Regiospecific Michael reaction of (+)-euryfuran with activated 1,4- benzoquinones

Article abstract of DOI:10.1016/S0040-4039(00)00463-9

(+)-Euryfuran cycloadds regiospecifically to activated monosubstituted 1,4-benzoquinones under mild conditions to give the corresponding Michael adducts which, depending on the quinone substituent, undergo in situ redox reactions to the respective euryfurylbenzoquinones. One of the reported Michael adducts undergoes a facile stereoselective cyclisation under oxidant conditions to afford a naphthofuro[4,3-c]benzopyran derivative. The regiospecificity of the Michael and cyclisation reactions are discussed. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00463-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3563–3566
Regiospecific Michael reaction of (+)-euryfuran with activated
1,4-benzoquinones
Jaime A. Valderrama,∗ Manuel Cortés,∗ David Pessoa-Mahana, Marcelo Preite and
Julio Benites
Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago-22, Chile
Received 16 November 1999; revised 7 March 2000; accepted 10 March 2000
Abstract
(+)-Euryfuran cycloadds regiospecifically to activated monosubstituted 1,4-benzoquinones under mild condi-
tions to give the corresponding Michael adducts which, depending on the quinone substituent, undergo in situ
redox reactions to the respective euryfurylbenzoquinones. One of the reported Michael adducts undergoes a facile
stereoselective cyclisation under oxidant conditions to afford a naphthofuro[4,3-c]benzopyran derivative. The
regiospecificity of the Michael and cyclisation reactions are discussed. © 2000 Elsevier Science Ltd. All rights
reserved.
Keywords: activated quinones; terpenes; Michael reaction; regiospecificity; redox reactions; cyclisation.
Several drimane-related natural products exhibit important biological activity including insect
antifeedant, plant growth regulation, cytotoxic, antimicrobial, molluscicidal, and anticomplemental
properties.1 Our interest to develop new cytotoxic quinones2–4 led us to study reactions to link (+)-
euryfuran (2), an antitumoral drimane5 having the 3,4-fused furan skeleton, to quinonoid compounds.
We report here preliminary results on the Michael reaction of (+)-euryfuran (2) with the highly reactive
1,4-benzoquinones 3a–c which provides a regiospecific access to euryfuran derivatives containing a
quinone fragment bonded to the 12-position.
∗
Corresponding authors. Tel: 56-2-6864432; fax: 56-2-6864744; e-mail: jvalderr@puc.cl (J. A. Valderrama)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00463-9
tetl 16743

3564
(+)-Euryfuran (2) was prepared via a two-step sequence from natural (+)-confertifolin (1) according
to our previously published procedure.6 The 1,4-benzoquinones 3a–c were selected as Michael acceptors
due to precedent reactions of quinone 3b with furans that provide access to furylbenzoquinones.7
The reaction of furan 2 and the unstable quinone 3a was firstly examined by in situ generation
of 3a from 2,5-dihydroxybenzaldehyde (1 equiv.) and silver(I) oxide in dichloromethane at room
temperature. The reaction proceeded rapidly (<1 min) to afford two products which were isolated
by flash chromatography. The major product was characterised as adduct 5a (35%)8 and the minor
product demonstrated spectral properties9 in accord with compound 4 (20%). However, when quinone 3a
prepared from 2,5-dihydroxybenzaldehyde and silver(I) oxide in a separate procedure was treated with 1
equiv. of euryfuran (2) in benzene at room temperature, compound 5a was obtained as the sole product
in 90% yield.
Next, we examined the reaction of euryfuran (2) with 1 equiv. of 2-acetyl-1,4-benzoquinone (3b)
in dichloromethane at room temperature. The reaction afforded after 5 hours a mixture of 2,5-
dihydroxyacetophenone along with two products which were isolated by flash cromatography. The less
polar compound was characterised as adduct 5b (17%) and the more polar product displayed spectral pro-
perties in accordance with quinone 6b (51% based on 3b). The presence of 2,5-dihydroxyacetophenone,
1
detected by H NMR and TLC analysis in the reaction mixture, indicated that 6b arose from a redox
reaction between adduct 5b and quinone 3b.
We studied the reaction of furan 2 with 1 equiv. of 2-methoxycarbonyl-1,4-benzoquinone (3c) in
dichloromethane at room temperature. In this case the reaction occurred slowly (20 h) affording a mixture
of quinone 6c (74% based on 3c) and methyl 2,5-dihydroxybenzoate. The absence of Michael adduct 5c
can be attributed to a slow addition of nucleophile 2 to quinone 3c, followed by a fast redox reaction
between the nascent Michael adduct 5c and quinone 3c.
The absence of quinone 6a in the reaction of furan 2 and quinone 3a could be explained assuming its
participation in the formation of furopyran 4. Apparently, compound 4 could arise from 6a via cyclisation
of zwitterion intermediate 7 formed through an intramolecular hydride ion transfer process10 (pathway a),
by intramolecular reaction of biradical intermediate 8 (pathway b) generated by hydrogen abstraction,11
or by cyclisation of intermediate 9 formed by proton transfer (pathway c, Scheme 1). In order to shed
some light on the course of the formation of 4, compound 5a was allowed to react with 1 equiv. of DDQ
in anhydrous dioxane under nitrogen atmosphere at room temperature, and the reaction progress was
monitored by TLC analysis using compound 4 as reference. The reaction proceeded rapidly (<1 min) to
give furopyran 4 as the sole product. The same result was obtained when the reaction was carried out
in darkness. These experiments support a stepwise ionic mechanism where compound 4 arises from the
cyclisation of intermediates 7 or 9.
Taking into account that the reaction of compound 2 with quinones 3a–c were performed using the
same conditions, it is reasonable to deduce that the absence of products type 4 in the reactions of 2
with 3b and 3c could be attributed to the redox potential of the quinone fragment in 6b and 6c which
does not facilitate an intramolecular hydride transfer reaction. This assumption was verified through an

3565
Scheme 1.
experiment where furylquinone 6c was recovered after being treated with DDQ in boiling toluene for 6
hours. This result does not disregard the fact that formation of 4a could proceed through a proton transfer
process. The reluctance towards cyclisation of 6b and 6c through this mechanism probably is related to
the less electrophilic character of the acetyl and metoxycarbonyl groups than the formyl group.
In view of the recent reported results12 on the conversion of Diels–Alder adducts of furans into
Michael adducts, we decided to monitor the reaction of 2 with 3c in order to have evidence on the
participation of possible Diels–Alder adduct intermediates on the formation of the Michael adducts.
1
The reaction progress was followed by H NMR analysis in CDCl3 at room temperature. The signals
of Diels–Alder adducts were not detected during the early stage of the reaction and after 90 minutes,
increasing production of furylquinone 6c and methyl gentisate were found. These results indicate that
the reaction of 2 with quinones 3a–c is initiated by a Michael addition to give the corresponding adducts
5a–c which, depending on the formation rate, undergo dehydrogenation reaction with the activated
1,4-benzoquinone 3a–c to give the corresponding furylquinones 6a–c. It is reasonable to assume that
regiospecific formation of the Michael adducts 5 is controlled by the nucleophilic attack of 2 to the
activated quinones 3a–c through the less hindered 12-position.
In summary, we report three examples on the regiospecific Michael reaction of (+)-euryfuran (2) with
activated 1,4-benzoquinones 3a–c that offer interesting possibilities to prepare a wide range of new
quinone-containing (+)-euryfuran derivatives for cytotoxic activity assays. Furthermore, the cyclisation
found on adduct 5a can be extended to the synthesis of new members of the furo[3,2-c]benzopyrans
series. Efforts along these lines are currently under way.
Acknowledgements
Financial support are gratefully acknowledged to FONDECYT (Grant 8980003).

3566
References
1. For a review on biological activity of drimanes, see: Jansen, J. M.; de Groot, A. Natural Product Report 1991, 309–318.
2. Valderrama, J. A.; Araya-Maturana, R.; González, M. F.; Tapia, R.; Fariña, F.; Paredes, M. C. J. Chem. Soc., Perkin Trans.
1 1991, 555–559.
3. Valderrama, J. A.; González, M. F.; Valderrama, C. Tetrahedron 1999, 55, 6039–6050.
4. Valderrama, J. A.; Fournet, A.; Valderrama, C.; Bastias, S.; Astudillo, C.; Rojas de Arias, A.; Inchausti, A.; Yaluff, G.
Chem. Pharm. Bull. 1999, 47, 1221–1226.
5. Gulavita, N. K.; Gunasekera, S. P.; Pomponi, S. A. J. Nat. Prod. 1992, 55, 506–508.
6. Cortés, M.; Razmilic, I.; López, J. Bull. Soc. Chim. Belg. 1987, 96, 631–632.
7. Kuser, P.; Frauenfelder, E. F.; Eugster, C. H. Helv. Chim. Acta 1971, 54, 969–979.
8. Selected data for compound 5a: yellow crystals mp 104–104.5°C; [α]2D2=+102.4 (c, 2.1; CHCl3); IR νmax (cm−1) 3423
(O-H), 2927 (C-H), 1650 (C_O); 1H NMR (CDCl3, 200 MHz) δ 11.36 (s, 1H, 30-OH), 9.60 (s, 1H, CHO), 7.30 (s, 1H,
H-11), 7.20 (d, 1H, J=9, 1 Hz, H-50), 6.94 (d, 1H, J=9.1 Hz, H-40), 5.72 (s, 1H, 60-OH), 2.70 (ddd: J=1.6, 6.5, 17.0 Hz,
1H, H-7eq), 2.42 (ddd: J=7.2, 11.3, 17.0 Hz, 1H, H-7ax), 2.01 (dd, 1H, J=10.8 Hz, H-1eq), 1.90–1.31 (m, 9H), 1.25 (s, 3H,
10-Me), 0.95 (s, 3H, 4α-Me), 0.92 (s, 3H, 4β-Me); 13C NMR (CDCl3, 50 MHz) δ 18.79, 18.94, 21.59, 21.59, 25.04, 33.16,
33.49, 34.07, 39.24, 41.86, 51.23, 117.21, 118.51, 119.44, 123.32, 126.06, 136.76, 138.90, 139.34, 149.94, 156.74, 196.66;
elemental analysis C22H26O4 (354.44); calcd: C, 74.55; H, 7.39; found: C, 75.02; H, 7.67.
9. Satisfactory spectroscopic and microanalytical data were obtained for all new compounds. Selected data for compound 4:
yellow crystals mp 143.5–144.5°C; [α]D22=−18.1 (c, 16; CHCl3); IR νmax (cm−1) 3146 (O-H), 2864 (C-H), 1646 (C_O);
1H NMR (CDCl3, 200 MHz) δ 11.47 (s, 1H, 30-OH), 10.64 (s, 1H, CHO), 7.26 (s, 1H, H-11), 7.14 (d, 1H, J=8.9 Hz, H-50),
6.72 (d, 1H, J=8.9 Hz, H-40), 5.47 (d, 1H, J=7.6 Hz, H-7ax), 2.40–2.04 (m, 3H, H-6+H-1); 1.81–1.26 (m, 6H), 1.18 (s,
3H, 10-Me), 1.01 (s, 3H, 4α-Me), 0.97 (s, 3H, 4β-Me); 13C NMR (CDCl3, 50 MHz) δ 18.46, 21.39, 22.00, 26.97, 33.29,
33.43, 34.34, 37.43, 42.48, 49.63, 69.35, 113.90, 116.67, 119.71, 120.95, 126.47, 136.29, 137.33, 143.47, 146.50, 157.17,
196.91; elemental analysis C22H24O4 (352.42); calcd: C, 74.98; H, 6.86; found: C, 75.23; H, 7.32.
10. For a review in this area, see: Becker, H.-B.; Turner, A. B. In Quinones as Oxidants and Dehydrogenating Agents; Patai,
S.; Rappaport, Z., Eds. The Chemistry of Quinonoid Compounds. John Wiley: New York, 1988; Vol. 2, pp. 1352–1384.
11. For a review in this area, see: Maruyama, K.; OIsuka, A. In Recent Advances in the Photochemistry of Quinones; Patai, S.;
Rappaport, Z., Eds. The Chemistry of Quinonoid Compounds. John Wiley: New York, 1988; Vol. 2, pp. 835–852.
12. Itoh, K.; Kitoh, K.; Sera, A. Heterocycles 1999, 51, 243–248.