Synthesis of isomeric polyacetylenes based on natural hydroxy matricaria esters

Article abstract of DOI:10.1016/j.tet.2009.07.082

The construction of a library of natural and related polyacetylenes using a convergent synthetic strategy based on a palladium mediated cross-coupling reaction is described. The systematic synthetic study led to all possible alkene isomers of the hydroxy matricaria esters 29-32, and the corresponding tiglates 1-4. The synthesis of many of these compounds is described for the first time.

Full text of DOI:10.1016/j.tet.2009.07.082

Tetrahedron 65 (2009) 8418–8427
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of isomeric polyacetylenes based on natural hydroxy matricaria esters
*
Solange Garrais, Jennifer Turkington, William P.D. Goldring
School of Chemistry and Chemical Engineering, Queen’s University Belfast, David Keir Building, Stranmillis Road, Belfast, Northern Ireland BT9 5AG, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2009
Received in revised form 9 July 2009
Accepted 28 July 2009
Available online 6 August 2009
The construction of a library of natural and related polyacetylenes using a convergent synthetic strategy
based on a palladium mediated cross-coupling reaction is described. The systematic synthetic study led
to all possible alkene isomers of the hydroxy matricaria esters 29–32, and the corresponding tiglates 1–4.
The synthesis of many of these compounds is described for the first time.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Polyacetylenes
Matricaria esters
Cross-coupling
Tuberculosis
1. Introduction
COOMe
O
O
O
A wide variety of polyacetylenes have been isolated from natural
sources for decades,1 and have been pursued in target synthesis for
over 50 years.2 Among this class of natural products are the
matricaria esters, which are structurally characterised by a conju-
gated ene–diyne–ene system. This core structure is commonly
substituted with alkyl groups, allylic alcohols and esters, in all
possible alkene isomer combinations.
Natural matricaria-type esters, such as the tiglate 4 and the
hydroxy ester 29, possess insecticidal activity,3 together with ac-
tivity against Mycobacterium tuberculosis, the cause of the bacterial
disease tuberculosis (TB), and Mycobacterium avium, a bacteria
which targets patients with immune deficiency, such as AIDS.4
Furthermore, other structurally related matricaria esters isolated in
Nature possess antibacterial and antitumour activity.5
The polyacetylenes continue to be pursued as targets for
synthesis, and a number of recent examples highlight the impor-
tance of, and interest in these natural compounds.6 In this article
we describe the syntheses of all possible alkene isomers of the
hydroxy matricaria esters 29–32, and the corresponding tiglates
1–4, using a convergent strategy based on palladium mediated
cross-coupling methodology. We also describe the construction of
related metabolites, such as the isomeric dimethyl esters 21–23,
and the diols 24–26.
O
O
1
MeOOC
2
O
O
COOMe
3
O
MeOOC
4
2. Results and discussion
Our plan for the construction of a library of matricaria-type
esters relied on the Sonogashira coupling reaction as the key step in
the assembly of the core diene–diyne structure. Therefore, a num-
ber of enyne subunits, readily accessible in both alkene isomers and
with the appropriate substitution, were required for this alkyne–
alkyne cross-coupling strategy. This includes, for example,
* Corresponding author. Tel.: þ44 (0)28 9097 4414; fax: þ44 (0)28 9097 6524.
E-mail address: w.goldring@qub.ac.uk (W.P.D. Goldring).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.082

S. Garrais et al. / Tetrahedron 65 (2009) 8418–8427
8419
a number of isomeric enyne alcohol (cf.11) and iodoalkyne ester (cf.
9) subunits, which in turn could be derived from the corresponding
vinyl iodide and acetylene.
previously prepared from (Z)-iodoacrylic acid via an isomerisation–
methylation sequence.11 We, however, employed a direct approach
and were pleased to observe the smooth isomerisation of (Z)-6, in
the presence of HI, into the vinyl iodide (E)-13 (Scheme 2).12 The
vinyl iodide (E)-13 was then coupled with ethynyltrimethylsilane to
give the enyne ester (E)-14 in quantitative yield over two steps.
Deprotection of the TMS-protected alkyne 14, using TBAF, gave the
enyne (E)-15 in 74% yield. Treatment of the alkyne 14 with silver
nitrate, and then iodine, led directly to the iodoalkyne (E)-16 in 86%
yield. Using a reduction–deprotection sequence the enyne alcohol
(E)-18 was elaborated from the ester 14, via the TMS-protected
alkyne 17, in 82% yield over two steps. The enyne 18 was converted
into either the bromoalkyne 19a, using silver nitrate and N-bro-
mosuccinimide,6a,c,13 or the iodoalkyne 19b, using iodine and
potassium hydroxide. The TMS-protected acetylene 17 could be
converted directly into the bromoalkyne 19a under the conditions
described above (viz. 18/19a). Finally, esterification of the alcohol
18 with tiglic acid under standard DCC coupling conditions gave an
inseparable 32:1 mixture of the isomeric tiglates (E)-20 and (Z)-12
in 93% combined yield.
Construction of the (Z)-enyne subunits started from commer-
cially available methyl propiolate (5). Treatment of the alkyne 5
with sodium iodide in acetic acid led exclusively to the (Z)-vinyl
iodide 6 in quantitative yield (Scheme 1).7 Under Sonogashira
coupling conditions the vinyl iodide 6 was coupled with ethynyl-
trimethylsilane to give the enyne ester (Z)-7 in quantitative yield.8
The enyne 7 was used to access a number of important coupling
partners required for our synthesis. For example, deprotection of
the TMS-protected alkyne 7, using TBAF, gave the enyne (Z)-8 in 73%
yield.8 Alternatively, deprotection of 7 with silver nitrate in a mix-
ture of ethanol and water, followed by treatment of the resulting
alkynyl silver salt with iodine gave the iodoalkyne (Z)-9 in 68%
yield.9
MeOOC
COOMe
COOMe
a
b
I
R
5
6
7, R = TMS
8, R = H
9, R = I
c
d
b
a
MeOOC
MeOOC
14, R = TMS
6
I
R
R
13
c
d
15, R = H
16, R = I
HO
HO
O
O
e
g
f
e
j
f or g
TMS
HO
HO
TMS
10
11
12
18, R = H
19a, R = Br
19b, R = I
17
Scheme 1. Reagents and conditions: (a) NaI, AcOH, 70 ꢀC, 99%; (b) TMSC^CH,
PdCl2(PPh3)2, CuI, Et3N, THF, 99% (7); (c) TBAF, THF, 0 ꢀC to rt, 73%; (d) AgNO3, EtOH/
H2O (1:1); then I2, CH2Cl2, 68%; (e) DIBALH, CH2Cl2, ꢁ78 ꢀC, 96%; (f) TBAF, THF, 0 ꢀC to
rt, 95%; (g) tiglic acid, DCC, DMAP, CH2Cl2, 90%.
h
i
O
O
The corresponding (Z)-enyne alcohol coupling partners were
elaborated from the enyne ester (Z)-7. During our synthetic studies
towards these subunits we examined the order of steps for the
conversion of 6 into 10. For example, we were disappointed to
discover the reduction of the ester 6, using DIBALH, followed by
Sonogashira coupling of the resulting vinyl iodide with ethynyl-
trimethylsilane gave the enyne 10 in 10% yield over two steps. The
overall yield of this two-step process was significantly improved
when the vinyl iodide 6 was coupled with TMS–acetylene, as de-
scribed earlier, followed by reduction of the resulting ester 7 with
DIBALH to give the allylic alcohol 10 in 96% yield over two steps.
Deprotection of the TMS-protected alkyne 10, using TBAF, gave the
enyne (Z)-11 in 95% yield.10 Finally, esterification of the alcohol 11
with tiglic acid under standard DCC coupling conditions gave an
inseparable 13:1 mixture of the isomeric tiglates (Z)-12 and (E)-20
in 90% combined yield.
20
Scheme 2. Reagents and conditions: (a) HI, benzene, 80 ꢀC, 99%; (b) TMSC^CH,
PdCl2(PPh3)2, CuI, Et3N, THF, 99% (14); (c) TBAF, THF, 0 ꢀC to rt, 74%; (d) AgNO3, EtOH/
H2O (1:1); then I2, CH2Cl2, 86%; (e) DIBALH, CH2Cl2, ꢁ78 ꢀC, 85%; (f) NaOH, MeOH,
ꢁ10 ꢀC, 97% (18); (g) NBS, AgNO3, acetone, 0 ꢀC, 84% (19a); (h) NBS, AgNO3, acetone,
0
ꢀC, 84%; (i) KOH, I2, MeOH, H2O, 64%; (j) tiglic acid, DCC, DMAP, CH2Cl2, 93%.
Construction of the enyne structures set the stage for a synthesis
of all possible hydroxy matricaria ester isomers, and the corre-
sponding tiglates, via cross-coupling of the appropriate terminal
alkyne and iodoalkyne subunits. We first set out to construct all
possible diene–diyne dimethyl ester isomers from the enyne ester
(E)-15 and the iodoalkyne ester (Z)-9. The coupling of 15 and 9,
under Sonogashira conditions (PdCl2(PPh3)2, CuI and diisopropyl-
amine), gave a mixture of the dimethyl esters (E,E)-21, (E,Z)-22 and
(Z,Z)-23 in 45%, 25% and 19% yield, respectively (Scheme 3). In
comparison, treatment of the enyne ester (Z)-8, under the same
conditions, gave the dimethyl ester (Z,Z)-23 in 80% yield. We did not
The isomeric (E)-series of coupling partners were synthesised in
a
similar manner from the vinyl iodide (E)-13, which was
COOMe
COOR
ROOC
a
COOMe
+
COOMe
+
MeOOC
(E)-15 + (Z)-9
21
22
23, R = Me
c
c
c
OH
RO
HO
b
(E)-19b + (Z)-11
OR
RO
d
OR
24, R = H
27, R = Ac
25, R = H
28, R = Ac
26
d
Scheme 3. Reagents and conditions: (a) PdCl2(PPh3)2, CuI, i-Pr2NH, THF, 45% (21), 25% (22) and 19% (23); (b) PdCl2(PPh3)2, CuI, Et3N, THF, 27% (24), 12% (25) and 23% (26);
(c) DIBALH, CH2Cl2, 80% (24), or 99% (25), or 58% (26); (d) Ac2O, DMAP, Et3N, CH2Cl2, 66% (27), or 80% (1:2, 27/28).

8420
S. Garrais et al. / Tetrahedron 65 (2009) 8418–8427
observe alkene isomerisation during the synthesis or purification of
this material.
Nature, employed a direct cross-coupling approach between the
appropriate terminal enyne alcohol and iodoalkyne ester subunits.
Forexample, the coupling reaction between the enyne alcohol (E)-18
and the iodoalkyne ester (E)-16, under Sonogashira conditions, gave
the hydroxy ester (E,E)-29 in 37% yield (Table 1). Together with the
desired product, the dimethyl ester (E,E)-21 and the diol (E,E)-24
wereisolated in 61% and 45%yield, respectively, whichaccounted for
the remainder of the mass balance. The best result was achieved for
the coupling reaction between (E)-18 and (Z)-9, which gave the hy-
droxy ester (Z,E)-30 in 55% yield, together with the corresponding
dimethyl ester (Z,Z)-23 and the diol (E,E)-24 in 40% and 27% yield,
respectively, whichaccounted fortheremainderof themassbalance.
The hydroxy matricaria esters (E,Z)-31 and (Z,Z)-32 were sep-
arately synthesised in 18% and 13% yield from the coupling
The NMR spectral data recorded for 21 were identical to the data
reported for this compound previously synthesised14 and isolated
in Nature.15 The NMR spectral data recorded for 22 were identical to
the data reported for this compound previously synthesised,14c,15b
but not yet isolated in Nature. To the best of our knowledge, this is
the first synthesis to be reported for the dimethyl ester (Z,Z)-23,
which has not yet been found in Nature.
We then set out to synthesise all possible diene–diyne diol
isomers. Coupling of the iodoalkyne (E)-19b with the terminal
alkyne (Z)-11 led to an inseparable mixture of the diols (E,E)-24,
(E,Z)-25 and (Z,Z)-26 in 27%, 12% and 23% yield, respectively (see
Scheme 3).16 In comparison, the diol (Z,Z)-26 was synthesised from
Table 1
Synthesis of the matricaria esters 29–32, via Sonogashira couplinga
Coupling partners
Terminal alkyne
Hydroxy matricaria ester
Yield %
37
Dimethyl ester
(yield %)
Diol (yield %)
Iodoalkyne ester
COOMe
(E)-18
(E)-16
(E,E)-21 (61)
(Z,Z)-23 (40)
(E,E)-24 (45)
HO
HO
29
MeOOC
(E)-18
(Z)-9
55
(E,E)-24 (27)
(Z,Z)-26 (41)
30
HO
9
COOMe
(Z)-11
(E)-16
18c
(E,E)-21 (49)
8
31
RO
MeOOC
(Z)-11
(Z)-9
13d
(Z,Z)-23 (86)
(Z,Z)-26 (40)
32, R = H
33, R = Ac
b
a
PdCl2(PPh3)2, CuI, i-Pr2NH, THF, rt.
Ac2O, DMAP, Et3N, CH2Cl2, 70%.
Isolated as a 19:1 mixture with the minor isomer (E,E)-29.
Isolated as an 8:1 mixture with the minor isomer (E,E)-30.
b
c
d
the enyne alcohol (Z)-11 in 99% yield. The diol isomers were
independently synthesised directly from the corresponding di-
methyl esters 21–23. For example, reduction of the dimethyl ester
(E,E)-21, using DIBALH, gave the corresponding diene–diyne diol
(E,E)-24 in 80% yield. The diols (E,Z)-25 and (Z,Z)-26 were obtained
by reduction of the corresponding dimethyl esters 22 and 23,
respectively.
partners (Z)-11 and (E)-16, or (Z)-11 and (Z)-9, respectively. Iso-
lation of the corresponding dimethyl ester by-products, 21 or 23,
accounted for the remainder of the mass balance based on the
iodoalkyne coupling partner (see Table 1). However, it is in-
teresting to note the isolation of the corresponding diol by-
product 26 did not account for the remainder of the mass balance
based on the enyne alcohol (Z)-11 used in both reactions. The
hydroxy esters 31 and 32 were isolated with a minor amount of
the C8–C9 double-bond isomers 29 and 30, respectively. The Z to E
isomerisation of related compounds has been reported in the
literature.15b,19
The 1H NMR spectral data recorded for the isomeric diols 24 and
26 were identical to the data reported for the compounds pre-
viously synthesised6d,14b,17 and isolated in Nature.15a,18 To the best
of our knowledge, a synthesis of the diol (E,Z)-25 has not yet been
reported, however the corresponding bis-acetate 28 was isolated in
Nature from Felicia filifolia and Centaurea ruthenica.18a,b
The bis-acetates (E,E)-27 and (E,Z)-28 were prepared from the
corresponding diols 24 and 25, using acetic anhydride with DMAP
and triethylamine, in 66% and 80% yield, respectively. Under these
conditions the reaction of (E,Z)-25 led to an inseparable 1:2 mixture
of the bis-acetates (E,E)-27 and (E,Z)-28, thus indicating some Z to E
isomerisation had occurred. The 1H NMR spectral data recorded for
27 and 28 were identical to the data reported for the compounds
isolated from natural sources.18a,b
The 1H NMR spectral data recorded for the hydroxy matricaria
ester (E,E)-29 were identical to the data reported for this compound
previously synthesised and isolated from natural sources.15a,20 The
1H NMR spectral data recorded for the isomer (E,Z)-31 were iden-
tical to the data reported for this compound isolated from natural
sources.15a,21
The acetoxy matricarica ester 33 was prepared from the hydroxy
ester (Z,Z)-32, using acetic anhydride with DMAP and triethyl-
amine, in 70% yield. The NMR spectral data recorded for (Z,Z)-32
and the acetate 33 were identical to the data reported for the
natural products isolated from Chrysothamnus nauseosus and
Chrysothamnus parryi.3,21
Our synthesis of the natural hydroxy matricaria esters 29, 31 and
32, and the isomer (Z,E)-30, which has not yet been isolated in

S. Garrais et al. / Tetrahedron 65 (2009) 8418–8427
8421
To the best of our knowledge, this is the first reported synthesis
3. Conclusions
of the matricaria esters 30–33. Furthermore, the hydroxy ester
(Z,E)-30 has not yet been found in Nature.
In conclusion, a library of natural and related isomeric matri-
caria-type esters, based on the polyacetylenic structure, were
synthesised in a convergent manner from enyne coupling partners.
This includes the dimethyl esters 21–23, the diols 24–26, the hy-
droxy matricaria esters 29–32 and the tiglates 1–4. Most notably,
we completed the first syntheses of the dimethyl ester (Z,Z)-23, the
diol (E,Z)-25, the matricaria esters 30–33 and the tiglates 1–3. Our
synthetic approach to polyacetylenes exposed some issues with the
palladium mediated alkyne–alkyne cross-coupling reaction, which
included the formation of dimeric self-coupled products. However,
the convergent nature of our synthetic approach could be
employed in the future for the construction of other diene–diyne
structures, thus expanding our library of polyacetylenes for
biological evaluation.
Based on the cross-coupling approach employed in our syn-
thesis of the hydroxy matricaria esters 29–32 we then set out to
synthesise the corresponding family of matricaria-type tiglates
1–4, of which 4 is the only natural member.22 We were disap-
pointed to discover our coupling experiments were characterised
by a low yield of the desired tiglate esters, together with the for-
mation of the dimethyl ester and bis-tiglate by-products. For ex-
ample, the coupling reaction between the enyne tiglate (E)-20 and
the iodoalkyne ester (E)-16 gave an inseparable mixture of the
tiglate (E,E)-1, the dimethyl ester (E,E)-21 and a product tentatively
assigned as the (E,E)-bis-tiglate dimer of (E)-20. The coupling re-
action between (Z)-12 and (E)-16 gave an inseparable mixture of
the tiglates (E,Z)-3 and (E,E)-1, together with the dimethyl ester 21
and the (Z,Z)-bis-tiglate dimer.
Our synthetic effort towards the tiglates 1–4, using a cross-
coupling approach, was complicated by alkene isomerisation and
the formation of the dimethyl ester and bis-tiglate by-products.
This prompted us to consider a simple and direct approach to their
synthesis using the hydroxy esters 29–32. For example, DCC cou-
pling of the hydroxy ester (E,E)-29 with tiglic acid in the presence of
DMAP gave the tiglate 1 in 79% yield (Table 2). Accordingly, the
tiglates 2–4 were synthesised from the hydroxy esters 30–32,
respectively. The tiglates 3 and 4 were isolated with a minor
amount of the C8–C9 double-bond isomers 1 and 2, respectively.
The 1H NMR spectral data recorded for the tiglate 4 were identical
to the data reported for this compound previously synthesised9 and
isolated in Nature from the roots of Solidago canadensis.22 The
tiglates 1–3 have not yet been found in Nature, and to the best of
our knowledge this is the first report of their synthesis.
4. Experimental
4.1. General details
Melting points were determined on a Stuart SMP10 electro-
thermal melting point apparatus and are uncorrected. Infrared
spectra were recorded on a Perkin Elmer RX I FT-IR spectrometer as
liquid films or as dilute solutions in spectroscopic grade chloroform
or deuterochloroform between two sodium chloride plates. IR
spectra of solids were recorded as KBr discs. Proton NMR spectra
were recorded on either a Bruker AVX300 (300 MHz), Bruker
DPX300 (300 MHz), or a Bruker DRX500 (500 MHz) spectrometer
as dilute solutions in deuterochloroform. Chemical shifts are ref-
erenced to residual protonated solvent (dH¼7.26 for CDCl3) and are
quoted in parts per million (ppm). The multiplicity of a signal is
designated by one of the following abbreviations: s¼singlet;
d¼doublet; t¼triplet; q¼quartet; br¼broad; m¼multiplet;
app.¼apparent; obsd¼obscured. All coupling constants, J, are
reported in Hertz and quoted to the nearest 0.1 Hz. Carbon-13 NMR
spectra were recorded on either a Bruker AVX300 (75 MHz),
a Bruker DPX300 (75 MHz) or a Bruker DRX500 (125 MHz) spec-
trometer as dilute solutions in deuterochloroform on a broad band
decoupled mode. Chemical shifts are referenced to residual pro-
tonated solvent (dC¼77.0 for CDCl3) and are quoted in parts per
million (ppm). Mass spectra were recorded on either a Micromass
GCT Premier or a Waters Micromass LCT Premier spectrometer
using electron ionisation (EI) at 70 eV or electrospray (ES) tech-
niques, respectively. Microanalytical data were obtained on a Per-
kin Elmer series II CHNS/O 2400 analyser by the Analytical Services
and Environmental Projects unit (ASEP) operating within the
School of Chemistry and Chemical Engineering at Queen’s Univer-
sity Belfast.
Table 2
Synthesis of the tiglates 1–4 from the hydroxy esters 29–32a
a
COOMe
29
O
O
O
1
MeOOC
a
30
O
2
O
O
O
O
a
a
COOMe
31
All reactions were monitored by thin layer chromatography
(TLC) using Merck silica gel 60 F254 precoated aluminium plates,
which were visualised with ultraviolet light and then developed
with basic potassium permanganate. Flash chromatography was
performed on either Fluorochem silica gel 60 or Davisil silica gel 60
as the stationary phase and the solvents employed were of ana-
lytical grade. Radial chromatography was performed using
a Chromatotron 7924T using a glass plate prepared with a 4 mm
layer of Merck 7749 grade silica gel with binder and fluorescent
indicator.
3
MeOOC
32
4
Hydroxy ester
Tiglate
Yield %
Unless stated otherwise, all commercially available reagents
were used as received. When necessary, commonly used organic
solvents were dried prior to use. Tetrahydrofuran (THF), diethyl
ether, toluene and benzene were distilled from sodium benzo-
phenone ketyl or dried by passing through towers of activated
alumina. Dichloromethane was distilled from calcium hydride.
Acetone was distilled from potassium carbonate. Triethylamine and
(E,E)-29
(Z,E)-30
(E,Z)-31
(Z,Z)-32
1
2
3
4
79
60
54b
36c
a
Tiglic acid, DCC, DMAP, CH2Cl2.
b
c
Isolated as a 10:1 mixture with the minor isomer (E,E)-1.
Isolated as a 6:1 mixture with the minor isomer (Z,E)-2.

8422
S. Garrais et al. / Tetrahedron 65 (2009) 8418–8427
diisopropylamine were distilled from potassium hydroxide. Sol-
vents were removed on a Bu¨chi rotary evaporator using water
aspirator pressure. Brine refers to a saturated aqueous solution of
sodium chloride. Petroleum ether refers to light petroleum ether
boiling in the range 40–60 ꢀC. Where necessary, reactions requiring
anhydrous conditions were performed under an atmosphere of
argon in oven dried apparatus.
(55 mL, 0.2 M). The reaction mixture was stirred for 30 min, and
then filtered and washed with water. The solid residue was dis-
solved in dichloromethane (55 mL, 0.2 M), and a saturated solution
of iodine in dichloromethane (100 mL) was added and the mixture
was stirred for 5 min. The resulting pink coloured mixture was
filtered, successively washed with a saturated aqueous solution of
sodium thiosulfate (40 mL) and water (40 mL), and then dried over
MgSO4, filtered, and concentrated in vacuo to leave the iodoalkyne 9
(1.60 g, 68%) as a brown solid; mp 70–72 ꢀC (petroleum ether); nmax
(film)/cmꢁ1 2952, 2152, 1715, 1601 and 979; dH (300 MHz, CDCl3)
4.1.1. (Z)-3-Iodoacrylic acid methyl ester (6).7 Methyl propiolate (5)
(4.9 mL, 59.0 mmol, 1 equiv) was added to a solution of sodium
iodide (13.27 g, 88.5 mmol,1.5 equiv) in acetic acid (35 mL,1.7 M) at
room temperature and then stirred at 70 ꢀC for 16 h. The mixture
was cooled to room temperature, diluted with water (60 mL) and
diethyl ether (60 mL), and then the separated aqueous phase was
extracted with diethyl ether (2ꢂ30 mL). The combined organic
extracts were neutralised with a 3 M aqueous solution of potassium
hydroxide, washed with brine (40 mL), and then dried over MgSO4,
filtered and concentrated in vacuo to leave the vinyl iodide 6
(12.50 g, quantitative) as a yellow oil; (Found: C, 22.5; H, 2.4.
C4H5O2I requires C, 22.6; H, 2.4%); nmax (film)/cmꢁ1 3064, 2950,
2841, 1729, 1598 and 808; dH (300 MHz, CDCl3) 7.47 (1H, d, J 8.8,
IHC]CH), 6.92 (1H, d, J 8.8, IHC]CH), 3.78 (3H, s, OCH3); dC
(75 MHz, CDCl3) 165.0, 129.5, 95.1, 51.6.
6.31 (1H, d,
J 11.4, CH]CHCOOMe), 6.10 (1H, d, J 11.4,
CH]CHCOOMe), 3.77 (3H, s, COOCH3); dC (75 MHz, CDCl3) 164.7,
130.4, 122.9, 90.7, 51.6, 20.9; m/z (EI) 235.9352 (Mþ, 100%, C6H5O2I
requires 235.9334).
4.1.5. (Z)-5-Trimethylsilanylpent-2-en-4-yn-1-ol (10).10a A solution
of diisobutylaluminium hydride (1.0 M) in hexanes (77 mL,
77 mmol, 2 equiv) was added dropwise to a solution of the ester 7
(7.00 g, 38 mmol, 1 equiv) in dichloromethane (190 mL, 0.2 M) at
ꢁ78 ꢀC and stirred for 4 h. The reaction mixture was quenched
with a 1 M aqueous solution of hydrochloric acid (22 mL) and then
allowed to warm to room temperature. The separated aqueous
phase was extracted with dichloromethane (3ꢂ40 mL), and the
combined organic extracts were then dried over MgSO4, filtered
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica using 10% ethyl acetate in petro-
leum ether as eluent to give the alcohol 10 (5.60 g, 96%) as a yellow
oil; Rf (10% ethyl acetate/petroleum ether) 0.17; nmax (film)/cmꢁ1
3337, 2961, 2900, 2148 and 1612; dH (300 MHz, CDCl3) 6.09 (1H, dt,
4.1.2. (Z)-5-Trimethylsilanylpent-2-en-4-ynoic acid methyl ester (7).8
A solution of the vinyl iodide 6 (12.0 g, 57 mmol, 1 equiv) in THF
(140 mL, 0.4 M) was sparged with argon over 20 min and then
PdCl2(PPh3)2 (0.39 g, 0.56 mmol, 0.01 equiv), CuI (0.10 g,
0.56 mmol, 0.01 equiv) and triethylamine (15.5 mL, 0.11 mol,
2 equiv) were sequentially added at 0 ꢀC, followed immediately by
trimethylsilylacetylene (7.8 mL, 56 mmol, 1 equiv). The stirred
reaction mixture was allowed to warm to room temperature over
16 h and then filtered through silica and washed with diethyl ether.
The filtrate was concentrated in vacuo and the residue was purified
by flash column chromatography on silica using 10% ethyl acetate in
petroleum ether as eluent to give the enyne ester (Z)-7 (10.31 g,
quantitative) as a yellow oil; (Found: C, 59.2; H, 8.0. C9H14O2Si re-
quires C, 59.3; H, 7.7); Rf (10% ethyl acetate/petroleum ether) 0.63;
nmax (film)/cmꢁ1 2959, 2901, 2150, 1718 and 1608; dH (300 MHz,
CDCl3) 6.16 (1H, d, J 11.6, MeOOCCH]CH), 6.10 (1H, d, J 11.6,
MeOOCCH]CH), 3.77 (3H, s, OCH3), 0.24 (9H, s, Si(CH3)3); dC
(75 MHz, CDCl3) 165.0, 129.1, 122.8, 108.3, 100.7, 51.4, ꢁ0.4.
J
11.0 and 6.3, CH]CHCH2), 5.58 (1H, dt, J 11.0 and 1.5,
CH]CHCH2), 4.40 (2H, dd, J 6.3 and 1.5, CH2OH), 1.97 (1H, br s,
OH), 0.18 (9H, s, Si(CH3)3); dC (75 MHz, CDCl3) 142.7, 110.4, 100.8,
100.5, 60.9, ꢁ0.1.
4.1.6. (Z)-2-Penten-4-yn-1-ol (11).10b Tetrabutylammonium fluo-
ride trihydrate (10.19 g, 39 mmol, 3 equiv) was added to a stirred
solution of the TMS-protected alkyne 10 (2.00 g, 13 mmol, 1 equiv)
in THF (86 mL, 0.15 M) at 0 ꢀC. The reaction mixture was allowed to
warm to room temperature over 3 h, and then diluted with a sat-
urated aqueous solution of ammonium chloride (50 mL) and
diethyl ether (50 mL). The separated organic layer was washed with
brine (40 mL), and then dried over MgSO4, filtered and concen-
trated in vacuo. The residue was purified by flash column chro-
matography on silica using 35% diethyl ether in pentane as eluent to
give the enyne alcohol 11 (1.00 g, 95%) as a yellow oil; Rf (50%
diethyl ether/petroleum ether) 0.30; nmax(film)/cmꢁ1 3294, 3035,
2930, 2872, 2095 and 1653; dH (300 MHz, CDCl3) 6.17 (1H, dt, J 11.0
and 6.3, CH]CHCH2), 5.57 (1H, dt, J 11.0 and 1.0, CH]CHCH2), 4.41
(2H, dd, J 6.3 and 1.0, CH2OH), 3.17 (1H, s, C^CH), 1.82 (1H, br s,
OH); dC (75 MHz, CDCl3) 143.5, 109.5, 83.2, 79.2, 60.8.
4.1.3. (Z)-5-Pent-2-en-4-ynoic acid methyl ester (8).8 Tetrabutyl-
ammonium fluoride trihydrate (3.44 g, 13.0 mmol, 1.5 equiv) was
added to a stirred solution of the TMS-protected alkyne 7 (1.60 g,
8.8 mmol, 1 equiv) in THF (60 mL, 0.15 M) at 0 ꢀC. The reaction
mixture was allowed to warm to room temperature over 3 h, and
then diluted with a saturated aqueous solution of ammonium
chloride (30 mL) and diethyl ether (30 mL). The separated aque-
ous phase was extracted with diethyl ether (3ꢂ30 mL) and the
combined organic extracts were washed with brine (50 mL), and
then dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography on silica
using 50% diethyl ether in pentane as eluent to give the enyne
ester 8 (0.70 g, 73%) as a yellow oil; Rf (50% diethyl ether/petro-
leum ether) 0.45; nmax (film)/cmꢁ1 2954, 2098, 1729 and 1615; dH
(300 MHz, CDCl3) 6.20 (1H, dd, J 11.6 and 0.8, CH]CHCOOCH3),
6.12 (1H, dd, J 11.6 and 2.5, CH]CHCOOCH3), 3.76 (3H, s, COOCH3),
3.61 (1H, dd, J 2.5 and 0.8, HC^C); dC (75 MHz, CDCl3) 164.7, 130.3,
122.1, 89.2, 79.4, 51.5.
4.1.7. (Z)-((E)-2-Methylbut-2-enoyloxy)pent-2-en-4-ynyl ester(12). Di-
cyclohexylcarbodiimide (0.55 g, 2.7 mmol, 1.1 equiv) and N,N-dime-
thylaminopyridine (59 mg, 0.50 mmol, 0.2 equiv) were added to
a stirred solution of tiglic acid (0.29 g, 2.7 mmol, 1.1 equiv) in
dichloromethane (11 mL, 0.15 M) at 0 ꢀC. The reaction mixture was
stirred for 30 min and then a solution of the alcohol 11 (0.20 g,
2.4 mmol, 1 equiv) in dichloromethane (10 mL, 0.25 M) was added
dropwise. The mixture was allowed to warm to room temperature
over 16 h, diluted with diethyl ether (20 mL), and then sequentially
washed with a saturated aqueous solution of NH4Cl (10 mL), a satu-
rated aqueous solution of NaHCO3 (10 mL) and brine (10 mL). The
organic layer was dried over MgSO4, filtered and concentrated in
vacuo to leave an inseparable 13:1 mixture of the tiglate esters (Z)-12
and (E)-20 (0.40 g, 90%) as a yellow oil; nmax (film)/cmꢁ1 2931, 2857,
2119, 1713 and 1652; data corresponding to the major isomer (Z)-12:
4.1.4. (Z)-5-Iodopent-2-en-4-ynoic acid ethyl ester (9). A solution of
silver nitrate (2.05 g, 12 mmol, 1.1 equiv) in a 1:1 mixture of ethanol
and water (40 mL, 0.3 M) was added slowly to a stirred solution of
the TMS-protected alkyne 7 (2.00 g, 11 mmol, 1 equiv) in ethanol

S. Garrais et al. / Tetrahedron 65 (2009) 8418–8427
8423
dH (300 MHz, CDCl3) 6.87 (1H, qq, J 7.1 and 1.4, C(CH3)]CH(CH3)), 6.10
(1H, ddt, J 11.0, 0.8 and 6.5, CH]CHCH2), 5.64 (1H, ddt, J 11.0, 2.3 and
1.5, CH]CHCH2), 4.89 (2H, dd, J 6.5 and 1.4, CH2O), 3.20 (1H, dd, J 2.3
and 0.3, HC^C), 1.82 (3H, q, J 1.2, C(CH3)]CH(CH3)), 1.78 (3H, dq, J 7.1
and 1.1, (CH3)]CH(CH3)); dC (75 MHz, CDCl3) 167.7, 138.7, 137.6, 128.3,
111.4, 83.9, 78.7, 62.1, 14.3, 11.9; m/z (EI) 164.0834 (Mþ, 80%, C10H12O2
requires 164.0837).
1 equiv) in ethanol (250 mL, 0.2 M). The reaction mixture was
stirred for 30 min, and then filtered and washed with water. The
solid residue was dissolved in dichloromethane (250 mL, 0.2 M),
and a saturated solution of iodine in dichloromethane (500 mL)
was added and the mixture was stirred for 5 min. The resulting pink
coloured mixture was filtered, successively washed with a satu-
rated aqueous solution of sodium thiosulfate (200 mL) and water
(200 mL), and then dried over MgSO4, filtered and concentrated in
vacuo to leave the iodoalkyne 16 (10.5 g, 86%) as a brown solid; mp
62–64 ꢀC (petroleum ether); nmax (film)/cmꢁ1 2951, 2175, 1719, 1617
and 1081; dH (300 MHz, CDCl3) 6.87 (1H, d, J 15.8, CH]CHCOOMe),
6.25 (1H, d, J 15.8, CH]CHCOOMe), 3.78 (3H, s, COOCH3); dC
(75 MHz, CDCl3) 165.9, 132.0, 125.1, 91.0, 51.9, 17.7; m/z (EI)
235.9353 (Mþ, 40%, C6H5O2I requires 235.9334).
4.1.8. (E)-3-Iodoacrylic acid methyl ester (13).12 A solution of
hydriodic acid in water (57% v/v, 2 mL, 0.15 equiv) was added to
a solution of the vinyl iodide (Z)-6 (25.00 g, 0.12 mol, 1 equiv) in
benzene (65 mL,1.8 M) and the reaction mixture was stirred at 80 ꢀC
for 3 days. The mixture was cooled to room temperature, and then
diluted with diethyl ether (60 mL) and a saturated aqueous solution
of sodium thiosulfate (20 mL). The separated aqueous phase was
extracted with diethyl ether (3ꢂ30 mL) and the combined organic
extracts were then dried over MgSO4, filtered and concentrated in
vacuo to leave the vinyl iodide (E)-13 (25.0 g, quantitative) as
a colourless solid; mp 48–50 ꢀC (lit.11a 41–44 ꢀC) (hexane); nmax
(film)/cmꢁ1 3155, 2954, 1722, 1593 and 742; dH (300 MHz, CDCl3)
7.89 (1H, d, J 14.8, IHC]C), 6.88 (1H, d, J 14.8, IHC]CH), 3.75 (3H, s,
OCH3); dC (75 MHz, CDCl3) 164.6, 136.1, 99.6, 51.9.
4.1.12. (E)-5-Trimethylsilanylpent-2-en-4-yn-1-ol (17).12 A solution
of diisobutylaluminium hydride (1.0 M) in hexanes (11 mL,
11 mmol, 2 equiv) was added dropwise to a solution of the ester
14 (1.00 g, 5.5 mmol, 1 equiv) in dichloromethane (28 mL, 0.2 M)
at ꢁ78 ꢀC and stirred for 4 h. The reaction mixture was quenched
with a 1 M aqueous solution of hydrochloric acid (15 mL) and
then allowed to warm to room temperature. The separated
aqueous phase was extracted with dichloromethane (3ꢂ10 mL),
and the combined organic extracts were dried over MgSO4, fil-
tered and concentrated in vacuo. The residue was purified by flash
column chromatography on silica using 10% ethyl acetate in pe-
troleum ether as eluent to give the alcohol 17 (0.72 g, 85%) as
a yellow oil; Rf (10% ethyl acetate/petroleum ether) 0.13; nmax
(film)/cmꢁ1 3338, 2960, 2900, 2178 and 1631; dH (300 MHz,
CDCl3) 6.28 (1H, dt, J 16.0 and 5.1, CH]CHCH2), 5.74 (1H, dt, J 16.0
and 1.9, CH]CHCH2), 4.17 (2H, dd, J 5.1 and 1.9, CH2OH), 2.02 (1H,
br s, OH), 0.18 (9H, s, Si(CH3)3); dC (75 MHz, CDCl3) 142.9, 110.2,
103.0, 95.3, 62.8, 0.0.
4.1.9. (E)-5-Trimethylsilanylpent-2-en-4-ynoic acid methyl ester
(14). A solution of the vinyl iodide 13 (10.0 g, 47 mmol, 1 equiv) in
THF (120 mL, 0.4 M) was sparged with argon over 20 min and then
PdCl2(PPh3)2 (0.32 g, 0.47 mmol, 0.01 equiv), CuI (89 mg,
0.47 mmol, 0.01 equiv) and triethylamine (13 mL, 94 mmol,
2 equiv) were sequentially added at 0 ꢀC, followed immediately by
trimethylsilylacetylene (6.6 mL, 47 mmol, 1 equiv). The stirred re-
action mixture was allowed to warm to room temperature over
16 h and then filtered through silica and washed with diethyl
ether. The filtrate was concentrated in vacuo and the residue was
purified by flash column chromatography on silica using 5% ethyl
acetate in petroleum ether as eluent to give the enyne ester (Z)-14
(8.50 g, quantitative) as a yellow oil; Rf (5% ethyl acetate/petroleum
ether) 0.43; nmax (film)/cmꢁ1 2957, 2255, 1721 and 1619; dH
(300 MHz, CDCl3) 6.74 (1H, d, J 15.9, MeOOCCH]CH), 6.24 (1H, d, J
15.9, MeOOCCH]CH), 3.73 (3H, s, OCH3), 0.21 (9H, s, Si(CH3)3); dC
(75 MHz, CDCl3) 166.2, 130.7, 125.1, 105.7, 101.2, 51.9, 0.3; m/z (EI)
182.0760 (Mþ, 20%, C9H14O2Si requires 182.0763).
4.1.13. (E)-2-Penten-4-yn-1-ol (18).23 A 2.5 M aqueous solution of
NaOH (3.2 mL, 8.1 mmol, 2.5 equiv) was added to a stirred solution
of the TMS-protected alkyne 17 (0.50 g, 3.2 mmol, 1 equiv) in
methanol (13 mL, 0.25 M) at ꢁ10 ꢀC and stirred for 2 h. The solution
was allowed to warm to room temperature and then concentrated
in vacuo. The residue was diluted with diethyl ether (10 mL) and
washed with brine (3ꢂ5 mL). The organic layer was dried over
MgSO4, filtered and concentrated in vacuo, and the residue was
purified by flash column chromatography on silica using 30%
diethyl ether in pentane as eluent to give the enyne alcohol 18
(0.26 g, 97%) as a yellow oil; Rf (50% diethyl ether/petroleum ether)
0.30; nmax (film)/cmꢁ1 3292, 3033, 2919, 2867, 2104 and 1632; dH
(300 MHz, CDCl3) 6.35 (1H, dt, J 16.0 and 4.9, CH]CHCH2), 5.74 (1H,
ddt, J 16.0, 2.1 and 1.9, CH]CHCH2), 4.18 (2H, dd, J 4.8 and 1.6,
CH2OH), 2.90 (1H, ddd, J 2.2, 1.5 and 0.6, C^CH), 1.66 (1H, br s, OH);
dC (75 MHz, CDCl3) 143.7, 109.1, 81.5, 77.9, 62.6.
4.1.10. (E)-5-Pent-2-en-4-ynoic acid methyl ester (15). Tetrabutyl-
ammonium fluoride trihydrate (1.29 g, 4.9 mmol, 1.5 equiv) was
added to a stirred solution of the TMS-protected alkyne 14 (0.60 g,
3.3 mmol, 1 equiv) in THF (22 mL, 0.15 M) at 0 ꢀC. The reaction
mixture was allowed to warm to room temperature over 3 h, and
then diluted with a saturated aqueous solution of ammonium
chloride (15 mL) and diethyl ether (15 mL). The separated aque-
ous phase was extracted with diethyl ether (3ꢂ15 mL) and the
combined organic extracts were washed with brine (25 mL), and
then dried over MgSO4, filtered and concentrated in vacuo. The
residue was purified by flash column chromatography on silica
using 30% diethyl ether in pentane as eluent to give the enyne
ester 15 (0.27 g, 74%) as a yellow oil; Rf (50% diethyl ether/petro-
leum ether) 0.55; nmax (film)/cmꢁ1 2954, 2856, 2106, 1727 and
4.1.14. (E)-5-Bromo-2-penten-4-yne-1-ol (19a).6c N-Bromosuccin-
imide (0.17 g, 0.98 mmol, 1.2 equiv) and silver nitrate (22 mg,
0.13 mmol, 0.02 equiv) were added to a solution of the alkyne 18
(0.10 g, 0.65 mmol, 1 equiv) in acetone (4.3 mL, 0.15 M) at 0 ꢀC and
stirred in the dark for 2 h. The reaction mixture was diluted with
cold water (16 mL) and ethyl acetate (10 mL), and then the sep-
arated aqueous phase was extracted with ethyl acetate (5ꢂ10 mL).
The combined organic extracts were dried over MgSO4, filtered
and concentrated in vacuo, and then the residue was purified by
flash column chromatography on silica using 5% diethyl ether in
dichloromethane to give the bromoalkyne 19a (0.10 g, 84%) as
a brown oil; Rf (20% ethyl acetate/petroleum ether) 0.32; nmax
(film)/cmꢁ1 3359, 2924, 2868, 2212, 1709 and 806; dH (300 MHz,
CDCl3) 6.31 (1H, dt, J 15.9 and 5.0, CH]CHCH2OH), 5.72 (1H, dt,
J 15.9 and 1.9, CH]CHCH2OH), 4.20 (2H, dd, J 4.9 and 1.8, CH2OH),
1621; dH (300 MHz, CDCl3) 6.73 (1H, dd,
J 16.0 and 2.4,
CH]CHCOOCH3), 6.32 (1H, d, J 16.0, CH]CHCOOCH3), 3.77 (3H, s,
COOCH3), 3.35 (1H, d, J 2.4, HC^C); dC (75 MHz, CDCl3) 165.9,
132.0, 124.2, 85.9, 80.1, 51.9; m/z (EI) 110.0371 (Mþ, 90%, C6H6O2
requires 110.0368).
4.1.11. (E)-5-Iodopent-2-en-4-ynoic acid ethyl ester (16). A solution
of silver nitrate (9.73 g, 57.0 mmol, 1 equiv) in a 1:1 mixture of
ethanol and water (190 mL, 0.3 M) was added slowly to a stirred
solution of the TMS-protected alkyne 14 (9.50 g, 52.0 mmol,

8424
S. Garrais et al. / Tetrahedron 65 (2009) 8418–8427
1.65 (1H, br s, OH); dC (75 MHz, CDCl3) 143.5, 109.7, 78.0, 62.5,
49.9.
(lit.14a 104.5–107.5 ꢀC) (petroleum ether); Rf (20% ethyl acetate/
petroleum ether) 0.25; nmax (film/cmꢁ1) 2954, 2254, 1716 and 1609;
dH (300 MHz, CDCl3) 6.82 (2H, d, J 16.1, CH]CHCOOMe), 6.38 (2H, d,
J 16.1, CH]CHCOOMe), 3.78 (6H, s, COOCH3); dC (75 MHz, CDCl3)
165.6, 133.5, 123.3, 81.2, 81.1, 52.1; m/z (EI) 218.0564 (Mþ, 100%,
C12H10O4 requires 218.0579); (ii) the dimethyl ester (E,Z)-22 (0.13 g,
25%) (eluted second) as a colourless solid; mp 77–79 ꢀC (lit.15b 76–
78 ꢀC) (petroleum ether); Rf (20% ethyl acetate/petroleum ether)
0.20; nmax (film/cmꢁ1) 2952, 2130, 1734, 1716 and 1610; dH
(300 MHz, CDCl3) 6.84 (1H, dd, J 15.8 and 0.9, CH]CHCOOMe), 6.37
(1H, d, J 15.8, CH]CHCOOMe), 6.31 (1H, d, J 11.4, CH]CHCOOMe),
6.24 (1H, dd, J 11.4 and 0.9, CH]CHCOOMe), 3.79 (3H, s, COOCH3),
3.78 (3H, s, COOCH3); dC (75 MHz, CDCl3) 165.7, 164.5, 133.1, 132.3,
123.6, 121.3, 84.2, 82.1, 81.7, 80.7, 52.1, 51.8; m/z (EI) 218.0569 (Mþ,
70%, C12H10O4 requires 218.0579); and (iii) the dimethyl ester (Z,Z)-
23 (50 mg, 19%) (eluted third) as a colourless solid; mp 104–106 ꢀC
(petroleum ether); Rf (20% ethyl acetate/petroleum ether) 0.18; nmax
(film/cmꢁ1) 3092, 2948, 2121, 1718 and 1599; dH (300 MHz, CDCl3)
6.27 (4H, s, CH]CHCOOCH3), 3.78 (6H, s, COOCH3); dC (75 MHz,
CDCl3) 164.4, 131.7, 121.4, 84.5, 81.7, 51.7; m/z (ES) 241.0488
(MþþNa, 70%, C12H10O4Na requires 241.0477).
4.1.15. (E)-5-Iodo-2-penten-4-yne-1-ol (19b).6c The alkyne 18
(0.24 g, 2.9 mmol, 1 equiv) was added to a solution of potassium
hydroxide (0.41 g, 7.3 mmol, 2.5 equiv) and iodine (0.81 g,
3.2 mmol, 1.1 equiv) in a 1:1 mixture of methanol and water
(7.0 mL, 0.4 M) at room temperature and stirred for 25 h. The re-
action mixture was concentrated in vacuo, and the residue was
diluted with water (10 mL) and diethyl ether (20 mL). The sepa-
rated aqueous phase was extracted with diethyl ether (2ꢂ20 mL)
and the combined organic extracts were then dried over MgSO4,
filtered and concentrated in vacuo. The residue was purified by
flash column chromatography on silica using 40% ethyl acetate in
petroleum ether as eluent to give the iodoalkyne 19b (0.39 g, 64%)
as a white solid; mp 62–63 ꢀC (lit.6c 61–63 ꢀC) (petroleum ether); Rf
(20% ethyl acetate/petroleum ether) 0.31; nmax (film)/cmꢁ1 3350,
2919, 2863, 1548 and 1091; dH (300 MHz, CDCl3) 6.29 (1H, dt, J 15.9
and 5.0, CH]CHCH2OH), 5.87 (1H, dt,
J
15.9 and 1.9,
CH]CHCH2OH), 4.23 (2H, dd, J 5.0 and 1.9, CH2OH), 1.65 (1H, br s,
OH); dC (75 MHz, CDCl3) 144.1, 110.3, 92.0, 62.5, 6.3.
4.1.16. (E)-((E)-2-Methylbut-2-enoyloxy)pent-2-en-4-ynyl ester
(20). Dicyclohexylcarbodiimide (0.68 g, 3.3 mmol, 1.1 equiv) and
N,N-dimethylaminopyridine (73 mg, 0.60 mmol, 0.2 equiv) were
added to a stirred solution of tiglic acid (0.33 g, 3.3 mmol, 1.1 equiv)
in dichloromethane (22 mL, 0.15 M) at 0 ꢀC. The reaction mixture
was stirred for 30 min and then a solution of the alcohol 18 (0.25 g,
3.0 mmol, 1 equiv) in dichloromethane (12 mL, 0.25 M) was added
dropwise. The mixture was allowed to warm to room temperature
over 16 h, diluted with diethyl ether (30 mL), and then sequentially
washed with a saturated aqueous solution of NH4Cl (15 mL), a sat-
urated aqueous solution of NaHCO3 (15 mL) and brine (15 mL). The
organic layer was dried over MgSO4, filtered and concentrated in
vacuo to leave an inseparable 32:1 mixture of the tiglate esters (E)-
20 and (Z)-12 (0.50 g, 93%) as a yellow oil; nmax (film)/cmꢁ1 2932,
2857, 2119, 1713 and 1652; data corresponding to the major isomer
4.2.2. (2E,8E)-, (2E,8Z)- and (2Z,8Z)-Deca-2,8-diene-4,6-diyne-1,10-
diols (24, 25 and 26). Following the general procedure using the
iodoalkyne alcohol (E)-19b (0.50 g, 2.4 mmol), the terminal alkyne
(Z)-11 (0.24 g, 2.9 mmol), PdCl2(PPh3)2 (50 mg, 0.07 mmol), CuI
(14 mg, 0.07 mmol), triethylamine (0.70 mL, 4.8 mmol) and THF
(8 mL), the resulting residue was purified by flash column chro-
matography on silica using 40% ethyl acetate in petroleum ether as
eluent to give an inseparable 2:1:2 mixture of the diols (E,E)-24,
(E,Z)-25 and (Z,Z)-26 (150 mg) in 27%, 12% and 23% yield,
respectively, as determined by proton NMR.
4.2.3. (2E,8E)-10-Hydroxydeca-2,8-diene-4,6-diynoic acid methyl
ester (29). Following the general procedure using the iodoalkyne
ester (E)-16 (0.70 g, 3.0 mmol), the enyne alcohol (E)-18 (0.24 g,
3.0 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol), CuI (6 mg,
0.03 mmol), diisopropylamine (0.83 mL, 6.0 mmol) and THF
(7.5 mL), the resulting residue was purified by repeated flash col-
umn chromatography on silica using 20–50% ethyl acetate in pe-
troleum ether as eluent to give: (i) the dimethyl ester (E,E)-21
(0.20 g, 61%) (eluted first); (ii) the hydroxy ester (E,E)-29 (0.21 g,
37%) (eluted second) as a colourless solid; mp 78–80 ꢀC (lit.20 80–
81 ꢀC) (petroleum ether); Rf (30% ethyl acetate/petroleum ether)
0.20; nmax (film/cmꢁ1) 3274, 2919, 2193, 1720 and 1613; dH
(300 MHz, CDCl3) 6.81 (1H, dd, J 15.9 and 0.6, CH]CHCOOCH3),
6.48 (1H, dt, J 15.9 and 4.6, CH]CHCH2OH), 6.32 (1H, d, J 15.9,
CH]CHCOOCH3), 5.90 (1H, dt, J 15.9 and 0.8, CH]CHCH2OH), 4.29
(2H, m, CH2OH), 3.77 (3H, s, COOCH3), 1.60 (1H, br s, OH); dC
(75 MHz, CDCl3) 165.9, 146.8, 132.3, 124.1, 108.3, 83.5, 82.4, 77.6,
73.8, 62.6, 52.0; m/z (EI) 190.0620 (Mþ, 100%, C11H10O3 requires
190.0630); and (iii) the diol (E,E)-24 (0.11 g, 45%) (eluted third).
(E)-20: dH (300 MHz, CDCl3) 6.87 (1H, qq,
J 7.1 and 1.4,
C(CH3)]CH(CH3)), 6.28 (1H, ddt, J 16.0, 0.5 and 5.6, CH]CHCH2),
5.72 (1H, ddt, J 16.0, 2.2 and 1.8, CH]CHCH2), 4.65 (2H, dd, J 5.6 and
1.3, CH2O), 2.90 (1H, dd, J 2.2 and 0.5, HC^C), 1.82 (3H, q, J 1.2,
C(CH3)]CH(CH3)), 1.78 (3H, dq, J 7.1 and 1.1, C(CH3)]CH(CH3)); dC
(75 MHz, CDCl3) 167.3, 138.8, 137.8, 128.2, 111.5, 81.0, 78.5, 63.4,
14.3, 11.9; m/z (EI) 164.0840 (Mþ, 70%, C10H12O2 requires 164.0837).
4.2. General procedure for the coupling reaction between
terminal alkynes and iodoalkynes
A solution of the iodoalkyne (1 equiv) in THF (0.4 M) was
sparged with argon over 20 min and then PdCl2(PPh3)2
(0.01 equiv), CuI (0.01 equiv) and either diisopropylamine (2 equiv)
or triethylamine (2 equiv) were added sequentially at room tem-
perature, followed immediately by the terminal alkyne (1.1 equiv).
The reaction mixture was stirred at room temperature for 16 h and
then filtered through silica, washed with diethyl ether, and then
concentrated in vacuo.
4.2.4. (2Z,8E)-10-Hydroxydeca-2,8-diene-4,6-diynoic acid methyl
ester (30). Following the general procedure using the iodoalkyne
ester (Z)-9 (0.44 g, 1.9 mmol), the enyne alcohol (E)-18 (0.15 g,
1.90 mmol), PdCl2(PPh3)2 (13 mg, 0.02 mmol), CuI (4 mg,
0.02 mmol), diisopropylamine (0.52 mL, 3.8 mmol) and THF (5 mL),
the resulting residue was purified by flash column chromatography
on silica using 30% ethyl acetate in petroleum ether as eluent to
give: (i) the dimethyl ester (Z,Z)-23 (83 mg, 40%) (eluted first); (ii)
the hydroxy ester (Z,E)-30 (0.20 g, 55%) (eluted second) as a colour-
less solid; mp 73–74 ꢀC (petroleum ether); Rf (30% ethyl acetate/
petroleum ether) 0.20; nmax (film/cmꢁ1) 3368, 2952, 2195, 1723,
1653 and 1597; dH (300 MHz, CDCl3) 6.46 (1H, dt, J 15.9 and 4.7,
CH]CHCH2OH), 6.23 (2H, s, CH]CHCOOCH3), 5.90 (1H, dt, J 15.9
4.2.1. (2E,8E)-, (2E,8Z)- and (2Z,8Z)-Deca-2,8-diene-4,6-diyndioic
acid dimethyl esters (21, 22 and 23). Following the general pro-
cedure using the iodoalkyne ester (Z)-9 (0.58 g, 2.5 mmol), the
enyne ester (E)-15 (0.27 g, 2.5 mmol), PdCl2(PPh3)2 (17 mg,
0.02 mmol), CuI (5 mg, 0.02 mmol), diisopropylamine (0.68 mL,
4.9 mmol) and THF (6 mL), the resulting residue was purified by
flash column chromatography on silica using 5% ethyl acetate in
petroleum ether as eluent to give: (i) the dimethyl ester (E,E)-21
(0.12 g, 45%) (eluted first) as a colourless solid; mp 105–107 ꢀC

S. Garrais et al. / Tetrahedron 65 (2009) 8418–8427
8425
and 2.0, CH]CHCH2OH), 4.28 (2H, br s, CH2OH), 3.79 (3H, s,
COOCH3), 1.68 (1H, br s, OH); dC (75 MHz, CDCl3) 164.8, 146.5, 130.9,
122.1, 108.5, 85.6, 84.6, 77.3, 74.1, 62.6, 51.7; m/z (EI) 190.0619 (Mþ,
50%, C11H10O3 requires 190.0630); and the diol (E,E)-24 (42 mg,
27%) (eluted third).
using 30% ethyl acetate in petroleum ether as eluent to give the diol
(E,E)-24 (0.12 g, 80%) as a colourless solid; mp 157–158 ꢀC (lit.15a
157–158 ꢀC) (petroleum ether); Rf (30% ethyl acetate/petroleum
ether) 0.13; nmax (film/cmꢁ1) 3189, 2932, 2908, 2871 and 1631; dH
(300 MHz, CDCl3) 6.41 (2H, dt, J 15.7 and 4.8, CH]CHCH2OH), 5.85
(2H, dt, J 15.6 and 1.6, CH]CHCH2OH), 4.26 (4H, dd, J 4.8 and 1.2,
CH2OH), 1.56 (2H, br s, OH); dC (75 MHz, CDCl3) 145.3, 109.0, 79.5,
74.5, 62.8; m/z (EI) 162.0677 (Mþ, 100%, C10H10O2 requires
162.0681).
4.2.5. (2E,8Z)-10-Hydroxydeca-2,8-diene-4,6-diynoic acid methyl
ester (31). Following the general procedure using the iodoalkyne
ester (E)-16 (0.70 g, 3.0 mmol), the enyne alcohol (Z)-11 (0.24 g,
3.0 mmol), PdCl2(PPh3)2 (21 mg, 0.03 mmol), CuI (6 mg,
0.03 mmol), diisopropylamine (0.83 mL, 6.0 mmol) and THF
(7.5 mL), the resulting residue was purified by repeated flash
column chromatography on silica using 20–30% ethyl acetate in
petroleum ether as eluent to give: (i) the dimethyl ester (E,E)-21
(0.16 g, 49%) (eluted first); (ii) a 19:1 mixture of the hydroxy
esters (E,Z)-31 and (E,E)-29 (0.10 g, 18%) (eluted second) as
a colourless solid; mp 37–38 ꢀC (lit.21 38 ꢀC) (petroleum ether); Rf
(30% ethyl acetate/petroleum ether) 0.20; nmax (film/cmꢁ1) 3416,
2952, 2201, 1721 and 1613; data corresponding to the major
isomer (E,Z)-31: dH (300 MHz, CDCl3) 6.81 (1H, dd, J 16.0 and 1.1,
CH]CHCOOCH3), 6.33 (1H, d, J 15.8, CH]CHCOOCH3), 6.31 (1H,
dt, J 11.1 and 6.4, CH]CHCH2OH), 5.68 (1H, ddt, J 11.0, 1.3 and 1.1,
CH]CHCH2OH), 4.42 (2H, dd, J 6.4 and 1.1, CH2OH), 3.76 (3H, s,
COOCH3), 1.95 (1H, br s, OH); dC (75 MHz, CDCl3) 165.8, 146.9,
132.5, 123.9, 108.8, 81.9, 80.9, 79.1, 78.6, 61.1, 52.0; m/z (EI)
190.0625 (Mþ, 100%, C11H10O3 requires 190.0630); and (iii) the
diol (Z,Z)-26 (0.10 g, 41%) (eluted third).
4.3.2. (2E,8Z)-Deca-2,8-diene-4,6-diyne-1,10-diol (25). Following the
general procedure using a solution of diisobutylaluminium hydride
(1.0 M) in hexanes (2.75 mL, 2.75 mmol), the dimethyl ester (E,Z)-22
(0.15 g, 0.68 mmol) and dichloromethane (3.5 mL), the resulting
residue was purified by flash column chromatography on silica using
30% ethyl acetate in petroleum ether as eluent to give the diol (E,Z)-
25 (0.11 g, quantitative) as a colourless solid; mp 50–52 ꢀC (petro-
leum ether); Rf (30% ethyl acetate/petroleum ether) 0.08; nmax (film/
cmꢁ1) 3367, 3306, 2920, 2903, 2839, 2202 and 1627; dH (300 MHz,
CDCl3) 6.42 (1H, dt, J 15.8 and 5.0, CH]CHCH2OH), 6.23 (1H, dt, J 11.1
and 6.4, CH]CHCH2OH), 5.86 (1H, ddt,
J 16.1, 2.0 and 0.9,
CH]CHCH2OH), 5.66 (1H, ddt, J 11.1, 1.5 and 0.9, CH]CHCH2OH),
4.41 (2H, dd, J 6.4 and 1.5, CH2OH), 4.25 (2H, dd, J 5.0 and 2.0,
CH2OH), 2.08 (2H, br s, OH); dC (75 MHz, CDCl3) 145.7, 145.2, 109.5,
108.7, 81.1, 79.5, 79.4, 74.0, 62.6, 61.1; m/z (EI) 162.0671 (Mþ, 100%,
C10H10O2 requires 162.0681).
4.3.3. (2Z,8Z)-Deca-2,8-diene-4,6-diyne-1,10-diol (26). A solution of
diisobutylaluminium hydride (1.0 M) in hexanes (5.1 mL, 51 mmol,
4 equiv) was added dropwise to a solution of the dimethyl ester
(Z,Z)-23 (0.28 g, 1.3 mmol, 1 equiv) in dichloromethane (6.5 mL,
0.2 M) at ꢁ78 ꢀC and stirred for 4 h. The reaction mixture was
quenched with a 1 M aqueous solution of hydrochloric acid (6 mL)
and then allowed to warm to room temperature. The separated
aqueous phase was extracted with dichloromethane (3ꢂ3 mL), and
the combined organic extracts were then dried over MgSO4, filtered
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography on silica using 30% ethyl acetate in petroleum
ether as eluent to give the diol (Z,Z)-26 (0.12 g, 58%) as a colourless
solid; mp 62–63 ꢀC (lit.17d 62–63 ꢀC) (petroleum ether); Rf (40%
ethyl acetate/petroleum ether) 0.25; nmax (film/cmꢁ1) 3304, 2012
and 1608; dH (300 MHz, CDCl3) 6.26 (2H, dt, J 10.8 and 6.4,
CH]CHCH2OH), 5.67 (2H, dt, J 10.8 and 0.9, CH]CHCH2OH), 4.43
(4H, dd, J 6.4 and 1.5, CH2OH), 1.65 (2H, br s, OH); dC (75 MHz,
CDCl3) 145.6, 109.1, 78.9, 78.5, 60.8; m/z (EI) 162.0685 (Mþ, 30%,
C10H10O2 requires 162.0681).
4.2.6. (2Z,8Z)-10-Hydroxydeca-2,8-diene-4,6-diynoic acid methyl
ester (32). Following the general procedure using the iodoalkyne
ester (Z)-9 (1.18 g, 5.0 mmol), the enyne alcohol (Z)-11 (0.41 g,
5.0 mmol), PdCl2(PPh3)2 (35 mg, 0.05 mmol), CuI (9 mg,
0.05 mmol), diisopropylamine (1.39 mL, 10 mmol) and THF
(12.5 mL), the resulting residue was purified by flash column
chromatography on silica using 40% ethyl acetate in petroleum
ether as eluent to give: (i) the dimethyl ester (Z,Z)-23 (0.47 g, 86%)
(eluted first); (ii) an 8:1 mixture of the hydroxy esters (Z,Z)-32 and
(Z,E)-30 (0.12 g, 13%) (eluted second) as a colourless solid; mp
47–48 ꢀC (lit.21 48 ꢀC) (petroleum ether); Rf (30% ethyl acetate/pe-
troleum ether) 0.20; nmax (film/cmꢁ1) 3422, 2951, 2198, 1718 and
1606; data corresponding to the major isomer (Z,Z)-32: dH
(300 MHz, CDCl3) 6.28 (1H, dt, J 11.0 and 6.4, CH]CHCH2OH), 6.23
(2H, s, CH]CHCOOCH3), 5.68 (1H, dt, J 11.0 and 1.3, CH]CHCH2OH),
4.41 (2H, dd, J 6.3 and 0.9, CH2OH), 3.70 (3H, s, COOCH3), 2.20 (1H,
br s, OH); dC (75 MHz, CDCl3) 164.7, 146.5, 131.1, 121.9, 108.9, 85.0,
81.9, 78.8, 78.6, 61.1, 51.7; m/z (EI) 190.0626 (Mþ, 100%, C11H10O3
requires 190.0630); and (iii) the diol (Z,Z)-26 (0.16 g, 40%) (eluted
third).
4.4. General acetylation procedure
4.3. General procedure for the reduction of the dimethyl
esters 21–23
Triethylamine (2 equiv) was added to a stirred solution of the
diol (1 equiv), acetic anhydride (4 equiv) and N,N-dimethylamino-
pyridine (0.2 equiv) in dichloromethane (0.2 M) at room tempera-
ture. The reaction mixture was stirred for 3 h and then sequentially
washed with water, brine and a saturated aqueous solution of
Na2CO3. The organic layer was dried over MgSO4, filtered and
concentrated in vacuo.
A solution of diisobutylaluminium hydride (1.0 M) in hexanes
(4 equiv) was added dropwise to a solution of the dimethyl ester
(1 equiv) in dichloromethane (0.2 M) at ꢁ78 ꢀC and stirred for 4 h.
The reaction mixture was quenched with a 1 M aqueous solution of
hydrochloric acid and then allowed to warm to room temperature.
The separated aqueous phase was extracted with dichloromethane
(3ꢂ), and the combined organic extracts were then dried over
MgSO4, filtered and concentrated in vacuo.
4.4.1. Acetic acid (2E,8E)-10-acetoxydeca-2,8-diene-4,6-diynyl ester
(27). Following the general procedure using triethylamine (85
0.60 mmol), the diol (E,E)-24 (50 mg, 0.31 mmol), acetic anhydride
(110 L, 1.2 mmol), N,N-dimethylaminopyridine (7 mg, 0.1 mmol)
mL,
m
4.3.1. (2E,8E)-Deca-2,8-diene-4,6-diyne-1,10-diol (24). Following the
general procedure using a solution of diisobutylaluminium hydride
(1.0 M) in hexanes (3.70 mL, 3.70 mmol), the dimethyl ester (E,E)-21
(0.20 g, 0.92 mmol) and dichloromethane (4.6 mL), the resulting
residue was purified by flash column chromatography on silica
and dichloromethane (1.5 mL), the resulting residue was purified
by flash column chromatography on silica using 30% ethyl acetate
in petroleum ether as eluent to give the bis-acetate (E,E)-27
(50 mg, 66%) as a yellow oil; Rf (20% ethyl acetate/petroleum ether)
0.21; nmax (film/cmꢁ1) 2930, 2206, 1737 and 1658; dH (300 MHz,

8426
S. Garrais et al. / Tetrahedron 65 (2009) 8418–8427
CDCl3) 6.31 (2H, dt, J 15.8 and 5.7, CH]CHCH2OAc), 5.82 (2H, dt,
J 15.6 and 1.5, CH]CHCH2OAc), 4.63 (4H, dd, J 5.8 and 1.5, CH2OAc),
2.09 (6H, s, COCH3); dC (75 MHz, CDCl3) 170.4, 140.0, 111.8, 79.2,
75.0, 63.6, 20.8; m/z (EI) 246.0884 (Mþ, 100%, C14H14O4 requires
246.0892).
and 1615; dH (300 MHz, CDCl3) 6.88 (1H, dq, J 7.0 and 1.2,
CH3CH]CCH3), 6.79 (1H, dd, J 15.8 and 0.9, CH]CHCOOCH3), 6.40
(1H, dt, J 16.0 and 5.3, CH]CHCH2O), 6.32 (1H, d, J 15.8,
CH]CHCOOCH3), 5.84 (1H, ddt, J 16.0, 1.7 and 0.9, CH]CHCH2O),
4.70 (2H, dd, J 5.3 and 1.7, CH2O), 3.76 (3H, s, COOCH3), 1.83 (3H, t, J
1.2, CH3CH]CCH3), 1.79 (3H, dq, J 7.0 and 1.2, CH3CH]CCH3); dC
(75 MHz, CDCl3) 167.2, 165.7, 141.8, 138.2, 132.5, 128.1, 123.9, 110.6,
82.9, 82.2, 77.9, 74.3, 63.3, 52.0, 14.4, 12.0; m/z (EI) 272.1035 (Mþ,
100%, C16H16O4 requires 272.1049).
4.4.2. Acetic acid (2E,8Z)-10-acetoxydeca-2,8-diene-4,6-diynyl ester
(28). Following the general procedure using triethylamine (85
0.60 mmol), the diol (E,Z)-25 (50 mg, 0.31 mmol), acetic anhydride
(110 L, 1.2 mmol), N,N-dimethylaminopyridine (7 mg, 0.1 mmol)
mL,
m
and dichloromethane (1.5 mL), the resulting residue was purified
by flash column chromatography on silica using 30% ethyl acetate
in petroleum ether as eluent to give an inseparable 1:2 mixture of
the bis-acetates (E,E)-27 and (E,Z)-28 (60 mg, 80%) as a yellow oil;
Rf (20% ethyl acetate/petroleum ether) 0.21; nmax (film/cmꢁ1) 2935,
2210 and 1741; data corresponding to the major isomer (E,Z)-28:
dH (300 MHz, CDCl3) 6.31 (1H, dt, J 15.8 and 5.8, CH]CHCH2OAc),
6.15 (1H, dt, J 11.0 and 6.6, CH]CHCH2OAc), 5.81 (1H, dt, J 15.6 and
2.2, CH]CHCH2OAc), 5.73 (1H, dt, J 11.0 and 1.5, CH]CHCH2OAc),
4.82 (2H, dd, J 6.6 and 1.5, CH2OAc), 4.62 (2H, dd, J 5.7 and 2.1,
CH2OAc), 2.09 (3H, s, COCH3), 2.07 (3H, s, COCH3); dC (75 MHz,
CDCl3) 170.9, 170.6, 140.4, 140.2, 111.8, 111.7, 80.8, 80.2, 79.4, 75.2,
63.8, 62.6, 21.0, 21.0; m/z (EI) 246.0883 (Mþ, 20%, C14H14O4 requires
246.0892).
4.5.2. (2Z,8E)-10-((E)-2-Methylbut-2-enoyloxy)deca-2,8-diene-4,6-
diynoic acid methyl ester (2). Following the general procedure using
dicyclohexylcarbodiimide (0.16 g, 0.79 mmol, 1.5 equiv), N,N-
dimethylaminopyridine (25 mg, 0.21 mmol, 0.4 equiv), tiglic acid
(79 mg, 0.79 mmol, 1.5 equiv), the alcohol (Z,E)-30 (0.10 g,
0.53 mmol, 1 equiv) and dichloromethane (6.5 mL), the resulting
residue was purified by flash column chromatography on silica
using 30% ethyl acetate in petroleum ether as eluent to give the
tiglate (Z,E)-2 (0.09 g, 60%) as yellow oil; Rf (10% ethyl acetate/pe-
troleum ether) 0.36; nmax (film/cmꢁ1) 2951, 2201, 1717 and 1653; dH
(300 MHz, CDCl3) 6.89 (1H, dq, J 7.1 and 1.3, CH3CH]CCH3), 6.39
(1H, dt, J 16.0 and 5.5, CH]CHCH2O), 6.23 (2H, s, CH]CHCOOCH3),
5.87 (1H, ddt, J 15.8, 1.7 and 0.7, CH]CHCH2O), 4.71 (2H, dd, J 5.5
and 1.7, CH2O), 3.77 (3H, s, COOCH3), 1.83 (3H, dq, J 1.3 and 1.1,
CH3CH]CCH3), 1.80 (3H, ddq, J 7.1, 1.1 and 0.9, CH3CH]CCH3); dC
(75 MHz, CDCl3) 167.2, 164.6, 141.3, 138.1, 131.2, 128.1, 121.9, 110.9,
85.3, 83.9, 77.5, 74.7, 63.4, 51.7, 14.4, 12.0; m/z (EI) 272.1043 (Mþ,
40%, C16H16O4 requires 272.1049).
4.4.3. (2Z,8Z)-10-Acetoxydeca-2,8-diene-4,6-diynoic acid methyl ester
(33). Following the general procedure using triethylamine (73
0.52 mmol), the alcohol 32 (0.10 g, 0.52 mmol), acetic anhydride
(100 L, 1.05 mmol), N,N-dimethylaminopyridine (13 mg,
mL,
m
0.10 mmol) and dichloromethane (2.6 mL), the resulting residue
was purified by flash column chromatography on silica using 30%
ethyl acetate in petroleum ether as eluent to give the acetoxy
matricaria ester (Z,Z)-33 (80 mg, 70%) as a yellow oil; Rf (20%
ethyl acetate/petroleum ether) 0.17; nmax (film/cmꢁ1) 2951, 2199,
1740 and 1605; dH (300 MHz, CDCl3) 6.23 (2H, s,
CH]CHCOOCH3), 6.18 (1H, dt, J 11.0 and 6.5, CH]CHCH2OAc),
5.77 (1H, dt, J 11.0 and 1.5, CH]CHCH2OAc), 4.81 (2H, dd, J 6.5
and 1.5, CH2OAc), 3.77 (3H, s, COOCH3), 2.07 (3H, s, COCH3); dC
(75 MHz, CDCl3) 170.6, 164.6, 140.8, 131.4, 121.7, 111.2, 84.7, 81.1,
79.6, 78.9, 62.2, 51.7, 20.7; m/z (EI) 232.0738 (Mþ, 100%, C13H12O4
requires 232.0736).
4.5.3. (2E,8Z)-10-((E)-2-Methylbut-2-enoyloxy)deca-2,8-diene-4,6-
diynoic acid methyl ester (3). Following the general procedure using
dicyclohexylcarbodiimide (95 mg, 0.46 mmol, 1.1 equiv), N,N-
dimethylaminopyridine (10 mg, 0.08 mmol, 0.2 equiv), tiglic acid
(46 mg, 0.46 mmol, 1.1 equiv), the alcohol (E,Z)-31 (0.08 g,
0.42 mmol, 1 equiv) and dichloromethane (5.0 mL), the resulting
residue was purified by flash column chromatography on silica
using 30% ethyl acetate in petroleum ether as eluent to give a 10:1
mixture of the tiglates (E,Z)-3 and (E,E)-1 (60 mg, 54%) as yellow oil;
Rf (10% ethyl acetate/petroleum ether) 0.33; nmax (film/cmꢁ1) 2952,
2928, 2205, 1714, 1651 and 1610; data corresponding to the major
isomer (E,Z)-3: dH (300 MHz, CDCl3) 6.88 (1H, dq, J 7.1 and 1.3,
CH3CH]CCH3), 6.80 (1H, dd, J 16.0 and 0.9, CH]CHCOOCH3), 6.32
(1H, d, J 16.0, CH]CHCOOCH3), 6.24 (1H, dt, J 10.9 and 6.4,
CH]CHCH2O), 5.75 (1H, ddt, J 11.1, 1.5 and 1.1, CH]CHCH2O), 4.88
(2H, dd, J 6.4 and 1.5, CH2O), 3.75 (3H, s, COOCH3), 1.82 (3H, dq, J 1.3
4.5. General procedure for the DCC coupling reaction
between the hydroxy matricaria esters and tiglic acid
Dicyclohexylcarbodiimide (1.5 equiv) and N,N-dimethylamino-
pyridine (0.4 equiv) were added to a stirred solution of tiglic acid
(1.5 equiv) in dichloromethane (0.15 M) at 0 ꢀC. The reaction mix-
ture was stirred for 30 min and then a solution of the alcohol
(1 equiv) in dichloromethane (0.25 M) was added dropwise. The
mixture was allowed to warm to room temperature over 16 h, di-
luted with diethyl ether, and then sequentially washed with a sat-
urated aqueous solution of NH4Cl, a saturated aqueous solution of
NaHCO3 and brine. The organic layer was dried over MgSO4, filtered
and concentrated in vacuo.
and 1.1, CH3CH]CCH3), 1.78 (3H, ddq, J 7.0, 1.1 and 0.9,
CH3CH]CCH3); dC (75 MHz, CDCl3) 167.6, 165.7, 141.9, 138.0, 132.6,
128.1, 123.7, 110.3, 81.8, 80.4, 79.2, 79.2, 62.2, 52.0, 14.3, 12.0; m/z
(EI) 272.1035 (Mþ, 70%, C16H16O4 requires 272.1049).
4.5.4. (2Z,8Z)-10-((E)-2-Methylbut-2-enoyloxy)deca-2,8-diene-4,6-
diynoic acid methyl ester (4). Following the general procedure using
dicyclohexylcarbodiimide (95 mg, 0.46 mmol, 1.1 equiv), N,N-
dimethylaminopyridine (10 mg, 0.08 mmol, 0.2 equiv), tiglic acid
(46 mg, 0.46 mmol, 1.1 equiv), the alcohol (Z,Z)-32 (0.08 g,
0.42 mmol, 1 equiv) and dichloromethane (5.0 mL, 0.15 M), the
resulting residue was purified by flash column chromatography on
silica using 30% ethyl acetate in petroleum ether as eluent to give
a 6:1 mixture of the tiglates (Z,Z)-4 and (Z,E)-2 (40 mg, 36%) as
yellow oil; Rf (10% ethyl acetate/petroleum ether) 0.38; nmax (film/
cmꢁ1) 2951, 2199, 1712, 1651 and 1606; data corresponding to the
major isomer (Z,Z)-4: dH (300 MHz, CDCl3) 6.88 (1H, dq, J 7.1 and
1.3, CH3CH]CCH3), 6.23 (2H, s, CH]CHCOOCH3), 6.22 (1H, dt, J 11.0
and 6.4, CH]CHCH2O), 5.77 (1H, dt, J 11.1 and 1.1, CH]CHCH2O),
4.89 (2H, dd, J 6.4 and 1.2, CH2O), 3.77 (3H, s, COOCH3), 1.82 (3H, q, J
1.3, CH3CH]CCH3), 1.78 (3H, dq, J 7.1 and 1.3, CH3CH]CCH3); dC
4.5.1. (2E,8E)-10-((E)-2-Methylbut-2-enoyloxy)deca-2,8-diene-4,6-
diynoic acid methyl ester (1). Following the general procedure using
dicyclohexylcarbodiimide (0.16 g, 0.79 mmol, 1.5 equiv), N,N-
dimethylaminopyridine (25 mg, 0.21 mmol, 0.4 equiv), tiglic acid
(79 mg, 0.79 mmol, 1.5 equiv), the alcohol (E,E)-29 (0.10 g,
0.53 mmol, 1 equiv) and dichloromethane (6.5 mL), the resulting
residue was purified by flash column chromatography on silica
using 30% ethyl acetate in petroleum ether as eluent to give the
tiglate (E,E)-1 (0.12 g, 79%) as yellow oil; Rf (10% ethyl acetate/pe-
troleum ether) 0.35; nmax (film/cmꢁ1) 2952, 2205, 1722, 1717, 1653

S. Garrais et al. / Tetrahedron 65 (2009) 8418–8427
8427
13. Hofmeister, H.; Annen, K.; Laurent, H.; Wiechert, R. Angew. Chem., Int. Ed. Engl.
1984, 23, 727–729.
(75 MHz, CDCl3) 167.6, 164.6, 141.4, 138.1, 131.3, 128.2, 121.7, 110.9,
84.9, 81.4, 79.5, 78.8, 62.3, 51.7, 14.3, 12.0; m/z (EI) 272.1043 (Mþ,
40%, C16H16O4 requires 272.1049).
14. (a) Bu’Lock, J. D.; Jones, E. R. H.; Turner, W. B. J. Chem. Soc. 1957, 1607–1617;
(b) Marvell, E. N.; Seubert, J.; Vogt, G.; Zimmer, G.; Moy, G.; Siegmann, J. R.
Tetrahedron 1978, 34, 1323–1332; (c) Barrett, A. G. M.; Hamprecht, D.; Oh-
kubo, M. J. Org. Chem. 1997, 62, 9376–9378; (d) Wei, X.; Taylor, R. J. K. Tet-
rahedron Lett. 1998, 39, 3815–3818; For the synthesis and isolation of 21. Also
see Ref. 15b.
Acknowledgements
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We thank the Nuffield Foundation (summer studentship to J.T.)
for their support of this work.
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