The first synthesis of coniochaetones A and (±)-B: Two benzopyranone derivatives

Article abstract of DOI:10.1055/s-1998-1628

An efficient synthesis of coniochaetone A and of racemate coniochaetone B was achieved by a short five-step procedure from methyl di-O-methyl-p-orsellinate. The key step is a cascade reaction of 2′-hydroxy-6′-methoxy-4′-methyl-2-(methylsulfinyl)- acetophenone with succindialdehyde in the presence of piperidine which allows the direct building of the tricyclic benzopyranone structure.

Full text of DOI:10.1055/s-1998-1628

March 1998
SYNLETT
259
The First Synthesis of Coniochaetones A and (±)-B: Two Benzopyranone Derivatives
a
b
b
Kenji Mori* , Gérard Audran , Honoré Monti
a
Department of Chemistry, Faculty of Science, Science University of Tokyo, Kagurazaka 1-3, Shinjuku-ku, Tokyo 162-0825, Japan
b
Laboratoire de Réactivité Organique Sélective associé au CNRS, Faculté des Sciences et Techniques de Saint Jérôme 13397 Marseille Cedex 20,
France
Received 12 December 1997
Abstract : An efficient synthesis of coniochaetone A and of racemate
coniochaetone B was achieved by a short five-step procedure from
methyl di-O-methyl-p-orsellinate. The key step is a cascade reaction of
2'-hydroxy-6'-methoxy-4'-methyl-2-(methylsulfinyl)-acetophenone with
succindialdehyde in the presence of piperidine which allows the direct
building of the tricyclic benzopyranone structure.
Some reports exist on the synthesis of chromones containing a five or
6
7
six-membered ring. One of these routes, described by Klutchko , was
efficient to obtain a fused cyclohexanoid ring chromone derivative by
using the sulfoxide chemistry. Herein, we present a modified strategy
8
leading to a short synthesis of 1 and of the racemate (±)-2 of the natural
product (Scheme 1).
9
The readily available methyl di-O-methyl-p-orsellinate
4
was
1
converted by treatment with BCl into the monomethylated methyl ester
A number of natural products exhibiting biological properties such as
3
10
2
5
.
The slightly exothermic reaction of
5
with sodium
chromones which are known as metabolites of fungi or pigments of
plants contain a benzopyranone skeleton. In 1995, Gloer and his co-
workers isolated from a coprophilous fungus Coniochaeta sarcardoi,
two antifungal cyclopentabenzopyran-4-ones which were named
3
methylsulfinylmethide (3 eq. NaH / 7 eq. DMSO, benzene, 50 °C, 1h)
11
4a
led to the formation of the β-ketosulfoxide 6 . Cascade reaction of 6
12
with succindialdehyde
(obtained by acidic hydrolysis of the
commercial Aldrich cis and trans mixture of 2,5-dimethoxy-
tetrahydrofuran with 0.2 N sulfuric acid then neutralization of the
coniochaetone A 1 and (+)-(R)-coniochaetone B 2 (Figure 1). Both 1
and 2 were also isolated in 1996 as new monoamine oxidase-
4b
solution with K CO ) in the presence of piperidine followed by in situ
thermal syn-elimination of methanesulfenic acid afforded the chromone
inhibitory components from an Ascomycete, Coniochaeta tetraspora.
The structural feature of these metabolites is a fused cyclopentanoid
ring which is not common for this class of compounds. To the best of
our knowledge, the only example of chromone bearing the same subunit
as coniochaetones is wrightiadione 3 isolated from the bark of Wrightia
tomentosa (Figure 1).
2
3
13
8
in 22% yield. The intermediate chromone 7 was not isolated. Then,
14
perruthenate oxidation of 8 gave the diketone 9 which was converted
to the free chromone 1 by treatment with BCl . The H and C-NMR
spectra of 1 were in agreement with those reported for the natural
1
13
5
3
15
product 1. The overall yield of 1 was 9.6% based on 4 (5 steps).
Alternatively, 8 was treated with acetic anhydride/pyridine in the
presence of a catalytic amount of DMAP to obtain 10. Following the
same procedure, demethylation of 10 with BCl afforded (±)-2 whose
3
1
13
16
H and C-NMR spectra were consistent with those reported for the
natural product 2. The overall yield of (±)-2 was 7.8% based on 4
(5 steps).
Figure 1
Scheme 1

260
LETTERS
SYNLETT
In conclusion, the first total synthesis of coniochaetone A 1 and of the
racemate of coniochaetone B (±)-2 has been achieved by a short five-
step procedure starting from methyl di-O-methyl p-orsellinate.
Presently, we are investigating the enantioselective synthesis of (R)-2 by
appropriate means.
(10) (a) Pulgarin, C.; Tabacchi, R. Helv. Chim. Acta 1989, 72, 1061-
1065. (b) Law, K.-K.; Chan, T.-L.; Tam, S. W. J. Org. Chem.
1979, 44, 4452-4453.
(11) Klutchko, S.; Cohen, M. P.; Shavel, J. R.; Von Strandtmann, M.
J. Heterocycl. Chem. 1974, 11, 183-188.
(12) Casale, J. F. Forensic Sci. Int. 1987, 33, 275-298.
Acknowledgment: G. A. thanks the Japan Society for the Promotion of
Science for a post-doctoral fellowship No. 95219 (1996-1997). This
work was supported by a Grant-in-Aid for Scientific Research of
Japanese Ministry of Education, Science, Sports and Culture.
(13) Experimental procedure:
In a distillation flask, a mixture of 3.0 g (12.2 mmol) of 2'-
hydroxy-6'-methoxy-4'-methyl-2-(methylsulfinyl) acetophenone
6, 4.2 g (12.2 mmol) of 25% aqueous succindialdehyde, 15 ml of
DMF and 0.3 ml of piperidine was slowly heated with stirring. At
105-110 °C the volatiles were distilled off and after 30 min, the
temperature was 140 °C and the volume was about one half of the
original one. The flask was cooled to rt and most of the DMF was
removed at reduced pressure. The black and viscous remaining
material was dissolved in hot MeOH, boiled with activated
charcoal, filtered and the solvent evaporated. Chromatography on
References and Notes
(1) (a) Valente, S.; De Rosa, M.; Maria Corbo, G.; Barbarito, N.;
Fumagalli, G.; Garlucci, A.; Zerillo, B.; Ciappi, G. Int. J.
Immunopathol. Pharmacol. 1997, 10, 45-47. (b) Matsuzaki, K.;
Tabata, N.; Tomoda, H.; Iwai, Y.; Tanaka, H.; Omura, S.
Tetrahedron Lett. 1993, 34, 8251-8254. (c) Saengchantara, S. T.;
Wallace, T. W. Nat. Prod. Rep. 1986, 3, 465-475.
silica gel (CHCl /MeOH : 50/1) afforded 672 mg (22%) of 8 as
3
colorless needles; m.p. 170-172 °C.
IR (KBr): υmax 3361, 1649, 1619, 1095, 1046 cm . H-NMR
(2) Dewick, P. M. The Flavonoids: Advances in Research since 1986;
-1
1
Harborne, J. B. Ed.; Chapman & Hall: New York, 1994.
(270 MHz, CDCl ): δ = 1.98 (dddd, J = 17.9, 9.6, 5.6 and 4.1 Hz,
3
(3) (a) Turner, W. B.; Aldridge, D. C. In Fungal Metabolites II,
Academic Press: New York, 1983, pp 3-43. (b) Yang, D. M.;
Takeda, Y.; Sankawa, U.; Shibata, S. Tetrahedron 1973, 29, 519-
528.
1H), 2.40-2.52 (m, 1H, partially overlapped), 2.43 (s, 3H), 2.78
(ddd, J = 17.7, 9.3 and 5.6 Hz, 1H), 3.03 (dddd, J = 17.7, 9.6, 4.8
and 1.5 Hz, 1H), 3.95 (s, 3H), 5.40 (ddd, J = 7.7, 3.8 and 1.5 Hz,
13
1H); 6.62 (s, 1H), 6.83 (s, 1H). C-NMR (67.8 MHz, CDCl ): δ =
3
(4) (a) Gloer, J. B.; Wang, H.-J.; Scott, J. A.; Malloch, D.
Tetrahedron Lett. 1995, 36, 5847-5850. (b) Fujimoto, H.; Inagaki,
M.; Satoh, Y.; Yoshida, E.; Yamazaki, M. Chem. Pharm. Bull.
1996, 44, 1090-1092.
22.1, 28.9, 29.3, 56.2, 71.6, 107.9, 110.4, 112.6, 123.2, 144.9,
159.5, 159.8, 167.9, 176.9. Anal. Calcd for C
5.73; Found C 67.91, H 5.68.
H O : C 68.28, H
14 14 4
(14) (a) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639-665. (b) Sulikowski, M. M.; Ellis Davies, G.
E. R.; Smith III, A. B. J. Chem. Soc. Perkin Trans 1, 1992, 979-
989.
(5) Lin, L.-J.; Topcu, G.; Lotter, H.; Ruangrungsi, N.; Wagner, H.;
Pezzuto, J. M.; Cordell, G. A. Phytochemistry 1992, 31, 4333-
4335.
4
(6) (a) Haddad, B.; Bethegnies, G.; Marcincal-Lefebvre, A. Il
Farmaco 1993, 48, 795-804. (b) Gesquière, J. C.; Dhaisne, J. M.;
Marcincal-Lefebvre, A.; Bar, D.; Vincent, A.; Dupuis, B. Ann.
Pharm. Fr. 1982, 40, 251-257. c) Watanabe, T.; Katayama, S.;
Nakashita, Y.; Yamauchi, M. J. Chem. Soc. Perkin Trans. 1 1978,
726-729. (d) Sanghvi, K. P.; Trivedi, K. N. J. Indian Chem. Soc.
1978, 6, 468-469.
(15) Properties of synthetic 1: colorless needles; m.p. 176-178 °C [ref.
m.p. 175 °C]. IR (KBr): υmax 3250, 3054, 1721, 1653, 1620, 1265
cm . H-NMR (270 MHz, CDCl ): δ = 2.40 (s, 3H), 2.63-2.73
(m, 2H), 3.03-3.12 (m, 2H), 6.64 (s, 1H), 6.76 (s, 1H), 12.18 (s,
1H). C-NMR (67.8 MHz, CDCl ): δ = 22.3, 26.1, 33.8, 108.1,
-1
1
3
13
3
108.5, 114.2, 117.8, 148.2, 156.3, 161.8, 178.1, 189.7, 197.4.
Anal. Calcd for C
4.32.
H
O : C 67.82, H 4.38; Found C 67.59, H
13 10
4
(7) Klutchko, S.; Von Strandtmann, M.; Shavel, J. R. US Pat.,
4
3862141, 1975.
(16) Properties of synthetic 2: colorless needles; m.p. 150-152 °C [ref.
-1
m.p. 148 °C]. IR (KBr): υmax 3376, 1652, 1619, 1209, 1049 cm .
(8) All the new compounds were characterized by spectroscopic (IR
and NMR) and elemental analyses.
1
H-NMR (270 MHz, CDCl ): δ = 1.95-2.10 (m, 1H), 2.31 (s, 3H),
3
2.40-2.52 (m, 1H), 2.74 (ddd, J = 18.1, 9.4 and 4.9 Hz, 1H), 3.04
(ddd, J = 18.1, 8.8 and 5.1 Hz, 1H), 5.35 (dd, J = 7.2 and 4.7 Hz,
1H); 6.54 (s, 1H), 6.62 (s, 1H), 12.20 (s, 1H). C-NMR (67.8
(9) Obtained in two steps from orcinol.
13
MHz, CDCl ): δ = 22.2, 29.4, 29.9, 70.9, 107.8, 109.0, 112.6,
3
121.1, 146.8, 157.6, 160.7, 172.1, 181.3. Anal. Calcd for
C H O : C 67.23, H 5.21; Found C 66.95, H 5.26.
13 12 4
a) carboxylation with anhydrous K CO in glycerol at 120 °C for 6 h.
2
3
(Kalamar, J.; Steiner, E.; Charollais, E.; Posternak, T. Helv. Chim. Acta 1974,
57, 2368-2376). b) permethylation of orsellenic acid with Me SO and
2
4
anhydrous K CO in refluxing acetone (Ramaswamy, S.; Malaiyandi, M.
2
3
Environ. Sci. Technol. 1985, 19, 507-512).