Synthesis of polyacetylenic acids isolated from Heisteria acuminata

Article abstract of DOI:10.1021/ol006946v

matrix presented Four linear polyacetylenic compounds were synthesized. Pentadeca-6,8,10-triynoic acid 1 and octadeca-8,10,12-triynoic acid 2 were synthesized by using acetylene coupling reactions. The syntheses of (Z)-hexadec-11-en-7,9-diynoic acid 3 and (Z)-octadec-12-en-7,9-diynoic acid 4 by using vinylic telluride coupling reactions were accomplished.

Full text of DOI:10.1021/ol006946v

ORGANIC
LETTERS
2
001
Vol. 3, No. 6
19-821
Synthesis of Polyacetylenic Acids
Isolated from Heisteria acuminata
8
Gilson Zeni,* Rodrigo B. Panatieri, Eliseo Lissner, Paulo H. Menezes,‡
Antonio L. Braga, and H e´ lio A. Stefani§
Departamento de Qu ´ı mica, Laborat o´ rio de Bioqu ´ı mica Toxicol o´ gica, UFSM,
97105-900 Santa Maria, RS, Brazil
gzeni@.quimica.ufsm.br
Received December 1, 2000
ABSTRACT
Four linear polyacetylenic compounds were synthesized. Pentadeca-6,8,10-triynoic acid 1 and octadeca-8,10,12-triynoic acid 2 were synthesized
by using acetylene coupling reactions. The syntheses of (Z)-hexadec-11-en-7,9-diynoic acid 3 and (Z)-octadec-12-en-7,9-diynoic acid 4 by
using vinylic telluride coupling reactions were accomplished.
3
Several examples of polyacetylenic compounds have been
isolated in recent years. New linear polyacetilenic com-
pounds 1, 2, 3, and 4 (Scheme 1) were isolated from the
and 5-lipoxygenase (5-LO). Polyacetylenes have also been
reported previously in the literature as potent inhibitors of
1
4
the arachidonic acid metabolism. Therefore, it may be
inferred that compounds 1-4 are, at least in part, responsible
for the antiinflammatory activity of preparations of Heisteria
5
acuminata bark used in folk medicine.
Scheme 1
The unusual structure, the interesting biological activities,
and the low availability of these compounds from natural
sources encouraged us to synthesize them. In a previous work
we have already reported the synthesis of polyacetylenic
6
montiporic acids A and B (Scheme 2). In this Letter we
wish to describe an easy route to compounds 1-4.
The retrosynthetic analysis of polyacetylenic acids 1 and
2
afforded two basic fragments: alkyldiyne system B and
bark of Heisteria acuminata by bioassay-guided fraction-
2
ation. These compounds were found to have potent antiin-
flammatory activity by inhibition of cyclooxygenase (COX)
Scheme 2
‡
Present address: Departamento de Qu ´ı mica Fundamental, UFPE,
Recife, PE, Brazil.
§
Present address: Faculdade de Ci eˆ ncias Farmac eˆ uticas, USP, S a˜ o Paulo,
SP, Brazil.
(1) Faulker, D. J. Nat. Prod. Rep. 1995, 12, 223 and earlier reviews
cited therein.
(2) Kraus, M. C.; Neszm e´ lyi, A.; Holly, S.; Wiedemann, B.; Nenniiger,
A.; Torssell, G. B. K.; Bohlin, L.; Wagner, H. J. Nat. Prod. 1998, 61, 422.
1
0.1021/ol006946v CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/21/2001

acetylenic alcohol A, which differ only in the number of
The synthesis of fragment A (Scheme 4) started with
carbons in the chain (Scheme 3).
alkylation of the lithium derivative of propargylic alcohol
1
0
with 1-bromobutane or 1-bromohexane, yielding the cor-
responding alcohols 9 in 83% and 89% yields. These
compounds were then subjected to prototropic migration of
Scheme 3
1
1
triple bond with KAPA to afford the desired terminal
acetylenic alcohols (fragment A) in 87 and 85% yields.
Subsequent coupling reaction of fragments A and B using
8
CuI and pyrrolidine yielded 10 in 90% and 93%. Oxidation
1
2
with chromium oxide/H
2
SO
4
afforded the desired acids 1
and 2 in 58% and 60% yields, respectively. The overall yield
of the sequence was 30% (1) and 34% (2).
The retrosynthetic analysis of polyacetylenic acids 3 and
4
afforded two fragments: vinylic telluride C and 1,3-
alkylidyine system D (Scheme 5).
The alkyldiynes B were synthesized according to Scheme
4. The appropriate terminal acetylene (n ) 3 or 4) was
Scheme 5
Scheme 4a
The fragment D was synthesized following the sequence
shown in Scheme 6, by the same procedure used for the
synthesis of compound 8 (Scheme 4). The overall yields of
fragment D were 40% and 43%.
Further, we synthesized fragment C (Scheme 6) by
1
3
hydrotelluration of the appropriate alkyne. The desired
(
(
(
10) Cossy, J.; Pete, J. P. Tetrahedron Lett. 1986, 27, 573.
11) Abrams, S. R. Can. J. Chem. 1984, 62, 1333.
12) Heilbron, I.; Jones, E. R. H.; Sondheimer, F. J. Chem. Soc. 1949,
6
04.
13) Zeni, G.; Formiga, H. B.; Comasseto, J. V. Tetrahedron Lett. 2000,
41, 1311.
(14) Zeni, G.; Comasseto, J. V. Tetrahedron Lett. 1999, 40, 4619.
a
(
i) n-BuLi, THF/I
2
; (ii) pyrrolidine, CuI; (iii) NaOH, xylene,
; (v)2 equiv of n-BuLi, THF/HMPA;
; (vii) pyrrolidine, CuI; (viii) CrO /H SO , -10
(
reflux; (iv) n-BuLi, THF/I
vi) KNH(CH NH
C.
2
(
°
)
2 3
2
3
2
4
1
(
15) Compound 1. H NMR (400 MHz, CD3OD) δ 0.95 (3 H, t, J ) 7.1
Hz); 1.43 (2 H, sex, J ) 7.5 Hz); 1.54 (2 H, quint, J ) 7.5 Hz); 1.58 (2 H,
quint, J ) 7.6 Hz); 1.70 (2 H, quint, J ) 7.5 Hz); 2.30 (2 H, t, J ) 7.5 Hz);
13
2
1
.33 (2 H, quint, J ) 6.9 Hz). C NMR (100 MHz, CDCl3) δ 13.30; 18.92;
9.25; 22.00; 24.10; 27.80; 30.20; 60.50; 60.90; 65.83; 66.42; 78.50; 79.83.
converted into the 1-iodoacetylene 5 by treatment with
1
MS m/z (%): 230 (55), 128 (100), 91 (50), 41 (32). Compound 2. H NMR
(400 MHz, CD3OD) δ 0.90 (3 H, t, J ) 7.3 Hz); 1.40 (2 H, quint, J ) 7.5
Hz); 1.41 (2 H, quint, J ) 7.5 Hz); 1.43 (2 H, sex, J ) 7.3 Hz); 1.47 (2 H,
quint, J ) 7.5 Hz); 1.52 (2 H, quint, J ) 7.3 Hz); 1.66 (2 H, quint, J ) 7.3
Hz); 2.23 (2 H, t, J ) 7.3 Hz); 2.28 (2 H, t, J ) 7.3 Hz); 2.30 (2 H, t, J )
7
n-BuLi/iodine in 78% (n ) 3) and 82% (n ) 4) yields.
Coupling reaction of 5 with 6 in the presence of pyrrolidine/
8
CuI yielded 7 in 95% and 93% yields, respectively, which
9
7.3 Hz); 13C NMR (100 MHz, CDCl ) δ 13.60; 19.25; 19.40; 22.10; 28.15;
by treatment with NaOH in xylene under reflux afforded
3
2
8.75; 28.83; 29.80; 30.23; 60.40; 60.50; 65.83; 65.95; 79.20; 79.40; MS
the diynes 8 in 70% and 73% yields. Compounds 8 were
then transformed into the corresponding fragment B by using
again n-BuLi/I in 85% and 87% yields, respectively.
2
1
m/z (%): 272 (20), 230 (8), 129 (100), 41 (70). Compound 3. H NMR
(400 MHz, CD3OD) δ 0.93 (3 H, t, J ) 7.2 Hz); 1.36 (2 H, sex, J ) 7.3
Hz); 1.39 (2 H, quint, J ) 7.5 Hz); 1.55 (2 H, quint, J ) 7.3 Hz); 1.63 (2
H, quint, J ) 7.6 Hz); 2.29 (2 H, t, J ) 7.3 Hz); 2.35 (2 H, td, J ) 7.0; 0.7
1
3
Hz); 5.48(1 H, dt, J ) 10.7; 1.1 Hz); 6.07 (1 H, dt, J ) 10.7; 7.5 Hz).
C
(
3) Dirsch, V.; Neszm e´ lyi, A.; Wagner, H. Pharm. Pharmacol. Lett. 1982,
NMR (100 MHz, CDCl3) δ 13.90; 19.55; 22.30; 24.35; 28.00; 28.43; 30.45;
2
, 184.
31.30; 34.05; 65.54; 72.30; 78.24; 84.38; 108.14; 147.81. MS m/z (%): 246
1
(
4) Redl, K.; Breu, W.; Davis, B.; Bauer, R. Planta Med. 1994, 60, 58.
(8), 146 (30), 129 (50), 117 (100), 91 (68). Compound 4. H NMR (400
(5) Morita, M.; Sato, S.; Yanagisawa, T.; Mihasi, H. Japanese Patent JP
MHz, CD3OD) δ 0.93 (3 H, t, J ) 7.2 Hz); 1.31 (2 H, quint, J ) 7.3 Hz);
1.35 (2 H, quint, J ) 7.3 Hz); 1.37 (2 H, sex, J ) 7.5 Hz); 1.39 (2 H,
quint, J ) 7.5 Hz); 1.42 (2 H, quint, J ) 7.4 Hz); 1.42 (2 H, quint, J ) 7.5
Hz); 1.61 (2 H, quint, J ) 7.3 Hz); 2.28 (2 H, t, J ) 7.4 Hz); 2.31 (2 H,
td, J ) 7.4; 0.6 Hz); 2.34 (2 H, qd, J ) 6.9; 1.2 Hz); 5.42 (1 H, dt, J )
10.9; 1.2 Hz); 6.07 (1 H, dt, J ) 10.9; 7.6 Hz). C NMR (100 MHz, CDCl3)
δ 14.02; 19.75; 22.36; 24.87; 28.39; 28.71; 28.88; 29.06; 30.05; 31.00;
65.34; 72.22; 78.29; 84.71; 108.26; 147.95. MS m/z (%): 271 (10), 245
(6), 187 (30), 164 (27), 117 (100), 91 (65).
0
3017043 A2, 1991; Chem. Abstr. 1991, 115, 142236.
6) Stefani, H. A.; Costa, I. M.; Zeni, G. Tetrahedron Lett. 1999, 40,
215.
7) Brandsma, L. In PreparatiVe Acetylenic Chemistry; Elsevier: Am-
sterdam, 1988.
(
9
(
13
(
(
8) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763.
9) Shostakovskii, N.; Bogdanova, A. V. In The Chemistry of Diacety-
lenes; John Wiley & Sons: New York, 1974.
820
Org. Lett., Vol. 3, No. 6, 2001

Scheme 6a
a
(i) 2 equiv of n-BuLi, THF/HMPA; (ii) KNH(CH
)
2 3
NH
2
2
; (iii) 2 equiv of n-BuLi, THF/I ; (iv) pyrrolidine, CuI; (v) NaOH, xylene,
2 3 3 2 4
reflux; (vi) THF, rt; (vii) EtOH, reflux; (viii) PdCl /CuI, MeOH/Et N; (ix) CrO /H SO , -10 °C.
vinylic tellurides were obtained in a 6:1 mixture of regio-
isomers, which were separated by column chromatography
in 48% yield. These compounds were then coupled to the
In summary, we have achieved the total synthesis of four
natural products with biological activity and very limited
access, using coupling-based methodologies.
1
4
appropriate alkyldiynes D using PdCl
2
/CuI in methanol to
afford 11 with the desired Z geometry of the double bond.
Acknowledgment. We are grateful to the FAPERGS,
CNPq, FIPE (UFSM) for financial support. The autors are
also grateful to Professor Joachim Demnitz (UFPE) for the
revision of this manuscript.
12
Chromium oxide/H
2
SO
4
(Scheme 4) gave the polyacetyl-
enic acid 3 and 4. The overall yields of the sequence were
1
13
2
4% (3) and 22% (4). The spectroscopy data15 ( H and
C
NMR) of compounds 1-4 are in agreement with the data
2
reported by Wagner and co-workers.
OL006946V
Org. Lett., Vol. 3, No. 6, 2001
821