A new approach to the pseudopterosins using an arene alkylation with a γ-methylene-γ-butyrolactone

Article abstract of DOI:10.1016/S0040-4039(00)02207-3

A short and practical route to the tricyclic core of an unnatural pseudopterosin diastereoisomer is presented. Key features are an arene alkylation with a γ-methylene-γ-butyrolactone, viz. 10→14, and an elaborate reduction sequence 14→17 which both procee

Full text of DOI:10.1016/S0040-4039(00)02207-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1193–1195
A new approach to the pseudopterosins using an arene alkylation
with a g-methylene-g-butyrolactone
David C. Harrowven,* Jonathan D. Wilden, Melloney J. Tyte, Michael B. Hursthouse and
Simon J. Coles
Department of Chemistry, The University, Southampton SO17 1BJ, UK
Received 9 November 2000; accepted 29 November 2000
Abstract—A short and practical route to the tricyclic core of an unnatural pseudopterosin diastereoisomer is presented. Key
features are an arene alkylation with a g-methylene-g-butyrolactone, viz. 10“14, and an elaborate reduction sequence 14“17
which both proceed diastereoselectively. © 2001 Elsevier Science Ltd. All rights reserved.
The pseudopterosins are a small family of glycosidal
diterpenes found in the Caribbean sea whip Pseu-
dopterogorgia elisabethae.1,2 They have attracted con-
siderable attention from synthetic and medicinal
chemists alike because they function as anti-inflam-
matory and analgesic agents with potencies substan-
tially greater than indomethacin.1–3 Their limited
availability from natural sources and the recent com-
mercialisation of pseudopterosin C as the active prin-
ciple of the topical skin cream Resilience® has done
much to popularise these molecules as synthetic
targets.4–8
7
H
H
H
H
HO
HO
HO
HO
HO
HO
HO
HO
4
1
3
1
2
3
4
c, d
a.
e.
OH
O
O
O
OH
OH
5
OR
OMe
RO
6 R = H
7 R = Me
8
b.
g.
O
MeO
O
EtO
EtO
f.
9 R = H
10 R = Me
O
P
h.
O
O
O
O
Br
O
O
11
12
13
Scheme 1. Reagents and conditions: (a) Ethyl acetoacetate, H2SO4, 0°C, 1 h;10 (b) MeI, K2CO3, acetone, reflux, 18 h, 94%; (c) H2,
Pd–C, EtOAc, rt, 10 h, 98%; (d) DIBAL-H, THF, −78°C, 90 min, 82%; (e) NBS, AIBN, CCl4, reflux, 2 h; (f) P(OEt)3, 100°C,
1 h, 63%; (g) 3 equiv. 13, KOtBu, THF, rt, 1 h, 88%; (h) MeI, K2CO3, acetone, reflux, 18 h, 88%.
Keywords: annulation; cyclisation; lactones; natural products; terpenes and terpenoids.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02207-3

1194
D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 1193–1195
13 next provided g-methylene-g-butyrolactone 9 as a
single geometric isomer, the phenol of which was pro-
tected as its methyl ether to provide our cyclisation
precursor 10 (Scheme 1).
Pleasingly, when 10 was warmed with triflic acid to
79°C for 15 minutes, spirolactone 14 was furnished in
91% yield as a 9:1 mixture of diastereoisomers. Cata-
lytic hydrogenation of the alkene next gave 15 with
complete control at the newly created stereogenic centre
(Fig. 1). With the stereocentres at C-3 and C-7 estab-
lished correctly for the pseudopterosin A–F aglycone 1
we expected to complete that synthesis via hydrogenol-
ysis of the benzyl ether: a reaction known to proceed
with inversion of configuration under neutral condi-
tions.11 However, lactone 15 remained stubbornly intact
even when exposed to a stoichiometric equivalent of
palladium on carbon at 200 atmospheres hydrogen
pressure! By contrast, reduction was readily accom-
plished when conducted in acidified methanol but fur-
nished ester 17 as single diastereoisomer, rather than
the anticipated C-4 epimer. Likewise, treatment of 14
under the aforementioned conditions also provided 17
Figure 1. ORTEP diagram of 15.
Twelve pseudopterosins (A–L) have been identified to
date. These are differentiated by a sugar moiety
attached to the catechol, the point of attachment of
that sugar to the catechol and by stereochemical differ-
ences in the aglycone. Four aglycones have been
reported: pseudopterosin A to F aglycone 1,1 pseu-
dopterosin G to J aglycone 2,2,7 pseudopterosin K and
L aglycone 3,2 and the unnatural diastereoisomer 4
(which until recently was thought to be pseudopterosin
G to J aglycone).2,7,8 In this Letter we report an
approach to a further stereoisomer of pseudopterosin in
which the hydrogen at C-4 and the methyl groups at
C-3 and C-7 are axially disposed.9 The key-step
involves is an arene alkylation with a g-methylene-g-
butyrolactone which proceeds with remarkable
diastereoselectivity.
in
a near quantitative yield, again as a single
diastereoisomer (Scheme 2). The relative stereochem-
istry was confirmed by cyclisation to hexahydro-
phenalene 18, an X-ray crystal structure of which
revealed that the C-4 hydrogen and the C-3 and C-7
methyl groups each adopt an axial orientation (Fig. 2).
The reduction of 14 and 15 was then examined in more
detail in order to determine the sequence of events
leading to 17. Interestingly, when 15 was stirred in
methanol containing a trace of dilute hydrochloric acid
it was smoothly transformed into alkene 16 in near
quantitative yield. Hydrogenation of 16 could then be
effected at ambient temperature and pressure under
neutral conditions giving 17 in 99% yield as a single
diastereoisomer. These results suggest that steric
encumbrance prevents direct hydrogenolysis of 15 and
that the stereochemical course of the reaction is dic-
tated by the axial C-7 methyl group.
Our approach began with
a Pechmann reaction
between 3-methylcatechol 5 and ethyl acetoacetate to
give coumarin 6.10 The phenol was then protected as its
methyl ether 7 and the alkene and carbonyl moieties
were reduced to give lactol 8. Union with phosphonate
9:1
MeO
MeO
MeO
MeO
MeO
a.
b.
c.
O
O
O
MeO
O
O
O
10
14
15
d.
H
H
MeO
MeO
MeO
MeO
MeO
MeO
e.
CO2Me
CO2Me
O
16
17
18
Scheme 2. Reagents and conditions: (a) CF3SO3H, 79°C, 15 min, 91%; (b) H2, Pd–C, EtOAc, rt, 3 h, 99%; (c) H2, Pd–C, MeOH,
cat. 2 M HClaq., 16 h, rt, 94%; (d) H2, Pd–C, MeOH, cat. 2 M HClaq., 16 h, rt, 89%; (e) CF3SO3H, 85°C, 10 min, 90%.

D. C. Harrow6en et al. / Tetrahedron Letters 42 (2001) 1193–1195
1195
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In conclusion, we have developed a short and practical
route to the tricyclic core of an unnatural pseu-
dopterosin diastereoisomer. Key features of our
approach are an arene alkylation with a g-methylene-g-
butyrolactone, viz. 10“14, and an elaborate reduction
sequence 14“17; both processes proceeding with
remarkable diastereoselectivity. We are presently seek-
ing a method to effect the hydrogenolysis of 14 with
inversion at the C-4 stereogenic centre as this would
provide a route to the pseudopterosin A–F aglycone 1.
7. Lazerwith, S. E.; Johnson, T. W.; Corey, E. J. Org. Lett.
Acknowledgements
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8. LeBrazidec, J. Y.; Kocienski, P. J.; Connolly, J. D.;
Muir, K. W. J. Chem. Soc., Perkin Trans. 1 1998, 2475.
9. We have used pseudopterosin numbering to describe
stereogenic centres.
The authors thank EPSRC for a Project Studentship
and a Quota Studentship (to J.D.W. and M.J.T.,
respectively).
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