Biomimetic cycloaddition approach to tropolone natural products via a tropolone ortho-quinone methide

Article abstract of DOI:10.1021/ol026467r

(figure presented) A study toward a possible biomimetic hetero Diels-Alder reaction is reported between humulene and a novel tropolone ortho-quinone methide. A suitable tropolone ortho-quinone methide precursor has been prepared from 3-methyl-2-furoate. H

Full text of DOI:10.1021/ol026467r

ORGANIC
LETTERS
2002
Vol. 4, No. 17
3009-3011
Biomimetic Cycloaddition Approach to
Tropolone Natural Products via a
Tropolone Ortho-quinone Methide
,†
Robert M. Adlington,† Jack E. Baldwin,* Alexander V. W. Mayweg,† and
Gareth J. Pritchard‡
Dyson Perrins Laboratory, UniVersity of Oxford, South Parks Road,
Oxford OX1 3QY, U.K., and Department of Chemistry, Loughborough UniVersity,
Loughborough, Leicestershire LE11 3TU, U.K.
jack.baldwin@chem.ox.ac.uk
Received July 4, 2002
ABSTRACT
A study toward a possible biomimetic hetero Diels−Alder reaction is reported between humulene and a novel tropolone ortho-quinone methide.
A suitable tropolone ortho-quinone methide precursor has been prepared from 3-methyl-2-furoate. Heating the ortho-quinone methide precursor
gave a tropolone ortho-quinone methide, which in the presence of humulene underwent a hetero Diels−Alder reaction to give a deoxy analogue
of epolone B.
Pycnidione (1) and epolone B (2) are members of a small
family of tropolone natural products isolated from a variety
of fungi (Figure 1).1-5 Both metabolites 1 and 2 have been
shown to induce erythropoietin gene expression and are thus
of interest as a potential alternative treatment for patients
with anemia.
We recently reported a model study toward a biomimetic
approach to these tropolone natural products via a hetero
Diels-Alder reaction.6 We proposed that pycnidione (1) is
biosynthesized via two consecutive hetero Diels-Alder
reactions of a novel tropolone o-quinone methide 3 with the
sesquiterpene backbone 4 (Scheme 1). To our knowledge,
The tropolone natural products in this series show striking
structural interrelationships, all featuring one or two identical
tropolone units fused to a hydrocarbon backbone.
† Oxford University.
‡ Loughborough University.
(1) Cai, P.; Smith, D.; Cunningham, B.; Brown-Shimer, S.; Katz, B.;
Pearce, C.; Venables, D.; Houck, D. J. Nat. Prod. 1998, 61, 791.
(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.
(3) Mayerl, F.; Gao, Q.; Huang, S.; Klohr, S. E.; Matson, J. A.;
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J. Antibiot. 1993, 46, 1082.
(4) Itoˆ, T. Agric. Biol. Chem. 1979, 43, 1237.
(5) Itoˆ, T.; Arai, T.; Oshashi, Y.; Sasada, Y. Agric. Biol. Chem. 1981,
45, 1689.
Figure 1. Structures of pycnidione (1) and epolone B (2).
10.1021/ol026467r CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/31/2002

Scheme 1. Retrosynthetic Approach to Pycnidione (1) and
Epolone B (2)
Scheme 2. Retrosynthetic Approach to Tropolone 6
n
protocol. Formylation of furan 12 using BuLi and DMF
followed by reduction and then oxidative ring expansion with
m-CPBA afforded the corresponding pyranulose, which was
subsequently activated as the acetate 13 using Ac2O/DMAP
conditions. Gratifyingly, it was found that heating the
pyranulose acetate 13 in the presence of an excess of
R-acetoxyacrylonitrile in toluene in a sealed tube for 6 h at
120 °C afforded the desired cycloadducts 14 and 15 as a
2:5 mixture in moderate but acceptable yield. Surprisingly,
the collapse of the cyanohydrin of cyloadducts 14 and 15 to
a stable bis ketone could not be achieved. This transforma-
tion, however, proceeded without difficulty if the carbonyl
of the cycloadducts was first reduced to give 16 and 17.
Subsequent efforts focused on the cleavage of the ether
bridge of 18.
such a tropolone ortho-quinone methide is a completely novel
reactive intermediate and has not been previously described.
The tropolone ortho-quinone methide 3 could be derived
from tropolone 5 by the elimination of water. Epolone B
(2) has been described as a possible biosynthetic precursor
of pycnidione (1), which is consistent with our proposal.1
Herein we report the synthesis of tropolone 6, a precursor
of the tropolone ortho-quinone methide 3, as well as the
synthesis of a deoxy analogue of epolone B (2).
Work by Sato has shown that ortho-(1-(alkylthio)alkyl)-
phenols are suitable precursors to benzo ortho-quinone
methides.7 Thus, it appeared to us that an alkylthio derivative
of 5, e.g., 6, would be a suitable target to prepare in order to
generate the tropolone ortho-quinone methide precursor.
The desired tropolone 6 was disconnected using a 1,3-
dipolar cycloaddition of an 3-oxidopyrylium ylide 8 and a
ketene equivalent as the key step (Scheme 2).8 The 3-oxi-
dopyrylium ylide 8 is available from a corresponding
pyranulose acetate 9, which in turn is derived from furan 10
via an oxidative ring expansion.
It was found that the most suitable method of cleaving
the ether bridge was via an iodo ether elimination of iodide
Scheme 3. Synthesis of Keto-alcohol 18a
The synthesis of 6 started with commercially available
3-methyl-2-furoate (11) (Scheme 3). Reduction of 3-methyl-
2-furoate with LiAlH4 afforded the corresponding alcohol,
which was protected as the TBS-ether 12 using a standard
(6) Baldwin, J. E.; Mayweg, A. V. W.; Neumann. K.; Pritchard, G. J.
Org. Lett. 1999, 1, 1933.
(7) Inoue, T.; Inoue, S.; Sato, K. Chem. Lett. 1989, 653; 1990, 55.
(8) For further examples of 1,3-dipolar cycloadditions with 3-oxidopy-
rylium species, see: Hendrickson, J. B.; Farina, J. S. J. Org. Chem. 1980,
45, 3359. Hendrickson, J. B.; Farina, J. S. J. Org. Chem. 1980, 45, 3361.
Sammes, P. G.; Street, L. J. J. Chem. Soc., Perkin Trans. 1 1983, 1261.
Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun. 1983, 666.
Sammes, P. G.; Street, L. J. J. Chem. Res. 1984, 196. Bromidge, S. M.;
Sammes, P. G.; Street, L. J. J. Chem. Soc., Perkin Trans. 1 1985, 1725.
Sammes, P. G.; Street, L. J. J. Chem. Soc., Perkin Trans. 1 1986, 281.
Bromidge, S. M.; Archer, D. A.; Sammes, P. G. J. Chem. Soc., Perkin
Trans. 1 1990, 353. Marshall, K. A.; Mapp, A. K.; Heathcock, C. H. J.
Org. Chem. 1996, 61, 9135. Wender, P. A.; Lee, H. Y.; Wilhelm, R. S.;
Williams, P. D. J. Am. Chem. Soc. 1989, 111, 8954. Magnus, P.; Diorazio,
L.; Donohoe, T. J.; Giles, M.; Pye, P.; Tarrant, J.; Thom, S. Tetrahedron
1996, 52, 14147.
a Reagents and conditions: (a) LiAlH4, Et2O/THF, rt, 99%;
(b)TBSCl, imidazole, DMF, rt, 90%; (c) n-BuLi, DMF, THF, from
-78 °C to rt, 93%; (d) NaBH4, EtOH/THF, rt, 1 h, 98%; (e)
m-CPBA, DCM, -78 °C, 3 h, 97%; (f) Ac2O, DMAP, pyridine, 0
°C, 90 min, 65%; (g) R-acetoxyacrylonitrile, toluene, 120 °C, 6 h,
54% overall; (h) NaBH4, CeCl3‚7H2O, MeOH, rt, 10 min, 99%;
(i) NaOMe, MeOH, rt, 30 min, 98%.
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Org. Lett., Vol. 4, No. 17, 2002

Scheme 4. Synthesis of Tropolone 6a
Scheme 5. Biomimetic Hetero Diels-Alder Reactiona
a Reagents and conditions: (v) humulene, p-xylene, sealed tube,
150 °C, 24 h, 22%.
could now be oxidized with Swern reagent, and the resulting
unstable exo-enone was immediately exposed to thiophenol
sodium salt in EtOH to afford enone 23. Removal of the
acetonide using aqueous acetic acid afforded the correspond-
ing diol, which was oxidized to the desired tropolone 6 using
TFAA-activated DMSO.
With the tropolone 6 in hand, the hetero Diels-Alder
reaction was attempted (Scheme 5). Humulene was used as
a model of the sesquiterpene backbone 4. It was found that
tropolone 6 acted directly as a precursor of the tropolone
ortho-quinone methide 3 without prior need for oxidation
of the thiol to the sulfoxide. Thus, heating tropolone 6 in
p-xylene in the presence of humulene at 150 °C for 24 h
afforded deoxy epolone B 24 in an encouraging yield. The
cycloadduct 24 features the regiochemistry and stereochem-
istry as would be expected from a concerted inverse electron-
demanding hetero Diels-Alder reaction between the C5-
C6 double bond10 of humulene and a novel tropolone ortho-
quinone methide 3.
In conclusion, we have developed a synthesis of tropolone
6 via a 3-oxidopyrylium 1,3-dipolar cycloaddition reaction.
Tropolone 6 acted as a precursor to the entirely novel
biomimetic tropolone ortho-quinone methide 3. This inter-
mediate reacted selectively, and without the need of any
protecting groups, with humulene to give a deoxy analogue
of epolone B (2), thus offering experimental support to a
possible hetero Diels-Alder biosynthesis of epolone B (2)
and pynidione (1).
a Reagents and conditions: (j) NaBH4, MeOH, rt, 20 min, 99%;
(k) NaBH4, CeCl3‚7H2O, then NaBH4 (2 equiv), 6 h, rt, 83%; (l)
Ac2O, DMAP, pyridine, 96%; (m) HF, MeCN, 96%; (n) (i) Tf2O,
NEt3, DCM, -20 °C; (ii) TBAI, MeCN, 92% overall; (o) activated
Zn, EtOH, 2 h, 78%; (p) 2-methoxypropene, PPTS, 0 °C, 2h, 88%;
(q) K2CO3, MeOH, 98%; (r) (ClCO)2, DMSO, DCM, -65 °C, then
N(iPr)2Et, -20 °C, 94%; (s) NaSPh, EtOH, 0 °C, 1 h, then rt, 2 h,
92%; (t) 70% aqueous AcOH, 48 h; (u) 4 equiv of TFAA and
DMSO, -60 °C, 1.5 h, then NEt3, -60 °C, 1.5 h, 64%.
20 (Scheme 4).9 The iodide was derived from keto-alcohol
18. Reduction of 18 with NaBH4 afforded diol 19. Further
experimentation showed that cycloadducts 14 and 15 could
be directly converted into diol 19 using a one-pot procedure
with 3 equiv of NaBH4. Protection of the diol 19 as the bis-
acetate, removal of the TBS group with aqueous HF in
MeCN, and activation of the alcohol as the triflate followed
by treatment with tetrabutylamonium iodide afforded iodide
20 in 84% yield over four steps.
Gratifyingly, iodide 20 efficiently underwent iodo-ether
elimination with the simultaneous loss of one of the acetyl
protecting groups when treated with activated zinc in
refluxing ethanol, affording exo-ene 21 in good yield.
Protection of the diol of 21 as the acetonide followed by the
saponification of the acetate afforded alcohol 22. The alcohol
Acknowledgment. The authors thank the EPSRC for a
studentship to A.V.W.M.
OL026467R
(9) Ohmori, N. J. Chem. Soc., Chem. Commun. 2001, 1552. Wender, P.
A.; Lee, H. Y.; Wilhelm, R. S.; Williams, P. D. J. Am. Chem. Soc. 1989,
111, 8954. Bernet, B.; Vasella, A. HelV. Chim. Acta 1984, 67, 1328.
(10) For an account of the reactivity of the double bonds of humulene,
see: Allen, F. H.; Brown, E. D.; Rogers, D.; Sutherland, J. K. J. Chem.
Soc., Chem. Commun. 1964, 1116.
Org. Lett., Vol. 4, No. 17, 2002
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