Preparation of unsymmetrical dialkyl acetylenedicarboxylates and related esters by enzymatic transesterification

Article abstract of DOI:10.1016/j.tetlet.2011.04.103

An unexpected highly selective mono-transesterification of symmetrical acetylenedicarboxylates with various alcohols occurred in the presence of Candida rugosa lipase. This reaction allows an efficient preparation of unsymmetrical acetylenedicarboxylates and related α,β-acetylenic esters.

Full text of DOI:10.1016/j.tetlet.2011.04.103

Tetrahedron Letters 52 (2011) 3443–3446
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Tetrahedron Letters
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Preparation of unsymmetrical dialkyl acetylenedicarboxylates and related
esters by enzymatic transesterification
⇑
Nisrine Sultan, Coralie Thomas , Luis Blanco, Sandrine Deloisy
Laboratoire de Synthèse Organique et Méthodologie, I.C.M.M.O. (UMR 8182-CNRS), Bât. 420, Université Paris-Sud 11, 91405 Orsay cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An unexpected highly selective mono-transesterification of symmetrical acetylenedicarboxylates with
Received 19 January 2011
Revised 19 April 2011
Accepted 26 April 2011
Available online 4 May 2011
various alcohols occurred in the presence of Candida rugosa lipase. This reaction allows an efficient prep-
aration of unsymmetrical acetylenedicarboxylates and related
a
,b-acetylenic esters.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Lipase
Transesterification
Acetylenic esters
Molecular sieves
1. Introduction
dichloride with 1 equiv of one alcohol and subsequent addition of
a small excess of a second alcohol allowed the preparation of acet-
ylenedicarboxylates with different substituents in the ester groups,
but a statistical ratio of the three possible diesters was obtained.11
For 30 years, enzymes, and particularly lipases, have become
important reagents in organic synthesis.12 In various examples,
lipase-catalyzed transesterification of diesters with an alcohol gave
a new diester with different alkoxy groups, but this selectivity was
generally driven by the enzyme recognition of a stereogenic center
or a bulky substituent.13 A plant extract could catalyze a formal
transesterification of caffeate derivatives (3-(3,4-dihydroxy-
phenyl)prop-2-enoates),14 and it was soon recognized that
7-Oxanorborna-2,5-diene-2,3-dicarboxylates
obtained
by
Diels–Alder reaction of furans with dialkyl acetylenedicarboxylates
are useful masked forms of the acetylenic partner.1 Such com-
pounds have been used in Michael additions or [3+2] cycloadditions
followed by a retro-Diels–Alder reaction to prepare ethylenic2 or
heterocyclic2c,3–5 products. To increase the scope of these se-
quences, an efficient access to unsymmetrical acetylenedicarboxy-
lates would be of great interest. In a literature example, the allyl
methyl acetylenedicarboxylate was prepared in low yield by the
reaction of methyl chloroformate with the lithium derivative of
allyl propiolate.6 In a patent, related to epothilone derivatives, the
synthesis of an unsymmetrical acetylenedicarboxylate was
reported by the reaction of acetylenedicarboxylic acid monomethyl
ester with a triazolo-thiazole.7 Flash vacuum pyrolysis at 500 °C of
1,2,4-trioxo-3-triphenylphosphoranylidenebutane derivatives,
obtained by the reaction of alkyl oxalyl chlorides with
alkoxycarbonylmethylenetriphenylphosphoranes, has allowed the
preparation of unsymmetrical acetylenedicarboxylates in moderate
yields by extrusion of Ph3PO.8,9 Acetylenedicarboxylates could also
be obtained by esterification of dibromofumaroyl dichloride fol-
lowed by elimination of the bromine atoms with zinc.10 This strat-
egy was proposed to overcome the difficulties related to the use of
acetylenedicarbonyl dichloride. Treatment of dibromofumaroyl
a,b-ethylenic esters could be prepared by transesterification of acti-
vated acrylate derivatives with alcohols in the presence of hydro-
lases.15 Numerous examples of lipase-catalyzed preparation of
such esters have been described in the literature.16 To our
knowledge, few enzyme-catalyzed reactions with
a,b-acetylenic
acid derivatives were reported. Treatment of ethyl propiolate with
aromatic amines afforded Michael addition products while, in the
presence of the Candida rugosa lipase,17 propargylamides were
formed.18 In an earlier report, formation of the monoethyl ester of
acetylenedicarboxylic acid was described by hydrolysis of diethyl
acetylenedicarboxylate in the presence of
a
-chymotrypsin.19 The
yield of the monoethyl ester was 24% after 1.6 h and the reaction
slowed down markedly thereafter. Addition of nucleophiles to the
triple bond was proposed to explain the enzyme inhibition.
This Letter is dealing with a one step method to prepare
unsymmetrical acetylenedicarboxylates by lipase-catalyzed
mono-transesterification of symmetrical acetylenedicarboxylates
with an alcohol.
⇑
Corresponding author. Tel.: +33 1 69 15 32 36; fax: +33 1 69 15 62 78.
E-mail address: sandrine.deloisy@u-psud.fr (S. Deloisy).
Present address: Institut des Sciences Moléculaires (UMR 5255-CNRS), Université
Bordeaux 1, 33405 Talence, France.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.103

3444
N. Sultan et al. / Tetrahedron Letters 52 (2011) 3443–3446
2. Results and discussion
O
OMe
O
OR'
O
R'OH (excess)
PTSA, cyclohexane
reflux (5 Å MS trap)
MeO
O
R'O
Preliminary experiments were run with 1.2/1 mixtures of 2,2-
dimethylpropanol (neopentyl alcohol) and dimethyl acetylenedi-
carboxylate (DMAD) in the presence of various lipase-containing
preparations. After 20 h at 20 °C in tert-butyl methyl ether, 1H
NMR spectra show no reaction in the presence of porcine pancre-
atic lipase (PPL), Pseudomonas cepacia lipase (lipase PS Amano) or
Pseudomonas fluorescens lipase (lipase AK Amano). With Candida
rugosa lipase (CRL) or an immobilized form of the Rhizomucor
miehei lipase (Lipozyme), conversions were 18 and 3%, respec-
tively. Thus, we focused our attention on the Candida rugosa lipase,
and the influence of various parameters in the reactions of ethylfu-
R' = Bu
7a 71%
7b 79%
R' = Oct
Scheme 1. Preparation of symmetrical acetylenedicarboxylates.
O
OR
O
O
OR'
O
O
OR'
O
CRL
+
R'OH
RO
RO
R'O
rylsilylmethanol
2
( Fig. 1)20,21 with commercially available
R = Me
7a
7b
7c
7d
7e
7f
7g
7h
7i
BuOH
OctOH
PhCH2CH2OH
6a
6b
6c
6d
6e
6f
6g
6h
6i
dimethyl and diethyl acetylenedicarboxylates, and with the corre-
sponding dibutyl and dioctyl esters 7a and 7b has been studied.
Dibutyl and dioctyl acetylenedicarboxylates 7a and 7b were
easily prepared by treatment of DMAD with butan-1-ol and oc-
tan-1-ol, respectively, in the presence of a catalytic amount of
para-toluenesulfonic acid in refluxing cyclohexane and a 5 Å
molecular sieves trap was used to remove the produced methanol
(Scheme 1).
Transesterification reactions catalyzed by Candida rugosa
lipase (CRL) were performed at 35 °C. After the indicated reac-
tion time, the silylmethyl ester/alcohol 2 ratio was determined
by 1H NMR spectroscopy (by integration of signals of the alcohol
and the esters at 3.56 and 4.13 ppm, respectively). A priori, these
reactions could give an unsymmetrical acetylenedicarboxylate 6
R = Me
R = Me
R = Me
R = Me
R = Me
R = Me
R = Me
R = Me
R = Et
7a
Me3CCH2OH
1
2
3
4
5
2
2
2
6j
6k
6l
7f
7f
7f
7b
Scheme 2. Lipase-catalyzed transesterifications.
and
a symmetrical diester 7 with two ethylfurylsilylmethyl
dibutyl ester 7a (compare entries 16–18). With dioctyl ester 7b, a
lower influence of the molecular sieves was observed (compare
entries 21–23). Use of petroleum ether as the solvent gave also a
higher reaction rate in the case of DMAD (compare entries 2–5)
but no influence was observed with the dibutyl and the dioctyl es-
ters (compare entries 17–20 and 22–25). The increased conversion
noticed in the presence of molecular sieves could be related to their
ability to adsorb low molecular weight alcohols. For the reactions in
petroleum ether in the presence of 5 Å molecular sieves, 1H NMR
spectra of the reaction mixtures before evaporation of the solvent
showed the absence of signals of methanol (entry 4) or ethanol (en-
try 11), the presence of butanol (entry 19) in a lower proportion
than expected (29%), and the expected amount of octanol (entry
24). Under the same conditions in the presence of 13 Å molecular
sieves, a similar trend was noticed but with a decreased ability to
adsorb low molecular weight alcohols: a tiny signal of methanol
was still present in the 1H NMR spectrum (entry 5) and 29% of
the expected ethanol and 89% of the expected butanol remained
in solution (entries 12 and 20, respectively).23 Under similar
reaction conditions, the reaction rate order is: diethyl ꢀ
dimethyl > dibutyl > dioctyl ester. To achieve generally high
conversions, we selected the experimental conditions hereafter:
petroleum ether as the solvent, 35 °C, 5 Å MS, 1.5/1 ratio of acety-
lenedicarboxylate to alcohol, 4 days reaction time. Under these
conditions, 94% of alcohol 2 was converted in the reaction with
DMAD (entry 6).
In order to determine the scope of this reaction, DMAD was trea-
ted with various alcohols in the presence of Candida rugosa lipase
under the optimized conditions cited above. A preparative experi-
ment was also run with diethyl acetylenedicarboxylate. Table 2
summarizes the conversions of the alcohols, the ratios of mono-
to di-transesterified products and the yields of the isolated unsym-
metrical diesters.
Ratios 6/7 were measured by gas chromatography on the crude
reaction mixtures. The retention times of the dibutyl, dioctyl,
di(2,2-dimethylpropyl) and di(trimethylsilylmethyl) acetylenedi-
carboxylates were previously determined, and the presence or
groups (Scheme 2, Table 1).
In all our experiments, analyses of the crude reaction mixtures
by 1H NMR and gas chromatography showed the formation of an
unsymmetrical diester 6 and no evidence of the presence of the
di-transesterified ester 7 (see below). Optimization of the reaction
conditions was mainly realized with diethyl acetylenedicarboxyl-
ate (entries 7–15) in order to obtain high conversion of the starting
alcohol 2. Initially, we have determined the conversions after 24 h
with 1.15/1 mixtures of the dicarboxylate and silylmethanol 2. In
tert-butyl methyl ether, the presence of 5 Å or 13 Å molecular sieves
(MS) gave an increase of the conversion from 60% to 75–77% (com-
pare entries 7–9). The drying effect of molecular sieves might ex-
plain the increase of the conversion, however we did not observe
any detectable hydrolysis of the diethyl acetylenedicarboxylate in
the experiment without molecular sieves. No beneficial influence
of triethylamine22 was noticed in this reaction. The conversion after
24 h was about 40% and various unidentified products have ap-
peared under these conditions (entry 10). In the presence of 13 Å
molecular sieves, the use of toluene (entry 15) or petroleum ether
(entry 12) as the solvent instead of tert-butyl methyl ether gave,
respectively, a decrease (66%) and an increase (85%) of the conver-
sion. An appreciable enhancement of the conversion was noticed
increasing the reaction time to two days (entry 13) or increasing
the initial ratio of the acetylenedicarboxylate to alcohol 2 to 1.5/1
(entry 14). In petroleum ether, the replacement of 13 Å molecular
sieves by 5 Å molecular sieves further accelerates the reaction
(compare entries 11 and 12). The beneficial influence of molecular
sieves in tert-butyl methyl ether was also evident in the case of
dimethyl acetylenedicarboxylate (compare entries 1–3) and with
Me3SiCH2OH
Me Me
1
2
3
4
5
n = 1, R1 = Et
n = 1, R1 = H
n = 2, R1 = Et
n = 3, R1 = Et
R1
O
Si OH
n
Figure 1. Silylalkanols used in the transesterifications.

N. Sultan et al. / Tetrahedron Letters 52 (2011) 3443–3446
3445
Table 1
Lipase-catalyzed transesterification of acetylenedicarboxylates with alcohol 2a
Entry
R
Solvent
Additive
Ratio 6/2
Entry
R
Solvent
Additive
Ratio 6/2
1
2
3
4
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
t-BuOMe
t-BuOMe
t-BuOMe
Petroleum ether
Petroleum ether
Petroleum ether
t-BuOMe
t-BuOMe
t-BuOMe
—
51/49
80/20
81/19
90/10
88/12
94/6
60/40
75/25
77/23
41/59d
96/4
14b
15
16
17
18
19
20
21
22
23
24
25
Et
Et
Petroleum ether
Toluene
t-BuOMe
t-BuOMe
t-BuOMe
Petroleum ether
Petroleum ether
t-BuOMe
t-BuOMe
t-BuOMe
13 Å MS
13 Å MS
—
5 Å MS
13 Å MS
5 Å MS
13 Å MS
-
5 Å MS
13 Å MS
5 Å MS
13 Å MS
93/7
5 Å MS
13 Å MS
5 Å MS
13 Å MS
5 Å MS
—
5 Å MS
13 Å MS
NEt3 (1 equiv)
5 Å MS
13 Å MS
13 Å MS
66/34
45/55
68/32
64/36
67/33
66/34
22/78
27/73
25/75
27/73
26/74
Bu
Bu
Bu
Bu
Bu
Oct
Oct
Oct
Oct
Oct
5
6b,c
7
8
9
10
11
12
13e
t-BuOMe
Petroleum ether
Petroleum ether
Petroleum ether
Petroleum ether
Petroleum ether
Et
Et
85/15
91/9
a
b
c
Unless otherwise noted, reactions were carried out at 35 °C for 24 h with 1.15/1 mixtures of acetylenedicarboxylate and alcohol 2, in the presence of Candida rugosa lipase.
A 1.5/1 mixture of acetylenedicarboxylate and alcohol 2 was used.
Reaction time was 4 days.
d
e
Unidentified by-products were also observed by 1H NMR.
Reaction time was 2 days.
absence of these symmetrical esters in the lipase-catalyzed reac-
tions was easily checked (entries 1, 2, 4 and 5). For the reaction of
alcohol 2 with diethyl acetylenedicarboxylate and the reactions of
alcohols 3 and 4 with DMAD (entries 7, 8 and 9), a very small peak
with a higher retention time than that of the unsymmetrical diester
was observed in the chromatograms. Gas chromatography/mass
spectrometry analysis of these samples has shown the expected
molecular mass of the di-transesterified compounds for these minor
products. In the other cases (entries 3, 6 and 10), no peak with a
retention time higher than that of the unsymmetrical diester was
present in the chromatograms. Mono-transesterified products were
generally isolated in yields in the range of 71–93% after evaporation
of the starting acetylenedicarboxylate under reduced pressure and
silica gel chromatography. The moderate yield of butyl methyl acet-
ylenedicarboxylate 6a (entry 1) is mainly due to a tedious chroma-
tography to separate the DMAD and the product (under reduced
pressure, the unsymmetrical diester 6a was also partially
evaporated).
For comparison, we have checked the transesterification of
DMAD with butanol, octanol or silylmethanol 2 in petroleum
ether at 35 °C in the presence of para-toluenesulfonic acid (10%)
using a 1.5/1 ratio of ester to the alcohol. After 4 days, about
78% conversions of butanol and octanol were noticed. In these
reactions, 88/12 and 81/19 mixtures, respectively, of mono- and
di-transesterified esters 6 and 7 were obtained. Under the same
conditions, addition of 5 Å molecular sieves decreased signifi-
cantly the conversion rates (e.g. 23% conversion of octanol after
4 days). Silylmethanol 2 was totally consumed, but the products
were mainly 2-ethylfuran and the Diels–Alder adduct of this
furan derivative with DMAD. Clearly, the lipase-catalyzed
transesterifications were faster and more selective than the
acid-catalyzed reactions. Moreover, this lipase allows efficient
transesterification with acid sensitive alcohols.
During the lipase-catalyzed transesterification of DMAD with
the 3-hydroxypropylsilane 5 in the presence of a new batch of
5 Å molecular sieves,24,25 formation of 2-ethylfuran and various
products resulting from [4+2] cycloaddition of this furan with acet-
ylenedicarboxylate derivatives was noticed. These by-products de-
creased using 5 Å molecular sieves of another supplier26 and were
absent in the presence of an old sample of 5 Å molecular sieves of a
third supplier.27 Clearly, silane 5 was unstable in petroleum ether
in the presence of the new batch of molecular sieves24 and 1,1-
dimethyl-1-sila-2-oxacyclopentane was obtained with release of
2-ethylfuran. Degradation of hydroxypropylsilane 5 was avoided
when the new batch of 5 Å molecular sieves24 was previously
washed with an aqueous NaOH solution followed by water before
air drying and reactivation (280 °C, 0.1 torr, 4 h).
The enzymatic preparation recovered after the reaction of
alcohol 2 with DMAD has been reused twice in similar experi-
ments. The same selectivity was obtained, but each reaction
showed about 10% decrease of the conversion with regard to the
precedent transesterification. In Contrast to
a
-chymotrypsin,19
the Candida rugosa lipase does not seem to be inhibited by the
acetylenedicarboxylates.
Table 2
Lipase-catalyzed transesterification of the unsymmetrical dies-
ter 6f with the alcohol 2 was also attempted, but no symmetrical
diester 7f was detected. Under the same reaction conditions with
methyl 3-(N-phenylcarbamoyl)propiolate 8 and alcohol 2, no
conversion was noticed after 4 days in contrast to the analogous
N-propylamidoester 9 for which 30% conversion was obtained
(Scheme 3). The low yield (11%) of the isolated corresponding
silylmethyl ester 10 was mainly due to the difficulties to separate
the product from the reactants.
The Candida rugosa lipase seems unsuitable to accept an acety-
lenedicarboxylic acid derivative with a too sterically demanding
substituent in the group away from the reactive center. It is well
known that the highly flexible saturated long chain carboxylates
are good substrates of this lipase and they could bind to the active
site in quite different conformations.28 So, the size of the substitu-
ent in the non-reactive part of these acetylenedicarboxylic acid
derivatives should play a very important role in the active site be-
cause of the rigidity of the acetylenic framework.
Preparation of unsymmetrical dicarboxylates 6a
Entry
Alcohol
Conv. (%)
Ratio 6/7
Diester 6 Yieldb (%)
1
2
3
4
5
6
7
8
9
BuOH
OctOH
PhCH2CH2OH
Me3CCH2OH
95
98
94
97
95
94
95
99
97
96
93/7
6a
6b
6c
6d
6e
6f
51
92
80c
92
93
78
80
71
82
84
100/0
100/0
98/2
1
98/2
2
100/0
99.5/0.5
98.5/1.5
96/4
2d
3
6j
6g
6h
6i
4
5
10
100/0
a
Unless otherwise noted, reactions were carried out for 4 days with a 1.5/1 ratio
of DMAD to the alcohol in the presence of 5 Å molecular sieves and a crude extract
containing the Candida rugosa lipase in petroleum ether at 35 °C.
b
Unless otherwise noted, yields of unsymmetrical diesters after silica gel column
chromatography.
c
Yield after distillation of reactants.
In this reaction, diethyl acetylenedicarboxylate was used.
d

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N. Sultan et al. / Tetrahedron Letters 52 (2011) 3443–3446
ˇ
5. (a) Fišera, L.; Pavlovic, D. Collect. Czech. Chem. Commun. 1984, 49, 1990–2000;
(b) Lyle, F. R. U.S. Patent 5 973 257, 1985; Chem. Abstr. 1985, 65, 2870.
6. Jungheim, L. N.; Sigmund, S. K. J. Org. Chem. 1987, 52, 4007–4013.
7. Höfle, G.; Glaser, N. PCT Int. Appl. WO 02/24712, 2002.
O
HNR
O
CRL
Me MeO
HNR
O
2
+
O
Si
Et
4 days
MeO
O
8. (a) Aitken, R. A.; Hérion, H.; Janosi, A.; Karodia, N.; Raut, S. V.; Seth, S.; Shannon,
I. J.; Smith, F. C. J. Chem. Soc., Perkin Trans. 1 1994, 2467–2472; (b) Aitken, R. A.;
Hérion, H.; Janosi, A.; Raut, S. V.; Seth, S.; Shannon, I. J.; Smith, F. C. Tetrahedron
Lett. 1993, 34, 5621–5622.
9. For the importance of the temperature in order to obtain the
acetylenedicarboxylate, see: Aitken, R. A.; Morrison, J. J. ARKIVOC 2008, X,
103–112.
10. Charlton, J. L.; Chee, G. Tetrahedron Lett. 1994, 35, 6243–6246.
11. Hashmi, A. S. K.; Grundl, M. A.; Rivas Nass, A.; Naumann, F.; Bats, J. W.; Bolte,
M. Eur. J. Org. Chem. 2001, 4705–4732.
12. (a) Wong, C.-H.; Whitesides, G. M. In Enzymes in Synthetic Organic Chemistry;
Tetrahedron organic chemistry series; Baldwin, J. E., Magnus, P. D., Eds.;
Pergamon, 1994; 12, (b) Poppe, L.; Novák, L. Selective Biocatalysis; VCH,
Weiheim: New York, 1996; (c) Itah, T.; Takagi, Y.; Murakami, T.; Hiyama, Y.;
Tsukube, H. In Preparative Biotransformations; Todd, C., Ed.; John Wiley & Sons:
Chichester, UK, 1996; (d) García-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev.
2005, 105, 313–354.
13. (a) Guibé-Jampel, E.; Rousseau, G. Tetrahedron Lett. 1987, 28, 3563–3564; (b)
Gutman, A. L.; Shapira, M. J. Chem. Soc., Chem. Commun. 1991, 1467–1468; (c)
Gutman, A. L.; Shapira, M.; Boltanski, A. J. Org. Chem. 1993, 57, 1063–1065; (d)
Ozasa, N.; Tokioka, K.; Yamamoto, Y. Biosci. Biotech. Biochem. 1995, 59, 1905–
1907; (e) Liljeblad, A.; Kanerva, L. T. Tetrahedron: Asymmetry 1999, 10, 4405–
4415; (f) Liljeblad, A.; Lindborg, J.; Kanerva, L. T. Tetrahedron: Asymmetry 2000,
11, 3957–3966; (g) Liljeblad, A.; Aksela, R.; Kanerva, L. T. Tetrahedron:
Asymmetry 2001, 12, 2059–2066; (h) Gedey, S.; Liljeblad, A.; Lázár, L.; Fülöp,
F.; Kanerva, L. T. Can. J. Chem. 2002, 80, 565–570.
14. Kojima, M.; Kondo, T. Agric. Biol. Chem. 1985, 49, 2467–2469.
15. (a) Ghogare, A.; Sudesh Kumar, G. J. Chem. Soc., Chem. Commun. 1989, 1533–
1535; (b) Ottolina, G.; Carrea, G.; Riva, S. J. Org. Chem. 1990, 55, 2366–2369; (c)
Margolin, A. L.; Fitzpatrick, P. A.; Dubin, P. L.; Klibanov, A. M. J. Am. Chem. Soc.
1991, 113, 4693–4694.
R = Ph
R = Pr
8
9
no reaction
Conv. = 30%
10
11%
O
Scheme 3. Transesterification of amidoesters.
O
Me Me
CRL
+
R' OH
R1
O
Si
4 days
MeO
O
n
2
3
4
5
n = 1, R1 = Et
n = 1, R1 = H
n = 2, R1 = Et
n = 3, R1 = Et
11
12
13
14
85%
68%
80%
75%
Scheme 4. Preparation of propiolates.
From a synthetic point of view, the ability of this lipase to
catalyze the transesterification of methyl propiolate with alco-
hols 2–5 is also interesting, because of the particularly mild
reaction conditions: no activation of the propiolic acid required,
neutral conditions, near to room temperature (Scheme 4).
16. (a) Ikeda, I.; Tanaka, J.; Suzuki, K. Tetrahedron Lett. 1991, 32, 6865–6866; (b)
Moris, F.; Gotor, V. J. Org. Chem. 1993, 58, 653–660; (c) Ema, T.; Maeno, S.; Takaya,
Y.; Sakai, T.; Utaka, M. J. Org. Chem. 1996, 61, 8610–8616; (d) Nakajima, N.;
Ishihara, K.; Matsumura, S.; Hamada, H.; Nakamura, K.; Furuya, T. Biosci. Biotech.
Biochem. 1997, 61, 1926–1928; (e) Geresh, S.; Elbaz, E.; Glaser, R. Tetrahedron
1993, 49, 4939–4944; (f) Takagi, Y.; Ino, R.; Kihara, H.; Itoh, T.; Tsukube, H. Chem.
Lett. 1997, 1247–1248; (g) Bisht, K. S.; Gross, R. A.; Kaplan, D. L. J. Org. Chem. 1999,
64, 780–789; (h) Cuiper, A. D.; Kouwijzer, M. L. C. E.; Grootenhuis, P. D. J.; Kellogg,
R. M.; Feringa, B. L. J. Org. Chem. 1999, 64, 9529–9537; (i) Haughton, L.; Williams,
J. M. J.; Zimmermann, J. A. Tetrahedron: Asymmetry 2000, 11, 1697–1701; (j)
Bakker, M.; Spruijt, A. S.; van Rantwijk, F.; Sheldon, R. A. Tetrahedron: Asymmetry
2000, 11, 1801–1808; (k) Sundby, E.; Perk, L.; Anthonsen, T.; Aasen, A. J.; Hansen,
T. V. Tetrahedron 2004, 60, 521–524; (l) Maruyama, T.; Kotani, T.; Yamamura, H.;
Kamiya, N.; Goto, M. Org. Biomol. Chem. 2004, 2, 524–527; (m) Akai, S.; Tanimoto,
K.; Kita, Y. Angew. Chem., Int. Ed. 2004, 43, 1407–1410; (n) Langille, N. F.; Panek, J.
S. Org. Lett. 2004, 6, 3203–3206; (o) Colombo, D.; Franchini, L.; Toma, L.;
Ronchetti, F.; Nakabe, N.; Konoshima, T.; Nishino, H.; Tokuda, H. Eur. J. Med.
Chem. 2005, 40, 69–74; (p) Vafiadi, C.; Topakas, E.; Wong, K. K. Y.; Suckling, I. D.;
Christakopoulos, P. Tetrahedron: Asymmetry 2005, 16, 373–379; (q) Gu, J.;
Ruppen, M. E.; Cai, P. Org. Lett. 2005, 7, 3945–3948; (r) Díaz-Rodríguez, A.;
Fernández, S.; Lavandera, I.; Ferrero, M.; Gotor, V. Tetrahedron Lett. 2005, 46,
5835–5838; (s) Weitkamp, P.; Vosmann, K.; Weber, N. J. Agric. Food. Chem. 2006,
54, 7062–7068; (t) Teng, R. W.; McManus, D.; Aylward, J.; Ogbourne, S.; Johns, J.;
Parsons, P.; Bacic, A. Fitoterapia 2009, 80, 233–236; (u) Chigorimbo-Murefu, N. T.
L.; Riva, S.; Burton, S. G. J. Mol. Catal. B: Enzymatic 2009, 56, 277–282; (v) Pérez, J.
A.; Trujillo, J. M.; López, H.; Aragón, Z.; Boluda, C. Chem. Pharm. Bull. 2009, 57,
882–884; (w) Chênevert, R.; Pelchat, N.; Morin, P. Tetrahedron: Asymmetry 2009,
20, 1191–1196.
3. Conclusion
Transesterification of acetylenedicarboxylates with alcohols oc-
curred in the presence of Candida rugosa lipase. Unexpectedly, a
highly selective mono-transesterification was noticed and unsym-
metrical acetylenedicarboxylates could be prepared in high yields.
This selectivity was due to the inability of this lipase to accept, in
the reactive site, propiolate ester derivatives with a too bulky
substituent in the b position.
Acknowledgments
We thank the lebanese Azm W Saada Foundation and the Inter-
national Relations Office of the University of Paris-Sud 11 for their
financial support given to N.S.
Supplementary data
Supplementary data (general procedure for the lipase-catalyzed
transesterification and spectroscopic data of the symmetrical dies-
ters 7a–b, unsymmetrical diesters 6a–j, amidoester 10 and propi-
olates 11–14) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2011.04.103.
17. Also named Candida cylindracea.
18. Rebolledo, F.; Brieva, R.; Gotor, V. Tetrahedron Lett. 1989, 30, 5345–5346.
19. Cohen, S. G.; Klee, L. H.; Weinstein, S. Y. J. Am. Chem. Soc. 1966, 88, 5302–5305.
20. Furylsilylalcanols were prepared using known reported methods, see: (a)
Djerourou, A.; Blanco, L. Tetrahedron Lett. 1991, 32, 6325–6326; (b) Díez-
González, S.; Paugam, R.; Blanco, L. Eur. J. Org. Chem. 2008, 3298–3307.
21. Various silylmethanol derivatives were prepared by lipase-catalyzed
transesterification, see Ref. [20a].
22. (a) Theil, F.; Ballschuh, S.; Schick, H.; Haupt, M.; Häfner, B.; Schwarz, S.
Synthesis 1988, 540–541; (b) Fadel, A.; Arzel, P. Tetrahedron: Asymmetry 1997,
8, 283–291.
23. No rationalization may be proposed about the influence of molecular sieves in
petroleum ether since dimethyl and diethyl acetylenedicarboxylates are poorly
soluble in this solvent.
24. Supplied by Roth.
25. This alcohol 5 was particularly prone to degradation. For example, it was
References and notes
1. (a) Xing, Y. D.; Huang, N. Z. J. Org. Chem. 1982, 47, 140–142; (b) Fry, A. J.;
Sherman, L. R.; Beaulieu, A. R.; Sherwin, C. J. Org. Chem. 1990, 55, 389–391; (c)
Saksena, A. K.; Girijavallabhan, V. M.; Chen, Y.-T.; Jao, E.; Pike, E.; Desai, J. A.;
Rane, D.; Ganguly, A. K. Heterocycles 1993, 35, 129–134; (d) Wei, K.; Gao, H.-T.;
Li, W. D. Z. J. Org. Chem. 1982, 47, 140–142.
2. (a) Mahajna, M.; Quistad, G. B.; Casida, J. E. Chem. Res. Toxicol. 1996, 9, 241–246;
(b) Blanco, L.; Bloch, R.; Bugnet, E.; Deloisy, S. Tetrahedron Lett. 2000, 41, 7875–
7878; (c) Soret, A.; Blanco, L.; Deloisy, S. Lett. Org. Chem. 2006, 3, 648–653; (d)
Albert, S.; Soret, A.; Blanco, L.; Deloisy, S. Tetrahedron 2007, 63, 2888–2900; (e)
Albert, S.; Blanco, L.; Deloisy, S. ARKIVOC 2009, Xiii, 78–96; (f) Hong, V.;
Kislukhin, A. A.; Finn, M. G. J. Am. Chem. Soc. 2009, 131, 9986–9994.
3. (a) Soret, A.; Guillot, R.; Rousseau, G.; Blanco, L.; Deloisy, S. Synlett 2007, 1284–
1288; (b) Soret, A.; Müller, C.; Guillot, R.; Blanco, L.; Deloisy, S. Tetrahedron
2011, 67, 698–705.
prepared from
a corresponding allylsilane by hydroboration followed by
oxidation and formation of 1,1-dimethyl-1-sila-2-oxacyclopentane and 2-
ethylfuran was noticed during storage or chromatography if borane derivatives
remained after the oxidation step.
4. (a) van Berkel, S. S.; Dirks, A. J.; Debets, M. F.; van Delft, F. L.; Cornelissen, J. J. L.
M.; Nolte, R. J. M.; Rutjes, F. P. J. T. ChemBioChem 2007, 8, 1504–1508; (b)
Buchanan, J. G.; Sable, H. Z. In Selective Organic Transformations; Thyagarajan, B.
S., Ed.; Wiley-Interscience: New York, 1972; 2, pp 1–95.
26. Supplied by Aldrich.
27. Supplied by Prolabo.
28. Holmquist, M.; Hæffner, F.; Norin, T.; Hult, K. Protein Sci. 1996, 5, 83–88.