One-pot gram-scale synthesis of γ-hydroxybutenolides through catalyst-free annulation of α-amino acids with α-keto acids in water

Article abstract of DOI:10.1016/j.tetlet.2017.01.080

A one-pot gram-scale synthetic route for the preparation of γ-hydroxybutenolides via catalyst-free annulation of α-amino acids with α-keto acids in water is reported. The method shows many advantages such as readily available starting materials, mild reaction conditions, operational simplicity, acceptable yields, and requiring no extra catalysts or additions. Furthermore, the method is innocuous to the environment, also is valuable to industry.

Full text of DOI:10.1016/j.tetlet.2017.01.080

Accepted Manuscript
One-pot gram-scale synthesis of γ-hydroxybutenolides through catalyst-free
annulation of α-amino acids with α-keto acids in water
Zhiqing He, Fang Fang, Jianguang Lv, Jianmin Zhang
PII:
S0040-4039(17)30111-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.080
TETL 48583
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 January 2017
16 January 2017
23 January 2017
Please cite this article as: He, Z., Fang, F., Lv, J., Zhang, J., One-pot gram-scale synthesis of γ-hydroxybutenolides
through catalyst-free annulation of α-amino acids with α-keto acids in water, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.01.080
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One-pot gram-scale synthesis of γ-
hydroxybutenolides through catalyst-free
annulation of α-amino acids with α-keto
acids in water
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Zhiqing Hea , Fang Fanga , Jianguang Lva , and Jianmin Zhang a,b,


Tetrahedron Letters
1
Tetrahedron Letters
One-pot gram-scale synthesis of γ-hydroxybutenolides through catalyst-free
annulation of α-amino acids with α-keto acids in water
Zhiqing Hea , Fang Fanga , Jianguang Lva , and Jianmin Zhanga,b, 
aDepartment of Chemistry, Innovative Drug Research Center, Shanghai University, Shanghai 200444, China
bKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A one-pot gram-scale synthetic route for the preparation of γ-hydroxybutenolides via catalyst-
free annulation of α-amino acids with α-keto acids in water is reported. The method shows many
advantages such as readily available starting materials, mild reaction conditions, operational
simplicity, acceptable yields, and requiring no extra catalysts or additions. Furthermore, the
method is innocuous to the environment, also is valuable to industry.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Butenolides
One-pot synthesis
In water
Catalyst-free
Introduction
through catalyst-free annulation of α-amino acids and α-keto
acids in water under mild reaction conditions (Scheme 1, route d).
Butenolides are a sort of very important subunits in the
structures of natural products and bioactive compounds, which
exhibit physiological effects including antisepsis, anticancer, and
antiphlogosis. Due to their using in medicine1 and synthesis of
natural products and bioactive molecules2, butenolides are
attracting wide attention in synthetic organic chemistry. As a
consequence, several methodologies have been developed to
synthesize these classes of compounds in literature.3 The most
direct method is via the oxidation of furans by oxygens under
severe conditions (Scheme 1, route a).4 For more specific
examples, intermolecular [2+2+1] carbonylative cycloaddition of
aldehydes with alkynes and subsequent oxidation to γ-
hydroxybutenolides is achieved by ruthenium-catalyst (Scheme 1,
route b).5 As an interesting example, BF3-catalyzed annulation of
keto acids with alkynes produces butenolides with the carbonyl
carbon of α-keto acids as the cyclization point (Scheme 1, route
c).6 Although some advances have been made in synthesis of
butenolides and the analogues, these methods are unfriendly to
the environment involving the use of expensive and toxic
catalysts or organic solvents.
All the reactants abound in human body and participate in
metabolism and structure transformation. Thus, the method is
innocuous to the environment, but also is valuable to industry.
The γ-hydroxybutenolide products have never been reported
except 3b because of the difficulty in their syntheses. Even 3b
was reported to prepared by up to 6 steps in just 34% overall
yield9 or obtained through three steps in 25% overall yield10.
As well known, the utilization of water as a solvent is an
aspect of Green Chemistry because of its benign environmental
character.7 In addition, compared with the various solvent
alternatives in organic chemistry, water is very cheap and
nontoxic. 8 Keeping this in our mind, we try to develop a Green
strategy to construct γ-hydroxybutenolides. Herein, we report a
one-pot gram-scale synthetic route of γ- hydroxybutenolides
Scheme 1 Literature approaches to butenolides and our design.
———
 Corresponding author. E-mail: jmzhang@shu.edu.cn (J. Zhang)

2
Tetrahedron Letters
Resules and discussion
Table 2
Substrate scopea
Initially, we chose the reaction of phenylalanine 1a with
pyruvic acid 2a as the model reaction to screen the reaction
conditions (Table 1). Phenylalanine 1a was treated with pyruvic
acid 2a in the presence of acetic acid (HOAc) in H2O (2 mL) at
80 °C for 24 h under air atmosphere. 5-hydroxy-3-methyl-4-
phenylfuran-2(5H)-one 3a was isolated in 15% yield (Table 1,
entry 1). The structure of 3a was unambiguously confirmed by
single crystal X-ray diffraction analysis.11 Increase of
concentration could raise the isolated yield over the same
reaction time (Table 1, entries 2, 3 and 4). When the loading of
2a was increased to 10 equiv, the desired product 3a was
obtained in 64% yield. Efforts to reduce the amount of 2a by
replacing HOAc with HClO4, CF3COOH, PhB(OH)2, BF3·Et2O,
p-toluenesulfonic acid (PTSA), or changing the solvent and
molar ratio are proved fruitless(Table 1, entries 5-13). The
highest yield of 3a was achieved in the absence of HOAc (Table
1, entries 14). Increasing or reducing the loading of 2a led to no
improvement of yield either (Table 1, entries 15-16). Moreover,
Slow addition of 2a, prolonging the reaction time or increasing
the reaction temperature could not further improve the yield of 3a
(Table 1, entries 18-19). Accordingly, the molar ratio of 1a/2a as
1:10 and the reaction temperature as 80 °C were selected as the
optimized reaction conditions (Table 1, entry 14).
With the optimized reaction conditions in hand, we started to
investigate the substrate scope (Table 2). Firstly, we used various
α-amino acids 1 to react with α-keto acids 2a. Substrates with
electron-donating or electron-withdrawing groups on the phenyl
a
Unless otherwise noted, all reactions were carried out with a molar ratio of
1/2 = 1:10 in 0.5 mL H2O at 80 °C for 24 h under air. Isolated yield based on
1.
Table 1
ring of the α-amino acids could successfully complete the
transformation and afforded the corresponding products in
59−76% isolated yields. Then, we changed the methyl of α-keto
acids 2a to ethyl, and reacted with various α-amino acids 1 to get
the corresponding products in 54−80% yields. All these reactions
were straightforward and obtained fairly good yields. Compared
with these results, electron-withdrawing groups on the phenyl
ring of the α-amino acids were conducive to the reaction, and the
influence of the R2 group showed no obvious regularity.
Optimization of the reaction conditionsa
Entry
Acid
Molar ratiob
T(oC)
Yield (%)c
1d
2e
3
HOAc
HOAc
HOAc
HOAc
HClO4
CF3COOH
PhB(OH)2
BF3·Et2O
PTSA
HOAc
HOAc
HOAc
HOAc
-
1:3:1
1:3:1
1:3:1
1:10:1
1:3:1
1:3:1
1:3:1
1:3:1
1:3:1
1:3:1
1:3:1
1:3:2
1:5:1
1:10:0
1:5:0
1:20:0
1:10:0
1:10:0
1:10:0
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
100
120
15
25
38
64
35
34
32
24
36
33
34
35
53
65
43
63
64
63
A plausible mechanism for the reaction of α-amino acids with
α-keto acids is proposed and depicted in Scheme 2. First, a Schiff
base 4 (ketimine) was generated from the condensation of amino
acid 1a and keto acid 2a,12 then decarboxylation of Schiff base 4
gave another Schiff base 5 (aldimine).13 5 underwent aldol type
condensation reaction with another molecule of α-keto acid
4
5
6
7
8
9
10f
11g
12
13
14
15
16h
17i
18
19
-
-
-
-
58
a
o
Unless specified, all reactions were performed in 0.5 mL H2O at 80 C for
b
c
d
24 h under air. Molar ratio refers to 1a/2a/acid. Isolated yield. The
e
f
solvent volume w as 2 mL. The solvent volume was 1 mL. The mixed
g
solvent was H2O and 1,4-dioxane (3:2). The mixed solvent was H2O and
THF (3:2). h The reaction time was prolonged to 72 h. i Slow addition of 2a.
Scheme 2 Proposed reaction mechanism for the synthesis.

Tetrahedron Letters
3
accompanied by the hydrolysis of imine to yield key intermediate
7.14 Finally,
intramolecular cyclization afforded γ-
hydroxybutenolide derivatives 3a.15
(c) Engelhardt, F. C.; Shi, Y. J.; Cowden, C. J.; Conlon, D. A.;
Pipik, B.; Zhou, G.; McNamara, J. M.; Dolling, U. H. J. Org.
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X. C.; Khalil, Z.; Capon, R. J. Org. Biomol. Chem. 2012, 10,
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Tetrahedron Lett. 2010, 51, 1710–1712; (c) Deore, P. S.; Argade,
N. P. Org. Lett. 2013, 15, 5826–5829; (d) Parsons, W. H.; Bois, J.
D. J. Am. Chem. Soc. 2013, 135, 10582–10585; (e) Miles, W. H.;
Jones, S. T.; George, J. S.; Tang, P. I.; Hayward, M. D.
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(a) Bassetti, M.; D'Annibale, A.; Fanfoni, A.; Minissi, F. Org. Lett.
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According to the proposed mechanism, we considered the
possibility that phenylacetaldehyde could be used in replacement
of amino acid and conducted the control experiment. Regrettably,
the result showed no expected product. To further explore the
scope and limitation of the present reaction, several aliphatic α-
amino acids 1 like leucine and alanine were used to experience
the standard conditions. As a result, the expected products were
not obtained. However, when we used methyl pyruvate to react
with phenylalanine 1a, the same product 3a was obtained in 52%
yield.
2.
3.
Conclusion
In summary, we have developed a one-pot synthetic route for
the preparation of γ-hydroxybutenolides through catalyst-free
annulation of α-amino acids with α-keto acids in water with
acceptable yields. One structure of newly resulting γ-
hydroxybutenolide was unambiguously confirmed by single
crystal X-ray diffraction analysis. The method shows many
advantages such as readily available starting materials, mild
reaction conditions, operational simplicity, acceptable yields, and
requiring no extra catalysts or additions. The entire synthetic
route is straightforward and convenient for gram-scale synthesis.
4.
5.
Miura, H.; Takeuchi, K.; Shishido, T. Angew. Chem. Int. Ed.
2016, 55, 278–282.
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Acknowledgments
1204.
We gratefully acknowledge the National Nature Science
Foundation of China (No. 21272151) for financial support.
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485–488.
11. The crystallographic coordinate of 3a has been deposited with the
deposition numbers CCDC 1477260 (see ESI† for details).
12. Huang, Y. M.; Zheng, C. W.; Zhao, G. J. Org. Chem. 2015, 80,
3798–3805.
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Supplementary Material
Supplementary data associated with this article can be found
in the online version, at
References and notes
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Tetrahedron Letters
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Research highlights
 One-pot catalyst-free synthesis of γ-hydroxybutenolides.
 The method uses water as solvent which is environmentally friendly.
 The product structure was confirmed by single crystal X-ray diffraction analysis.
 The synthetic route is straightforward and convenient for gram-scale synthesis.