, S.; Thongpanchang, T.
Tetrahedron Lett. 2009, 50, 4217–4220.
H
C
Sakulsombut, M. Physical organic chemistry of oxiranyl “remote”
anions derived from epoxy ketoester: competition between keto-
and ester-stabilization [M.Sc. Thesis in Organic Chemistry].
Bangkok: Faculty of Graduate Studies, Mahidol University; 2004.
Iammsard S. Ether Stabilized Oxiranyl remote Anions [M.Sc.
thesis in Organic Chemistry]. Bangkok: Faculty of Graduate
Studies, Mahidol University; 2010.
LDA, THF
-78 o
C
8.
9.
OH
11
Williams, P. G.; Miller, E. D.; Asolkar, R. N.; Jensen, P. R.;
Fenical, W. J. Org. Chem. 2007, 72(14), 5025-5034.
O
10. Lee, S. J.; Cassady, J. M.; Hurley, L. H. J. Am. Chem. Soc. 1996,
118 (24), 5553-5561.
OH
11. Xu, J. B.; Lin, Y.; Dong, S. H.; Wang, F.; Yue, J. M. J. Nat. Prod.
2013, 76 (10), 1872-1880.
12
12. Marco-Contelles, J.; Molina, M. T.; Anjum, S. Chem. Rev. 2004,
104 (6), 2857-2900.
O
H
R
O
OMe
(a) Labadie, G. R.; Luna. L. E.; Gonzalez-Sierra, M.; Cravero, R.
M. Eur. J. Org. Chem. 2003, 3429-3434. (b) Mandal. M.; Yun,
M.; Dudley, G.; Lin, S.; Tan, D. S.; Danishefsky, S. D. J. Org.
Chem. 2005, 70, 10619-10637. (c) Tanimoto, H.; Kato, T.; Chida,
N. Tetrahedron Lett. 2007, 48, 6267-6270.
O
O
R
O
13. Matsubara, T.; Takahashi, K.; Ishihara, J.; Hatakeyama, S. Angew.
Chem. Int. Ed. 2014, 53,757-760.
14. Leiyang, Lv.; Barry, B. S.; Zhiping, L. J. Org. Chem. 2017, 82,
5487-5491.
15. Tan, Z.; Negishi, E. I. Org. Lett. 2006, 8, 2783-2785.
16. Park, H. S.; Kwon, D. W.; Lee, K.; Kim, Y. H. Tetrahedron Lett.
2008, 49, 1616-1618.
17. Scott, K.; Stonehouse, J.; Keeler, J.; Hwang, Z. L.; Shaka, A. J. J.
Am. Chem. Soc. 1995, 117, 4199-4200.
18. Selective NOE spectra, HMBC spectra and stereochemistry
assignment of 8f and 8g are presented in the ESI.
19. (a) Kowalski, C.; Creary, X.; Rollin, A. J.; Burke, M. C. J. Org.
Chem. 1978, 13, 2601–2607; (b) Woo, E. P.; Mak, K. T.
Tetrahedron Lett. 1974, 47, 4095-4098.
20. Hedidi, M.; Maillard, J.; Erb, W.; Lassagne, F.; Halauko, Y. S.;
Ivashkevich, O. A.; Matulis, V. E.; Roisnel, T.; Dorcet, V.;
Scheme 5. Reaction of the oxiranyl remote anions of ,-epoxy
cinnamate derivatives with fluorenone.
In conclusion, an investigation of the oxiranyl remote anions
derived from ,-epoxy cinnamate derivatives and their reactions
with variety of electrophiles were described. Chelation between
the lithium atom and an ester group via a five-membered cyclic
intermediate plays a key role in the stabilization of the anion. The
oxiranyl remote anions of an ester could be applied in the
preparation of various ,-epoxy--butyrolactones, a useful

5
Hamzé, M.; Fajloun, Z.; Baratte, B.; Ruchaud, S.; Bach, S.;
Bentabed-Ababsa, G.; Mongin, F. Eur. J. Org. Chem. 2017, 5903–
5915.
Highlights
 -anion of an epoxy cinnamate could
Oxiranyl remote anions from epoxy cinnamates
and their application towards the synthesis of
,-epoxy--butyrolactones
Leave this area blank for abstract info.
Patpanat Sermmai, Nopporn Ruangsupapichat, Tienthong Thongpanchang*
OMe
O
H
O
O
R
O
R
O
R
O
OMe
R1
R2
O
O
Li-base
Li
R2
R1
Ester-chelation
, -epoxy- -butyrolactone
 

15 examples, 8-53% yields
be generated and stabilized by its
ester group.
 The generated anion could react with
various electrophiles, including
ketones.
Declaration of interests
 ,-epoxy--butyrolactones could be
prepared by this novel remote anion
chemistry.
☒ The authors declare that they have no known
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
☐The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
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