The synthesis of epi-epoxydon utilising the Baylis-Hillman reaction

Article abstract of DOI:10.1016/S0040-4039(02)00529-4

(±)-epi-Epoxydon was synthesised by means of a triethylaluminium/tri-n-butylphosphine-catalysed Baylis-Hillman reaction between an O-protected epoxidised hydroxyquinol core and paraformaldehyde, constituting the first application of the Baylis-Hillman reaction to a highly functionalised β-substituted enone.

Full text of DOI:10.1016/S0040-4039(02)00529-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3573–3576
The synthesis of epi-epoxydon utilising the Baylis–Hillman
reaction
Thorsten Genski and Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 18 February 2002; revised 8 March 2002; accepted 15 March 2002
Abstract—( )-epi-Epoxydon was synthesised by means of a triethylaluminium/tri-n-butylphosphine-catalysed Baylis–Hillman
reaction between an O-protected epoxidised hydroxyquinol core and paraformaldehyde, constituting the first application of the
Baylis–Hillman reaction to a highly functionalised b-substituted enone. © 2002 Elsevier Science Ltd. All rights reserved.
We have
a
long-standing interest in synthetic
activity.5,6 We considered the possibility of preparing
such compounds from the corresponding cyclo-
hexenones via the Baylis–Hillman reaction.8 Thus, for
example, epoxydon 5 and epi-epoxydon 6 would be
approaches to epoxycyclohexenone-based natural prod-
ucts. Recent examples include tricholomenyn A 1,1
manumycin A 22 and scyphostatin 3.3
prepared from the Baylis–Hillman reaction between
formaldehyde and enones 7 and 8, respectively, as
shown in Scheme 1.
A number of related epoxycyclohexenone-based natural
products are known which contain additional hydroxy-
alkyl substituents.4–7 Examples are panepoxydon 4,4
epoxydon 55 and epi-epoxydon 6.6 Panepoxydon is a
potent NF-kB inhibitor,4 and epoxydon and epi-epoxy-
don exhibit antifungal, antibacterial and phytotoxic
The Baylis–Hillman reaction has attracted considerable
interest due to its potential for forming a carbon–car-
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00529-4

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T. Genski, R. J. K. Taylor / Tetrahedron Letters 43 (2002) 3573–3576
bon bond between the a-position of an activated
alkene and an aldehyde/ketone or imine in one step by
nucleophilic catalysis using a tertiary amine or phos-
phine.8 The reaction proceeds best with sterically
unhindered alkenes; b-substituted alkenes usually
require increased pressure and often afford mixtures of
E- and Z-isomeric products.8 Recently it has been
demonstrated that the Baylis–Hillman reaction of b-
substituted alkenes can be carried out at atmospheric
pressure by the use of sulfides,9a,9b selenides9a,9c and
tertiary amines9d in the presence of titanium(IV) tetra-
chloride, as well as DABCO in combination with
lithium perchlorate,9e DMAP,9f DBU9g and 3-hydrox-
yquinuclidine in water/formamide.9h In most synthetic
applications the Baylis–Hillman reaction has been
applied to simple activated alkenes at an early stage of
the synthetic route, or if utilised at a more advanced
stage, the substrate has contained little if any function-
ality other than the activated alkene itself.10 Thus, the
successful application of the Baylis–Hillman reaction
to the synthesis of epoxydon 5 and epi-epoxydon 6, as
shown in Scheme 1, would demonstrate the utility of
the procedure with functionalised, b-substituted
enones.
Thus, as reported,14 addition of p-benzoquinone to
1,3-cyclopentadiene afforded endo-adduct 9 in good
yield after recrystallisation. A number of attempts
were made to reduce selectively one carbonyl group of
9 but the best yield of the corresponding hydroxy
ketone was only 8%. We therefore first carried out the
epoxidation of 9. This was achieved in good yield, and
with complete exo-stereoselectively, using tert-butyl
hydroperoxide (TBHP, 2 equiv.) and 1,5,7-triazabicy-
clo[4.4.0]dec-5-ene (TBD, 0.05 equiv.).15 Reduction of
epoxide 10 using L-Selectride® or Super-Hydride® was
totally stereoselective giving 11 in 52% yield in both
cases. Tetra-n-butylammonium borohydride16 gave a
mixture of 11 and 12 (64%; 74% based on recovered
starting material; 11:12=6.4:1), which could be sepa-
rated by chromatography on silica (Et2O/petrol ether,
5:1). Retro-Diels–Alder reaction of separated 11 and
12 took place efficiently in refluxing diphenyl ether to
give trans-epoxy alcohol 8 in 94% yield and the cis-
epimer 7 in 71% yield.
Silyl protected analogues epoxy quinols 13 and 14
were also prepared (Scheme 2). Attempts to prepare
the trimethylsilyl-derivative 13a of the trans-epoxy
alcohol 8 were unsuccessful: the trimethylsilyl-deriva-
tive of 11 decomposed on thermolysis, and the
trimethylsilylation product of epoxyquinol 8 proved to
be extremely unstable to purification on silica. Fortu-
nately, the triethylsilyl analogue 13b could be obtained
directly from alcohol 8 in 86% yield after chromatog-
raphy. The t-butyldimethylsilyl (TBS)-derivative 13c
was prepared in a similar way, albeit in lower yield
A number of routes have been described to prepare
the epoxy quinols 7 and 8, and the silylated analogues
13 and 14, required for this study.11,12 We developed a
streamlined version of Ogasawara’s route12a (Scheme
2);13 after the completion of this part of our study
Lubineau and Billault published a closely related route
to epoxy quinol 8.12b
Scheme 2.

T. Genski, R. J. K. Taylor / Tetrahedron Letters 43 (2002) 3573–3576
3575
(13c was also obtained in 76% yield by thermolysis of
the silylated analogue of 11). The direct silylation route
was not so straightforward with the cis-epoxy alcohol
7, however. Triethylsilylation of 7 using triethylsilyl
chloride/imidazole gave complete epimerisation to pro-
duce 13b in 71% yield. Similar equilibration processes
have been reported before.5 No epimerisation was
observed using TBSOTf/2,6-lutidine, however, with 14c
being obtained in 59% yield. The retro-Diels–Alder
reaction sequence could also be employed to prepare a
sample of 14c devoid of its epimer.
that decomposition of the substrates and the product
occurred when the reaction temperature exceeded 5°C.
The longer reaction times also resulted in somewhat
lower yields. The order in which the reagents were
added turned out to be crucial to the outcome of the
process. The epoxyquinols were unstable when exposed
n
to Bu3P before addition of triethylaluminium. Thus,
paraformaldehyde, Et3Al and nBu3P were added rapidly
in that order. Increasing the number of equivalents of
both catalysts together (0.4 equiv. Et3Al, 1 equiv.
nBu3P) led mainly to decomposition of the substrates,
while raising the concentration of nBu3P alone (2.6
equiv.) did not have any significant effect on the
product yield (34%). These results imply that Et3Al is
responsible for the decomposition of the starting mate-
rial. Decreasing the amount of both catalysts (0.05
With the epoxy quinols in hand, we set out to examine
the suitability of various Baylis–Hillman protocols for
this class of highly functionalised substrate (Scheme 3).
We realised that the correct choice of conditions would
be crucial as epoxy quinols are known to be prone to
aromatisation, and epoxydon and epi-epoxydon have
been reported to be unstable in the presence of weak
bases such as aqueous sodium acetate or pyridine.5,6 All
attempts to convert the unprotected epoxy quinols 7
and 8 directly into racemic epoxydon and epi-epoxy-
don, respectively, using formaldehyde under amine
catalysis (DMAP, DABCO, 3-quinuclidinol and Et3N)
gave only decomposition. However, when triethylalu-
minium in the presence of tri-n-butylphosphine17 was
utilised, the formation of a more polar product was
observed, although we were unable to isolate it from
the reaction mixture. When moving on to study the use
of the silylated hydroxy quinols in the Baylis–Hillman
reaction, we therefore concentrated our efforts on the
Et3Al/nBu3P catalytic system.
n
equiv. Et3Al, 0.1 equiv. Bu3P), resulted in longer times
(10 h) and a reduced yield (15%). Comparison of the
amount of recovered starting material also indicates its
instability towards the catalytic system, since twice as
much was regained at lower concentration of the cata-
lysts. It should be noted, however, that the Lewis acid
n
was essential, as the use of Bu3P alone caused enone
decomposition (and triphenylphosphine alone gave no
reaction).
The only product isolated from this study was the
trans-epoxy ketone adduct 15c, and when unreacted
starting material was recovered, the only isomer
observed was the trans-epoxy ketone 13c. It could be
that selective decomposition of 14c (or of the cis-isomer
of adduct 15c) was occurring. Alternatively, the cis-iso-
mer of adduct 15c could undergo epimerisation. The
most likely explanation, given the facile epimerisation
observed during the base-mediated silylation of 7
(Scheme 2), is that under these Baylis–Hillman condi-
tions 14c is epimerised to 13c by way of an intermediate
such as 16. When more material is available the Baylis–
Hillman reaction of pure 14c will be studied in order to
clarify this point.
In the initial studies a mixture of 13c and 14c (ca. 12:1)
and paraformaldehyde (2 equiv.) in dichloromethane
was treated with 30 mol% of tri-n-butylphosphine and
11 mol% of triethylaluminium at temperatures between
−20°C and 0°C for 3–10 hours. The Baylis–Hillman
product 15c was observed in all cases (5–39%) along
with unreacted starting material. It was noticed (TLC)
Scheme 3.

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T. Genski, R. J. K. Taylor / Tetrahedron Letters 43 (2002) 3573–3576
With optimised conditions established, the conversion
of 13b and 13c into epi-epoxydon 6 was carried out
(Scheme 3). Thus, 13c gave 15c in 42% isolated yield,
and 13b gave 15b in 44% yield (with 43% of recovered
13b). Desilylation was effected using pyridine–HF com-
plex; removal of the TBS group was rather slow and
low yielding but fortunately the triethylsilyl group was
removed in 3 hours and in 70% yield. The structure of
the racemic epi-epoxydon 6 thus produced was con-
Soc. 1980, 102, 7987; (c) Nagata, T.; Ando, Y.; Hiroto,
A. Biosci. Biotechnol. Biochem. 1992, 56, 810; (d)
Kamikubo, T.; Hiroya, K.; Ogasawara, K. Tetrahedron
Lett. 1996, 37, 499 and references therein.
7. For more complex examples see: Bugni, T. S.; Abbanat,
D.; Bernan, V. S.; Maiese, W. M.; Greenstein, M.; Van
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1
firmed by comparing its H NMR spectroscopic data
and melting point (76°C; lit.18 78.5–79°C) with the
Anke, H. Z. Naturforsch., Sect.
C 1993, 48, 843
literature.18
(Oligosporons).
8. For reviews see: Ciganek, E. Organic Reactions 1997, 51,
201; Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033;
for a recent example see: Shi, M.; Jiang, J.-K.; Li, C.-Q.
Tetrahedron Lett. 2002, 43, 127.
In conclusion, we have carried out what we believe to
be the first application of the Baylis–Hillman reaction
to a highly functionalised molecule (containing epoxide
and protected alcohol moieties in addition to the b-sub-
stituted enone) and utilised the adduct to prepare the
bioactive natural product, ( )-epi-epoxydon. We are
currently optimising this methodology and applying it
to the synthesis of more complex natural products.
9. (a) Kataoka, T.; Iwama, T.; Tsujiyama, S.-i.; Iwamura,
T.; Watanabe, S.-i. Tetrahedron 1998, 54, 11813; (b) Shi,
M.; Jiang, J.-K. Tetrahedron 2000, 56, 4793; (c) Jauch, J.
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Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539; (f)
Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39,
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10. For recent examples see: Sugahara, T.; Ogasawara, K.
Synlett 1999, 419; Iwabuchi, Y.; Sugihara, T.; Esumi, T.;
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11. (a) Matcheva, K.; Beckmann, M.; Schomburg, D.; Win-
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and IR-spectroscopy and by HRMS.
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15. Genski, T.; Macdonald, G.; Wei, X.; Lewis, N.; Taylor,
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Acknowledgements
We are grateful to the Deutscher Akademischer Aus-
tauschdienst (DAAD) and Elsevier Science for stu-
dentship support (T.G.). We also thank Dr. Peter
O’Brien (University of York) for helpful discussions.
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