AgNO3 catalyzed cyclization of propargyl-Meldrum's acids in aqueous solvent: highly selective synthesis of Z-γ-alkylidene lactones

Article abstract of DOI:10.1016/j.tetlet.2009.07.050

γ-Alkylidene lactones have attracted considerable attention due to their diverse biological activities and ubiquitous structural units in natural products. Herein, an efficient AgNO₃ catalyzed highly regio- and stereo-selective cyclization of p

Full text of DOI:10.1016/j.tetlet.2009.07.050

Tetrahedron Letters 50 (2009) 5406–5408
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Tetrahedron Letters
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AgNO3 catalyzed cyclization of propargyl-Meldrum’s acids in aqueous
solvent: highly selective synthesis of Z-c-alkylidene lactones
c
a,
Wei Jia a, Si Li a, Miao Yu b, , Wei Chen , Ning Jiao
*
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, China
b Department of Radiology, Chinese PLA General Hospital, No. 28, Fuxing Road, Beijing 100853, China
c Chinese PLA Postgraduate Medical School, No. 28, Fuxing Road, Beijing 100853, China
a r t i c l e i n f o
a b s t r a c t
Article history:
c
-Alkylidene lactones have attracted considerable attention due to their diverse biological activities and
Received 7 June 2009
Revised 7 July 2009
Accepted 10 July 2009
Available online 14 July 2009
ubiquitous structural units in natural products. Herein, an efficient AgNO3 catalyzed highly regio- and
stereo-selective cyclization of propargyl-Meldrum’s acids in aqueous solvent was developed, which pro-
vides a practical synthetic strategy for the synthesis of substituted Z-c-alkylidene butyrolactones under
neutral reaction conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
c
-Alkylidene lactones are widely distributed in a vast array of
decarboxylation reactions of alkynes and 5-alkylidene Meldrum’s
natural bioactive molecules,1,2 such as cyanobacterin,2a atranone,2b
growth regulating reagent,2c and goniobutenolides2d (Fig. 1). Their
enolester moiety makes them of great importance in the areas of
pharmaceuticals. Many of these enolesters possess interesting
and powerful biological properties such as anticancer,3 anti-HIV,4
and antibiotic and cytotoxic activity,5 and therefore have been
developed as drugs.
acids leading to substituted Z-c
-alkylidene butyrolactones.13
Although this method overcame the above shortages by the tan-
dem processes using easily prepared precursor of acetylenic acids
as starting materials, the high loading of metal catalyst
(40 mol %) limits its application, and leaves room for further
improvement. Based on our above-mentioned results, we envi-
sioned that a Lewis acid which is stable in water, could facilitate
this transformation from propargyl-Meldrum’s acids to substituted
In the past decades, lots of useful synthetic methods have been
developed for these
c
-alkylidene lactones, among which, transition
c-alkylidene butyrolactones via cyclization–hydrolysis–decarbox-
metals such as mercury,6 palladium,7 rhodium,8 silver,9,10 gold,11
and copper12 catalyzed cyclization reactions of acetylenic acids
present one of the most attractive and straightforward synthetic
approaches (Scheme 1). Despite their efficiencies, there are still
some drawbacks: (1) All of the above transformations started from
acetylenic acids, which required several synthetic steps from the
corresponding propargyl malonic esters generating wasted from
reagents, solvents, and purifications (Scheme 1); (2) base was re-
quired in most of these reactions; (3) furthermore, when Ag+ salts
were used as catalysts in these reactions, the reported literatures
indicate that a dark environment was required for these reactions,
and the stereoselectivity was low (E/Z isomers, 1:1).9 Recently, the
development of new synthetic methods through concise and eco-
nomical routs has attracted a great deal of attention. Herein, we
demonstrate a practical AgNO3 catalyzed highly regio- and ste-
reo-selective cyclization of propargyl-Meldrum’s acids leading to
ylation13 in an aqueous solvent.
O
O
Ph
Ph
O
H
O
H
NH
O
HO
Ph
O
OH
O
i-Bu
O
MeO
OH
O
O
O
Goniobutenolides
Growth regulating reagent
Atranone F
O
H
O
O
3
O
O
O
OH
Cl
Cyanobacterin 1
OMe
R
Xerulin (R = Me)
Xerulinic acid (R = COOH)
substituted Z-c-alkylidene butyrolactones in aqueous solvent un-
AcO
der neutral reaction conditions (Scheme 1).
We have recently reported a novel Cu/Fe cocatalyzed highly
selective tandem conjugate addition–cyclization–hydrolysis–
O
OH
O
O
Peridinin
Figure 1. Selected examples of
* Corresponding author. Tel./fax: +86 10 8280 5297 (N.J.).
E-mail addresses: yum301fsk@163.com (M. Yu), jiaoning@bjmu.edu.cn (N. Jiao).
c-alkylidene lactones frameworks.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.050

W. Jia et al. / Tetrahedron Letters 50 (2009) 5406–5408
5407
Table 2
OH OH
R2
The silver-catalyzed cyclization–hydrolysis–decarboxylation reaction of substituted
O
propargyl-Meldrum’s acid 1a
O
O
Decarboxylation
R2
OH
R1
R2
O
O
AgNO3, 5 mol %
R1
OR OR
Hydrolysis
[M]
R2
Ref.
O
O
H2O : DMF = 2 : 1
100 oC , t
O
O
R2
R1
R1
1
Z-2
AgNO3, 1-5 mol %
O
O
Entry
1
R1
R2
t (min)
Yield of Z-2b (%)
R2
O
aqueous solvent
O
iPr
40
60
60
50
50
50
50
50
60
60
87 (Z-2a)
71 (Z-2b)
81 (Z-2c)
46 (Z-2d)
85 (Z-2e)
62 (Z-2f)
63 (Z-2g)
59 (Z-2h)
45 (Z-2i)
75 (Z-2j)
R1
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
This work
4-Me-C6H4
iPr
R1
4-F-C6H4
iPr
4-OMe-C6H4
4-Br-C6H4
iPr
iPr
Scheme 1. Synthesis of substituted
metal-catalyzed reactions.
c-alkylidene butyrolactones via transition
Ph
Ph
Ph
Ph
Ph
4-Me-C6H4
Ph
Furfuryl
iBu
With this hypothesis in mind, after a great deal of screening, we
are pleased to find that Ag2CO3 can smoothly complete this conver-
sion starting from propargyl-Meldrum’s acids 1a highly regio- and
10
1j
cHex
a
1 (0.25 mmol), AgNO3 (0.0125 mmol) and aqueous solvent (H2O:DMF = 2:1,
1.5 mL) were allowed to react at 100 °C under air.
stereo-selectively giving c-alkylidene butyrolactones Z-2a in 71%
b
Isolated yield.
yield, no E-2a was observed (Table 1, entry 4). Further studies indi-
cated that the efficiency of this transformation was obviously af-
fected by the ratio of the aqueous solvent (Table 1, cf. entries 2,
5, and 6). After screening on different silver catalysts and solvents,
we found that the direct cyclization of propargyl-Meldrum’s acids
1a catalyzed by AgNO3 (5 mol %) using the mixture of H2O/DMF
(2:1) as solvent at 100 °C led to the highest efficiency (87% yield,
entry 7). Notably, 82% yield of Z-2a was obtained when only
1 mol % of AgNO3 was employed as the catalyst (Table 1, entry 8).
Compared with the reported silver-catalyzed cyclization of
acetylenic acids,9 our approach uses propargyl-Meldrum’s acids
as starting materials, which is the precursor of the above-men-
tioned acetylenic acids. With our method, the reactions are carried
out in aqueous solvent (H2O/DMF = 2:1) under neutral reaction
conditions, and are easily handled without the requirement of dark
environment. Furthermore, the regio- and stereoselectivity are
bromoaryl substituted product Z-2e was afforded in 85% yield,
which could be amenable to further functional-group transforma-
tions. A wide range of substituents at R2 position, such as alkyl,
aryl, and heteroaryl groups, reacted successfully and yielded the
expected 4-substituted Z-c-alkylidene butylroactones, respectively
(Table 2, 45–75%, entries 6–10).
In conclusion, we have developed a silver catalyzed efficient
highly selective tandem cyclization–hydrolysis–decarboxylation
of substituted propargyl-Meldrum’s acids leading to Z-c-alkyl-
idene butyrolactones. Compared with the reported transition me-
tal-catalyzed cyclization of acetylenic acids, propargyl-Meldrum’s
acids, which are the precursor of the above-mentioned acetylenic
acids, are used as starting materials. This developed method is eas-
ily handled in aqueous solvent under neutral reaction conditions
with low catalyst loading. Further studies on the synthetic applica-
tions are ongoing in our laboratory.
high leading to Z-c-alkylidene butyrolactones.
Under these optimized conditions, the scope of this cyclization–
hydrolysis–decarboxylation reaction was examined (Table 2). Var-
ious substituted propargyl-Meldrum’s acids 1 proceeded efficiently
producing Z-2 in moderate to good yield. Aryl substituents with
both electron withdrawing and electron donating at R1 position
participated well (Table 2, entries 2–5). It is noteworthy that 4-
Acknowledgments
Financial support from Peking University, National Science
Foundation of China (Nos. 20702002, 20872003), National Basic
Research Program of China (973 Program) (Grant No.
2009CB825300), and Ph.D. Programs Foundation of Ministry of
Education of China (No. 20070001808) is greatly appreciated. We
also thank Jiaojiao Xu in this group for reproducing the results of
entries 1 and 9 in Table 2.
Table 1
The silver-catalyzed cyclization–hydrolysis–decarboxylation reaction of propargyl-
Meldrum’s acid 1aa
O
O
[Ag] cat.
Supplementary data
O
O
H2O:DMF
100 oC, t
O
O
Supplementary data (experimental details and NMR spectra)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2009.07.050.
Ph
Ph
1a
Z-2a
Entry
[Ag] (mol %)
H2O:DMF
t (min)
Yield of Z-2ab (%)
1
2
3
4
5
6
7
8
AgOAc (20)
AgNO3 (20)
Ag2O (10)
Ag2CO3 (10)
AgNO3 (20)
AgNO3 (20)
AgNO3 (5)
AgNO3 (1)
2:1
2:1
2:1
2:1
4:1
1:1
2:1
2:1
40
40
40
40
50
50
40
40
65
87
54
71
52
17
87
82
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