One-step biomimetic conversion of a furanoheliangolide into an eremantholide using Stryker's reagent

Article abstract of DOI:10.1016/j.tetlet.2008.04.071

The conversion of a furanoheliangolide structure (15-deoxygoyazensolide) into an eremantholide one (eremantholide C) was achieved by tandem hydride conjugate addition-intramolecular carbanion addition using Stryker's reagent.

Full text of DOI:10.1016/j.tetlet.2008.04.071

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3877–3880
One-step biomimetic conversion of a furanoheliangolide
into an eremantholide using Stryker’s reagent
a
b
Daiane Cristina Sass , Vladimir Constantino Gomes Heleno ,
c
a,
*
Jo a˜ o Luis Callegari Lopes , Mauricio Gomes Constantino
a
Departamento de Qu ı´ mica, Faculdade de Filosofia, Ci eˆ ncias e Letras de Ribeir a˜ o Preto, Universidade de S a˜ o Paulo,
Avenida dos Bandeirantes, 3900, 14040-901 Ribeir a˜ o Preto, SP, Brazil
b
N u´ cleo de Pesquisas em Ci eˆ ncias Exatas e Tecnol o´ gicas, Universidade de Franca, Avenida Dr. Armando de Salles Oliveira,
01, 14404-600 Franca, SP, Brazil
2
c
Departamento de F ı´ sica e Qu ı´ mica, Faculdade de Ci eˆ ncias Farmac eˆ uticas de Ribeir a˜ o Preto, Universidade de S a˜ o Paulo,
Avenida do Caf e´ s/n, 14040-903 Ribeir a˜ o Preto, SP, Brazil
Received 7 March 2008; revised 3 April 2008; accepted 10 April 2008
Available online 15 April 2008
Abstract
The conversion of a furanoheliangolide structure (15-deoxygoyazensolide) into an eremantholide one (eremantholide C) was achieved
by tandem hydride conjugate addition–intramolecular carbanion addition using Stryker’s reagent.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Synthesis; Natural products; Furanoheliangolides; Eremantholides; Stryker’s reagent
Eremantholides are sesquiterpene lactones containing a
complex polycyclic structure as shown in the example
O
O
O
O
R
1
H
(
Fig. 1). A number of these natural compounds have been
O
O
R
O
1
–5
found in Brazilian plants.
H
OH
The biological activity of some eremantholides, which
R
2
6
7
8,9
includes trypanocidal, antibacterial, anti-inflammatory
H
O
O
1
0
O
O
and anti-tumor properties, has prompted several research
groups to propose syntheses, both total and partial, for
1 R =
R =
(Eremantholide A)
(Eremantholide B)
5
R
1
=
=
R
2
2
= CH
3
3
(15-Deoxygoyazensolide)
(Lychnopholide)
1
1–18
these compounds.
2
Nevertheless, most efforts in these synthetic works are
directed toward the obtention of eremantholide A (1) and
just a few were undertaken toward other eremantholide
structures or some generic part of eremantholides
structures.
6 R
7 R
1
R
= CH
3 R =
R =
(Eremantholide C)
1
=
R
2
= CH
2
OH (Goyazensolide)
1
6-(1-Methyl-1-
4
propenyl)-
eremantholide
Biotransformation by fungi has also been used, as
described by Barrero et al., to convert lychnopholide
Fig. 1. Examples of eremantholides and furanoheliangolides.
1
9
(
6) (a furanoheliangolide) into 16-(1-methyl-1-propen-
yl)eremantholide (4). This result supports the hypothesis
that the eremantholides are biogenetically derived from
furanoheliangolides. It should be noted that these authors
have also tried to perform the same reaction by using
*
Corresponding author. Tel.: +55 16 3602 3747; fax: +55 16 3602 4838.
E-mail address: mgconsta@usp.br (M. G. Constantino).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.071

3878
D. C. Sass et al. / Tetrahedron Letters 49 (2008) 3877–3880
chemical reagents such as NaBH and Bu SnH, but no
eremantholide could be obtained in this way.
The two products obtained in our reaction were sepa-
rated by column chromatography and identified by NMR
4
3
1
13
This biotransformation is formally equivalent to a
hydride conjugate addition (to the lactone a-methylenic
group) followed by an intramolecular addition of the inter-
mediate carbanion to the carbonyl carbon of the nearby
ester group. This is exactly the kind of transformation that
techniques, such as H NMR,
C NMR, gCOSY,
gHMQC, gHMBC, and J-resolved. The identity between
the obtained product 3 and eremantholide C was confirmed
1
13
through careful comparison of all H and C NMR data
of our synthetic material with previously known and pub-
2
0,21
33,34
can be promoted by Stryker’s reagent,
research groups have recently demonstrated.
We have thus decided to treat a sample of the natural
as we and other
lished data for the natural product,
including verifica-
2
2–26
tion of J values and 2D NMR data. A perfect match was
the result of this comparison.
1
,27–30
1
product 15-deoxygoyazensolide
with the Stryker’s
Product 9 was initially analyzed by H NMR. A remark-
1
reagent under similar conditions as used in our previous
experiments. Rather surprisingly, we found that the
reagent is highly selective: only the a-methylenic double
bond of the lactone was affected.
Our results indicate that the conjugate addition of
hydride is a faster process, producing the intermediate
carbanion (8) in short time. Cyclization of (8) to form
eremantholide C (3) is a slower process: prematurely
quenching the reaction (after 5 h) produced a mixture of
able similarity with the H NMR spectrum of the starting
material (5) was instantly noted. A further detailed com-
parison with 15-deoxygoyazensolide previously published
3
0
data led to the straightforward proposition of structure
9 for this product; the stereochemistry of the methyl group
on position 13 was the only point that needed further
clarification.
For this purpose, theoretical calculations for possible J
values between H7 and H11 were carried out. Both possi-
bilities were considered (H11a and H11b) and calculations
(
3) and (9) in a ratio of 4:5.
3
2
By extending the reaction time for a further 14 h period,
were undertaken by the use of PCMODEL program.
The results, shown in Table 1, leave no doubt that com-
pound 9 has an H11 in a position, exactly as proposed in
Scheme 1. By the way, this is also the stereochemistry that
3
5
the ratio of 3 to 9 was raised to 64:17.
The conformation of the furanoheliangolides molecules
is very peculiar, as we can see with a molecular model, and
is also confirmed by X-ray analysis of several natural prod-
3
1
ucts. In Figure 2 is shown the most stable conformation
Table 1
for enolate 8, as determined by molecular mechanics pro-
Experimental and calculated J values (Hz) between H7 and H11 in
32
grams: it is clear, in the picture, that the cyclization to
produce eremantholide 3 is favored by the appropriate
positioning of the reacting atoms (carbanion and car-
bonyl). Moreover, the conformation depicted in Figure 2
also shows that the stereochemistry to be expected for the
cyclization product is exactly the stereochemistry of the
natural eremantholide C (3). The cyclization product
obtained in our synthesis was indeed identical to the natu-
ral product 3.
compound 9 and its C11 epimer
a
J
Calculated
Experimental
J(7,11a)
J(7,11b)
J(7,11)
a
8.98
2.06
—
—
—
11.6
PCModel.
O
O
O
O
O
O
[
(Ph
3
P)CuH]
6
O
O
3
(Fast)
(Slow)
H
O
O
O
O
5
8
Early
Quenching
4
'
'
O
O
1
4
2
1
9
1'
2
10
O
H
3'
O
8
3
7
15
4
6
13
1
1
5
H
O
12
O
9
Scheme 1. Transformation of 15-deoxygoyazensolide (5) into eremantho-
lide C (3).
Fig. 2. Most stable conformation of enolate 8.

D. C. Sass et al. / Tetrahedron Letters 49 (2008) 3877–3880
3879
we could predict from the examination of Figure 2: the
ester group is clearly blocking the upper face of the lactone
ring, so we should expect the proton to be captured on the
other face, thus producing 9 as shown in Scheme 1.
Compound 9 is a new product, but we should note that
there are natural products with similar structure, contain-
11. Boeckman, R. K., Jr.; Heckendorn, D. K.; Chinn, R. L. Tetrahedron
Lett. 1987, 28, 3551–3554.
1
2. McDougal, P. G.; Oh, Y. I.; VanDeveer, D. J. Org. Chem. 1989, 54,
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9
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1
5. Takao, K.; Ochiai, H.; Yoshida, K.; Hashizuka, T.; Koshimura, H.;
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In conclusion, we point out that the reaction here
reported, besides demonstrating a remarkable selectivity
of Stryker’s reagent, can be used either to transform
furanoheliangolides into eremantholides through a bio-
mimetic pathway or as a method to reduce a-methylene
lactones to a-methyl lactones. We are currently investigat-
ing the application of this reaction to other natural
furanoheliangolides.
1
17. Rosales, A.; Este
005, 117, 323–326.
´
vez, R. E.; Cuerva, J. M.; Oltra, J. E. Angew. Chem.
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2
1. Lee, D. W.; Yun, J. Tetrahedron Lett. 2005, 46, 2037–2039.
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Acknowledgments
1
901–1903.
The authors thank the Fundaßc a˜ o de Amparo a` Pesquisa
do Estado de S a˜ o Paulo (FAPESP), the Conselho Nacional
de Desenvolvimento Cient ´ı fico e Tecnol o´ gico (CNPq), the
Coordenaßc a˜ o de Aperfeißcoamento de Pessoal de N ´ı vel
Superior (CAPES) and the Financiadora de Estudos e Pro-
jetos (FINEP) for financial support. We thank also Profes-
sor Norberto Peporine Lopes for the mass spectra.
2
4. Agapiou, K.; Cauble, D. F.; Krische, M. J. J. Am. Chem. Soc. 2004,
126, 4528–4529.
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Phytochemistry 1976, 15, 1775–1776.
8. Borella, J. C.; Lopes, J. L. C.; Leit a˜ o Filho, H. F.; Semir, J.; Diaz, J.
G.; Hetz, W. Phytochemistry 1992, 31, 692–695.
9. Crotti, A. E. M.; Cunha, W. R.; Lopes, N. P.; Lopes, J. L. C. J. Braz.
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0. Heleno, V. C. G.; Crotti, A. E. M.; Constantino, M. G.; Lopes, N. P.;
Lopes, J. L. C. Magn. Reson. Chem. 2004, 42, 364–367.
1. See, for instance, Ref. 5.
2. PCMODEL, Version 7.0, Serena Software, PO Box 3076, Bloomington,
IN 474-23076.
33. Heleno, V. C. G.; Oliveira, K. T.; Lopes, N. P.; Lopes, J. L. C.;
2
2
2
2
3
Supplementary data
1
13
The supplementary data contain H and C NMR spec-
tra, including 2D spectra, and tables with summaries of
NMR data. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.tetlet.2008.04.071.
3
3
Ferreira, A. G. Magn. Reson. Chem., in press, doi:10.1002/mrc.2220.
3
4. LeQuesne, P. W.; Levery, S. B.; Menachery, M. D.; Brennan, T. F.;
Raffauf, R. F. J. Chem. Soc., Perkin Trans. 1 1978, 1572–1580.
5. Experimental: 15-deoxygoyazensolide (6) (30 mg, 0.087 mmol), dry
toluene (5 mL), and Stryker’s reagent (90 mg, 0.044 mmol), recently
prepared according to Ref. 20, were mixed and stirred at room
temperature for 5 h. After this period another portion of Stryker’s
reagent (90 mg, 0.044 mmol) was added and the mixture was stirred
for a further 14 h period, always at room temperature. The reaction
was quenched with 2 mL of saturated ammonium chloride solution.
The mixture was stirred for 1 h. During this period a white precipitate
was formed. The reaction mixture was filtered and the residue was
washed with ethyl acetate. The organic phase of the filtered mixture
was separated and the aqueous phase was extracted with ethyl acetate
References and notes
3
1
. Vichnewski, W.; Takahashi, A. M.; Nasi, A. M. T. T.; Gonßcalves, D.
C. R. G.; Dias, D. A.; Lopes, J. N. C.; Goedken, V. L.; Gutierrez, A.
B.; Herz, W. Phytochemistry 1989, 28, 1441–1451.
2
3
4
5
6
. Cunha, W. R.; Lopes, J. L. C.; Vichnewski, W.; D ´ı az, J. G.; Herz, W.
Phytochemistry 1995, 39, 387–389.
. Bohlmann, F.; Singh, P.; Zdero, C.; Ruhe, A.; King, R. M.;
Robinson, H. Phytochemistry 1982, 21, 1669–1673.
. Bohlmann, F.; Zdero, C.; King, R. M.; Robinson, H. Phytochemistry
1980, 19, 2663–2668.
. Sakamoto, H. T.; Flausino, D.; Castellano, E. E.; Stark, C. B. W.;
Gates, P. J.; Lopes, N. P. J. Nat. Prod. 2003, 66, 693–695.
. Oliveira, A. B.; Sa u´ de, D. A.; Perry, K. S. P.; Duarte, D. S.; Raslan,
D. S.; Boaventura, M. A. D.; Chiari, E. Phytother. Res. 1996, 10, 292–
(3 ꢀ 5 mL). The combined organic phases were dried with MgSO
4
and the solvent was removed under vacuum. The residue was purified
by column chromatography on silica gel, eluting with benzene/ethyl
acetate (9:1). We have thus obtained the two purified materials
295.
7
. Sa u´ de, D. A.; Barrero, A. F.; Oltra, J. E.; Just ´ı cia, J.; Raslan, D. S.;
Silva, E. A. Rev. Bras. Farmacog. 2002, 12, 7–10.
described below. Eremantholide C (3): 19 mg (64%) of white solid, mp
1
229–230 °C. H NMR (CDCl
3
, 500 MHz), d (ppm): 1.19 (s, 3H); 1.49
= 1.5, J = 0.9 Hz); 2.06 (dd, 1H, J = 13.6,
= 11.9 Hz); 2.06 (dd, 3H, J = 2.4, J = 1.6 Hz); 2.41 (dd, 1H,
= 13.6, J = 2.6 Hz); 2.85 (dd, 1H, J = 7.0, J = 4.2 Hz); 4.14
= 11.9, J = 4.2, J = 2.6, J = 0.6 Hz); 4.98 (dddq, 1H,
= 2.7, J = 2.4, J = 0.6 Hz); 5.07 (dd, 1H, J = 2.0,
= 1.5 Hz); 5.32 (dd, 1H, J = 2.0, J = 0.9 Hz); 5.61 (s, 1H); 6.03
= 2.7, J = 1.6 Hz). C NMR (CDCl , 125 MHz), d
(ppm): 18.9 (CH ); 20.3 (CH ); 20.6 (CH ); 21.9 (CH ); 43.7 (CH );
8. R u¨ ngeler, P.; Castro, V.; Mora, G.; G o¨ ren, N.; Vichnewski, W.; Pahl,
H. L.; Merfort, I.; Schmidt, T. J. Bioorg. Med. Chem. 1999, 7, 2343–
(s, 3H); 1.90 (dd, 3H, J
1
2
1
J
J
2
1
2
2352.
1
2
1
2
9. Koch, E.; Klaas, C. A.; R u¨ ngeler, P.; Castro, V.; Mora, G.;
(dddd, 1H, J
1
2
3
4
Vichnewski, W.; Merfort, I. Biochem. Pharmacol. 2001, 62, 795–
J
J
1
= 7.0, J
2
3
4
1
801.
2
1
2
1
3
1
0. Raffauf, R. F.; Huang, P. K. C.; LeQuesne, P. W.; Levery, S. B.;
(dq, 1H, J
1
2
3
Brennan, T. F. J. Am. Chem. Soc. 1975, 97, 6884–6886.
3
3
3
3
2

3880
D. C. Sass et al. / Tetrahedron Letters 49 (2008) 3877–3880
5
(
9.8 (C); 62.5 (CH); 78.5 (CH), 81.5 (CH); 89.9 (C); 104.5 (CH); 106.2
C); 116.1 (CH ); 130.2 (C); 134.6 (CH); 142.0 (C); 175.4 (C@O);
86.7 (C); 205.1 (C@O). IR mmax (liquid film): 3395; 2973; 2923; 1775;
J
J
J
J
1
3
4
1
= 11.6, J
= 1.4, J
2
= 9.2, J
= 0.6 Hz); 5.05 (dddq, 1H, J
3
= 2.2 Hz); 4.92 (dddd, 1H, J = 11.6, J
2
= 9.2, J = 2.9, J
1
2
= 2.2,
= 2.4,
2
4
1
3
1
1
= 0.6 Hz); 5.63 (q, 1H, J = 1.4 Hz); 5.78 (s, 1H); 5.99 (dq, 1H,
ꢁ1
þ
13
699; 1659; 1585 cm . HRMS (ESI-TOF): calcd for C19H22NaO6
= 2.9, J
, 125 MHz), d (ppm): 15.4 (CH
); 38.4 (CH); 44.8 (CH ); 55.2 (CH); 67.9 (CH); 80.3 (CH), 88.9
(C); 105.1 (CH); 126.9 (CH ); 128.6 (C); 133.2 (CH); 135.3 (C); 166.3
(C@O); 176.6 (C@O); 186.8 (C@O); 203.9 (C@O). IR mmax (liquid
2
= 1.7 Hz); 6.08 (dq, 1H, J
1
= 1.4, J
2
= 0.8 Hz). C NMR
(MNa+) 369.1314, found 369.1304. 11a,13-Dihydro-15-deoxygoya-
(CDCl
(CH
3
3
); 18.1 (CH
3
); 20.5 (CH ); 21.6
3
1
zensolide (9): 5 mg (17%) of colorless oil. H NMR (CDCl
3
,
3
2
5
3
00 MHz), d (ppm): 1.35 (d, 3H, J = 6.7 Hz); 1.50 (s, 3H); 1.91 (dd,
H, J = 1.45, J = 0.8 Hz); 2,12 (dd, 3H, J = 2.4, J = 1.7 Hz); 2.20
= 13.4, = 1.4 Hz); 2.35 (dd, 1H, = 13.4,
= 11.6 Hz); 2.40 (dq, 1H, J = 11.6, J = 6.7 Hz); 3.00 (ddd, 1H,
2
1
2
1
2
ꢁ1
(dd, 1H,
J
1
J
2
J
1
film): 2979; 2941; 1779; 1716; 1665; 1576 cm . HRMS (ESI-TOF):
calcd for C19H23O6 (MH+) 347.1495, found 347.1501.
þ
J
2
1
2