Flexible synthesis of vulpinic acids from tetronic acid

Article abstract of DOI:10.1016/j.tetlet.2007.07.094

Several vulpinic acids were synthesized in a few steps from a single precursor, the tetronic acid. This commercial compound was converted in a few steps to an iodide. Suzuki-Miyaura cross-couplings involving this common intermediate and various arylboronates allowed to gain access to several vulpinic acids (or methyl pulvinates). Among them, two natural products, vulpinic acid and pinastric acid, were prepared.

Full text of DOI:10.1016/j.tetlet.2007.07.094

Tetrahedron Letters 48 (2007) 6421–6424
Flexible synthesis of vulpinic acids from tetronic acid
Catherine Willis, Ewen Bodio, Yann Bourdreux, C e´ lia Billaud, Thierry Le Gall*
and Charles Mioskowski
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, B aˆ t. 547, 91191 Gif-sur-Yvette, France
Received 29 June 2007; revised 13 July 2007; accepted 16 July 2007
Available online 21 July 2007
Dedicated to the memory of the late Dr Charles Mioskowski
Abstract—Several vulpinic acids were synthesized in a few steps from a single precursor, the tetronic acid. This commercial com-
pound was converted in a few steps to an iodide. Suzuki–Miyaura cross-couplings involving this common intermediate and various
arylboronates allowed to gain access to several vulpinic acids (or methyl pulvinates). Among them, two natural products, vulpinic
acid and pinastric acid, were prepared.
ꢀ
2007 Elsevier Ltd. All rights reserved.
8
Pulvinic acids 1a and vulpinic acids 1b are pigments
bis(trimethylsilyloxy)diene with oxalyl chloride. In this
found in lichens and mushrooms, especially in boletes.
Letter, we describe a flexible approach to vulpinic acids
which also makes use of a Suzuki–Miyaura cross-cou-
pling as a key step to complete the carbon skeleton of
the target compounds (Scheme 1). The two components
of the coupling are an arylboronate and an iodide 3,
which are prepared in a few steps from commercially
1
These compounds display various biological properties.
0
0
Variegatic acid (3,3 ,4,4 -tetrahydroxypulvinic acid) has
2
been shown to have antioxidant properties. Studies in
our laboratory have shown that other pulvinic deriva-
3
tives also have interesting antioxidant activities. Hence,
9
it was of great interest to develop methods allowing to
synthesize these compounds or their analogs in an effi-
cient fashion.
available tetronic acid (4).
We chose to introduce an iodine atom on the butenolide
because of the known high reactivity of iodides in palla-
OH
10
Ar1
dium-mediated cross-couplings.
CO R
2
1
a: R = H
Ar2
1b: R = CH
3
O
O
The preparation of iodide 3 is described in Scheme 2.
Tetronic acid was converted to 4-benzyloxy-2(5H)-fura-
none 5 using either a Mitsunobu reaction with benzyl
1a,b
Several syntheses of pulvinic acids and vulpinic acids
11
alcohol or an alkylation with benzyl bromide in a basic
4
have been described. Recently, we designed an ap-
medium. The latter method was found more convenient
on a large scale. The reaction of the anion generated by
treatment of 5 with butyllithium at ꢀ78 ꢁC in THF with
proach to symmetrical pulvinic acids (in which the two
5
aryl groups are identical). An approach leading to
non-symmetrical pulvinic compounds which uses a
Suzuki–Miyaura cross-coupling as a key step for the
introduction of the aryl moiety bonded to the lactone
12
methyl benzoylformate then led to alcohol 6, obtained
as a mixture of diastereomers, which were partially sep-
arated by silica gel column chromatography. Several
6
7
was described by us and by Langer et al. The triflate
employed in this coupling was derived from the corre-
sponding enol obtained by cyclocondensation of a 1,3-
OH
OBn
CO Me
OH
Ar
I
CO H
2
2
O
Ph
O
Ph
O
O
O
O
Keywords: Natural products; Vulpinic acid; Pulvinic acid; Tetronic
acid; Suzuki–Miyaura cross-coupling.
2
3
4
*
Corresponding author. Tel.: +39 1 6908 7105; fax: +39 1 6908
991; e-mail: thierry.legall@cea.fr
Scheme 1. Retrosynthetic plan for the synthesis of pulvinic acids from
tetronic acid.
7
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.094

6422
C. Willis et al. / Tetrahedron Letters 48 (2007) 6421–6424
OBn
OH
CO Me
The Suzuki–Miyaura cross-coupling of iodide 3 with
several arylboronates 8a–d was then carried out, under
OH
OBn
a
b
2
O
4
O
O
Ph
conditions similar to those previously used from the cor-
O
O
O
(
6
5
6
responding triflate prepared using a different approach.
syn/anti = 1/1)
The catalyst employed was thus Pd(PPh ) Cl and the
3
2
2
reaction proceeded at reflux for 2 h in a THF/2 M aque-
ous Na CO mixture. The results are summarized in
OBn
OBn
c
CO Me
d
I
CO Me
2
2
2
3
O
3
Ph
Table 1. The expected adducts 9a–d were obtained in
O
Ph
O
O
1
6
5
5–93% yield after chromatographic purification. In
7
two cases, compounds 10 resulting from a cleavage of
the benzyl enol ether function were also obtained
Scheme 2. Synthesis of iodide 3. Reagents and conditions: (a) K
BnBr, DMF, room temp., 12 h, 75% or BnOH, Ph P, DEAD, room
temp., 12 h, 85%; (b) (i) n-BuLi, THF, ꢀ78 ꢁC, 20 min, (ii) methyl
benzoylformate, ꢀ78 ꢁC to room temp., 12 h, 67%; (c) (CF CO) O,
DMAP (cat.), Et N, CH Cl , 4 h, 0 ꢁC, 88%; (d) I , CAN, CH CN,
0 ꢁC, 4.5 h, 78%.
2 3
CO ,
3
(entries 1 and 4). The debenzylation probably occurred
after the cross-coupling reaction. We had also observed
such debenzylations on some occasions in couplings
3
2
3
2
2
2
3
6
involving triflates. In compounds 9, the Z-isomer
4
occurred in 6–12%.
deshydratation conditions were tested starting from
both isomers. Using trifluoroacetic anhydride in the
presence of triethylamine and a catalytic amount of
DMAP in methylene chloride, both isomers were
converted efficiently to alkene 7. This compound was
obtained mainly as a E-stereomer, containing 5–10%
of the Z-stereomer. The two isomers can be distin-
Hydrogenolysis of the benzyl protecting groups of com-
pounds 9a–c was then performed by treatment under
hydrogen (1 atm) over palladium on charcoal (Table 2).
1
3
Two conditions were employed. The reaction of com-
pound 9a in methylene chloride led to the corresponding
adduct, vulpinic acid 10a (entry 1). However, the reac-
tion was still incomplete after 48 h. Starting material
9a was recovered in 16% yield, while 10a was obtained
in 44% yield as pure E-isomer, the remaining minor Z-
isomer being easily removed by chromatography. The
spectroscopic data of 10a are in good agreement with
guished on the basis of the chemical shifts observed in
1
H NMR (CDCl , 400 MHz) for the methyl and the
3
1
4
benzylic methylene protons. For example, the signals
for the methyl groups appear at 3.45 ppm for the major
E-isomer and at 3.83 ppm for the minor Z-isomer. The
difference may be attributable to an anisotropic shield-
ing effect of the benzylic phenyl group on the methyl
group of the E-isomer. Similar observations were made
in the spectra of the compounds 3 and 9a–d synthesized
from 7. Clear-cut evidence of the E-configuration of the
major isomer was eventually obtained by comparing the
final compounds synthesized from it with the natural
products. The selective formation of the E-isomer of 7
from alcohol 6 may be attributed to either steric or elec-
tronic reasons. A study of the formation of alkenes from
various substituted analogs of compound 6 should be
necessary to give a rationale concerning the origin of
the observed selectivity.
4
k,7a
those reported for vulpinic acid in the literature.
Other conditions, which had been previously described
4
h
by Ramage et al. for the deprotection of benzylated
pulvinic esters, were applied to the other substrates 9b
and 9c. The reactions, performed in DMF in the pres-
ence of hydrochloric acid, lasted for 2.5 h, leading to
4
k,7b,17
the expected vulpinic acids 10b (pinastric acid)
and 10c, obtained after chromatographic purification
1
8
as pure E-isomers in 71% and 68% yield, respectively.
In conclusion, we have developed a practical, flexible
approach for the synthesis of vulpinic acids in a few
steps from commercially available tetronic acid. It relies
on a key Suzuki–Miyaura cross-coupling involving a
common intermediate, iodide 3. Two of the compounds
prepared, vulpinic acid and pinastric acid, are natural
products. This strategy is currently further developed
to gain access to natural pulvinic acids as well as various
analogs.
The iodation of compound 7 was performed in good
yield with the use of iodine and ammonium cerium(IV)
1
5
nitrate at 40 ꢁC in acetonitrile. Iodide 3 was thus
obtained in four steps from tetronic acid in 39% overall
yield.
Table 1. Suzuki–Miyaura cross-couplings of iodide 3 with boronates 8
R1
PdCl2(PPh3)2
R1
R1
THF, 2 M aq. Na CO
2
3
OBn
CO Me
OH
3
+
O
2
+
CO2Me
Ph
B
R2
R2
R2
8
0 °C, 2 h
O
O
Ph
O
O
O
8
9
10
1
2
Entry
Boronate
R
R
Product
E/Z ratio in 9
Yield of 9 (%)
Yield of 10 (%)
1
2
3
4
8a
8b
8c
8d
H
OMe
H
H
H
OH
H
9a
9b
9c
9d
94/6
91/9
91/9
88/12
55
77
93
62
16
—
—
31
Cl

C. Willis et al. / Tetrahedron Letters 48 (2007) 6421–6424
6423
Table 2. Hydrogenolysis of compounds 9a–c
R1
R1
OBn
H2
OH
CO Me
CO Me
2
2
R2
R2
O
Ph
10% Pd / C
O
O
Ph
O
9
10
1
2
Entry
Boronate
R
R
Product
Yield (%)
a
b
1
2
3
9a
9b
H
OMe
H
H
H
OH
10a
10b
10c
44
71
68
c
c
9c
a
b
c
2 2
Reaction in CH Cl , 48 h.
The starting material was recovered in 16% yield.
Reaction in DMF, containing concentrated HCl, 2.5 h.
Acknowledgment
9. For syntheses of other naturally occuring lactones that
make use of alkylidenation and Suzuki cross-coupling, see:
(
a) Boukouvalas, J.; Lachance, N.; Ouellet, M.; Trudeau,
A financial support by the CNRS to C.W. is gratefully
acknowledged.
M. Tetrahedron Lett. 1998, 39, 7665–7668; (b) Boukouv-
alas, J.; Pouliot, M. Synlett 2005, 343–345; (c) Antane, S.;
Caufield, C. E.; Hu, W.; Keeney, D.; Labthavikul, P.;
Morris, K.; Naughton, S. M.; Petersen, P. J.; Rasmussen,
B. A.; Singh, G.; Yang, Y. Bioorg. Med. Chem. Lett. 2006,
References and notes
1
76–180.
1
. For reviews, see: (a) Zografos, A. L.; Georgiadis, D.
Synthesis 2006, 3157–3188; (b) Gill, M.; Steglich, W. Prog.
Chem. Org. Nat. Prod. 1987, 51, 1–317; (c) Rao, Y. S.
Chem. Rev. 1976, 76, 625–694.
10. For reviews on the Suzuki–Miyaura reaction, see: (a)
Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58,
9633–9695; (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995,
95, 2457–2483.
2
. Kasuga, A.; Aoagi, Y.; Sugahara, T. J. Food Sci. 1995, 60,
11. Bajwa, J. S.; Anderson, R. C. Tetrahedron Lett. 1990, 31,
6973–6976.
1
113–1115.
3
. Meunier, S.; Han e´ danian, M.; Desage-El Murr, M.;
Nowaczyk, S.; Le Gall, T.; Pin, S.; Renault, J.-P.; Boquet,
D.; Cr e´ minon, C.; Mioskowski, C.; Taran, F. ChemBio-
Chem 2005, 6, 1234–1241.
12. The reaction of the anion of a methyl 4-aryltetronate with
4-methoxybenzoylformate has been reported; see Ref. 4g.
13. Cossy, J.; Bellosta, V.; Ranaivosata, J. L.; Gille, B.
Tetrahedron 2001, 57, 5173–5182.
4
. (a) Volhard, J. Liebigs Ann. Chem. 1894, 282, 1–21; (b)
Asano, M.; Kameda, Y. Ber. Dtsch. Chem. Ges. 1935, 68,
14. For a related discussion on the characterization of
1
pulvinones stereoisomers by H NMR, see: Campbell, A.
1
1
568; (c) Akermark, B. Acta Chem. Scand. 1961, 15, 1695–
700; (d) Beaumont, P. C.; Edwards, R. L.; Elsworthy, G.
C.; Maidment, M. S.; Pick, J. H.; Stevenson, D. F. M. J.
Chem. Soc., Perkin Trans. 1 1985, 1567–1576.
J. Chem. Soc. (C) 1968, 2968–2974; (e) Weinstock, J.;
Blank, J. E.; Oh, H. J.; Sutton, B. M. J. Org. Chem. 1979,
15. Zhang, F. J.; Li, Y. L. Synthesis 1993, 565–567.
16. Representative procedure for the Suzuki–Miyaura cross-
coupling: All the solvents were degassed. To a solution of
iodide 3 (50 mg, 0.108 mmol) in THF (5.5 mL) were
4
4, 673–675; (f) Knight, D. W.; Pattenden, G. J. Chem.
Soc., Perkin Trans. 1 1979, 62–69; (g) Knight, D. W.;
Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1979, 84–88;
3 2 2
added Pd(PPh ) Cl (4 mg, 5.4 lmol, 5 mol %), a solution
(
h) Ramage, R.; Griffiths, G. J.; Sweeney, J. N. A. J.
of 4-methoxyphenylboronic acid pinacol ester (37.9 mg,
0.162 mmol, 1.5 equiv) in THF (2 mL), and 2 M aqueous
Na CO (2.4 mL). The reaction mixture was refluxed for
Chem. Soc., Perkin Trans. 1 1984, 1547–1553; (i) Patten-
den, G.; Pegg, N.; Smith, A. G. Tetrahedron Lett. 1986,
2
3
2
7, 403–406; (j) Gedge, D. R.; Pattenden, G.; Smith, A. G.
2 h under argon. After cooling to room temperature,
water (5.5 mL) and saturated aqueous NH Cl (2 mL)
were added. The aqueous layer was extracted with
CH Cl (3 · 5 mL), the combined organic layers were
dried (MgSO ), filtered and concentrated under vacuum.
J. Chem. Soc., Perkin Trans. 1 1991, 2127–2131; (k)
Pattenden, G.; Pegg, N.; Kenyon, R. J. Chem. Soc., Perkin
Trans. 1 1991, 2363–2371.
. Heurtaux, B.; Lion, C.; Le Gall, T.; Mioskowski, C. J.
Org. Chem. 2005, 70, 1474–1477.
. (a) Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.;
Mioskowski, C.; Amekraz, B.; Moulin, C. Angew. Chem.,
Int. Ed. 2003, 42, 1289–1293; (b) Desage-El Murr, M.;
Nowaczyk, S.; Le Gall, T.; Mioskowski, C. Eur. J. Org.
Chem. 2006, 1489–1498.
4
2
2
5
6
4
Silica gel chromatography (9:1 to 6:4 pentane/AcOEt)
afforded 9b (E/Z isomers ratio: 91/9) as a yellow solid
(37 mg, 77%). Compound 9b: Mp = 138–139 ꢁC; TLC:
f
R = 0.6 (7:3 pentane/AcOEt); IR (KBr pellet)
m
max = 3031, 2953, 2843, 1776, 1726, 1630, 1602, 1514,
ꢀ
1 1
1433, 1292, 1258, 1163, 1045, 941, 833, 759, 698 cm ; H
7
. (a) Ahmed, Z.; Langer, P. J. Org. Chem. 2004, 69, 3753–
NMR (400 MHz, CDCl ): d (major isomer) = 7.67 (d,
3
3
2
757; (b) Ahmed, Z.; Langer, P. Tetrahedron 2005, 61,
055–2063.
J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 7.42–7.24 (m,
8H), 6.98 (d, J = 8.7 Hz, 2H), 4.97 (s, 2H), 3.85 (s, 3H),
3.39 (s, 3H); signal belonging to the Z-isomer: d (minor
8
. (a) Langer, P.; Stoll, M. Angew. Chem., Int. Ed. 1999, 38,
803–1805; (b) Langer, P.; Schneider, T.; Stoll, M. Chem.
1
3
1
3
isomer) = 4.56 (s, 2H); C NMR (CDCl , 100 MHz):
Eur. J. 2000, 6, 3204–3214; (c) Langer, P.; Eckardt, T.;
Schneider, T.; G o¨ bel, C.; Herbst-Irmer, R. J. Org. Chem.
d = 168.1, 166.8, 160.7, 160.2, 141.6, 134.4, 131.4, 131.2,
129.2, 129.0, 128.7, 128.7, 128.6, 120.7, 116.2, 114.1,
108.7, 75.1, 55.4, 52.4 (two non-identified aromatic CH
signals overlap).
2
001, 66, 2222–2226; (d) Langer, P. Synlett 2006, 3369–
3
381.

6424
C. Willis et al. / Tetrahedron Letters 48 (2007) 6421–6424
1
7. For a recent paper dealing with the previously unknown
concentrated under vacuum. Silica gel chromatography
(9:1 to 1:3 pentane/AcOEt) afforded pinastric acid (10b) as
a yellow solid (13 mg, 71%). The spectroscopic data agree
antitumor properties of pinastric acid, see: Dias, D.;
White, J. M.; Urban, S. Nat. Prod. Res. 2007, 21, 366–376.
8. Representative procedure for the hydrogenolysis: To a
suspension of 10% Pd/C (26 mg) and compound 9b
4
k,7b,17
1
well with those reported in the literature.
Compound
10b: Mp = 203–205 ꢁC (lit. 207–209 ꢁC); IR (KBr pellet)
max = 3745, 3018, 2959, 2841, 2535, 1772, 1674, 1600,
1514, 1493, 1441, 1370, 1308, 1278, 1254, 1189, 1063, 1024,
4
k
(
23 mg, 0.052 mmol) in DMF (2 mL) were added two
m
drops of concentrated HCl. The reaction mixture was
placed under a hydrogen atmosphere at 1 atm, under
vigorous stirring, for 2.5 h. Hydrogen was replaced by
argon, then the suspension was filtered over a short pad of
Celite, which was washed with THF. After concentration,
ether (20 mL) was added and the organic phase was washed
ꢀ1
1
959, 905, 844, 700 cm
3
; H NMR (400 MHz, CDCl ):
d = 8.14 (d, J = 8.9 Hz, 2H), 7.45–7.40 (m, 3H), 7.30–7.25
(m, 2H), 6.98 (d, J = 8.9 Hz, 2H), 3.89 (s, 3H), 3.86 (s, 3H);
1
3
3
C NMR (CDCl , 100 MHz): d = 171.7, 166,1, 159.6,
158.6, 155.0, 132.1, 130.0, 129.4, 128.5, 128.1, 121.6, 115.2,
2 4
several times with water, dried (Na SO ), filtered and
113.9, 105.3, 55.3, 54.3.