Synthesis of carboxyl-tethered symmetric conjugated polyenes as fluorescent transmembrane probes of lipid bilayers

Article abstract of DOI:10.1002/ejoc.200390187

The synthesis of a new series of fluorescent transmembrane probes in which two hydrophilic methyl ester or carboxyl groups are connected by a polymethylene chain, with four, five or six conjugated double bonds in a central position, is reported. The length of the linear structures was designed to match the width of typical lipid bilayers. These bolaamphiphilic compounds result, with overall yields higher than 80%, from an easy Pd^II-catalyzed double cross-coupling between terminal acetylene esters and conjugated 1,ω-dihalopolyenes, followed by selective triple bond partial reduction with activated zinc, and iodine isomerization to the all-(E) isomer. An alternative approach, based on a Stille double cross-coupling between the appropriate all-(E)-ω-halopolyenes and (E)-bis(tributylstannyl)ethene, yielded mixtures that could not be resolved by standard chromatographic methods due to the presence of other simultaneous coupling reactions, which are also discussed in detail. Nevertheless, the Stille method can be of utility for the obtention of carbonyl-polyene conjugated analogs. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390187

FULL PAPER
Synthesis of Carboxyl-Tethered Symmetric Conjugated Polyenes as Fluorescent
Transmembrane Probes of Lipid Bilayers
[b]
[a]
Ernesto Quesada,[a,b] A. Ulises Acuna, and Francisco Amat-Guerri*
˜
Keywords: Amphiphiles / Membranes / Lipids / Polyenes / Cross-coupling
The synthesis of a new series of fluorescent transmembrane
probes in which two hydrophilic methyl ester or carboxyl
groups are connected by a polymethylene chain, with four,
five or six conjugated double bonds in a central position, is
reported. The length of the linear structures was designed to
match the width of typical lipid bilayers. These bolaamphi-
philic compounds result, with overall yields higher than 80%,
from an easy PdII-catalyzed double cross-coupling between
terminal acetylene esters and conjugated 1,ω-dihalopoly-
enes, followed by selective triple bond partial reduction with
activated zinc, and iodine isomerization to the all-(E) isomer.
An alternative approach, based on a Stille double cross-
coupling between the appropriate all-(E)-ω-halopolyenes
and (E)-bis(tributylstannyl)ethene, yielded mixtures that
could not be resolved by standard chromatographic methods
due to the presence of other simultaneous coupling reactions,
which are also discussed in detail. Nevertheless, the Stille
method can be of utility for the obtention of carbonyl-polyene
conjugated analogs.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
design to a series of similar polyene groups, and communi-
cated the preliminary data of a new family of transmem-
brane fluorescent probes, with a symmetric bolaamphiphile
structure with methyl ester or carboxyl groups as polar
heads (compounds 4 and 5, respectively, Scheme 1) and
with four, five or six conjugated all-(E) double bonds in
The biamphiphilic structure of the bipolar transmem-
brane lipids of Archaebacteria stabilizes these primitive or-
ganisms against hostile environments.[1] The same concept,
with two hydrophilic groups connected by a linear apolar
chain (a bolaamphiphile),[2] with a length matching that of
natural or synthetic membranes, has been used for the in-
clusion of predetermined chemical groups into mem-
branes.[3] When this group is a fluorescent chromophore,[4]
the resulting structure allows one to probe the physical and
chemical properties of bilayers, with the added advantage
of knowing with accuracy the transverse location of the
sensing group.
We have previously reported new amphiphilic fluorescent
probes consisting of linear C12-, C15- or C18-chain fatty ac-
ids with a conjugated pentaene distal group.[5] These com-
pounds widened the scope of application of linear conju-
gated polyenes to membrane research, a field pioneered by
Sklar and co-workers[6] with the development of fluorescent
membrane probes with four conjugated double bonds (pari-
naric acids). To restrict the uncertainty of the transverse
location within the bilayer of the distal sensing group, we
have recently applied the biomimetic membrane-spanning
[a]
´
´
Instituto de Quımica Organica, C.S.I.C.
Juan de la Cierva 3, 28006 Madrid, Spain
Fax: (internat.) ϩ 34-91/564-4853
E-mail: famat@fresno.csic.es
Scheme 1. i) 1/2 ratio ϭ 3:1 (mol), [PdCl2(PPh3)2] (10 mol %), CuI
(20 mol %), Et2NH, THF, Ar, room temperature, 3 h, Ͼ 95%; ii)
Zn(Cu/Ag), MeOH/H2O (1:1), room temperature, 24 h, Ն 95%; iii)
I2 (trace), hexane, Ar, reflux, 15 min, Ͼ 95%; iv) KOH (10 equiv.),
EtOH (95%), Ar, reflux, 5 h; then 0°, HCl (5%), Ն 95%
[b]
´
´
Instituto de Quımica Fısica Rocasolano, C.S.I.C.
Serrano 119, 28006 Madrid, Spain
Fax: (internat.) ϩ 34-91/564-2431
E-mail: roculises@iqfr.csic.es
1308
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0407Ϫ1308 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 1308Ϫ1318

Carboxyl-Tethered Symmetric Conjugated Polyenes
FULL PAPER
the central position of the molecule.[7] These probes were the latter intermediates has been used recently for the stere-
specifically designed for comparative studies of the dynamic ocontrolled synthesis of several conjugated trienediyne sys-
fluctuations of the inner part of lipid bilayers as a function tems.[11] Nevertheless, in the present work we preferred the
of lipid composition, with time-resolved fluorescence tech- SonogashiraϪHagihara reaction due to its milder exper-
niques.
imental conditions and its compatibility with many func-
In the present work we describe in detail the synthesis of tional groups.
a series of bolaamphiphilic polyenic compounds through
In our hands, compounds 3 were formed at room tem-
the so-called acetylenic approach, which basically consists perature, with yields higher than 95% after reaction times
of an sp-sp2 transition-metal-mediated cross-coupling by a of a few hours, with a molar ratio alkyne/dihalopolyene of
SonogashiraϪHagihara reaction, followed by partial re- 3:1. As expected, (E)/(Z) mixtures of polyenes 2 yielded the
duction of the triple bond of the ene-yne compound so gen- same mixtures of isomeric products 3, because the reaction
erated. The SonogashiraϪHagihara reaction is a versatile proceeds with complete chemo- and stereoselectivity and
CϪC bond-forming reaction that has previously been used stereospecificity. all-(E)-3 isomers were readily separated
for the synthesis of related transmembrane probes with from these mixtures by selective precipitation at room tem-
emitting fluorene[4a] or anthracene[4c] groups. We also re- perature from n-pentane, a solvent in which compounds 3
port on the application of the Stille reaction to obtain the with one (Z)-configured double bond are soluble. This sep-
conjugated heptaene compounds 8a and 8b (Scheme 2), and aration can be avoided if only all-(E) isomers 4 are sought,
discuss the divergent results found in the case of the com- because (Z)-configured double bonds can easily be iso-
pound 8c, a homolog of the former esters 4.
merized by a final treatment with traces of iodine (see be-
low). This alternative simplifies the synthetic process and
allows the use of the starting 1,ω-dihalopolyenes 2 in the
form of (E)/(Z) mixtures.
Traces of the corresponding alkyneϪalkyne homocoup-
ling products were detected in some of the former cross-
coupling reaction mixtures (highest observed yield 5%,
products not shown), and could also be separated from the
all-(E)-3 products by washing with n-pentane. The PdII-cat-
alyzed homocoupling process is an expected secondary re-
action when PdII species are used as a metal source,[12] but
the cross-coupling products 3 were formed in almost quan-
titative yield with 10 mol % of [PdCl2(PPh3)2] (relative to
2). Complete exclusion of oxygen is important to prevent
oxidation of the in situ-formed Pd0 species, the active cata-
lyst of the cross-coupling (see below). When the Pd0 catalyst
[Pd(PPh3)4] was used instead, also under rigorous exclusion
of oxygen, much longer reaction times (Ͼ 24 h) were neces-
sary for completing the reaction, with the added disadvan-
Scheme 2. i) 6/7 ratio ϭ 2:1 (mol), Pd0 from [PdCl2(PPh3)2] ϩ DI-
BAL in THF (8 mol %), DMF, Ar, room temperature, 12 h
Results and Discussion
Synthesis of Polyene Probes by sp-sp2 Double Cross-
Coupling Followed by Selective Partial Reduction
(Acetylenic Approach)
Probes 4 and 5 have been synthesized as shown in tage of the simultaneous degradation in the medium of both
Scheme 1. The first step was palladium-catalyzed the starting dihalopolyenes 2 and the catalyst, in the latter
SonogashiraϪHagihara double cross-coupling reaction[8] case detected by precipitation of metallic Pd0.
between terminal acetylenic methyl esters 1 and conjugated The triple-to-double-bond reduction in the resulting po-
a
1,ω-dihalopolyenes 2 with two, three or four double bonds lyenediyne compounds 3 may be carried out by several
to give polyenediyne compounds 3, which already have a methods.[13] Isolated triple bonds in structures with several
bipolar structure. Although the cross-coupling of 1,2-dihal- conjugated double bonds have been efficiently and selec-
oethenes with terminal alkynes has been frequently used to tively semihydrogenated to double bonds in the presence of
obtain the related 3-ene-1,5-diyne system,[9] and the exten- Lindlar or similar catalysts,[14] although this method often
sion of this method to two-step couplings made it possible fails when the triple bond is conjugated with one or more
to reach asymmetric structures, to the best of our knowl- double bonds. In that case, the result depends on the num-
edge this is the first time that conjugated 1,ω-dihalopoly- ber of double bonds and on the relative position of the tri-
enes with more than one double bond have been employed ple bond,[15] and the isolation of the resulting polyene usu-
for the synthesis of symmetric polyenediyne compounds ally requires complex purification processes. A more pro-
such as 3 by said double cross-coupling reaction. Terminal mising alternative is the use of activated metals as reduc-
acetylenes are usually activated for their reaction with sp2 tants.[16] More specifically, the use of zinc activated by CuII
centres by the formation of alkynyllithium or alkynyl Grig- acetate and AgI nitrate in water (Boland Zn activation[17]
)
nard intermediates or, more recently, through intermediates is gaining importance as a clean, mild and efficient method
with other metals — mainly Zn, B or Sn — which are sub- for the selective semireduction of triple bonds conjugated
sequently involved in transition-metal-catalyzed pro- with double bonds to (Z)-alkenes, without affecting the
cesses.[10] The reaction of dibromotriene 2b with some of double bonds or any isolated triple bond in the molecule.[18]
Eur. J. Org. Chem. 2003, 1308Ϫ1318
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E. Quesada, A. U. Acun˜a, F. Amat-Guerri
FULL PAPER
The use of this and related methods in the synthesis of natu- ratio), even though the expected reaction products 8a and
ral products with several conjugated double bonds, by semi- 8b, respectively, do not have the proper length for their use
reduction of conjugated alkynes generated through metal- as membrane-spanning probes. In the presence of
catalyzed sp-sp2 cross-coupling, is known as the acetylenic [PdCl2(PPh3)2] or [PdCl2(CH3CN)2], two PdII catalysts
approach.[17b] This combination has been shown to be an widely employed in the synthesis of polyene systems by
efficient route for obtaining conjugated polyene compounds Stille coupling,[24] 8a and 8b were obtained with yields of
with stereochemical control,[19] and in some cases is the 15 and 40%, respectively. Higher yields — 40 and 70% —
only practical way for just obtaining the target product.[20]
were obtained using the Pd0 species generated in situ by the
We have successfully used this approach for the selective reduction of [PdCl2(PPh3)2] with DIBAL (Negishi’s cata-
semireduction of the polyenediyne compounds 3 to the cor- lyst[25]), a species used in the synthesis of highly unsaturated
responding (Z,...,Z)-polyenes, always attaining yields higher natural products when the former PdII catalysts were not
than 95%. The resulting polyenes are not stable in wet particularly effective.[26]
CHCl3 or wet CDCl3, and shortly after the dissolution of
The lower yield of 8a relative to 8b, obtained with any of
any (Z,...,Z) isomer in nontreated CDCl3, the respective the three former catalysts under comparable reaction con-
(Z,...,E) and (E,...,E) isomers can be detected in the 1H ditions, could be a consequence of the lower electron den-
NMR spectrum. This isomerization must be due to traces sity at the Sn-bound carbon atom in the intermediate
of HCl/DCl in the solvent, because the reaction is absent in monocoupling product from 6a and 7, with regard to the
alumina-filtered and dried CDCl3. Similar acid-catalyzed same product from 6b and 7. This difference would give rise
(Z) Ǟ (E) isomerizations have been observed in some reti- to a lower reactivity of the former monocoupling product
noic acid derivatives and in other highly conjugated polyene with another molecule of 6a. In fact, traces of the mono-
1
systems.[21] This might be an easy, albeit slow, procedure coupling product from 6a and 7 were detected in the H
for the isomerization of the former (Z,...,Z)-polyenes to the NMR spectrum of the crude reaction mixtures.
corresponding all-(E) isomers 4. However, a gradual poly-
The synthesis of the pentaene diester 8c was then at-
ene loss was also observed in chloroform solution, even at tempted by coupling the iododiene ester 6c with 7, in the
low temperature, so that the preferred procedure was the presence of [PdCl2(PPh3)2]/DIBAL catalyst, i.e. the catalyst
use of traces of iodine in hexane, because in this way the that gave higher yields in the former couplings. However,
isomerization reaction yielding 4 was completed in a few even with careful exclusion of oxygen, the reaction product
minutes, without product degradation. A final alkaline hy- was always a mixture containing ca. 85% of the expected
drolysis produced the target diacids 5 after careful acidifi- probe 8c (as estimated from the absorption spectrum, Fig-
cation and washing.
ure 1) and ca. 15% (overall) of the corresponding tetraene,
The former sequence (Scheme 1) yielded the diacids 5 hexaene (4e, formerly obtained in pure form through the
with good overall yields (Ն 80%) and can be extended to acetylenic approach, Scheme 1), and heptaene diesters.
obtain similar compounds with different chain length, num- Traces (less than 5%) of the starting iododiene 6c were also
ber of conjugated double bonds or stereochemistry. Com- found (1H NMR spectroscopy), but not the monocoupling
pounds 3Ϫ5 are thermally stable as solids for several product from 6c and 7 (compound IV in Scheme 4, below).
months if kept in a cool and dark place, and their solubility The polyene components of the mixture, with very similar
in EtOH or DMSO is in the range of 1Ϫ10 µ. These pro- polarity, could not be separated by standard TLC on silica
bes have been designed to span the width of typical lipid gel using different eluents (a single spot was always ob-
bilayers, i.e. with a maximum expanded length of 35Ϫ43 served), even after silver nitrate impregnation. The fraction
[22]
˚
A,
so that the terminal polar groups can reach the two of tetraene diester was much higher (ca. 70%) using as cata-
opposite membrane surfaces, and the polyene chromophore
is located in the bilayer centre.
Synthesis of Polyene Probes by Direct sp2-sp2 Double
Cross-Coupling (Stille Approach)
An alternative synthetic approach, also assayed here to
obtain bolaamphiphilic polyene probes, consists of the di-
rect sp2-sp2 stitching cross-coupling between all-(E)-halopo-
lyenes 6 (Scheme 2) and the easily accessible bis(stannane)
(E)-bis(tributylstannyl)ethene (7), in the presence of pal-
ladium catalysts under conditions of the Stille reaction.[23]
This initially promising approach would yield all-(E)-poly-
enes 8 in only one fully stereo- and regioselective step. (E)/
(Z) isomeric mixtures of 6 may also be used in the coupling,
because the reaction products could be converted into the
corresponding all-(E) isomers with traces of iodine, as
above. We first studied the reaction between the model
Figure 1. Absorption spectrum of the raw product from the Stille
cross-coupling reaction 6c and 7, showing the assignments of the
observed maxima (see Scheme 4); EtOH, 22 °C; the spectrum of
bromotrienes 6a and 6b, and the bis(stannane) 7 (2:1 molar the tetraene diester 4a is included for comparison
1310
Eur. J. Org. Chem. 2003, 1308Ϫ1318

Carboxyl-Tethered Symmetric Conjugated Polyenes
FULL PAPER
lyst any of the former PdII species [PdCl2(PPh3)2] or
[PdCl2(CH3CN)2]. The selectivity of the reaction and the
yield of tetraene diester were similar when using Pd0 com-
plexes having the poor electron-donating ligands trifuryl-
phosphane or triphenylarsane (Farina’s conditions[27]), al-
though these complexes strongly increase the cross-coupling
rate in Stille reactions, providing a successful route to un-
saturated natural products.[28] In all these cases, the selec-
tivity of the coupling 6c and 7 was scarcely improved by
changing the reaction time, the catalyst amount (in the
range 4Ϫ10 mol % of 7) or the sequence and way of ad-
dition of the reactants.
Although some aspects of the Stille reaction mechanism
are not completely understood, and some formerly estab-
lished points are now being questioned,[29] the former re-
sults can be understood by reference to the commonly ac-
cepted cycle of Pd0 catalysis (Scheme 3).[23] When PdII spec-
Scheme 3. Catalytic cycle in Stille cross-coupling reactions (adapted
from ref.[23c]
)
ies are used, an initial reduction to Pd0 yields, at the same ine in 6c by the tributylstannyl group from 7, yielding com-
time, the stannaneϪstannane homocoupling by-product, a pound III, in a process that could compete with the trans-
process favored by traces of oxygen due to the easy Pd0 metalation of step 2 in Scheme 3. Intermediate III would
Ǟ PdII back oxidation, especially in stannanes with several produce the observed tetraene diester through Pd0-cata-
conjugated double bonds.[30] In fact, this homocoupling has lyzed coupling with 6c, or through PdII-catalyzed homo-
been used for synthetic purposes.[31] Step 1 of the catalytic coupling III ϩ III. The higher fraction of the tetraene dies-
cycle is an oxidative addition of the electrophile producing ter when PdII species were used as catalysts supports the
the intermediate A, and, when a halovinyl group is involved, existence of the latter homocoupling. The homocoupling of
the initial stereochemistry of the double bond is retained. 6c (not shown) could also give rise to the tetraene diester.
Step 2, usually the limiting process in Stille couplings, is the However, in our case this process does not take place be-
SnϪPd transmetalation with production of the intermedi- cause no reaction was observed when 6c was treated under
ate B.[32] Step 3 is a final reductive elimination to yield the the same reaction conditions but in the absence of 7. The
coupling product and regenerating the catalytically active hexaene diester 4e could also result from homocoupling of
Pd0 species.
IV, the product from the reaction 6c and 7.
A similar lack of selectivity was formerly found in direct
In the PdII-catalyzed process between 6c and 7, the initial
homocoupling reaction of 7 would produce all-(E)-1,4-bis- Stille cross-coupling reactions between highly unsaturated
(tributylstannyl)-1,3-butadiene (I, Scheme 4) and all-(E)- conjugated systems and unsaturated bis(stannanes). Mix-
1,6-bis(tributylstannyl)-1,3,5-hexatriene (II), the reaction of tures of conjugated polyenes with a different number of
any of which with two mol-equiv. of 6c would yield the double bonds,[33] or mixtures of homocoupling by-products
corresponding hexaene 4e and heptaene diesters. The occur- from halogen/tin exchange[34] were obtained, but in all the
rence of the starting compound 6c in the reaction mixtures cases the target products were easily separated by standard
can be partially explained by this stannane-consuming chromatography. In spite of the frequent presence of by-
homocoupling. The formation of polyene compounds can products, these cross-coupling reactions have been applied
also be explained by the PdII-catalyzed exchange of the iod- with success to the synthesis of carotenoids.[35]
Scheme 4. Possible competing reactions for the appearance of the observed products in the Stille cross-coupling 6c and 7
Eur. J. Org. Chem. 2003, 1308Ϫ1318
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E. Quesada, A. U. Acun˜a, F. Amat-Guerri
FULL PAPER
(quint, J ϭ 6.6 Hz, 2 H, 9-H), 1.60 (quint, J ϭ 7.2 Hz, 2 H, 3-H),
1.92 (t, J ϭ 2.7 Hz, 1 H, 12-H), 2.16 (dt, J ϭ 2.7, 6.6 Hz, 2 H, 10-
H), 2.29 (t, J ϭ 7.2 Hz, 2 H, 2-H), 3.65 (s, 3 H, CH3). 1c: 1H NMR
(300 MHz, CDCl3): δ ϭ 1.45Ϫ1.25 (m, 14 H, 4-H to 10-H), 1.51
(quint, J ϭ 6.9 Hz, 2 H, 11-H), 1.62 (quint, J ϭ 7.2 Hz, 2 H, 3-H),
1.94 (t, J ϭ 2.6 Hz, 1 H, 14-H), 2.19 (dt, J ϭ 2.6, 6.9 Hz, 2 H, 12-
H), 2.29 (t, J ϭ 7.2 Hz, 2 H, 2-H), 3.66 (s, 3 H, CH3) ppm. (1E,3E)-
1,4-Diiodo-1,3-butadiene (2a) was synthesized from acetylene, as
described.[38] 1,6-Dibromo-1,3,5-hexatriene [all-(E)/(1Z,3E,5E),
1:4] (2b) was obtained as described.[39] 1,8-Dibromo-1,3,5,7-octate-
traene [all-(E)/(1Z,3E,5E,7E), 1:4] (2c), all-(E)-7-bromo-2,4,6-hep-
tatrienal (6a) and ethyl all-(E)-7-bromo-2,4,6-heptatrienoate (6b)
were synthesized as follows: (2E,4E)-5-bromo-2,4-pentadienal[39]
(1.0 g, 6.21 mmol) was treated with triethyl phosphonoacetate in
10  K2CO3 in water[40] to yield ester 6b (yield 1.33 g, 93%); this
ester (0.80 g, 3.46 mmol) was reduced to the corresponding allylic
alcohol with 2 equiv. of DIBAL in toluene/CH2Cl2 at Ϫ78 °C (yield
0.62 g, 95%). This unstable alcohol was immediately oxidized to
the all-(E)-aldehyde 6a with activated MnO2 (yield 0.58 g, 95%),
and this aldehyde (0.30 g, 1.6 mmol) was treated at Ϫ50 °C with
the ylide generated from (bromomethyl)triphenylphosphonium
bromide by treatment with tBuOK in THF, yielding 2c. Purifi-
cation by column chromatography (silica gel, hexane/ethyl acetate,
9:1). Yield 0.36 g, 86%. 2c: 1H NMR (300 MHz, CDCl3): δ ϭ
6.15Ϫ6.25 [m, 4 H, 3-H to 6-H in all-(E) isomer], 6.10Ϫ6.45 [m, 5
H, 3-H, 6-H, 7-H, 8-H in (1Z,3E,5E,7E) isomer], 6.37 [d, J ϭ
13.5 Hz, 2 H, 1-H, 8-H in all-(E) isomer], 6.65 [d, J ϭ 8.7 Hz, 1
H, 1-H in (1Z,3E,5E,7E) isomer], 6.50Ϫ6.70 [m, 2 H, 4-H, 5-H in
(1Z,3E,5E,7E) isomer], 6.77 [dd, J ϭ 10.8, 13.5 Hz, 1 H, 2-H in
(1Z,3E,5E,7E) isomer], 6.80Ϫ6.70 [m, 2 H, 2-H, 7-H in all-(E) iso-
mer] ppm. FT IR (KBr): ν˜max ϭ 3078, 3023, 2936, 1604, 1436,
1329, 1008, 936, 693 cmϪ1. EI MS (70 eV): m/z (%) ϭ 262 (8) [Mϩ],
According to the above results, it can be concluded that
the Stille reaction, as shown here, is not a convenient
method for the synthesis of polyene esters such as 8c, due to
the generation of mixtures of compounds with very similar
chromatographic properties on standard silica gel chroma-
tography, although the reaction can be used for reaching
the carbonyl-polyene conjugated compounds 8a and 8b.
The previously commented acetylenic approach should be
preferred for the synthesis of bolaamphiphilic polyene
structures such as 8c.
Experimental Section
General Remarks: All solvents were freshly distilled prior to use.
THF was distilled from sodium/benzophenone; dichloromethane,
hexane, and pentane from CaH2, and diethylamine from BaO. All
reactions were carried out under total absence of oxygen in oven-
dried Schlenk-type flasks, and the solvents were deoxygenated by
several vacuum-argon cycles. Analytical thin layer chromatography
was performed on precoated aluminium silica gel plates, Merck
60F254, 0.25 mm. Flash column chromatography was carried out
on silica gel (Merck, 230Ϫ400 mesh). Melting points were meas-
ured with a ReichertϪKofler hot-stage microscope and are uncor-
rected. Yields are referred to isolated pure compounds. Elemental
analyses were done with a Carlo Erba CHN-1108 microanalyser.
1H and 13C NMR spectra were taken at 30 °C, unless otherwise
noted, with Varian Gemini-200, INOVA-300, -400 or -500 spec-
trometers. Chemical shifts are reported in parts per million (ppm),
using as internal reference the proton signal of the trace of undeut-
erated solvent or the carbon signal of the deuterated solvent: δ ϭ
1
7.26 and 77.0 ppm in CDCl3;
δ ϭ 2.45 and 39.5 ppm in
185 (4), 183 (5), 174 (6), 149 (5), 104 (100), 91 (21). 6a: H NMR
[D6]DMSO; and δ ϭ 7.40 and 128.7 ppm in C6D6. Abbreviations:
s (singlet), d (doublet), t (triplet), q (quadruplet), quint (quintet),
m (complex multiplet). Carbon and proton assignments are based
on DEPT, HSQC and HMQC experiments. The fractions of (E)/
(Z) isomers were calculated from 1H NMR relative integrals of
characteristic signals. Infrared spectra (in cmϪ1) were recorded with
PerkinϪElmer 681 or FT-Spectrum One spectrophotometers. Mass
spectra were recorded by electron impact (70 eV) with a low-resolu-
tion HewlettϪPackard 5973 spectrometer, in the direct injection
mode. High resolution mass spectra were determined with an Auto-
SpecEQ EI apparatus. UV/Vis absorption spectra were registered
with Varian CARY-3E or PerkinϪElmer Lambda-2 spectrophoto-
meters.
(400 MHz, CDCl3): δ ϭ 6.22 (d, J ϭ 7.9 Hz, 1 H, 2-H), 6.46 (dd,
J ϭ 10.8, 15.2 Hz, 1 H, 4-H), 6.56 (dd, J ϭ 10.8, 15.2 Hz, 1 H, 5-
H), 6.66 (d, J ϭ 13.6 Hz, 1 H, 7-H), 6.85 (dd, J ϭ 10.8, 13.6 Hz,
1 H, 6-H), 7.08 (dd, J ϭ 10.4, 15.6 Hz, 1 H, 3-H), 9.58 (d, J ϭ
7.9 Hz, 1 H, 1-H) ppm. 6b: 1H NMR (300 MHz, CDCl3): δ ϭ 1.29
(t, J ϭ 7.2 Hz, 3 H, CH3), 4.2 (q, J ϭ 7.2 Hz, 2 H, CH2), 5.95 (d,
J ϭ 15.2 Hz, 1 H, 2-H), 6.33 (dd, J ϭ 10.8, 14.8 Hz, 1 H, 4-H),
6.44 (dd, J ϭ 10.8, 14.8 Hz, 1 H, 5-H), 6.55 (d, J ϭ 13.6 Hz, 1 H,
7-H), 6.80 (dd, J ϭ 10.8, 13.6 Hz, 1 H, 6-H), 7.25 (dd, J ϭ 10.8,
15.2 Hz, 1 H, 3-H) ppm. Methyl all-(E)-14-iodo-11,13-tetradecadi-
enoate (6c) was prepared immediately prior to use as follows: 1)
11-bromoundecanoic acid was treated with triphenylphosphane to
yield (11-carboxyundecyl)triphenylphosphonium bromide;[41] 2)
this salt (2.70 g, 5 mmol) was converted into the corresponding yl-
ide by reaction with sodium bis(trimethylsilyl)amide (10 mmol),
and the ylide was then treated with freshly prepared (E)-3-iodopro-
penal (0.91 g, 5 mmol) in dry THF,[42] yielding 14-iodo-11,13-tetra-
decadienoic acid [yield 0.95 g, 54%, (11E,13E)/(11Z,13E), 4:6]; 3)
the former mixture was converted into the all-(E) isomer with
traces of iodine in wet chloroform (yield 0.90 g, 95%); 4) a final
esterification of the acid as above (MeOH/SOCl2) produced the
unstable iododiene ester 6c (yield 0.80 g, 85%). 1H NMR
(400 MHz, CDCl3): δ ϭ 1.27 (broad s, 10 H, 4-H to 8-H), 1.37
(quint, J ϭ 7.2 Hz, 2 H, 9-H), 1.63 (quint, J ϭ 7.2 Hz, 2 H, 3-H),
2.03 (ddt, J ϭ 1.2, 6.8, 7.2 Hz, 2 H, 10-H), 2.35 (t, J ϭ 7.2 Hz, 2
H, 2-H), 3.66 (s, 3 H, CH3), 5.72 (dt, J ϭ 6.8, 15.2 Hz, 1 H, 11-
H), 5.96 (dddt, J ϭ 0.4, 1.6, 10.8, 15.2 Hz, 1 H, 12-H), 6.15 (dt,
J ϭ 0.4, 14.4 Hz, 1 H, 14-H), 6.98 (ddd, J ϭ 0.8, 10.8, 14.4 Hz, 1
H, 13-H) ppm. (E)-Bis(tributylstannyl)ethene (7) was obtained as
Materials: Chemicals were purchased from Aldrich, Lancaster or
Across, and were used without further purification. Methyl 10-un-
decynoate (1a) was obtained (95% yield) by esterification of the
corresponding acid with MeOH/SOCl2.[4a] 1H NMR (400 MHz,
CDCl3): δ ϭ 1.30 (m, 6 H, 5-H to 7-H), 1.38 (m, 2 H, 4-H), 1.50
(quint, J ϭ 6.8 Hz, 2 H, 8-H), 1.60 (quint, J ϭ 7.2 Hz, 2 H, 3-H),
1.92 (t, J ϭ 2.6 Hz, 1 H, 11-H), 2.16 (dt, J ϭ 2.6, 6.8 Hz, 2 H, 9-
H), 2.29 (t, J ϭ 7.2 Hz, 2 H, 2-H), 3.63 (s, 3 H, CH3) ppm. 13C
NMR (100 MHz, CDCl3): δ ϭ 18.2 (C-9), 24.7 (C-3), 28.9, 28.8,
28.7, 28.5, 28.3 (C-4 to C-8), 33.8 (C-2), 51.2 (CH3), 67.0 (C-11),
84.4 (C-10), 173.9 (CϭO) ppm. Methyl 11-dodecynoate (1b) and
methyl 13-tetradecynoate (1c) were prepared from 9-dodecyn-1-ol
and 3-tetradecyn-1-ol, respectively, by triple bond zipper isomeriz-
ation to the terminal position,[36] Jones oxidation to the corre-
sponding carboxylic acid[37] and esterification, as above. Overall
yields Ͼ 60% from 36 mmol of starting alkynol. 1b: 1H NMR
(300 MHz, CDCl3): δ ϭ 1.20Ϫ1.45 (m, 10 H, 4-H to 8-H), 1.50 described.[43] All the palladium catalysts were purchased from com-
1312 Eur. J. Org. Chem. 2003, 1308Ϫ1318

Carboxyl-Tethered Symmetric Conjugated Polyenes
FULL PAPER
mercial sources. The Pd0 catalyst for Stille couplings was freshly
generated in situ by reduction of [PdCl2(PPh3)2] (1 equiv.) with DI-
BAL (2 equiv., 1  solution in THF) in dry THF under an inert
gas, according to the Negishi method.[25] The Pd0 catalysts used
under Farina conditions[27] were prepared in situ by treating the
Pd0 complex [tris(dibenzylideneacetone)dipalladium(0)] with trifur-
ylphosphane or triphenylarsane.
mixture. Yield 9 mg, 19%. Yellow crystals, m.p. 69Ϫ70 °C (pen-
tane). Rf ϭ 0.73 (hexane/EtOAc, 7:3). 1H NMR (400 MHz,
CDCl3): δ ϭ 1.30 (m, 12 H, 4-H to 6-H, 23-H to 25-H), 1.38 (m,
4 H, 7-H, 22-H), 1.52 (quint, J ϭ 7.2 Hz, 4 H, 8-H, 21-H), 1.61
(quint, J ϭ 7.3 Hz, 4 H, 3-H, 26-H), 2.30 (t, J ϭ 7.6 Hz, 4 H, 2-
H, 27-H), 2.33 (dt, J ϭ 2.2, 7.2 Hz, 4 H, 9-H, 20-H), 3.66 (s, 6 H,
2 ϫ CH3), 5.63 (dt, J ϭ 2.2, 15.6 Hz, 2 H, 12-H, 17-H), 6.25 (m, 2
H, 14-H, 15-H), 6.50 (ddd, J ϭ 3.2, 7.2, 15.6 Hz, 2 H, 13-H, 16-
H) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 19.7 (C-9, C-20), 24.9
(C-3, C-26), 28.6, 28.8, 28.9, 29.06, 29.09 (C-4 to C-8, C-21 to C-
25), 34.1 (C-2, C-27), 51.5 (CH3), 80.2 (C-11, C-18), 95.1 (C-10, C-
19), 113.1 (C-12, C-17), 133.2 (C-14, C-15), 140.1 (C-13, C-16),
174.3 (CO) ppm. IR (KBr): ν˜max ϭ 2940, 2860, 2210, 1735, 1470,
1440, 1175, 990 cmϪ1. EI MS (70 eV): m/z (%) ϭ 468 (38) [Mϩ],
437 (5), 311 (15), 183 (21), 169 (51), 155 (100), 141 (68), 129 (62).
UV (CHCl3): λmax (ε, L·molϪ1·cmϪ1) ϭ 343 (77000), 326 (74000),
312 nm (45000); UV (1,4-dioxane): λmax (ε, L·molϪ1·cmϪ1) ϭ 310
(49000), 325 (85000), 341 nm (92000). C30H44O4 (468.67): calcd. C
76.88, H 9.46; found C 76.63, H 9.40.
Synthesis of Polyenediyne Diesters 3 by Sonogashira؊Hagihara
Double Cross-Coupling
General Procedure: Deoxygenated Et2NH (2 mL), [PdCl2(PPh3)2]
(0.01 mmol) and CuI (0.02 mmol) were added (room temperature,
stirring) to a solution of the appropriate acetylenic ester 1
(0.3 mmol) and dihalopolyene 2 (0.1 mmol) in dry THF (2.5 mL)
in a Schlenk flask under argon. After completion of the reaction
(ca. 3 h), the mixture was filtered through a short Celite pad, elut-
ing with CH2Cl2, and the residual waxy solid remaining after sol-
vent evaporation was purified by column chromatography [silica
gel, hexane/ethyl acetate, 9:1 to 7:3], yielding 3 as the all-(E) isomer
(reactions with 2a) or as 1:4 mixture of (E/Z) isomers (E,E,E)/
(Z,E,E) (reactions with 2b) or (E,E,E,E)/(Z,E,E,E) (reactions with
2c) (yields 95Ϫ97%). The all-(E) isomer could be separated by
selective precipitation with pentane at room temperature. The acids
corresponding to all-(E) esters 3a and 3b were obtained by alkaline
hydrolysis (see below).
(12Z,14E,16E)-3b: Obtained from 1a and 2b, all-(E)/(1Z,3E,5E),
1:4 isomer mixture. Yield 36 mg, 77%. Yellow waxy oil. Rf ϭ 0.73
1
(hexane/EtOAc, 7:3). H NMR (500 MHz, CDCl3): δ ϭ 1.30 (br.
s, 12 H, 5-H to 7-H, 22-H to 24-H), 1.38 (m, 4 H, 4-H, 25-H), 1.51
(q, J ϭ 7.0 Hz, 4 H, 8-H, 21-H), 1.61 (q, J ϭ 7.0 Hz, 4 H, 3-H,
26-H), 2.29 (t, J ϭ 7.0 Hz, 2 H, 27-H), 2.30 (t, J ϭ 7.0 Hz, 2 H, 2-
H), 2.33 (dt, J ϭ 2.5, 7.0 Hz, 2 H, 20-H), 2.39 (dt, J ϭ 2.5, 7.0 Hz,
2 H, 9-H), 5.46 (dt, J ϭ 2.5, 11.0 Hz, 1 H, 17-H), 5.65 (dt, J ϭ
2.5, 15.0 Hz, 1 H, 12-H), 6.31 (m, 1 H, 14-H), 6.34 (dd, J ϭ 7.0,
11.0 Hz, 1 H, 16-H), 6.59 (dd, J ϭ 11.5, 15.5 Hz, 1 H, 15-H), 6.74
(dd, J ϭ 11.5, 15.0 Hz, 1 H, 13-H) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 28.0, 28.2, 28.6, 28.66, 28.69, 28.75, 28.8, 28.9, 29.0,
33.8, 51.1, 77.9, 80.1, 94.8, 98.3, 110.9, 113.3, 130.8, 133.8, 138.0,
140.1, 173.7 (CϭO) ppm.
Dimethyl all-(E)-Dotriaconta-15,17-diene-13,19-diynedioate [all-(E)-
3a]: Obtained from 1c and 2a. Yield 50 mg, 95%. White crystals,
m.p. 72Ϫ73 °C. Rf ϭ 0.61 (hexane/diethyl ether, 3:2). 1H NMR
(400 MHz, CDCl3): δ ϭ 1.27 (m, 24 H, 4-H to 9-H, 24-H to 29-
H), 1.37 (quint, 4 H, J ϭ 6.8 Hz, 10-H, 23-H), 1.52 (quint, 4 H,
J ϭ 7.6 Hz, 11-H, 22-H), 1.61 (quint, J ϭ 7.2 Hz, 4 H, 3-H, 30-
H), 2.30 (t, J ϭ 7.2 Hz, 4 H, 2-H, 31-H), 2.32 (dt, J ϭ 2.0, 7.2 Hz,
4 H, 12-H, 21-H), 3.66 (s, 6 H, 2 ϫ CH3), 5.62 (ddt, J ϭ 2.0, 3.0,
14.4 Hz, 2 H, 15-H, 18-H), 6.50 (dd, J ϭ 3.0, 14.4 Hz, 2 H, 16-H,
17-H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 19.7 (C-12, C-21),
25.0 (C-3, C-30), 28.7, 28.9, 29.11, 29.14, 29.2, 29.41, 29.45, 29.5
(C-4 to C-11, C-22 to C-29), 34.1 (C-2, C-31), 51.4 (CH3), 79.8 (C-
14, C-19), 94.9 (C-13, C-20), 113.2 (C-15, C-18), 139.6 (C-16, C-
17), 174.3 (CO) ppm. IR (KBr): ν˜max ϭ 2870, 2800, 2155, 1710,
1145, 950 cmϪ1. EI MS (70 eV): m/z (%) ϭ 526 (46) [Mϩ], 495 (32),
463 (4), 328 (23), 185 (22), 171 (49), 157 (51), 141 (71), 129 (100),
117 (53), 105 (25), 91 (30). UV (CHCl3): λmax (ε, L·molϪ1·cmϪ1) ϭ
312 (55000), 298 nm (53000). C34H54O4 (526.79): calcd. C 77.52, H
10.33; found C 77.25, H 9.81.
all-(E)-Octacosa-12,14,16-triene-10,18-diynedioic Acid: Obtained
by hydrolysis of all-(E)-3b. Light yellow solid, m.p. 140Ϫ142 °C.
1
Rf ϭ 0.53 (CH2Cl2/EtOH, 9:1). H NMR (500 MHz, [D6]DMSO):
δ ϭ 1.21 (m, 16 H, 4-H to 7-H, 22-H to 25-H), 1.29 (q, J ϭ 7.0 Hz,
4 H, 8-H, 21-H), 1.43 (q, J ϭ 7.0 Hz, 4 H, 3-H, 26-H), 2.13 (t, J ϭ
7.0 Hz, 4 H, 2-H, 27-H), 2.29 (dt, J ϭ 2.5, 7.0 Hz, 4 H, 9-H, 20-
H), 5.70 (dt, J ϭ 2.5, 15.5 Hz, 2 H, 12-H, 17-H), 6.34 (dd, J ϭ 3.0,
7.0 Hz, 2 H, 14-H, 15-H), 6.48 (ddd, J ϭ 3.0, 7.0, 15.5 Hz, 2 H, 13-
H, 16-H), 11.80 (br. s, 2 H, 2 ϫ CO2H) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ ϭ 19.0 (C-9, C-20), 24.5 (C-3, C-26), 28.1, 28.3,
28.4, 28.5, 28.6 (C-4 to C-8, C-21 to C-25), 33.7 (C-2, C-27), 80.5
(C-11, C-18), 95.3 (C-10, C-19), 113.1 (C-12, C-17), 133.5 (C-14,
all-(E)-Dotriaconta-15,17-diene-13,19-diynedioic Acid: Obtained by
hydrolysis of all-(E)-3a. White crystals, m.p. 178 °C. Rf ϭ 0.70
(CH2Cl2/EtOH, 95:5). 1H NMR (400 MHz, [D6]DMSO, 80 °C):
δ ϭ 1.26 (br. s, 24 H, 5-H to 10-H, 23-H to 28-H), 1.35 (m, 4 H,
4-H, 29-H), 1.47 (m, 8 H, 3-H, 11-H, 22-H, 30-H), 2.15 (t, J ϭ
7.2 Hz, 4 H, 2-H, 31-H), 2.33 (dt, J ϭ 2.0, 7.2 Hz, 4 H, 12-H, 21-
H), 5.76 (m, 2 H, 15-H, 18-H), 6.52 (m, 2 H, 16-H, 17-H) ppm.
13C NMR (100 MHz, [D6]DMSO, 70 °C): δ ϭ 18.6 (C-12, C-21),
24.2 (C-3, C-30), 27.7, 27.8, 28.0, 28.2, 28.3, 28.40, 28.41, 30.1 (C-
4 to C-11, C-22 to C-29), 33.6 (C-2, C-31), 79.7 (C-14, C-19), 94.6
(C-13, C-20), 113.2 (C-15, C-18), 139.2 (C-16, C-17), 173.9 (CO)
ppm. IR (KBr): ν˜max ϭ 3080, 2960, 2890, 2250, 1715, 1490, 980,
740. EI MS (70 eV): m/z (%) ϭ 498 (7) [Mϩ], 369 (2), 355 (4), 327
(4), 314 (5), 299 (4), 272 (4), 199 (4), 171(30), 157 (36), 143 (59), 129
(100), 117 (56), 105 (34), 91 (44). HRMS (EI): calcd. for C32H50O4
498.37091; found 498.37039.
C-15), 140.2 (C-13, C-16), 174.5 (CϭO) ppm. IR (KBr): ν˜max
ϭ
3000, 2920, 2860, 2210, 1700, 1470, 1269, 990 cmϪ1. EI MS (70 eV):
m/z (%) ϭ 440 (34) [Mϩ], 297 (17), 283 (8), 169 (48), 155 (100), 141
(78), 129 (65).
Dimethyl all-(E)-Tetratriaconta-15,17,19-triene-13,21-diynedioate
[all-(E)-3c]: Obtained from 1c and 2b, all-(E)/(1Z,3E,5E), 1:4 iso-
mer mixture. Described in ref.[7]
Dimethyl all-(E)-Triaconta-12,14,16,18-tetraene-10,20-diynedioate
[all-(E)-3d]: Obtained from 1a and 2c, all-(E)/(1Z,3E,5E,7E), 1:4
isomer mixture. Yield 9 mg, 18%. Yellow solid, m.p. 74Ϫ76 °C.
Rf ϭ 0.21 (hexane/EtOAc, 9:1). 1H NMR (400 MHz, CDCl3): δ ϭ
1.31 (m, 12 H, 4-H to 6-H, 25-H to 27-H). 1.39 (quint, J ϭ 7.2 Hz,
4 H, 7-H, 24-H), 1.53 (quint, J ϭ 7.2 Hz, 4 H, 8-H, 23-H), 1.62
(quint, J ϭ 7.2 Hz, 4 H, 3-H, 28-H), 2.30 (t, J ϭ 7.2 Hz, 4 H, 2-
H, 29-H), 2.33 (dt, J ϭ 2.4, 7.2 Hz, 4 H, 9-H, 22-H), 3.66 (s, 6 H,
Dimethyl all-(E)-Octacosa-12,14,16-triene-10,18-diynedioate [all-
(E)-3b]: Obtained from 1a and 2b, all-(E)/(1Z,3E,5E), 1:4 isomer 2 ϫ CH3), 5.62 (dt, J ϭ 2.4, 15.6 Hz, 2 H, 12-H, 19-H), 6.27 (m, 2
Eur. J. Org. Chem. 2003, 1308Ϫ1318 1313

E. Quesada, A. U. Acun˜a, F. Amat-Guerri
FULL PAPER
H, 14-H, 17-H), 6.35 (m, 2 H, 15-H, 16-H), 6.54 (dd, J ϭ 7.2, product in hexane (200 mL) was refluxed 15 min under Ar with
15.6 Hz, 2 H, 13-H, 18-H) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ iodine-saturated hexane (60 µL) and the solution was filtered
19.8 (C-9, C-22). 24.9 (C-3, C-28), 28.7, 28.77, 28.81, 28.86, 28.92,
through a short silica gel pad while hot, the solvent was evaporated
29.1, 29.6 (C-4 to C-8, C-23 to C-27), 34.1 (C-2, C-29), 51.4 (CH3),
to 5 mL and the corresponding all-(E) isomer 4 was separated from
80.4 (C-11, C-20), 95.0 (C-10, C-21), 112.4 (C-12, C-19), 133.7, the cooled (Ϫ20 °C) residual solution by filtration. Yield 95%. High
133.3 (C-14 to C-17), 140.4 (C-13, C-18), 174.3 (CϭO) ppm. FT purity samples were obtained by crystallization from acetone at
IR (KBr): ν˜max ϭ 2917, 2580, 2220, 1737, 1460, 1441, 1303, 1246,
1204, 1170, 1001 cmϪ1. EI MS (70 eV): m/z (%) ϭ 494 (44) [Mϩ],
463 (4), 337 (6), 323 (6), 207 (10), 195 (20), 181 (66), 167 (100), 155
(36), 141 (44), 129 (39), 117 (24), 105 (15), 91 (33). UV (CHCl3):
λmax (ε, L·molϪ1·cmϪ1) ϭ 310 (59000), 353 (86000), 373 nm
(90000); UV (1,4-dioxane): λmax (ε, L·molϪ1·cmϪ1) ϭ 334 (63000),
351 (113000), 373 nm (128000). C32H46O4 (494.71): calcd. C 77.69,
H 9.37; found C 77.49, H 9.28.
Ϫ20 °C.
Dimethyl all-(E)-Dotriaconta-13,15,17,19-tetraenedioate (4a): Ob-
tained by reduction/isomerization of all-(E)-3a. Yield 48 mg, 90%
overall. White crystals, m.p. 81Ϫ83 °C. 1H NMR (300 MHz,
CDCl3): δ ϭ 1.25 (br. s, 28 H, 4-H to 10-H, 23-H to 29-H). 1.37
(quint, J ϭ 7.5 Hz, 4 H, 11-H, 22-H), 1.64 (quint, J ϭ 7.2 Hz, 4
H, 3-H, 30-H), 2.08 (dt, J ϭ 6.9, 7.2 Hz, 4 H, 12-H, 21-H), 2.30
(t, J ϭ 7.5 Hz, 4 H, 2-H, 31-H), 3.66 (s, 6 H, 2 ϫ CH3), 5.68 (dt,
J ϭ 7.2, 14.4 Hz, 2 H, 13-H, 20-H), 6.25 (m, 6 H, 14-H to 19-H)
ppm. 13C NMR (300 MHz, CDCl3): δ ϭ 25.0, 29.1, 29.2, 29.25,
29.3, 29.4, 29.5, 29.6, 32.9, 34.1, 51.5, 130.5, 130.8, 132.5, 135.2,
174.4 ppm. IR (KBr): ν˜max ϭ 3000, 2918, 2842, 1738, 1728, 1170,
985 cmϪ1. EI MS (70 eV): m/z (%) ϭ 530 (100) [Mϩ], 499 (20), 467
(5), 345 (7), 331 (20), 317 (17), 285 (10), 145 (11), 131 (23), 117
(26), 105 (31), 91 (47). UV (CHCl3): λmax (ε, L·molϪ1·cmϪ1) ϭ 293
(49000), 306 (73000), 321 nm (65000); UV (1,4-dioxane): λmax (ε,
L·molϪ1·cmϪ1) ϭ 291 (47000), 303 (64000), 318 nm (58000).
C34H58O4 (530.82): calcd. C 76.93, H 11.01; found C 76.84, H
10.89.
(12Z,14E,16E,18E)-3d: Obtained from 1a and 2c, all-(E)/
(1Z,3E,5E,7E), 1:4 isomer mixture. Yield 37 mg, 75%. Yellow oil.
1
Rf ϭ 0.21 (hexane/EtOAc, 9:1). H NMR (300 MHz, CDCl3): δ ϭ
1.31 (m, 12 H, 4-H to 6-H, 25-H to 27-H), 1.37 (m, 4 H, 7-H, 24-
H), 1.51 (m, 4 H, 8-H, 23-H), 1.62 (q, J ϭ 7.2 Hz, 4 H, 3-H, 28-
H), 2.24 (m, 2 H, 9-H), 2.30 (t, J ϭ 7.2 Hz, 4 H, 2-H, 29-H), 2.40
(dt, J ϭ 2.4, 6.9 Hz, 2 H, 22-H), 3.66 (s, 6 H, 2 ϫ CH3), 5.44 (dt,
J ϭ 2.1, 11.1 Hz, 1 H, 12-H), 5.63 (dt, J ϭ 2.4, 15.3 Hz, 1 H, 19-
H), 6.34 (m, 4 H, 14-H to 17-H), 6.54 (m, 1 H, 13-H), 6.77 (m, 1
H, 18-H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 19.7 (C-9), 19.8
(C-22), 24.9 (C-3, C-28), 28.3, 28.66, 28.72, 28.8, 28.9, 28.9, 29.0,
29.0, 29.1, 29.2, 29.28, 29.3 (C-4 to C-8, C-23 to C-27), 34.0 (C-2,
C-29), 51.4 (CH3), 78.0 (C-11), 80.3 (C-20), 95.0 (C-21), 98.5 (C-
10), 110.3 (C-12), 112.5 (C-19), 131.2, 133.5, 133.9, 134.4 (C-14 to
C-17), 138.4 (C-13), 140.3 (C-18), 174.2 (CϭO) ppm.
Dimethyl (13Z,15E,17E,19Z)-Dotriaconta-13,15,17,19-tetraenedio-
ate [(13Z,15E,17E,19Z) Isomer of 4a]: Obtained by reduction of
all-(E)-3a. Yield 50 mg, 95%. White crystals, m.p. 45Ϫ47 °C. Rf ϭ
1
0.68 (hexane/diethyl ether, 3:2). H NMR (400 MHz, CDCl3): δ ϭ
1.26 (br. s, 28 H, 4-H to 10-H, 23-H to 29-H), 1.38 (quint, J ϭ
6.4 Hz, 4 H, 11-H, 22-H), 1.62 (quint, J ϭ 7.6 Hz, 4 H, 3-H, 30-
H), 2.19 (ddt, J ϭ 1.2, 7.2, 7.6 Hz, 4 H, 12-H, 21-H), 2.30 (t, J ϭ
7.2 Hz, 4 H, 2-H, 31-H), 3.66 (s, 6 H, 2 ϫ CH3), 5.45 (dt, J ϭ 7.6,
10.8 Hz, 2 H, 13-H, 20-H), 6.03 (dt, J ϭ 10.8, 11.2 Hz, 2 H, 14-H,
19-H), 6.26 (dd, J ϭ 3.2, 11.2 Hz, 2 H, 15-H, 18-H), 6.50 (dt, J ϭ
Dimethyl all-(E)-Dotriaconta-13,15,17,19-tetraene-11,21-diynedio-
ate [all-(E)-3e]: Obtained from 1b and 2c, all-(E)/(1Z,3E,5E,7E),
1:4 isomer mixture. Yield 10 mg, 19%. Yellow solid, m.p. 79Ϫ81
°C. Rf ϭ 0.60 (hexane/diethyl ether, 3:2). 1H NMR (300 MHz,
CDCl3): δ ϭ 1.29 (m, 16 H, 4-H to 7-H, 26-H to 29-H), 1.37 (m,
4 H, 8-H, 25-H), 1.53 (quint, J ϭ 7.8 Hz, 4 H, 9-H, 24-H), 1.62
(quint, J ϭ 7.2 Hz, 4 H, 3-H, 30-H), 2.30 (t, J ϭ 7.6 Hz, 4 H, 2-
H, 31-H), 2.34 (dt, J ϭ 2.4, 7.2 Hz, 4 H, 10-H, 23-H), 3.66 (s, 6 H,
2 ϫ CH3), 5.61 (dt, J ϭ 2.4, 15.3 Hz, 2 H, 13-H, 20-H), 6.30 (m, 4
H, 15-H to 18-H), 6.54 (m, 2 H, 14-H, 19-H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 19.8 (C-10, C-23), 24.9 (C-3, C-30), 28.7,
28.8, 29.0, 29.1, 29.2, 29.3 (C-4 to C-9, C-24 to C-29), 34.1 (C-2,
C-31), 51.4 (CH3), 80.4 (C-12, C-21), 95.1 (C-11, C-22), 112.4 (C-
13, C-20), 133.3, 133.7 (C-15 to C-18), 140.4 (C-14, C-19), 174.3
(CϭO) ppm. FT IR (KBr): ν˜max ϭ 2920, 2585, 2220, 1730, 1468,
1437, 1306, 1240, 1207, 1174, 997 cmϪ1. EI MS (70 eV): m/z (%) ϭ
522 (100) [Mϩ], 491 (8), 351 (10), 337 (8), 195 (18), 181 (52), 167
(74), 155 (30), 141 (33), 129 (30), 117 (19), 105 (12), 91 (25). UV:
λmax (ε, L·molϪ1·cmϪ1) ϭ (CHCl3) 310 (59000), 353 (86000), 373
nm (90000); UV (1,4-dioxane): λmax (ε, L·molϪ1·cmϪ1) ϭ 334
(63000), 351 (113000), 373 nm (128000). C34H50O4 (522.76): calcd.
C 78.12, H 9.64; found C 77.92, H 9.85.
1
2.8, 11.2 Hz, 2 H, 16-H, 17-H) ppm. H NMR (300 MHz, C6D6,
20 °C): δ ϭ 1.44 (br. s, 28 H, 4-H to 10-H, 23-H to 29-H), 1.60 (m,
4 H, 11-H, 22-H), 1.82 (quint, J ϭ 6.6 Hz, 4 H, 3-H, 30-H), 2.37
(t, J ϭ 7.5 Hz, 4 H, 2-H, 31-H), 2.44 (dt, J ϭ 6.6, 6.9 Hz, 4 H, 12-
H, 21-H), 3.61 (s, 6 H, 2 ϫ CH3), 5.72 (dt, J ϭ 7.8, 10.2 Hz, 2 H,
13-H, 20-H), 6.41 (m, 2 H, 14-H, 19-H), 6.55 (m, 2 H, 15-H, 18-
H), 6.86 (m, 2 H, 16-H, 17-H) ppm. 13C NMR (75 MHz, C6D6, 20
°C): δ ϭ 25.3, 28.3, 29.4, 29.6, 29.8, 29.9, 29.96, 29.98, 30.1, 34.1,
50.9, 128.7, 129.5, 132.8, 133.5, 173.3 ppm. FT IR (KBr): ν˜max
ϭ
2918, 2851, 1731, 1644, 1437, 1260, 1225, 1200, 1171, 990, 803
cmϪ1. EI MS (70 eV): identical to the spectrum of 4a. HRMS (EI):
calcd. for C34H58O4 530.43351; found 530.43347. UV (1,4-diox-
ane): λmax (ε, L·molϪ1·cmϪ1) ϭ 295 (38000), 308 (58000), 323 nm
(52000).
Dimethyl all-(E)-Octacosa-10,12,14,16,18-pentaenedioate (4b): Ob-
tained by reduction/isomerization of 3b, all-(E)/(12Z,14E,16E), 1:4
isomer mixture. Yield 42 mg, 89% overall. Pale-yellow crystals.
Rf ϭ 0.75 (hexane/EtOAc, 7:3). 1H NMR (500 MHz, CDCl3): δ ϭ
1.28 (br. s, 16 H, 4-H to 7-H, 22-H to 25-H), 1.37 (q, J ϭ 6.5 Hz,
4 H, 8-H, 21-H), 1.61 (q, J ϭ 7.0 Hz, 4 H, 3-H, 26-H), 2.09 (dt,
J ϭ 6.5, 7.0 Hz, 4 H, 9-H, 20-H), 2.30 (t, J ϭ 7.0 Hz, 4 H, 2-H,
Synthesis of all-(E)-Polyene Diesters 4
General Procedure: A slurry of Zn powder freshly activated under
[17]
Ar with Cu(OAc)2·H2O and AgNO3
in MeOH/water (1:1;
3 mL) was added to a solution of the appropriate polyenediyne 3
(0.10 mmol) in methanol (0.5 mL) at room temperature and with 27-H), 3.66 (s, 6 H, 2 ϫ CH3), 5.70 (dt, J ϭ 7.0, 15.0 Hz, 2 H, 10-
stirring. After 24 h, the reaction mixture was filtered (Celite,
CH2Cl2) and the subsequent workup afforded (95% yield) the pure
H, 19-H), 6.07 (dd, J ϭ 9.0, 15.0 Hz, 11-H, 18-H), 6.19 (m, 6 H,
12-H, 17-H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 24.9 (C-3, C-
(Z,all-E,Z) isomer [products from all-(E)-3 isomers] or a (Z,E,all- 26), 29.1, 29.2, 29.3 (C-4 to C-8, C-21 to C-25), 32.9 (C-9, C-20),
E,Z)/(Z,Z,all-E,Z), 1:4 mixture of isomers [products from 3 in the
form of (E,all-E)/(Z,all-E), 1:4 mixtures of isomers]. Each former
34.1 (C-2, C-27), 51.4 (CH3), 130.6, 130.9, 132.4, 132.9 (C-11 to C-
18), 135.6 (C-10, C-19), 177.1 (CϭO) ppm. FT IR (KBr): ν˜max
ϭ
1314
Eur. J. Org. Chem. 2003, 1308Ϫ1318

Carboxyl-Tethered Symmetric Conjugated Polyenes
FULL PAPER
2919, 2848, 1739, 1640, 1471, 1436, 1242, 1172, 1003 cmϪ1. EI MS 96Ϫ98 °C. Rf ϭ 0.84 (hexane/EtOAc, 7:3). 1H NMR (300 MHz,
(70 eV): m/z (%) ϭ 472 (48) [Mϩ], 441 (10), 315 (9), 301 (26), 145
(39), 131 (80), 117 (100), 105 (58), 91 (97). HRMS (EI): calcd. for
CDCl3): δ ϭ 1.27 (br. s, 20 H, 4-H to 8-H, 25-H to 29-H), 1.37
(quint, J ϭ 7.2 Hz, 4 H, 9-H, 4-H), 1.61 (quint, J ϭ 7.2 Hz, 4 H,
C30H48O4 472.35526; found 472.35759. UV (CHCl3): λmax (ε, 3-H, 30-H), 2.09 (dt, J ϭ 6.9, 7.2 Hz, 4 H, 10-H, 23-H), 2.30 (t,
L·molϪ1·cmϪ1) ϭ 306 (29000), 320 (60000), 335 (95000), 353 nm
J ϭ 7.2 Hz, 4 H, 2-H, 31-H), 3.66 (s, 6 H, 2 ϫ CH3), 5.71 (dt, J ϭ
(92000); UV (1,4-dioxane): λmax (ε, L·molϪ1·cmϪ1) ϭ 306 (28000), 6.9, 14.7 Hz, 2 H, 11-H, 22-H), 6.15 (m, 10 H, 12-H to 21-H) ppm.
318 (52000), 333 (78000), 351 nm (80000).
13C NMR (75 MHz, CDCl3): δ ϭ 24.9 (C-3, C-30), 29.12, 29.14,
29.20, 29.27, 29.3, 29.4 (C-4 to C-9, C-24 to C-29), 32.9 (C-10, C-
23), 34.1 (C-2, C-31), 51.4 (CH3), 130.6, 130.9, 132.5, 132.9, 133.3
(C-12 to C-21), 135.8 (C-11, C-22), 174.3 (CϭO) ppm. IR (KBr):
ν˜max ϭ 3000, 2918, 2842, 1738, 1728, 1170, 985 cmϪ1. EI MS: m/z
(%) ϭ 526 (100) [Mϩ], 495 (9), 355 (7), 341 (22), 171 (17), 129 (52),
117 (59), 105 (40), 91 (62). UV (CHCl3): λmax (ε, L·molϪ1·cmϪ1) ϭ
306 (34000), 320 (71000), 362 (120000), 382 nm (124000). C34H54O4
(526.79): calcd. C 77.52, H 10.33; found C 77.64, H 10.42.
Dimethyl (10Z,12E,14E,16E,18Z)-Octacosa-10,12,14,16,18-penta-
enedioate [(10Z,12E,14E,16E,18Z) Isomer of 4b]: Obtained by re-
duction of all-(E)-3b. Yield 45 mg, 95%. Pale yellow crystals, m.p.
73Ϫ75 °C. Rf ϭ 0.75 (hexane/EtOAc, 7:3). 1H NMR (500 MHz,
CDCl3): δ ϭ 1.29 (br. s, 16 H, 4-H to 7-H, 22-H to 25-H), 1.38 (q,
J ϭ 6.9 Hz, 4 H, 8-H, 21-H), 1.61 (q, J ϭ 7.0 Hz, 4 H, 3-H, 26-
H), 2.19 (dt, J ϭ 7.0, 8.0 Hz, 4 H, 9-H, 20-H), 2.30 (t, J ϭ 7.5 Hz,
4 H, 2-H, 27-H), 3.66 (s, 6 H, 2 ϫ CH3), 5.47 (dt, J ϭ 8.0, 10.5 Hz,
2 H, 10-H, 19-H), 6.04 (dd, J ϭ 11.5, 11.5 Hz, 2 H, 11-H, 18-H),
6.27 (m, 4 H, 12-H, 13-H, 16-H, 17-H), 6.50 (dd, J ϭ 11.5, 14.0 Hz,
2 H, 14-H, 15-H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 24.9 (C-
3, C-26), 29.1, 29.2, 29.3, 29.6 (C-4 to C-9, C-20 to C-25), 34.1 (C-
2, C-27), 51.5 (CH3), 128.4, 128.7, 132.7, 133.0, 133.2 (C-10 to C-
19), 174.3 (CϭO) ppm. FT IR (KBr): ν˜max ϭ 2920, 2849, 1740,
1644, 1435, 1384, 1250, 1209, 1176, 995, 710 cmϪ1. EI MS (70 eV):
identical to the spectrum of 4b. HRMS (EI): calcd. for C30H48O4
472.35526; found 472.35360. UV (1,4-dioxane): λmax (ε,
L·molϪ1·cmϪ1) ϭ 307 (23000), 321 (41000), 337 (60000), 356 nm
(61000).
Hydrolysis of Diesters 4 to the Corresponding Diacids 5
General Procedure: A suspension of each ester 4 (0.10 mmol) in
95% EtOH (2 mL) with powdered KOH (10 mmol) was refluxed
for 5 h, the reaction mixture was cooled, acidified (pH ϭ 1, 5%
HCl), and the precipitated solid was filtered, washed successively
with water, EtOH and toluene, and dried. Yield 95%. Pure samples
of diacids 5 were obtained by crystallization from toluene at Ϫ20
°C.
all-(E)-Dotriaconta-13,15,17,19-tetraenedioic Acid (5a): Yield
48 mg, 96%. White crystals, m.p. 126Ϫ128 °C. Rf ϭ 0.22 (CH2Cl2/
EtOH, 95:5). 1H NMR (300 MHz, [D6]DMSO, 70 °C): δ ϭ 1.26
(br. s, 28 H, 4-H to 10-H, 23-H to 29-H), 1.36 (quint, J ϭ 6.9 Hz,
4 H, 11-H, 22-H), 1.50 (quint, J ϭ 7.2 Hz, 4 H, 3-H, 30-H), 2.07
(dt, J ϭ 6.6, 6.9 Hz, 4 H, 12-H, 21-H), 2.18 (t, J ϭ 7.2 Hz, 4 H, 2-
H, 31-H), 5.70 (dt, J ϭ 6.9, 14.4 Hz, 2 H, 13-H, 20-H), 6.07 (dd,
J ϭ 9.6, 14.8 Hz, 2 H, 14-H, 19-H), 6.20 (m, 4 H, 15-H to 18-H),
Dimethyl (10Z,12Z,14E,16E,18Z)-Octacosa-10,12,14,16,18-penta-
enedioate [(10Z,12Z,14E,16E,18Z) Isomer of 4b]: Obtained by re-
duction of (12Z,14E,16E)-3b. Yield 46 mg, 97%. Yellow crystals,
1
m.p. 69Ϫ70 °C. H NMR (400 MHz, CDCl3): δ ϭ 1.29 (br. s, 16
H, 4-H to 7-H and 22-H to 25-H), 1.38 (q, J ϭ 6.8 Hz, 4 H, 8-H,
21-H), 1.61 (q, J ϭ 7.2 Hz, 4 H, 3-H, 26-H), 2.19 (dt, J ϭ 7.2,
7.6 Hz, 4 H, 9-H, 20-H), 2.30 (t, J ϭ 7.2 Hz, 4 H, 2-H, 27-H), 3.66
(s, 6 H, 2 ϫ CH3), 5.50 (m, 2 H, 10-H, 19-H), 6.05 (dd, J ϭ 10.8,
11.2 Hz, 2 H, 11-H, 18-H), 6.27 (m, 3 H, 12-H, 13-H, 17-H), 6.47,
6.52, 6.69 (3 m, each 1 H, 14-H to 16-H) ppm.
11.90 (br. s,
2
H, 2 ϫ CO2H) ppm. 13C NMR (75 MHz,
[D6]DMSO, 70 °C): δ ϭ 24.1 (C-3, C-30), 28.2, 28.3, 28.40, 28.43,
28.5 (C-4 to C-11, C-21 to C-29), 31.7 (C-12, C-21), 33.4 (C-2, C-
31), 130.2, 130.4, 132.0 (C-14 to C-19), 134.3 (C-13, C-20), 173.8
(CϭO) ppm. IR (KBr): ν˜max ϭ 3050, 2960, 2875, 2800, 1690, 1680,
1210, 918 cmϪ1. EI MS (70 eV): m/z ϭ 502 (36) [Mϩ], 303 (14),
171 (3), 159 (4), 131 (28), 117 (39), 105 (53), 91 (100), 79 (48), 69
(38). HRMS (EI): calcd. for C32H54O4 502.40221; found 502.40165.
Dimethyl all-(E)-Tetratriaconta-13,15,17,19,21-pentaenedioate (4c):
Obtained by reduction/isomerization of 3c, all-(E)/(15Z,17E,19E),
1:4 isomer mixture. Described in ref.[7]
Dimethyl all-(E)-Triaconta-10,12,14,16,18,20-hexaenedioate (4d):
all-(E)-Octacosa-10,12,14,16,18-pentaenedioic Acid (5b): Yield
42 mg, 95%. Pale yellow crystals, m.p. 146Ϫ148 °C. Rf ϭ 0.43
(CH2Cl2/EtOH, 95:5). 1H NMR (500 MHz, [D6]DMSO): δ ϭ 1.20
(br. s, 16 H, 4-H to 7-H, 22-H to 25-H), 1.30 (quint, J ϭ 7.0 Hz,
4 H, 8-H, 21-H), 1.43 (quint, J ϭ 7.0 Hz, 4 H, 3-H, 26-H), 2.02
(dt, J ϭ 7.0, 7.0 Hz, 4 H, 9-H, 20-H), 2.13 (t, J ϭ 7.0 Hz, 4 H, 2-
H, 27-H), 5.68 (dt, J ϭ 7.0, 15.5 Hz, 2 H, 10-H, 19-H), 6.05 (dd,
J ϭ 9.5, 15.0 Hz, 2 H, 11-H, 18-H), 6.18 (m, 6 H, 12-H to 17-H),
Obtained
by
reduction/isomerization
of
3d,
all-(E)/
(12Z,14E,16E,18E), 1:4 isomer mixture. Yield 45 mg, 90% overall.
1
Yellow crystals, m.p. 90Ϫ92 °C. Rf ϭ 0.3 (hexane/EtOAc, 7:3). H
NMR (300 MHz, CDCl3): δ ϭ 1.29 (br. s, 16 H, 4-H to 7-H, 24-
H to 27-H), 1.38 (quint, J ϭ 7.5 Hz, 4 H, 8-H, 23-H), 1.61 (quint,
J ϭ 7.2 Hz, 4 H, 3-H, 28-H), 2.09 (dt, J ϭ 6.9, 7.2 Hz, 4 H, 9-H,
22-H), 2.30 (t, J ϭ 7.5 Hz, 4 H, 2-H, 29-H), 3.66 (s, 6 H, 2 ϫ CH3),
5.71 (dt, J ϭ 7.2, 14.7 Hz, 2 H, 10-H, 21-H), 6.09 (dd, J ϭ 9.3,
14.7 Hz, 11-H, 20-H), 6.22 (m, 8 H, 12-H to 19-H) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 24.9 (C-3, C-26), 29.1, 29.2, 29.3 (C-4 to
C-8, C-23 to C-27), 32.9 (C-9, C-22), 34.1 (C-2, C-29), 51.5 (CH3),
130.5, 130.9, 132.5, 132.9, 133.3 (C-11 to C-20), 135.8 (C-10, C-
21), 174.4 (CϭO) ppm. IR (KBr): ν˜max ϭ 2919, 2849, 1738, 1622,
1436, 1174, 1005 cmϪ1. EI MS (70 eV): m/z (%) ϭ 498 (100) [Mϩ],
467 (10), 341 (6), 327 (19), 171 (11), 157 (15), 143 (21), 129 (33),
117 (36), 105 (23), 91 (36). UV (CHCl3): λmax (ε, L·molϪ1·cmϪ1) ϭ
306 (34000), 320 (71000), 362 (120000), 382 nm (124000). C32H50O4
(498.74): calcd. C 77.06, H 10.10; found C 76.99, H 10.53.
11.82 (br. s,
2
H, 2 ϫ CO2H) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ ϭ 24.4 (C-3, C-26), 28.4, 28.6 (C-4 to C-8, C-21 to
C-25), 32.1 (C-9, C-20), 35.6 (C-2, C-27), 130.6, 130.8, 132.4, 132.8
(C-11 to C-18), 135.2 (C-10, C-19), 174.3 (CϭO) ppm. IR (KBr):
ν˜max ϭ 3011, 2920, 2849, 1705, 1433, 1253, 996 cmϪ1. EI MS
(70 eV): m/z (%) ϭ 444 (46) [Mϩ], 287 (8), 145 (24), 131 (53), 117
(67), 105 (43), 91 (100). HRMS (EI): calcd. for C28H44O4
444.32396; found 444.32528.
all-(E)-Tetratriaconta-13,15,17,19,21-pentaenedioic Acid (5c): De-
scribed in ref.[7]
Dimethyl all-(E)-Dotriaconta-11,13,15,17,19,21-hexaenedioate (4e):
Obtained by reduction/isomerization of 3e, all-(E)/(1Z,3E,5E,7E),
1:4 isomer mixture. Yield 47 mg, 89% overall. Yellow crystals, m.p.
all-(E)-Triaconta-10,12,14,16,18,20-hexaenedioic Acid (5d): Yield
45 mg, 96%. Yellow crystals. Rf ϭ 0.5 (CH2Cl2/EtOH, 95:5). 1H
NMR (400 MHz, [D6]DMSO, 70 °C): δ ϭ 1.26 (br. s, 16 H, 4-H
Eur. J. Org. Chem. 2003, 1308Ϫ1318
1315

E. Quesada, A. U. Acun˜a, F. Amat-Guerri
FULL PAPER
to 7-H, 24-H to 27-H), 1.36 (quint, J ϭ 7.2 Hz, 4 H, 8-H, 23-H), H, 3-H, 14-H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 14.3 (CH3),
1.50 (quint, J ϭ 7.2 Hz, 4 H, 3-H, 28-H), 2.08 (dt, J ϭ 7.2, 7.8 Hz, 60.4 (CH2), 121.4, 131.3, 134.1, 136.4, 140.1 (C-2, C-4 to C-13, C-
4 H, 9-H, 22-H), 2.18 (t, J ϭ 7.6 Hz, 4 H, 2-H, 29-H), 5.74 (dt, 15), 144.0 (C-3, C-14), 167.0 (CϭO) ppm. FT IR (KBr): ν˜max
ϭ
J ϭ 7.2, 14.8 Hz, 2 H, 10-H, 21-H), 6.10 (dd, J ϭ 9.6, 15.3 Hz, 2 3435, 2990, 1703, 1622, 1375, 1305, 1239, 1135, 1014 cmϪ1. EI MS
H, 11-H, 20-H), 6.20 (m, 8 H, 12-H to 19-H) ppm. 13C NMR (70 eV): m/z (%) ϭ 328 (100) [Mϩ], 309 (2), 283 (13), 255 (10), 235
(100 MHz, [D6]DMSO, 70 °C): δ ϭ 24.1 (C-3, C-28), 28.14, 28.16, (13), 219 (8), 209 (29), 191 (14), 179 (28), 165 (35), 153 (25), 141
28.23, 28.3, 28.4 (C-4 to C-8, C-23 to C-27), 31.8 (C-9, C-22), 33.4 (43), 128 (41), 115 (69), 105 (29), 91 (78). HRMS (EI): calcd. for
(C-2, C-29), 130.3, 130.5, 132.1, 132.5, 132.9 (C-11 to C-20), 135.0
(C-10, C-21), 173.9 (CϭO) ppm. IR (KBr): ν˜max ϭ 3060, 2916, L·molϪ1·cmϪ1) ϭ 397.3 (31000), 416.0 (49000), 441.8 nm (52000).
2849, 1701, 1616, 1423, 1166, 998 cmϪ1. EI MS (70 eV): m/z (%) ϭ
The corresponding octaene diesters 8 (n ϭ 0, m ϭ 8, R ϭ OEt)
470 (40) [Mϩ], 313 (8), 181 (9), 171 (20), 155 (33), 143 (44), 129 and nonaene diesters 8 (n ϭ 0, m ϭ 9, R ϭ OEt) were detected by
C20H24O4 328.16746; found 328.16675. UV (CHCl3): λmax (ε,
(78), 117 (78), 105 (51), 91 (100).
EI MS in the raw material separated by column chromatography
{respective [Mϩ] signals at m/z (%) ϭ 354 (31) and 380 (2)}, as well
as by UV/Vis spectroscopy.
all-(E)-Dotriaconta-11,13,15,17,19,21-hexaenedioic Acid (5e): Yield
48 mg, 96%. Yellow crystals. Rf ϭ 0.51 (CH2Cl2/EtOH, 95:5). H
1
NMR (300 MHz, 70 °C): δ ϭ 1.26 (br. s, 20 H, 4-H to 8-H, 25-H
to 29-H), 1.36 (quint, J ϭ 6.9 Hz, 4 H, 9-H, 24-H), 1.50 (quint,
J ϭ 7.2 Hz, 4 H, 3-H, 30-H), 2.08 (dt, J ϭ 6.9, 6.9 Hz, 4 H, 10-H,
23-H), 2.18 (t, J ϭ 7.2 Hz, 4 H, 2-H, 31-H), 5.74 (dt, J ϭ 6.9,
14.7 Hz, 2 H, 11-H, 22-H), 6.09 (m, 2 H, 12-H, 21-H), 6.24 (m, 8
H, 13-H to 20-H), 11.66 (br. s, 2 H, 2 ϫ CO2H) ppm. 13C NMR
(75 MHz, [D6]DMSO, 70 °C): δ ϭ 24.1 (C-3, C-30), 28.1, 28.2,
28.36, 28.38 (C-4 to C-9, C-24 to C-29), 31.8 (C-10, C-23), 33.4 (C-
2, C-31), 130.3, 130.5, 132.1, 132.5, 132.8 (C-12 to C-21), 135.0 (C-
11, C-22), 173.8 (CϭO) ppm. IR (KBr): ν˜max 3058, 2912, 2853,
1706, 1620, 1410, 1128, 1008 cmϪ1. EI MS (70 eV): m/z (%) ϭ 498
(100) [Mϩ], 484 (4), 420 (3), 341 (8), 327 (29), 171 (15), 157 (23),
143 (34), 129 (60), 117 (69), 105 (47), 91 (75).
Dimethyl all-(E)-Triaconta-11,13,15,17,19-pentaenedioate (8c): Im-
pure compound, obtained from 6c and 7. Mixture of 8c (85%) and
the corresponding tetraene diester 8 (n ϭ 9, m ϭ 4, R ϭ OMe),
hexaene diester 4e and heptaene diester 8 (n ϭ 9, m ϭ 7, R ϭ
OMe) (15% total). Yield 85 mg, ca. 60% overall. Data deduced for
the main product 8c: Rf ϭ 0.49 (hexane/EtOAc, 4:1). 1H NMR
(400 MHz, CDCl3, 30 °C): δ ϭ 1.30 (m, 4-H, 8-H, 23-H, 27-H),
1.4 (m, 9-H, 22-H), 1.63 (m, 3-H, 28-H), 2.09 (dt, J ϭ 6.6, 7.2 Hz,
10-H, 21-H), 2.30 (t, J ϭ 7.5 Hz, 2-H, 29-H), 3.66 (s, 2 ϫ CH3),
5.69 (m, 11-H, 20-H), 6.15 (m, 12-H to 19-H) ppm. FT IR (neat):
ν˜max ϭ 2923, 2851, 1738, 1437, 1260, 1172, 993, 802 cmϪ1. EI MS
(70 eV): m/z (%) ϭ 500 (14) [Mϩ], 329 (3), 289 (6), 213 (6), 183 (4),
157 (8), 143 (15), 131 (52) 117 (66), 105 (58), 91 (100). Signal of
hexaene 4e at m/z (%) ϭ 526 (1) [Mϩ].
Synthesis of Polyene Compounds 8 by Stille Double Cross-Coupling
General Procedure: A THF solution of Pd0 catalyst, freshly pre-
pared by reduction of [PdCl2(PPh3)2] with DIBAL[25] (0.4 mL, ca.
11 µmol), was added to a mixture of the appropriate all-(E)-ω-
halopolyene 6 (280 µmol) and (E)-bis(tributylstannyl)ethane (7)
(84 mg, 139 µmol) in dry DMF, with stirring and under argon.
After 12 h, the subsequent workup yielded a solid that was purified
by column chromatography (silica gel, hexane/ethyl acetate, 1:1).
The remaining halopolyene 6 was recovered in the same chroma-
tography. Very pure samples of polyenes 8a and 8b were isolated
by crystallization from hexane with traces of ethanol. Product 8c
was a mixture of polyene compounds.
Acknowledgments
Supported by the Spanish Direccion General de Ensen˜anza Su-
´
´
´
´
perior e Investigacion Cientıfica, Ministerio de Educacion y Cul-
tura (Projects PB96-0852 and BQU2000-1500). E. Q. acknowledges
a doctoral fellowship from the same source.
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ν˜max ϭ 3436, 2917, 1663, 1617, 1586, 1261, 1149, 1016, 802 cmϪ1
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EI MS (70 eV): m/z (%) ϭ 240 (22) [Mϩ], 231 (4), 214 (3), 205 (4),
165 (8), 153 (9), 141 (14), 135 (15), 128 (19), 115 (26), 105 (13), 97
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