Studies toward the Biomimetic Synthesis of Tropolone Natural Products via a Hetero Diels-Alder Reaction

Article abstract of DOI:10.1021/ol991067y

(matrix presented) Analogues of the tropolone natural products pycnidione and epolone B were synthesized via a hetero Diels-Alder reaction of benzotropolone 10 with humulene. The quinone methide benzotropolone 13 was generated in situ by thermalisation of

Full text of DOI:10.1021/ol991067y

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1933-1935
Studies toward the Biomimetic
Synthesis of Tropolone Natural
Products via a Hetero Diels−Alder
Reaction
Jack E. Baldwin,* Alexander V. W. Mayweg, Karin Neumann, and
Gareth J. Pritchard
The Dyson Perrins Laboratory, UniVersity of Oxford, South Parks Road,
Oxford, OX1 3QY, U.K.
jack.baldwin@chem.ox.ac.uk
Received September 20, 1999
ABSTRACT
Analogues of the tropolone natural products pycnidione and epolone B were synthesized via a hetero Diels−Alder reaction of benzotropolone
10 with humulene. The quinone methide benzotropolone 13 was generated in situ by thermalisation of benzotropolone 10. Benzotropolone 10
was derived from phthalic acid via carbonyl ylide 8a followed by an intramolecular 1,3-dipolar cycloaddition and subsequent acid-catalyzed
ring opening.
Pycnidione (1), epolone B (2), and eupenifeldin (3) are
members of a family of tropolone fungal metabolites recently
isolated (Figure 1).1-3 Pycnidione has been extracted from
Phoma sp. strain MF5726 isolated from soil collected on
Korase Island, Federated States of Micronesia. Pycnidione
was also isolated from a culture of fungus OS-F69284, along
with epolone B. Eupenifeldin was extracted from cultures
of Eupenicillium brefeldanium ATCC 74184 and differs from
pycnidione only in the stereochemistry at the C9 ring
junction. All three natural products have been shown to
possess interesting biological activities. Pycnidione and
epolone B induced erythropoietin gene expression and are
thus of interest as a potential alternative treatment of patients
with anemia due to chronic renal failure.1 Pycnidione was
further shown to inhibit stromelysin, an enzyme postulated
to cause cartilage degradation, one of the proposed causes
for arthritis.4 Eupenifeldin was shown to have in vivo
antitumor activity in the P388 leukemia model.3
All three metabolites show a high degree of structural
similarity, each featuring identical tropolone rings attached
to a sesquiterpene backbone. The 11-membered sesquiterpene
ring shows great resemblance to humulene, differing only
in the hydroxy functionality at C11. Biosynthetically, these
fungal metabolites can be viewed as addition products of
tropolones5 to a sesquiterpene such as humulene, which may
be hydroxylated prior or after addition (Scheme 1). We
(1) Cai, P.; Smith, D.; Cunningham, B.; Brown-Shimer, S.; Katz, B.;
Pearce, C.; Venables, D.; Houck, D. J. Nat. Prod. 1998, 61, 791-795.
(2) Harris, G. H.; Hoogsteen, K.; Silverman, K. C.; Raghoobar, S. L.;
Bills, G. F.; Lingham, R. B.; Smith, J. L.; Dougherty, H. W.; Cascales, C.;
Pala´ez, F. Tetrahedron 1993, 49, 2139-2144.
(3) Mayerl, F.; Gao, Q.; Huang, S.; Klohr, S. E.; Matson, J. A.;
Gustavson, D. R.; Pirnik, D. M.; Berry, R. L.; Fairchild, C.; Rose, W. C.
J. Antibiot. 1993, 46, 1082-1088.
(4) MacNaul, K. L.; Chartrain, N.; Lark, M.; Tocci, M. J.; Hutchinson,
N. I. J. Biol. Chem. 1990, 28, 17238-17245.
(5) For tropolone biosynthesis, see: (a) O’Sullivan, M. C.; Schwab, J.
M. Bioorg. Chem. 1995, 23, 131-143. (b) Scott, A. I.; Guilford, H.; Lee,
E. J. Am. Chem. Soc. 1971, 93, 3534-3536.
10.1021/ol991067y CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/13/1999

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

It was thus found that a thermal retro-hetero Diels-Alder
reaction of the protected benzotropolones 10 or 11, with the
extrusion of formaldehyde at 150 °C, generated the required
tropolone quinone methide 13 in situ. This was trapped
initially by 1-methylcyclohexene to give the inverse electron
demand hetero Diels-Alder adduct 14 (Scheme 4).
Scheme 3a
Scheme 4a
a Reagents and conditions: (g) sealed tube, excess 1-methylcy-
clohexene, 150 °C, 24 h, 62%; (h) sealed tube, humulene (1.5
equiv), p-xylene, 150 °C, 24 h, 60%; (i) sealed tube, 10 (4 equiv),
p-xylene, 150 °C, 24 h, 20%.
Thermolosis of benzotropolone 10 followed by a hetero
Diels-Alder reaction in situ with 1.5 equiv of humulene in
p-xylene at 150 °C afforded the least hindered monosubsti-
tuted epolone B analogue 15 with correct regiochemistry in
good yield.12 Addition of the second tropolone proved to be
less facile, presumably due to steric factors. However,
reaction with an additional 4 equiv of tropolone 10 in xylene
gave pycnidione analogue 16 in 20% yield as a 1:1 mixture
of diastereomers.13
a Reagents and conditions: (a) N(iPr)2Et (1 equiv), ClCH2OCH2-
CCH, DMF, rt., 6 h, 65%; (b) isobutyl chloroformate (1 equiv),
NEt3 (1 equiv), THF, then CH2N2 (3 equiv)/Et2O, -15 to -5 °C,
24 h, 51%; (c) Rh2(OAc)4 (3 mol %), CH2Cl2, rt, 5h, 74%; (d) 6 N
HCl, 1,4-dioxane, rt., 3 h, 93%; (e) NaH, MeI, DMF, rt, 6 h, 73%;
(f) NaH, BnBr, DMF, 50 °C, 68%.
In summary, an efficient synthesis of benzotropolone 10
was devised which, via thermolosis, could undergo a tandem
retro-hetero Diels-Alder/hetero Diels-Alder reaction with
humulene to give natural product analogues of epolone B
(3) and pycnidione (1). Further results and experimental
details will be published in due course.
cycle 9. Acid-catalyzed ring opening of 9 yielded tricyclic
tropolone 7, with the methylene acetal still in place.10
Protection of the free hydroxy functionality as either the
methyl or benzyl ether using standard protocol afforded
tropolones 10 and 11. Subsequent removal of the acetal
functionality to yield the diol 12 was met with considerable
resistance, and results will be reported in due course.
Funk et al. have reported that 4H-1,3-dioxins can be
thermally converted to R,â-unsaturated aldehydes via a retro
Diels-Alder reaction with the extrusion of formaldehyde.11
Acknowledgment. We thank the EPSRC for a student-
ship to A.V.W.M. and the European Commission for a
Marie-Curie-Researchscholarship to K.N.
OL991067Y
(10) Structures of 9, 11, and 15 were confirmed by single-crystal X-ray
crystallography and details will be reported in due course.
(11) Funk, R. L.; Bolton, G. L. J. Am. Chem. Soc. 1988, 110, 1290-
1292.
(12) Compounds 15 and 16 were fully characterised by 1H NMR, 13C
NMR, IR, MS, and HRMS.
(13) Diastereomers were separated by HPLC; details will be reported in
due course.
Org. Lett., Vol. 1, No. 12, 1999
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