to pycnidione.1 Hence a further hetero Diels-Alder reaction
of 3 with 5 would afford pycnidione. All three natural
products were isolated in an enantiomerically pure form
though it is not clear whether, biosynthetically, the addition
of the tropolone occurs enzymatically or nonenzymatically.
Studies toward the synthesis of the quinone methide
tropolone precursor 6 are currently in progress. To determine
whether a hetero Diels-Alder reaction is a chemically
feasible biomimetic strategy for the synthesis of these
tropolone sesquiterpenes, benzotropolone 7, a model of 6,
was developed. This benzotropolone was synthetically more
accessible and the fused benzene ring provided a more
manageable compound. The model, however, features op-
posite regiochemistry to that of the biomimetic precursor 6.
Instead of the hydroxylsesquiterpene 4, humulene was used
as a model of the 11-membered ring backbone.
Carbonyl ylides and their use in synthesis via 1,3-dipolar
cycloadditions to acetylenic dipolarophiles have been well
documented.7 Recently this strategy has been applied to the
synthesis of novel annulated benzotropolones.8 The shown
retrosynthesis seemed a viable strategy for the construction
of benzotropolone 7 (Scheme 2).
Figure 1. Structures of pycnidione (1), eupenifeldin (2), and
epolone B (3).
Scheme 2. Retrosynthetic Approach to Benzotropolone 7
Scheme 1. Retrosynthetic Approach to Pycnidione (1) and
Epolone B (3)
Benzotropolone 7 was thus prepared starting from com-
mercially available phthalic acid (Scheme 3). Formation of
the monoester using (propargyloxy)methyl chloride9 followed
by conversion to a mixed anhydride and subsequent treatment
with an excess of CH2N2 gave the R-diazoketone 8. Exposure
of this R-diazoketone to Rh2(OAc)4 in CH2Cl2 resulted in
the formation of a reactive metal-carbenoid intermediate
which underwent intramolecular carbonyl ylide (8a) forma-
tion and subsequent 1,3-dipolar cycloaddition to give tetra-
propose that these natural products can be formed via a hetero
Diels-Alder reaction of quinone methide tropolone 5 with
the 11-membered sesquiterpene 4. The quinone methide
species can be derived from dihydroxy species 6, through
the elimination of water.6 Cai et al. have recently suggested
that monotropolone epolone B (3) is a biosynthetic precursor
(7) (a) Padwa, A.; Fryxell, G. E.; Zhi, L. J. Am. Chem. Soc. 1990, 112,
3100-3109. (b) Padwa, A.; Carter, S. P.; Nimmesgern, H.; Stull, P. D. J.
Am. Chem. Soc. 1988, 110, 2894-2900. (c) Toshikazu, I.; Jitsuhiro, K.;
Tsubokura, Y. Bull. Chem. Soc. Jpn. 1981, 54, 240-244.
(6) For general o-quinone methide generation in aromatic systems, see:
(a) Chambers, J. D.; Crawford, J.; Williams, H. W. R.; Dufresne, C.;
Scheigetz, J.; Bernstein, M. A.; Lau, C. K. Can. J. Chem. 1992, 70, 1717-
1732. (b) Talley, J. J. J. Org. Chem. 1985, 50, 1695-1699. (c) Chiba, K.;
Hirano, T.; Kitano, Y.; Tada, M. J. Chem. Soc., Chem. Commun. 1999,
691-692.
(8) (a) Friedrichsen, W.; Plu¨g, C. Tetrahedron Lett. 1992, 33, 7509-
7510. (b) Friedrichsen, W.; Plu¨g, C. J. Chem. Soc., Perkin Trans. 1 1996,
1035-1040. (c) Friedrichsen, W.; Plu¨g, C.; Debaerdemaeker, T. J. Prakt.
Chem. 1997, 339, 205-316.
(9) Hasan, A.; Srivastava, P. C. J. Med. Chem. 1992, 35, 1435-1439.
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Org. Lett., Vol. 1, No. 12, 1999