Stereoselective synthesis of hex-2-(E)-en-4-yn-1,6-dioates and E,Z-muconic acid diesters via organo-catalyzed self-coupling of propiolates

Article abstract of DOI:10.1016/j.tetlet.2005.02.098

Alkyl propiolate couples with itself in the presence of catalytic DABCO under very mild conditions to provide a quantitative yield of E-hex-2-en-4-yne dioates. Hydrogenation of these enyne dioates using Lindlar catalyst provides the corresponding E,Z-diene dioate, a common structural motif found in an array of natural products.

Full text of DOI:10.1016/j.tetlet.2005.02.098

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 2547–2549
Stereoselective synthesis of hex-2-(E)-en-4-yn-1,6-dioates and
E,Z-muconic acid diesters via organo-catalyzed
self-coupling of propiolates
P. Veeraraghavan Ramachandran,* Michael T. Rudd and M. Venkat Ram Reddy
Department of Chemistry, 560 Oval Drive, Purdue University, West Lafayette, IN 47907-2084, USA
Received 31 January 2005; revised 14 February 2005; accepted 16 February 2005
Abstract—Alkyl propiolate couples with itself in the presence of catalytic DABCO under very mild conditions to provide a quan-
titative yield of E-hex-2-en-4-yne dioates. Hydrogenation of these enyne dioates using Lindlar catalyst provides the corresponding
E,Z-diene dioate, a common structural motif found in an array of natural products.
Ó 2005 Elsevier Ltd. All rights reserved.
O
We had reported that, while attempting a Baylis–Hill-
man reaction of ethyl acrylate with a-acetylenic ketones,
we stumbled upon a novel 1,4-diazabicyclo[2.2.2]octane
(DABCO)-catalyzed coupling of acetylenic ketones via a
carbon–oxygen bond yielding divinyl ethers.1 This org-
ano-catalysis reaction is feasible only when the terminus
of the acetylene is free. We could extend this reaction to
include the cross-condensation of terminal and internal
acetylenic ketones under carefully controlled conditions
(Scheme 1).1
DABCO
(1%)
O
EtO
OEt
OEt
0.5 M, CH Cl
2
2
°
0 C, <1 min.
O
Scheme 2.
These types of conjugated E-enyne diesters and the cor-
responding E,E- or E,Z-diene diesters or their deriva-
tives are part of several natural products.2 For
example, muconic acid ester is a precursor for the syn-
thesis of macrocyclic trichothecane esters, a class of
compounds belonging to potent cytostatic materials
with known antibiotic, antifungal, antiviral, and anti-
tumor properties. One such compound, verrucarin A is
shown in Figure 1.2 Apart from their synthetic potential,
the corresponding diacids have been reported to
exhibit bacteriostatic activity against Bacillus subtilis
When we undertook to cross couple 4-phenyl-3-butyn-2-
one with ethyl propiolate, we encountered an instanta-
neous, quantitative, and stereodefined self-condensation
of the ester via a carbon–carbon bond to form diethyl E-
2-en-4-yn-1,6-dioate (Scheme 2).
O
(10%)
O
N
O
N
O
0.5M, CH2Cl2
0 C, rt, 1 h
H
H
O
80%
Ph
Ph
O
°
+
O
O
(10%)
O
O
O
O
O
Scheme 1.
muconic acid
diester
HO
O
Keywords: Enynes; E,Z-Dienes; Muconic acid esters; Self-coupling;
DABCO.
*
Corresponding author. Tel.: +1 765 494 5303; fax: +1 765 494
0239; e-mail: chandran@purdue.edu
Figure 1. Verrucarin A.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.098

2548
P. V. Ramachandran et al. / Tetrahedron Letters 46 (2005) 2547–2549
and Saccharomyces cerevisiae at concentrations >0.2%.3
These diacids are also useful as cross-linking agents for
OH-containing materials, such as cellulose, and as inter-
mediates for insecticides.3 Accordingly, several synthe-
ses of muconic acid diesters have been reported.4
tion. Decreasing the catalyst further results in an incom-
plete reaction. We chose 1% catalyst at 0 °C as the
standard condition for the reaction with the catalyst
being removed at the end of the reaction by filtration
through a pad of silica. We prepared a series of aromatic
and aliphatic propiolate esters via DCC mediated esteri-
fication of propiolic acid, including esters from chiral
alcohols. In all of the cases, we experienced no difficulty
in forming the enyne diesters (Scheme 3). In fact, the
reactions of aromatic esters were highly instantaneous
and exothermic and were carried out under controlled
conditions at low temperature.
A literature search revealed a stoichiometric reaction of
methyl propiolate with triethylamine, N-methylpiperidine,
or N-methylpyrrolidine to form the enyne dioate in
moderate to high yields.5 A patent also disclosed the
dimerization of propiolate esters in the presence of
10% of a tertiary amine at temperatures ranging from
À10 to 100 °C for several hours.3,6 Numerous amines,
including DABCO, pyridine and picoline were reported
to be effective. It is surprising that there has been no
earlier reference to this patent, although several applica-
tions of muconic acid esters have since been reported.
The proposed mechanism of the catalytic cycle is as fol-
lows (Scheme 4).
We converted a representative enyne diester, diethyl 2E-
en-4-yn-1,6-dioate, to (E,Z)-muconic acid diester
(Scheme 5). Hydrogenation using Lindlar catalyst pro-
vided the corresponding E,Z-diene dioate. Selective
enzymatic hydrolysis of the E,Z-diester and conversion
to various other difunctionalized dienes is known.7 This
diene has also been applied in Diels–Alder reactions.8
Our experiments established that long reaction times
and extreme conditions are not necessary for the cou-
pling. This study focused on the limitations of the
instantaneous and catalyzed reaction. No influence of
solvents was observed. Various amines, aromatic and
aliphatic, were tested as organic catalysts. Differing from
the claim in the patent, pyridine and picoline were inef-
fective for catalysis. TMEDA compares well with the
efficacy of DABCO. However, DBU failed to catalyze
the reaction (Table 1).
A typical experimental procedure for the preparation of
diisopinocampheyl hex-2-(E)-en-4-yn-1,6-dioate and the
corresponding E,Z-dienoate is as follows. To a solution
Examination of the catalytic turnover revealed that
0.1 mol % of DABCO is sufficient to catalyze the reac-
COOR
H
O
OR
O—
O
COOR
H
O
N
OR
C
OR
OR
—
Table 1. Amine-catalyzed coupling of propiolates
H
COOR
ROOC
H
N
Entry Catalyst
%
Catalyst
Solvent Reaction
time
%
Conversion
O
1
DABCO 10
DABCO 10
CH2Cl2 <1 min
Hexane <1 min
99
99
99
99
99
99
70
90
0
RO
2
OR
3
DABCO 10
DABCO 10
DABCO 10
DABCO 10
EtOAc
<1 min
O
4
CH3CN <1 min
Toluene <1 min
5
Scheme 4.
6
THF
<1 min
7
Et3N
TMEDA 10
DBU 10
Pyridine 10
10
CH2Cl2 <1 min
CH2Cl2 <1 min
8
9
CH2Cl2
CH2Cl2
CH2Cl2
1 h
1 h
1 h
O
10
11
12
13
14
15
0
OEt
Picoline
DABCO
DABCO
DABCO
DABCO
10
1
0
H2
EtO
OEt
CH2Cl2 <1 min
99
96
80
20
O
Lindlar
EtO
O
0.1
0.01
CH2Cl2
THF
THF
15 min
24 h
24 h
O
99%
0.001
Scheme 5.
O
0.1-1% DABCO, 0 ºC
1-15 min.
O
COOH
ROH, DCC, DMAP
OR
CH Cl ,0-25ºC 6h
OR
0.5M, CH Cl RO
2
2
2
2
> 99% yield
60-80% yield
O
O-
O-
,
O-
,
O-
,
RO = EtO-, CH -(CH ) CH -O-,
3
2 10
2
,
O-
Scheme 3.

P. V. Ramachandran et al. / Tetrahedron Letters 46 (2005) 2547–2549
2549
of isopinocampheol (1.56 g, 10 mmol) and propiolic acid
Acknowledgements
(0.65 g, 9.25 mmol) in CH2Cl2 (5 mL) at 0 °C was added
a combined solution of DCC (1.91 g, 9.25 mmol) and
DMAP (0.011 g, 0.0925 mmol) in CH2Cl2 (5 mL) over
a period of 1 h. The reaction was stirred for an addi-
tional 5 h. The reaction mixture was then filtered, and
washed with ether. Following evaporation of the sol-
vents, the crude product was purified by silica gel chro-
matography (95/5 hexanes/ethyl acetate) to yield 1.44 g
(75%) of the propynoate product. To a solution of isopino-
campheyl propiolate (1.03 g, 5 mmol) in CH2Cl2 (5 mL)
at 0 °C was added DABCO (0.0056 g, 0.05 mmol).
The reaction immediately turned dark, and was stirred
for 15 min. The volatiles were then evaporated, and
the crude reaction mixture was purified by silica gel
chromatography (95/5 hexanes/ethyl acetate) to yield
1.02 g (99%) of the corresponding enyne product. To a
stirred solution of enyne dioate (1.02 g, 2.5 mmol) and
hexanes (5 mL) was added Lindlar catalyst (0.04 g),
and quinoline (0.1 mL). The reaction flask was exposed
to H2(g) and the uptake of hydrogen was monitored.
When the reduction was complete, the volatiles were
evaporated, and the crude reaction mixture was purified
by silica gel chromatography (95/5 hexanes/ethyl
acetate) to yield 0.83 g (80%) of the corresponding diene
product.
The financial assistance from the Herbert C. Brown
Center for Borane Research is gratefully acknowledged.
References and notes
1. Ramachandran, P. V.; Reddy, M. V. R.; Rudd, M. T.
Tetrahedron Lett. 1999, 40, 3819.
2. Tamm, C.; Jeker, N. Tetrahedron 1989, 45, 2385, and
references cited therein.
3. Pollart, K. A. U.S. Patent 3,383,403. Chem. Abstr. 1968, 69,
P35475k.
4. (a) Tsuji, J.; Imamura, S. Japan 68 00,489. Chem. Abstr.
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Chem. 1981, 46, 5242; (c) Mohr, P.; Tori, M.; Grossen, P.;
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Chem. Soc., Perkin Trans. 1 1994, 1983; (g) Lu, X.; Huang,
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6. No mention of the stereochemistry of the double bond is
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7. Martin, M.-E.; Planchenault, D.; Huet, F. Tetrahedron
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8. (a) Rigby, J. H.; Ateeq, H. S.; Charles, N. R.; Cuisiat, S. V.;
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In conclusion, we have found that alkyl propiolates cou-
ple with themselves in the presence of 0.1 M equiv of
DABCO under very mild conditions to provide a quan-
titative yield of E-hex-2-en-4-yne dioates. Hydrogena-
tion of these enyne dioates using Lindlar catalyst
provides the corresponding E,Z-diene dioate. We be-
lieve that this procedure will find applications in organic
synthesis.