Inspired by the facile formation of 5, we decided to explore
the use of quinones bearing electron-withdrawing groups
(EWG) for synthesizing aflatoxin B2, which contains a
similar furo[2,3-b]benzofuran ring system. We were also
encouraged by a previous report of 2-acetyl-1,4-benzo-
quinone reacting similarly with dihydrofuran6 and by the
work of Brimble and co-workers on the reactivity of 2-(4-
methylbenzenesulfinyl)-1,4-benzoquinone with 2-trimethyl-
siloxyfuran.7 Our approach to aflatoxin B2 is summarized
in Scheme 2, where the electron-withdrawing group is an
circumvent the difficulties associated with direct deprotection
of 10, a reduction, deprotection, and reoxidation strategy was
used. Quinone 10 was converted to hydroquinone 11 by a
modification of the Hibino and Weinreb procedure.8 Oxida-
tion of 11 using DDQ in benzene gave the unstable quinone
8, which was isolated and used in the next step without
further purification. The reaction of 8 with dihydrofuran in
acetonitrile gave the tricycle 6 in 59% overall yield in two
steps from 11. Solvent choice was significant in this reaction,
with the polar solvent acetonitrile giving the best results.
With the completion of the racemic furobenzofuran core
(6) of aflatoxin B2, it remained to deoxygenate the existing
phenolic hydroxyl and replace the aldehyde with a phenolic
hydroxyl (Scheme 4).
Scheme 2
Scheme 4a
aldehyde or optically pure sulfoxide, leading to formal
racemic and stereoselective syntheses of aflatoxin B2,
respectively.
a Key: (a) Tf2O, DMAP, pyridine, CH2Cl2, 0 °C; (b) urea‚H2O2,
TFAA, CH2Cl2, rt; (c) Raney Ni, MeOH, rt.
Synthesis of Racemic 2. The synthesis of methoxy-
substituted quinone aldehyde 8 and its subsequent reaction
with dihydrofuran, giving 6, is outlined in Scheme 3. The
To deoxygenate the phenolic hydroxyl group of 6, it was
first converted to the trifluoromethanesulfonate ester (triflate,
TfO) using triflic anhydride in pyridine and methylene
chloride with catalytic DMAP, giving 12 in 80% yield.
Baeyer-Villiger oxidation of aldehyde 12 using urea-
hydrogen peroxide and trifluoroacetic anhydride9 gave the
aryl formate 13 in 28% yield.
Scheme 3a
(4) (a) Bando, Toshikazu, Shishido, Kozo Synlett 1997, 665. (b) Pirrung,
M. C.; Lee, Y. R. Tetrahedron Lett. 1996, 37, 2391. (c) Rapoport, H.;
Civitello, E. R. J. Org. Chem. 1994, 59, 3775. (d) Koreeda, M.; Dixon, L.
A.; Hsi, J. D. Synlett 1993, 555. (e) Kraus, G. A.; Johnston, B. E.; Applegate,
J. M. J. Org. Chem. 1991, 56, 5688. (f) Horne, S.; Weeratunga, G.; Rodrigo,
R. J. Chem. Soc., Chem. Commun. 1990, 39. (g) Wolff, S.; Hoffmann, H.
M. R. Synthesis 1988, 760. (h) Sloan, C. P.; Cuevas, J. C.; Quesnelle, C.;
Snieckus, V. Tetrahedron Lett. 1988, 29, 4685. (i) Weeratunga, G.; Horne,
S.; Rodrigo, R. J. Chem. Soc., Chem. Commun. 1988, 721. (j) Castellino,
A. J.; Rapoport, H. J. Org. Chem. 1986, 51, 1006. (k) Roberts, J. C.;
Sheppard, A. H.; Knight, J. A.; Roffey, P. J. Chem. Soc. C 1968, 22. (l)
Bu¨chi, G.; Weinreb, S. M. J. Am. Chem. Soc. 1971, 93, 746. (m) Bu¨chi,
G.; Foulkes, D. M.; Kurono, M.; Mitchell, G. F.; Schneider, R. S. J. Am.
Chem. Soc. 1967, 89, 6745. (n) Knight, J. A.; Roberts, J. C.; Roffey, P. J.
Chem. Soc. C 1966, 1308.
a Key: (a) (i) H2 (1 atm), 10% Pd-C, EtOAc, (ii) 6 N HCl,
Et2O; (b) DDQ, PhH; (c) dihydrofuran, CH3CN, 0 °C, 2 h, then rt,
2 h.
(5) Noland, W. E.; Kedrowski, B. L. J. Org. Chem. 1999, 64, 596.
(6) Kuser, P.; Frauenfelder, E. F.; Eugster, C. H. HelV. Chim. Acta 1971,
54, 969.
(7) (a) Brimble, M. A.; Elliott, R. J. R. Tetrahedron 1997, 53, 7715. (b)
Brimble, M. A.; Duncalf, L. J.; Reid, D. C. W. Tetrahedron: Asymmetry
1995, 6, 263. (c) Brimble, M. A.; Brimble, M. T.; Gibson, J. J. J. Chem.
Soc., Perkin Trans. 1 1989, 179. (d) Brimble, M. A.; Gibson, J. J.
Tetrahedron Lett. 1987, 28, 4891.
(8) Hibino, S.; Weinreb, S. M. J. Org. Chem. 1977, 42, 1175.
(9) Cooper, M. S.; Heaney, H.; Newbold, A. J.; Sanderson, W. R. Synlett
1990, 533.
quinone acetal 10 was synthesized in two steps from
commercially available o-vanillin as described by Hibino and
Weinreb.8 Attempts were made to deprotect the acetal of 10
leading directly to 8, but this resulted in decomposition. To
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Org. Lett., Vol. 2, No. 14, 2000