Synthesis of natural polyacetylenes bearing furan rings

Article abstract of DOI:10.1021/np9000637

The first total syntheses of four new polyacetylene compounds have been achieved using convergent routes, which involved Cadiot-Chodkiewicz copper-catalyzed cross-coupling reactions to sp-sp centers as the key steps. 19-Furan-2-ylnonadeca-5,7-diynoic acid (1), 19-furan-2-ylnonadeca-5,7-diynoic acid methyl ester (2), 2-pentacosa-7,9-diynylfuran (3), and 21-furan-2- ylhenicosa-14,16-diyn-1-ol (4) were stable and could be readily identified, isolated, and purified in high overall yields.

Full text of DOI:10.1021/np9000637

J. Nat. Prod. 2009, 72, 857–860
857
Synthesis of Natural Polyacetylenes Bearing Furan Rings
Daniela A. Barancelli, Anderson C. Mantovani, Cristiano Jesse, Cristina W. Nogueira, and Gilson Zeni*
Laborato´rio de S´ıntese, ReatiVidade, AValiac¸a˜o, Toxicolo´gica e Farmacolo´gica de Organocalcogeˆnios-CCNE-UFSM,
97105-900-Santa Maria, RS, Brazil
ReceiVed February 3, 2009
The first total syntheses of four new polyacetylene compounds have been achieved using convergent routes, which
involved Cadiot--Chodkiewicz copper-catalyzed cross-coupling reactions to sp-sp centers as the key steps. 19-Furan-
2-ylnonadeca-5,7-diynoic acid (1), 19-furan-2-ylnonadeca-5,7-diynoic acid methyl ester (2), 2-pentacosa-7,9-diynylfuran
(3), and 21-furan-2-ylhenicosa-14,16-diyn-1-ol (4) were stable and could be readily identified, isolated, and purified in
high overall yields.
Conjugated triple bonds are common structural units in a large
number of natural products, many of which exhibit potent and varied
biological activities and play important ecological roles.1 These
polyacetylenes have proven to be important biologically active
compounds that can be used as antibacterial,2 antimicrobial,3
antifungal, and antiviral agents.4 They also exhibit larvicidal
activity5 and cytotoxicity toward a range of cell lines.6 In addition,
they are key structural moieties in synthetic compounds with
unusual electrical, optical, or structural properties, which have found
applications in material science.7
Scheme 1. Retrosynthetic Analysis of Polyacetylenes 1 and 4
Recently, four new polyacetylenes, 19-furan-2-yl-nonadeca-5,7-
diynoic acid (1), 19-furan-2-ylnonadeca-5,7-diynoic acid methyl
ester (2), 2-pentacosa-7,9-diynylfuran (3), and 21-furan-2-ylheni-
cosa-14,16-diyn-1-ol (4) (Figure 1) were isolated from the roots of
Polyalthia eVecta, a small tree found in the northeastern part of
Thailand.8 These compounds were found to have potent antiplas-
modial and antiviral activities against Herpes simplex type 1.
As part of our efforts toward the synthesis and biological activity
of heterocyclic and polyacetylenic compounds,9 we became inter-
ested in the development of a synthesis route and the relationship
between the structure and biological properties of these four
bioactive polyenes. The present paper deals with a convergent route
for the first synthesis of polyacetylenes 1-4 (Figure 1), using
copper-catalyzed cross-coupling reactions to sp-sp centers, as the
key steps. Metal-catalyzed acetylenic cross-coupling has been
extensively employed for the synthesis of a wide variety of organic
compounds ranging from small organic molecules to macromol-
ecules, including polyacetylenes.10
Scheme 2. Synthesis of Fragment 5a and 5ba
a Reagents and conditions: (i) THF, 1 equiv of n-BuLi at -20 °C, 4 h, 1,4-
dibromobutane or 1,11-dibromoundecane at -20 °C to rt, overnight; (ii)
HMPA/THF (3 mL/mmol; 1:2), 2 equiv of n-BuLi (-78 °C), 18 h, rt; (iii) NaOH,
toluene, reflux; 12 h; (iv) THF, 1 equiv of n-BuLi at -20 °C, 1 h, THF/I2 at
-40 °C to rt, overnight.
protecting group on the triple bond of 9 was carried out with NaOH
in toluene under reflux,14 affording the terminal alkynes 10a in
58% and 10b in 82% yield. Compounds 10a and 10b were
transformed into the corresponding fragments 5a and 5b by reaction
with 1 equiv of n-BuLi followed by the reaction of lithium acetylide
intermediate with 1 equiv of iodine15 in 80% and 82% yield,
respectively (Scheme 2).
Results and Discussion
The retrosynthetic analysis of polyacetylenes 1 and 4, based on
metal-catalyzed acetylenic cross-coupling, afforded two basic
fragments, furyl iodide systems 5a and 5b and acetylenic alcohols
6a and 6b, which differ only in the number of carbons in the chain
(Scheme 1).
The synthesis of polyacetylenes 1 and 2 were carried out
following the sequence showed in Scheme 3. The copper-catalyzed
Cadiot-Chodkiewicz16 coupling of fragment 5b (n ) 10) with the
commercial alcohol 6a using CuI and pyrrolidine17 yielded 11
(75%). Oxidation with PDC in DMF18 provided acid 1 in 49%
The furyl iodides 5a and 5b were synthesized according to
Scheme 2. Our synthesis started with the alkylation of 2-furyllithium
(prepared from the metalation of furan using 1 equiv of n-BuLi in
THF at -20 °C for 4 h)11 with 1,4-dibromobutane or 1,11-
dibromoundecane,12 yielding the corresponding bromides 7a
(n ) 3) in 88% and 7b (n ) 10) 96% yield, respectively. The
reaction of commercially available alcohol 8 with 2 equiv of n-BuLi,
at -78 °C, gave the dilithiated intermediate that reacted with 7a
or 7b in the presence of HMPA/THF (3 mL/mmol; 1:2) as solvent,
at room temperature,13 yielding the corresponding alcohols 9a and
9b in 70% and 50% yield, respectively. The removal of the
19
yield. Esterification of 1 using MeOH in the presence of SOCl2
afforded the corresponding polyacetylenic ester 2 in 65% yield.
The synthesis of fragment 6b (Scheme 4) began by the treatment
of 2-propyn-1-ol with 2 equiv of n-BuLi in HMPA/THF13
(3 mL/mmol; 1:2) to generate the corresponding lithium dianion,
which was subsequently quenched with 1-bromododecane to afford
alcohol 12 in 85% yield. This compound was subjected to
prototropic migration of the triple bond with potassium 3-amino-
propanamide (KAPA)20 to afford the terminal alkyne 6b in 70%
* To whom correspondence should be addressed. Fax: +55 55 3220 9462.
E-mail: gzeni@pq.cnpq.br.
10.1021/np9000637 CCC: $40.75  2009 American Chemical Society and American Society of Pharmacognosy
Published on Web 04/14/2009

858 Journal of Natural Products, 2009, Vol. 72, No. 5
Barancelli et al.
Figure 1. Polyacetylenes 19-furan-2-ylnonadeca-5,7-diynoic acid (1), 19-furan-2-ylnonadeca-5,7-diynoic acid methyl ester (2), 2-pentacosa-
7,9-diynylfuran (3), and 21-furan-2-ylhenicosa-14,16-diyn-1-ol (4) isolated from the roots of Polyalthia eVecta.
Scheme 3. Synthesis of Polyacetylenes 1 and 2a
a Reagents and conditions: (i) pyrrolidine, CuI, overnight, rt; (ii) PDC, DMF, 4 h, rt; (iii) MeOH, SOCl2, 15 h, rt.
Scheme 4. Synthesis of Polyacetylene 4a
a Reagents and conditions: (i) HMPA/THF (3 mL/mmol; 1:2), 2 equiv of n-BuLi (-78 °C), 18 h, rt; (ii) KHN(CH2)3NH2, 12 h, r.t.; (iii) pyrrolidine, CuI, overnight, rt.
Scheme 5. Retrosynthetic Analysis of Polyacetylene 3
Further, we synthesized fragment 13 (Scheme 6) by alkylation
of the dilithium derivative prepared from the alcohol 8 with
commercial 1-bromopentadecane,13 yielding protected acetylene 17
(65%). Deprotection removed the acetylene protected group14
selectively to generate the free acetylene 18 in 68% yield. The
terminal alkyne produced was converted to the corresponding
alkynyl iodide 13 by treatment with n-BuLi/iodine15 in 74% yield.
Finally, with subunits 13 and 14 in hand, Cadiot-Chodkiewicz
cross-coupling was carried out using CuI and pyrrolidine17 at room
temperature, providing the target diyne 3 in 87% yield (Scheme
6).
yield. Subsequent coupling of fragment 5a and 6b using CuI and
pyrrolidine17 gave the polyacetylene 4 in 61% yield.
In summary, the efficient total synthesis of the four natural
polyacetylenes 1-4 has been achieved using highly convergent
routes. These involved copper-catalyzed cross-coupling reactions
to afford sp-sp centers as the key step. It is noteworthy that the
polyacetylene counterparts were, in all cases, highly unsaturated
1,3-diyne moieties that were stable and could be isolated, purified,
and identified. In addition, the spectroscopic data of compounds
1-4 are in agreement with the data reported by Phonkerd and co-
workers.8 Specifically, in order to study the structure-activity
relationships of these natural polyacetylenes and to evaluate changes
to the length of the carbon chains of these compounds, the syntheses
of analogues of these diynes are currently underway in our
laboratories.
Following the successful sp-sp connection for the retrosynthesis
described in Scheme 1, the preparation of polyacetylenic 3 was
performed following a parallel route (Scheme 5).
The nucleophilic fragment 14 was the first targeted precursor,
and its synthesis was achieved starting with deprotonation of the
commercial furan with n-BuLi in THF, generating the 2-lithium
furan intermediate. The alkylation of this anion using 1,6-dibro-
mohexane gave the bromide12 15 in 93% yield. Deprotonation of
both terminal alkyne and hydroxy groups of 8, using 2 equiv of
n-BuLi, at -78 °C, followed by treatment of the dianion with
bromide 15 using HMPA/THF13 (3 mL/mmol; 1:2) as solvent, led
to the expected condensation product 16 in acceptable yield (50%).
Deprotection of the triple bond by base treatment (NaOH/toluene,
reflux)14 gave fragment 14 in a yield of 65% (Scheme 6).

Natural Polyacetylenes Bearing Furan Rings
Journal of Natural Products, 2009, Vol. 72, No. 5 859
Scheme 6. Synthesis of Polyacetylene 3a
a Reagents and conditions: (i) THF, 1 equiv of n-BuLi at -20 °C, 4 h, 1,6-dibromohexane at -20 °C to rt, overnight; (ii) HMPA/THF (3 mL/mmol; 1:2), 2 equiv
of n-BuLi (-78 °C), 18 h, rt; (iii) NaOH, toluene, reflux, 12 h; (iv) HMPA/THF (3 mL/mmol; 1:2), 2 equiv of n-BuLi (-78 °C), 18 h, rt; (v) NaOH, toluene, reflux,
12 h; (vi) THF, 1 equiv of n-BuLi at -20 °C, 1 h, THF/I2 at -40 °C to rt, overnight; (vii) pyrrolidine, CuI, overnight, rt.
Experimental Section
intensity) 229 (14), 150 (14), 122 (8), 94 (14), 80 (100), 52 (10); HRMS
m/z calcd for C10H15BrO 230.0306, found 230.0309.
General Experimental Procedures. Proton nuclear magnetic
resonance spectra (1H NMR) were obtained at 400 MHz. Spectra were
recorded in CDCl3 solutions. The chemical shifts are reported (ppm)
using the δ 7.26 signal of CDCl3 (1H NMR) and the δ 77.23 signal of
CDCl3 (13C NMR) as internal standards. EIMS were obtained on a
Shimadzu GCMS-QP2010Plus spectrometer. High-resolution mass
2-(11-Bromoundecyl)furan (7b). In a reaction similar to that of
7a, 1,11-dibromoundecane yielded 5.760 g (96%) of 7b: 1H NMR
(CDCl3, 400 MHz) δ 7.30-7.27 (m, 1H), 6.29-6.25 (m, 1H),
5.98-5.94 (m, 1H), 3.40 (t, J ) 6.8 Hz, 2H), 2.60 (t, J ) 7.5 Hz, 2H),
1.85 (quint, J ) 7.1 Hz, 2H), 1.62 (quint, J ) 7.1 Hz, 2H), 1.37-1.15
(m, 14H); 13C NMR (CDCl3, 100 MHz) δ 156.4, 140.4, 109.9, 104.4,
33.8, 32.7, 29.4, 29.3, 29.3, 29.2, 29.0, 28.6, 28.1, 27.9, 27.9; MS (EI,
70 eV) m/z (relative intensity) 299 (26), 218 (17), 136 (14), 122 (32),
94 (87), 80 (100), 52 (22); HRMS m/z calcd for C15H25BrO 300.1088,
found 300.1091.
spectra were recorded on
a double-focusing magnetic sector
mass spectrometer using EI at 70 eV. IR spectra were obtained from a
Shimadzu IR-Prestige-21 spectrometer. Column chromatography was
performed using silica gel (230-400 mesh). Thin-layer chromatography
(TLC) was performed using silica gel GF254, 0.25 mm thickness. For
visualization, TLC plates were either placed under ultraviolet light or
stained with iodine vapor or acidic vanillin. The following solvents
were dried and purified by distillation from the reagents indicated:
tetrahydrofuran from sodium with a benzophenone ketyl indicator. All
other solvents were ACS or HPLC grade unless otherwise noted. Air-
and moisture-sensitive reactions were conducted in flame-dried or oven-
dried glassware equipped with tightly fitted rubber septa and under a
positive atmosphere of dry nitrogen or argon. Unless otherwise
mentioned, all chemicals and materials were used as received from
commercial suppliers without further purification.
General Procedure for the Preparation of the 2-(n-Bromo-n-
alkyl)furan Derivatives.12 Dry THF (40 mL) was cooled to -20 °C
in a 100 mL two-neck flask, and n-butyllithium (10 mL of 2.4 M
solution in hexane, 24 mmol) was added with stirring under Ar. Freshly
distilled furan (1.7 mL, 24 mmol) was added, dropwise, into the
n-butyllithium solution. The mixture was stirred for 4 h at -20 °C,
then the appropriate alkyl bromide (20 mmol) was added dropwise with
vigorous stirring, and the mixture was left overnight at room temper-
ature. The reaction was quenched by the addition of saturated NH4Cl
aqueous solution (20 mL) and extracted with EtOAc (3 × 20 mL).
The organic phase was separated and dried over MgSO4, and the solvent
removed under reduced pressure using a rotary evaporator. The residue
was purified by column chromatography on silica gel using n-hexane
as eluent to give 2-(n-bromo-n-alkyl)furan. Selected spectra and
analytical data for 2-(4-bromobutyl)furan (7a): This compound (3.555
g) was prepared in 88% yield as yellow oil, from 1,4-dibromobutane:
1H NMR (CDCl3, 200 MHz) δ 7.33-7.27 (m, 1H), 6.32-6.24 (m,
1H), 6.03-5.95 (m, 1H), 3.42 (t, J ) 6.5 Hz, 2H), 2.66 (t, J ) 6.5 Hz,
2H), 2.07-1.64 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 155.3, 140.91,
110.0, 105.0, 33.4, 32.0, 27.0, 26.5; MS (EI, 70 eV) m/z (relative
intensity) 201 (23), 122 (17), 94 (26), 80 (100), 53 (34); HRMS m/z
calcd for C8H11BrO 201.9993, found 201.9998.
General Procedure for the Copper-Catalyzed Coupling Reaction
of Alkynes with Iodide Derivative.17 To a two-neck round-bottom
flask, under Ar, were added the appropriate iodide (1 mmol), the
pyrrolidine (3 mL), and the alkyne (1.2 mmol) at room temperature.
The temperature was decreased to 0 °C, and CuI (0.038 g, 0.2 mmol)
was added. The reaction mixture was allowed to stir at room temperature
overnight. After this time, the solution was diluted by satured NH4OH/
NH4Cl aqueous solution (20 mL) and extracted with EtOAc (3 × 20
mL). The organic phase was separated and dried over MgSO4, and the
solvent was removed under reduced pressure using a rotary evaporator.
The residue was purified by column chromatography on silica gel using
EtOAc/n-hexane (40:60) as eluent. Selected spectra and analytical data
for 21-furan-2-ylhenicosa-14,16-diyn-1-ol (4): yield 0.240 g (65%);
1H NMR (CDCl3, 200 MHz) δ 7.30-7.27 (m, 1H), 6.30-6.25 (m,
1H), 6.01-5.96 (m, 1H), 3.66-3.58 (m, 2H), 2.63 (t, J ) 7.3 Hz, 2H),
2.30-2.20 (m, 4H), 1.77-1.70 (m, 2H), 1.61-1.46 (m, 10H),
1.41-1.22 (m, 14H); 13C NMR (CDCl3, 100 MHz) δ 155.7, 140.7,
110.0, 104.8, 77.7, 68.0, 65.5, 65.1, 63.0, 32.8, 29.5, 29.5, 29.5, 29.4,
29.4, 29.4, 29.0, 28.8, 28.3, 27.7, 27.3, 27.1, 25.7, 19.1, 18.9; MS (EI,
70 eV) m/z (relative intensity) 366 (27), 350 (4), 224 (14), 182 (67),
157 (100), 128 (94), 80 (80), 54 (46); IR (KBr) (νmax, cm-1) 3420,
3124, 2922, 2846, 2183, 2140, 1597, 1506, 1467, 1415, 1176, 1141,
1058, 1035, 1003, 883; HRMS m/z calcd for C25H38O2 370.2872, found
370.2877.
1
2-Pentacosa-7,9-diynylfuran (3): yield 0.356 g (89%); H NMR
(CDCl3, 400 MHz) δ 7.31-7.27 (m, 1H), 6.29-6.25 (m, 1H),
5.99-5.95 (m, 1H), 2.61 (t, J ) 7.4 Hz, 2H), 2.24 (t, J ) 6.7 Hz, 4H),
1.68-1.59 (m, 2H), 1.58-1.47 (m, 4H), 1.46-1.31 (m, 6H), 1.30-1.21
(m, 22H), 0.88 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
156.3, 140.6, 109.9, 104.5, 77.5, 77.2, 65.3, 65.2, 31.9, 29.6, 29.6, 29.6,
29.6, 29.6, 29.4, 29.3, 29.0, 28.8, 28.5, 28.4, 28.3, 28.1, 27.8, 27.8,
22.6, 19.1, 19.1, 14.0; MS (EI, 70 eV) m/z (relative intensity) 406 (21),
210 (30), 130 (40), 104 (36), 90 (53), 80 (100), 54 (25); IR (KBr)
(νmax, cm-1) 3128, 2911, 2843, 2180, 2141, 1599, 1506, 1469, 1418,
1175, 1138, 1069, 1005, 883; anal. (%) calc for C29H46O, C 84.81, H
11.21, found C 84.61, H 10.87.
2-(6-Bromohexyl)furan (15). This compound (4.278 g) was prepared
in 93% yield from 1,6-dibromohexane: 1H NMR (CDCl3, 200 MHz) δ
7.34-7.25 (m, 1H), 6.33-6.20 (m, 1H), 6.02-5.92 (m, 1H), 3.43-3.33
(m, 2H), 2.68-2.54 (m, 2H), 1.96-1.76 (m, 2H), 1.74-1.53 (m, 2H),
1.52-1.25 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 156.3, 140.5, 109.9,
104.6, 33.8, 32.5, 28.1, 27.8, 27.7, 27.2; MS (EI, 70 eV) m/z (relative
19-Furan-2-ylnonadeca-5,7-diyn-ol (11): yield 0.256 g (75%); 1H
NMR (CDCl3, 200 MHz) δ 7.33-7.27 (m, 1H), 6.20-6.24 (m, 1H),

860 Journal of Natural Products, 2009, Vol. 72, No. 5
Barancelli et al.
J.; Platas, G.; Diez, M. T.; Vicente, F.; Dorso, K.; Abruzzo, G.; Wilson,
K. J. Nat. Prod. 2004, 67, 1900. (d) Lerch, M. L.; Harper, M. K.;
Faulkner, D. J. J. Nat. Prod. 2003, 66, 667. (e) Faulkner, D. J. Nat.
Prod. Rep. 1995, 12, 223.
5.99-5.92 (m, 1H), 3.67 (t, J ) 6.2 Hz, 2H), 2.61 (t, J ) 7.4 Hz, 2H),
2.39-2.16 (m, 5H), 1.75-1.54 (m, 6H), 1.39-1.19 (m, 16H); 13C NMR
(CDCl3, 100 MHz) δ 156.6, 140.5, 109.9, 104.4, 77.6, 76.8, 65.6, 65.1,
62.1, 31.6, 29.4, 29.4, 29.3, 29.2, 29.0, 28.9, 28.7, 28.2, 27.9, 27.8,
24.5, 19.0, 18.9; MS (EI, 70 eV) m/z (relative intensity) 342 (1), 310
(5), 156 (22), 130 (29), 94 (53), 80 (100), 66 (19); anal. (%) calc for
C23H34O2, C 80.65, H 10.01, found C 80.44, H 9.78.
(2) Young, K.; Jayasuriya, H.; Ondeyka, J. G.; Herath, K.; Zhang, C.;
Kodali, S.; Galgoci, A.; Painter, R.; Brown-Driver, V.; Yamamoto,
R.; Silver, L. L.; Zheng, Y.; Ventura, J. I.; Sigmund, J.; Ha, S.; Basilio,
A.; Vicente, F.; Tormo, J. R.; Pelaez, F.; Youngman, P.; Cully, D.;
Barrett, J. F.; Schmatz, D.; Singh, S. B.; Wang, J. Antimicrob. Agents
2006, 50, 519.
(3) (a) Kobaisy, M.; Abramowski, Z.; Lermer, L.; Saxena, G.; Hancock,
R. E. W.; Towers, G. H. N.; Doxsee, D.; Stokes, R. W. J. Nat. Prod.
1997, 60, 1210. (b) Fusetani, N.; Toyoda, T.; Asai, N.; Matsunaga,
S.; Maruyama, T. J. Nat. Prod. 1996, 59, 796.
(4) Rashid, M. A.; Gustafson, K. R.; Cardellina, J. H.; Boyd, M. R. Nat.
Prod. Lett. 2001, 15, 21.
(5) Arnason, J. T.; Philogene, B. J. R.; Berg, C.; MacEachern, A.;
Kaminski, J.; Leitch, L. C.; Morand, P.; Lam, J. Phytochemistry 1986,
25, 1609.
(6) Ito, A.; Cui, B.; Chavez, D.; Chai, H.-B.; Shin, Y. G.; Kawanishi, K.;
Kardono, L. B. S.; Riswan, S.; Farnsworth, N. R.; Cordell, G. A.;
Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 2001, 64, 246.
(7) (a) Luu, T.; Elliott, E.; Slepkov, A. D.; Eisler, S.; McDonald, R.;
Hegmann, F. A.; Tykwinski, R. R. Org. Lett. 2005, 7, 51. (b) Eisler,
S.; Slepkov, A. D.; Elliot, E.; Luu, T.; McDonald, R.; Hegmann, F. A.;
Tykwinski, R. R. J. Am. Chem. Soc. 2005, 127, 2666. (c) Umeda, R.;
Morinaka, T.; Sonoda, M.; Tobe, Y. J. Org. Chem. 2005, 70, 6133.
(d) Marsden, J. A.; Haley, M. M. J. Org. Chem. 2005, 70, 10213.
(8) Kanokmedhakul, S.; Kanokmedhakul, K.; Kanikeaw, I.; Phonkerd, N.
J. Nat. Prod. 2006, 69, 68.
(9) (a) Stein, A. L.; Alves, D.; da Rocha, J. T.; Nogueira, C. W.; Zeni, G.
Org. Lett. 2008, 10, 4983. (b) Alves, D.; Luchese, C.; Nogueira, C. W.;
Zeni, G. J. Org. Chem. 2007, 18, 6726. (c) Prediger, P.; Moro, A. V.;
Nogueira, C. W.; Savegnago, L.; Menezes, P. H.; Rocha, J. B. T.;
Zeni, G. J. Org. Chem. 2006, 71, 3786. (d) Barros, O. S. D.; Nogueira,
C. W.; Stangherlin, E. C.; Menezes, P. H.; Zeni, G. J. Org. Chem.
2006, 71, 1552. (e) Zeni, G.; Larock, R. C. Chem. ReV. 2006, 106,
4644. (f) Oliveira, J. M.; Zeni, G.; Malvestiti, I.; Menezes, P. H.
Tetrahedron Lett. 2006, 47, 8183. (g) Alves, D.; Nogueira, C. W.;
Zeni, G. Tetrahedron Lett. 2005, 46, 8761. (h) Zeni, G.; Larock, R. C.
Chem. ReV. 2004, 104, 2285. (i) Zeni, G.; Panatieri, R. B.; Lissner,
E.; Menezes, P. H.; Braga, A. L.; Stefani, H. A. Org. Lett. 2001, 6,
819.
Synthesis of 19-Furan-2-ylnonadeca-5,7-diynoic Acid (1).18 Py-
ridinium dichromate (PDC) (0.66 g, 1.75 mmol) was added to the
solution of alcohol 11 (0.17 g, 0.5 mmol) in DMF (1 mL). The mixture
was stirred for 4 h and poured into H2O. The product was extracted
with Et2O (3×). The organic extract was washed successively with
H2O and dilute HCl solution and dried over MgSO4, and the solvent
removed under reduced pressure using a rotary evaporator. The residue
was purified by column chromatography on silica gel using EtOAc/n-
1
hexane (40:60) as eluent: yield 0.872 g (49%); H NMR (CDCl3, 400
MHz) δ 7.30-7.27 (m, 1H), 6.30-6.23 (m, 1H), 5.99-5.93 (m, 1H),
2.60 (t, J ) 7.5 Hz, 2H), 2.49 (t, J ) 7.4 Hz, 2H), 2.35 (t, J ) 6.9 Hz,
2H), 2.24 (t, J ) 7.0 Hz, 2H), 1.84 (quint, J ) 7.1 Hz, 2H), 1.62 (quint,
J ) 7.1 Hz, 2H), 1.51 (quint, J ) 7.3 Hz, 2H), 1.35-1.23 (m, 14H);
13C NMR (CDCl3, 50 MHz) δ 179.1, 156.5, 140.5, 109.9, 104.4, 78.0,
75.6, 66.3, 64.9, 32.5, 29.5, 29.4, 29.4, 29.3, 29.1, 29.0, 28.7, 28.2,
27.9, 27.9, 23.1, 19.1, 18.5; IR (KBr) (νmax, cm-1) 3446-2370, 2918,
2846, 2150, 1690, 1598, 1508, 1463, 1443, 1412, 1205, 1180, 1009,
885; anal. (%) calc for C23H32O3, C 77.49, H 9.05, found C 77.82, H
8.83.
Synthesis of 19-Furan-2-ylnonadeca-5,7-diynoic Acid Methyl
Ester (2).19 To a solution of 1 (0,178 g, 0.5 mmol) in absolute MeOH
(1 mL) was added 0.03 mL of SOCl2. The mixture was stirred at room
temperature for 15 h, and the solvent was removed in vacuo. The residue
was purified by column chromatography on silica gel using EtOAc/n-
1
hexane (20:80) as eluent: yield 0.121 g (65%); H NMR (CDCl3, 200
MHz) δ 7.30-7.27 (m, 1H), 6.29-6.25 (m, 1H), 5.98-5.94 (m, 1H),
3.67 (s, 3H), 2.60 (t, J ) 7.5 Hz, 2H), 2.44 (t, J ) 7.3 Hz, 2H), 2.33
(t, J ) 6.8 Hz, 2H), 2.23 (t, J ) 7.0 Hz, 2H), 1.84 (quint, J ) 7.0 Hz,
2H), 1.62 (quint, J ) 7.3 Hz, 2H), 1.50 (quint, J ) 7.3 Hz, 2H),
1.34-1.22 (m, 14H); 13C NMR (CDCl3, 50 MHz) δ 173.3, 156.5, 140.5,
109.9, 104.4, 77.9, 75.8, 66.2, 65.0, 51.5, 32.6, 29.4, 29.4, 29.3, 29.2,
29.1, 29.0, 28.7, 28.2, 27.9, 27.9, 23.4, 19.1, 18.6; IR (neat) (νmax, cm-1
)
3462, 3115, 2924, 2852, 2256, 2164, 1597, 1506, 1462, 1435, 1159,
1148, 1074, 1074, 1107, 885; anal. (%) calc for C24H34O3, C 77.80, H
9.25, found C 77.52, H 8.79.
(10) Chinchilla, R.; Najera, C. Chem. ReV. 2007, 107, 874.
(11) Zeni, G.; Lu¨dtke, D. S.; Nogueira, C. W.; Panatieri, R. B.; Braga,
A. L.; Silveira, C. C.; Stefani, H. A.; Rocha, J. B. T. Tetrahedron
Lett. 2001, 42, 8927.
Acknowledgment. We are grateful to Conselho Nacional de
Desenvolvimento Cient´ıfico e Tecnolo´gico, Coordenac¸a˜o de Aperfe-
ic¸oamento de Pessoal de N´ıvel Superior (SAUX) and Fundac¸a˜o de
Amparo a` Pesquisa do Estado do Rio Grande do Sul, for the fellowship
and financial support.
(12) Lissi, A. E.; Encinas, V. M.; Castan˜eda, F.; Olea, A. F. J. Phys. Chem.
1980, 84, 251.
(13) Cossy, J.; Pete, J. P. Tetrahedron Lett. 1986, 27, 573.
(14) Neenan, T. X.; Whitesides, G. M. J. Org. Chem. 1988, 53, 2489.
(15) Coleman, B. E.; Cwynar, V.; Hart, D. J.; Havas, F.; Mohan, J. M.;
Patterson, S.; Ridenour, S.; Schmidt, M.; Smith, E.; Wells, A. J. Synlett
2004, 1339.
(16) Since the use of Cadiot-Chodkiewicz classical conditions led to a
lower yield of cross-coupling product, we carried out the reaction under
Alami’s improved conditions.17
Supporting Information Available: Experimental procedures,
additional experimental details for the preparation of all compounds,
and 1H and 13C NMR spectra for all reaction products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(17) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763.
(18) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 5, 399.
(19) Kazemi, F.; Kiasat, A. R.; Mombaini, B. Phosphorus, Sulfur, Silicon
Relat. Elem. 2004, 179, 1187.
References and Notes
(1) (a) Senn, M.; Gunzenhauser, S.; Brun, R.; Se´quin, U. J. Nat. Prod.
2007, 70, 1565. (b) Tian, Y.; Wei, X.; Xu, H. J. Nat. Prod. 2006, 69,
1241. (c) Parish, C. A.; Huber, J.; Baxter, J.; Gonzalez, A.; Collado,
(20) Abrams, S. R. Can. J. Chem. 1984, 62, 1333.
NP9000637