Synthesis of polyacetylenic acids isolated from Nanodea muscosa

Article abstract of DOI:10.1016/j.tetlet.2005.10.032

The first total synthesis of two linear polyacetylenic compounds is described. The synthesis of (E)-octadec-13-en-11-ynoic acid 1 and (E)-octadec-13-en-9,11-diynoic acid 2 by using the vinylic telluride coupling reaction was accomplished.

Full text of DOI:10.1016/j.tetlet.2005.10.032

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8761–8764
Synthesis of polyacetylenic acids isolated from Nanodea muscosa
Diego Alves, Cristina W. Nogueira and Gilson Zeni*
ˆ
Laborato´rio de Sı´ntese, Reatividade, Avaliac¸a˜o Farmacolo´gica e Toxicologica de Organocalcogenios, CCNE,
UFSM, Santa Maria, Rio Grande do Sul, CEP 97105-900, Brazil
Received 21 September 2005; revised 29 September 2005; accepted 11 October 2005
Available online 27 October 2005
Abstract—The first total synthesis of two linear polyacetylenic compounds is described. The synthesis of (E)-octadec-13-en-11-ynoic
acid 1 and (E)-octadec-13-en-9,11-diynoic acid 2 by using the vinylic telluride coupling reaction was accomplished.
Ó 2005 Elsevier Ltd. All rights reserved.
Several examples of acetylenic and polyacetylenic
compounds have been isolated in recent years.1 Many
of these natural products have shown biological activi-
ties ranging from antibacterial, fungicidal and in vitro
antitumor properties to cell division inhibition.2 In
addition, these compounds could also be potent inhibi-
tors of the arachidonic acid metabolism.3 Recently,
two new linear polyacetylenic acids [(13E)-octadec-13-
en-11-ynoic acid] 1 and [(13E)-octadec-13-en-9,11-diy-
noic acid] 2 (Fig. 1) were isolated from the aerial parts
of Nanodea muscosa, a small herb found in extreme
southern regions of South America.4 These authors
also elucidated the structure of compounds 1 and 2 by
spectroscopic methods and assigned their absolute
stereochemistry.
Many different classes of organotellurium compounds
have been prepared and studied to date, vinylic tellu-
rides are certainly the most useful and promising com-
pounds in view of their usefulness in the organic
synthesis.6 In addition to their utility in the field of
organic chemistry, toxicological and pharmacological
aspects of organotellurium compounds have also been
recently reviewed.7
However, the use of tellurium chemistry for the syn-
thetic organic chemists or as a tool in organic synthesis
has been hampered due to a bad reputation related to
the bad smell, toxicity or instability of these compounds.
In fact, these comments are correct to a particular group
of the tellurium compounds, but they are not a rule
for all tellurium compounds. In our lab, we have used
a lot of different classes of tellurium compounds and
observed that tellurides or ditellurides, bearing an alkyl
group with a low molecular weight, present a bad smell.
Conversely, when these alkyl groups present any addi-
tional substituent, the corresponding tellurides or ditel-
lurides are practically odorless.
In a previous work, we have already reported the syn-
thesis of polyacetylenic acids isolated from Heisteria
acuminata, utilizing, as a tool, the tellurium chemistry.5
COOH
Other tellurium compounds, such as trihalides, diaryl
tellurides and ditellurides are solid, very stable (can be
stored in the lab in a simple flask for a long time)
and completely odorless. In addition, the vinylic tellu-
rides, one of the most used classes of tellurium com-
pounds, containing an aromatic, aliphatic saturated or
unsaturated chains, which are odorless compounds,
can be easily prepared, purified and stored as a com-
mon chemical used in the lab. Another reason that has
hindered the development of the organotellurium chem-
istry is that the toxicological studies are still scarce in the
literature, however, they are meant. Some authors have
1
COOH
2
Figure 1.
Keywords: Vinylic tellurides; Palladium cross-coupling; Polyacetylenes;
Enynes.
*
Corresponding author. Tel.: +11 55 55 2208140; fax: +11 55 55 220
8031; e-mail: gzeni@quimica.ufsm.br
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.032

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D. Alves et al. / Tetrahedron Letters 46 (2005) 8761–8764
HO
B
H
COOH
1
2
TeBu
A
C
COOH
HO
H
Scheme 1.
described that organotellurium compounds are less toxic
than their selenium derivatives8 and others have indi-
cated that organotellurium compounds are more toxic
than organoselenium compounds.7 We are sure that
no highly specialized techniques are required in the han-
dling of organotellurium compounds and work with
these compounds is very similar to work with any other
classes of chemical compounds such as organoselenium,
organosulfur, organotin and organophosphorus.
1) DIBAL-H
toluene / hexane
reflux
TeBu
H
2) BuTeBr, LiCl
A
52%
Scheme 2.
Polyacetylenic acid 1 was synthesized following the
sequence shown in Scheme 3. The synthesis of alkynyl
system B began by the treatment of propargylic alcohol
with 2 equiv of n-BuLi in HMPA/THF11 to generate
the corresponding dianion, which was subsequently
quenched with 1-bromononane to afford alcohol 3 in
83% yield. This compound was subjected to prototropic
migration of triple bond with potassium 3-aminopro-
panamide (KAPA)12 to afford the desired terminal acet-
ylenic alcohol B in 78% yield. The cross-coupling
reaction of B with the (E)-vinylic telluride A using
PdCl2/CuI in methanol13 afforded 4 in 75% yield, with
the desired E geometry of the double bond. The cou-
pling reaction occurs with the retention of the double
bond geometry since starting from pure E adduct of
the vinylic tellurides only E enynes 4 were obtained.
The stereochemistry of the obtained enynes was easily
As a part of our efforts toward the total synthesis of
polyacetylenic natural products,5,9 we became interested
in the synthesis of these two polyacetylenic acids 1 and
2. The challenge of this synthesis is to build the requisite
E-stereochemistry of the double bond. It could be easily
achieved using one of the most important behaviors of
the vinylic tellurides; their high stereospecific synthesis
and reactivity.
The retrosynthetic analysis of compounds 1 and 2 affor-
ded three basic fragments: (E)-vinylic telluride A, alkyne
B and 1,3-alkadiyne system C. Both polyacetylenic acids
1 and 2 could be derived from the (E)-vinylic telluride A,
a key intermediate to this synthesis (Scheme 1).
1
Firstly, we synthesized the (E)-vinylic telluride A by the
hydroalumination of the 1-hexyne followed by the reac-
tion with BuTeBr/LiCl in 52% yield (Scheme 2).10
established, since the H NMR spectrum of compound
4 showed a doublet of triplets at 6.03 ppm with coupling
constant of 15.7 and 7.1 Hz and a doublet of triplets at
OH
H
HO
4
iv
i
iii
COOH
HO
1
3
ii
H
+
TeBu
HO
B
Scheme 3. Reagents and conditions: (i) 2 equiv of n-BuLi, THF, HMPA, 1-bromononane, 83%. (ii) KHN(CH2)3NH2, 78%. (iii) PdCl2, CuI, MeOH,
Et3N, 75%. (iv) PDC, DMF, 80%.

D. Alves et al. / Tetrahedron Letters 46 (2005) 8761–8764
8763
H
H
HO
+
TeBu
HO
i
C
v
HO
5
6
ii
OH
9
H
iv
vi
HO
OH
iii
COOH
I
7
2
OH
HO
8
Scheme 4. Reagents and conditions: (i) 2 equiv of n-BuLi, THF, HMPA, 1-bromoheptane, 80%. (ii) KHN(CH2)3NH2, 76%. (iii) Pyrrolidine, CuI,
4-iodo-2-methylbut-3-yn-2-ol, 85%. (iv) NaOH, toluene, reflux, 71%. (v) PdCl2, CuI, MeOH, Et3N, reflux, 74%. (vi) PDC, DMF, 78%.
5.44 ppm with coupling constant of 15.7 and 1.4 Hz.
These coupling constants confirm the trans relationship
of the hydrogens attached to the double bond.
ture–activity relationship of these compounds will be
reported elsewhere in the near future.
Next, the oxidation of 4 using PDC in DMF14 gave
polyacetylenic acid 1 in 80% yield. The overall yield of
total synthesis was 38%.
Acknowledgements
We are grateful to FAPERGS, CAPES and CNPq for
financial support. CNPq is also acknowledged for fel-
lowship (D.A. and G.Z.).
Polyacetylenic acid 2 was synthesized according to
Scheme 4. The synthesis of fragment C started with
the alkylation of the dilithium derivative of propargylic
alcohol with 1-bromoheptane,11 yielding alcohol 5 in
80%. This compound was subjected to prototropic
migration of triple bond with KAPA12 to afford termi-
nal acetylenic alcohol 6 in 76% yield. Subsequent cou-
pling reaction of acetylenic alcohol 6 with alkynyl
iodide 7 using CuI and pyrrolidine15 yielded diyne 8 in
85%. Treatment of compound 8 with NaOH in toluene
under reflux16 afforded 1,3-alkadiyne system C in 71%
yield. This terminal diyne was coupled to the (E)-vinylic
telluride A using PdCl2/CuI in methanol,13 under reflux,
giving the enediyne system 9 in 74% yield. The oxidation
with PDC in DMF14 provided the corresponding poly-
acetylenic acid 2 (78%). The overall yield of this total
synthesis was 21%.
References and notes
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In summary, we have completed, for the first time, the
total synthesis of two natural products in mild reaction
conditions and in satisfactory yields, using palladium
cross-coupling-based methodologies and vinylic tellu-
rides as a key intermediate. We have shown in this study
that the use of vinylic tellurides is an efficient strategy
to achieve stereospecifically double bonds in poly-
unsaturated natural products. The investigation on the
pharmacology and toxicology, as well as, the struc-

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13-en-9,11-diynoic acid (2): yellow oil; H NMR: CDCl3,
400 MHz, d (ppm): 6.27 (dt, J = 15.9, 7.3 Hz, 1H), 5.48 (d,
J = 15.9 Hz, 1H), 2.37–2.28 (m, 4H), 2.11 (q, J = 7.1 Hz,
2H), 1.63 (quint., J = 7.4 Hz, 2H), 1.53 (quint.,
J = 7.4 Hz, 2H), 1.34 (m, 10H), 0.89 (t, J = 7.1 Hz, 3H);
13C NMR: CDCl3, 100 MHz, d (ppm): 13.8, 19.5, 22.1,
24.6, 28.2, 28.6, 28.7, 28.9, 30.7, 32.9, 33.9, 65.3, 72.8, 74.1,
83.4, 108.6, 148.2, 179.3.
17. (13E)-Octadec-13-en-11-ynoic acid (1): yellow oil; 1H
NMR: CDCl3, 400 MHz, d (ppm): 6.04 (dt, J = 15.7;
6.9 Hz, 1H), 5.44 (dt, J = 15.7; 1.8 Hz, 1H), 2.24–2.39
(m, 4H), 2.07 (q, J = 7.4 Hz, 2H), 1.15–1.50(m, 18H), 0.88
(t, J = 6.7 Hz, 3H); 13C NMR: CDCl3, 100 MHz, d (ppm):