Substituent effects in the transannular cyclizations of germacranes. Synthesis of 6-epi-costunolide and five natural steiractinolides

Article abstract of DOI:10.1016/j.tet.2008.09.017

The occurrence and orientation of substituents in the 10-membered ring characteristic of germacranes is determinant in the stereochemical outcome of the acid-promoted transannular cyclization of these metabolites. An explanation of the synthesis of eudesm

Full text of DOI:10.1016/j.tet.2008.09.017

Tetrahedron 64 (2008) 10896–10905
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Substituent effects in the transannular cyclizations of germacranes. Synthesis
of 6-epi-costunolide and five natural steiractinolides
´
Redouan Azarken, Francisco M. Guerra, F. Javier Moreno-Dorado, Zacarıas D. Jorge,
Guillermo M. Massanet
*
´
´
´
´
´
´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Cadiz, Polıgono Rıo San Pedro s/n, 11510 Puerto Real, Cadiz, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2008
Received in revised form 30 August 2008
Accepted 1 September 2008
Available online 17 September 2008
The occurrence and orientation of substituents in the 10-membered ring characteristic of germacranes is
determinant in the stereochemical outcome of the acid-promoted transannular cyclization of these
metabolites. An explanation of the synthesis of eudesmanolides and guaianolides produced by the
Umbelliferae family of plants is advanced. The syntheses of the natural products 6-epi-costunolide and
five steiractinolides are reported.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
Sesquiterpenolides produced by Umbelliferae plants present
a stereochemical pattern different to that found in Compositae
Sesquiterpenolides are metabolites produced mainly by the
Compositae (Asteraceae) family of plants although some of them
originate in other Angiosperm families as Umbelliferae (Apiaceae),
Magnoliaceae, and even in fungi.1
plants. This particularity was reported by Holub and Budesinsky,
who corrected the structures of more than 90 sesquiterpenolides
produced by umbelliferous plants based on their spectroscopic
data.9
A great majority of sesquiterpenolides can be classified into four
major groups according to their carbocyclic skeleton: germacra-
nolides (10-membered ring), eudesmanolides (6,6-bicyclic com-
pounds), guaianolides (5,7-bicyclic compounds), and elemanolides
(six-membered ring).2
Some sesquiterpenolides display interesting biological proper-
ties. For instance, thapsigargin is a guaianolide, which has become
an important tool in the study of the mechanism of intracellular
calcium signaling.3 It presents a remarkable selectivity for the
SERCA pumps involved in the active transport of calcium ions to the
intracellular stores that has made of it a widely used SERCA in-
hibitor. In addition, thapsigargin has been appointed as a possible
therapeutic agent against prostate cancer, given its ability to induce
apoptosis in prostate cancer cells.4 This molecule has been targeted
by the Ley group, which recently published its first and only total
synthesis.5 We have also reported a synthetic approach to 11,13-
dihydroxyguaianolides closely related to thapsigargin.6
Three main features are displayed by the majority of these
compounds: (i) a hydroxyl or acyloxy group
a to the carbonyl of the
lactone instead of the typical exo-methylene system, (ii) a cis-b,b
lactone fusion, epimer at C-6 to most natural sesquiterpenolides,
and (iii) an A/B ring junction different to that found in sesquiter-
penes from Compositae plants.
Holub and Budesinsky proposed that these features can be
explained by admitting that the enzymatic pool of the Umbelliferae
and Compositae plants cyclize the trans,trans-farnesyl diphosphate
in different conformations (Scheme 1).10
Umbelliferae
Compositae
PPO
OPP
This interesting metabolite is produced by plants of the genus
Thapsia,7 which belongs to the Umbelliferae family of plants. This
botanic family encompasses about 3000 species of plants
distributed along 300 genera.8
O
O
OR
O
O
* Corresponding author. Tel.: þ34 956 016366; fax: þ34 956 016393.
E-mail address: g.martinez@uca.es (G.M. Massanet).
Scheme 1. Holub’s proposed conformation of trans,trans-farnesyl diphosphate in
Compositae and Umbelliferae plants.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.017

R. Azarken et al. / Tetrahedron 64 (2008) 10896–10905
10897
Nevertheless, since several Umbelliferae-type sesquiter-
penes have also been isolated from some Compositae plants,
an alternative hypothesis can be advanced to explain the dif-
ferences in the stereochemistry (Fig. 1). Starting from the ac-
cepted conformation of the trans,trans-farnesyl diphosphate
(structure I, Scheme 2), sesquiterpenolides from Umbelliferae
can be formed through a different sequence of events follow-
ing the formation of the germacrane intermediate (structure II,
Scheme 2). A different orientation of the oxidation step, in which
PPO
I
II
route b
route a
H
a b-oriented hydroxyl group is set (structure VI, Scheme 2), would
oxidation at C-6
lead to a conformational equilibrium, the conformation with both
methyl groups down prevailing (structure VII, Scheme 2). Further
cyclization of the cyclodecadiene ring would lead to generic
structure IX (Scheme 2) typical of umbelliferous plants.
In this paper, we will demonstrate that the obscure role of the
enzymes that catalyze the biogenesis of sesquiterpenolides in
Umbelliferae plants can be explained in terms of stability of the
different conformers of the germacradiene precursor. The main
OH
6
6
H
HO
VI UU-conformation
conformational
equilibrium
III
idea is that it is possible to transform
a dominant UU-conformation11 (a germacrane from Compositae)
into DD-conformation germacrane (a germacrane from
Umbelliferae) just by installing a -oriented hydroxyl group at
a germacrane in
HO
H
O
VII DD-conformation
a
IV
O
b
carbon C-6 (Scheme 2, route b). This would cause such a steric
hindrance in the UU-conformation so as to induce the flipping to
a DD-conformation.
OR
O
O
H
VIII
The cyclization of this DD-conformer would lead to eudes-
manolides or guaianolides with the stereochemistry typical of
Umbelliferae. The basis of our expectations regarding this
conformational equilibrium is depicted in Scheme 3.
The confirmation of this hypothesis would not only explain
the biogenetic origin of these metabolites but more importantly,
O
OR
V
O
Compositae
O
O
IX
H
Umbelliferae
Scheme 2. Alternative explanation to the biosynthesis of sesquiterpenolides from
Compositae and Umbelliferae plants.
would open up
thapsigargin.
a synthetic route to compounds such as
2. Results and discussion
Compositae
Umbelliferae
Commercial germacranolides are scarce but fortunately, costu-
nolide 1, a germacranolide available from the roots of Saussurea
lappa, seemed a suitable substrate to be transformed into a
1
R
R
10
14
OR'
11
O
6
6b-hydroxygermacrane (Scheme 4). When it comes to germa-
13
cranes, two important problems must be addressed. First, these
metabolites are very prone to cyclize under acidic conditions, so
acid medium should carefully be avoided. Second, the flexibility of
the 10-membered ring is very often manifested as broad signals in
the 1H NMR spectrum and duplicated signals in the 13C NMR,
complicating the interpretation of the data.
The synthetic sequence commenced with the reduction of the
lactone ring present in costunolide 1 (Scheme 4). Direct reduction
with lithium aluminum hydride led to a complex mixture.
This transformation had to be carried out in two steps. A first
reduction with DIBAL produced a mixture of lactols 2 in 76% yield,
which displayed a complex 1H NMR spectrum, and that was sub-
mitted directly to a subsequent reduction with sodium borohy-
dride, affording diol 3 in 82% yield.12 The next step consisted in the
selective protection of the primary alcohol as a tert-butyldime-
thylsilyl ether by treatment of 3 with TBDMSCl and triethylamine,
yielding 4 in 83% yield.
Inversion of the configuration of carbon C-6 proved to be very
troublesome. Some Mitsunobu procedures were assayed, with
negative results. We opted then for an oxidation–reduction se-
quence. Nevertheless, the oxidation of alcohol 4 to germacranone 5
also resulted to be very difficult as the treatment under most
common oxidative conditions only led to complex mixtures. After
exhaustive experimentation, finally Dess–Martin periodinane
afforded germacranone 5 in good yield (80%).13 The acetic acid
O
O
O
15
12
O
(a) germacranolides
R
R'
R'
R'
A
B
OR''
H
H
O
O
O
(b) eudesmanolides
10
H
H
H
R'
R'
OR''
R
R
1
B
A
6
H
O
O
(c) guaianolides
R'
O
O
R
R'
R'
OR'
H
H
O
O
O
O
(d) elemanolides
Figure 1. Main differences between sesquiterpenolides from Compositae and
Umbelliferae plants.

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R. Azarken et al. / Tetrahedron 64 (2008) 10896–10905
H
O
O
HO
X
OH
OH
X
X
OH
H
HO
O
H
O
H
O
O
X = CH2 (costunolide) or
βH, αMe (11,13- dihydrocostunolide)
HO
H
O
O
Scheme 3. Retrosynthetic analysis of Umbelliferae-type eudesmanolides and guaianolides.
produced in this oxidation had to be carefully neutralized
with pyridine to avoid the cyclization to the corresponding
eudesmane.14
The carbonyl group in germacranone 5 could not be reduced
with sodium borohydride, the starting material being recovered
unreacted. The reduction was then carried out with lithium alu-
DD-conformation suggests that its cyclization should lead to
a 10 Me,5 H-eudesmane.
a
b
Effectively, when 8 was submitted to treatment with p-tolue-
nesulfonic acid in dichloromethane, natural steiractinolide16 9 was
isolated in 70% yield together with a minor amount of steir-
actinolide 1017 that could be identified by comparing its 1H and 13
C
minum hydride affording the desired
60% yield.
b
-hydroxygermacrane 6 in
NMR data with those reported in the literature (Scheme 5).17
Compound 9 displayed NOEs showed in Figure 2b, confirming its
At this stage, germacrane 6 already bears the appropriate 6-
structure as
5bH,6aH,7aH,10aMe-eudesman-4,15-en-6,7-olide.
b
-hydroxyl group needed for the conformational change to occur.
Thus, we have proven that the stereochemical course of the hy-
droxylation at C-6, or more appropriately, the conformational lock
To confirm this fact, alcohol 6 was treated with p-toluenesulfonic
acid, giving rise to a complex mixture that displayed in the 1H NMR
spectrum a series of overlapped signals corresponding to a mixture
of furan rings, from which little information could be obtained.
We decided then to continue the sequence in order to transform
6 into 6-epi-costunolide 8, where the cyclization outcome could be
tested again. To this end, alcohol 6 was deprotected with TBAF in
THF at 0 ꢀC, affording diol 7 in nearly quantitative yield. The allylic
hydroxyl group was then oxidized to the corresponding lactone, by
employing MnO2/C, giving rise to 6-epi-costunolide 8 in 90% yield.
Extensive NOE studies of 8 showed that methyls at C-4 and C-10
were below the plane of the molecule (Fig. 2a). This finding is in
accordance with Bohlmann and Zdero earlier observations. These
two authors reported the isolation of 6-epi-costunolide 8 from
Geigeria rigida.15 The occurrence of this germacranolide in a
produced by the fashioning of a
g-lactone ring determines the
conformation of the germacrane and the resultant stereochemistry
of the eudesmane after the cyclization.
Many eudesmanolides from Umbelliferae plants bear a hydroxyl
group at C-1.2 This hydroxyl group can be prepared by in-
corporating an epoxide ring in carbons C-1 and C-10 of the ger-
macradiene precursor. To this end, 6-epi-costunolide 8 was treated
with m-CPBA, giving rise to epoxide 11 that spontaneously opened
when it was submitted to purification by chromatography on silica
gel affording alcohol 12 (64% yield) and minor amounts of the
isomeric alkenes 13 and 14 (Scheme 5). Lactones 12–14 displayed
an
a-oriented angular methyl, and definitively all the stereo-
chemical features found in eudesmanolides from Umbelliferae
plants. Lactones 12–14 have also been isolated from G. rigida.15
NaBH4
MeOH
DIBAL
CH2Cl2
0 °C, 2h
76%
0 °C
O
OH
3
O
82%
OH
O
OH
2
1
TBDMSCl
DMP
LiAlH4
EtO2
-78 °C, 2h
60%
Et3N
CH2Cl2
4 h
CH2Cl2, py
rt, 15 min
80%
OH
O
OTBDMS
OTBDMS
4
5
83%
MnO2
Et2O
rt, 48h
90%
TBAF
THF
0 °C, 15 min
95%
OH
O
O
OH
OTBDMS
OH
6
8
7
Scheme 4. Synthetic approach to 6-epi-costunolide 8.

R. Azarken et al. / Tetrahedron 64 (2008) 10896–10905
10899
H
prepared starting from 11,13-dihydrocostunolide by a similar
sequence to that described for 10. When compound 19 was
submitted to Sharpless allylic epoxidation, the epoxyalcohol 20
was formed in 75% yield. Finally, it was observed that 20, upon
standing in CDCl3, smoothly transformed into a mixture of guaianes
21 and 22 in 60% and 38% yields, respectively (Scheme 7). Never-
theless, the stereochemistry of the ring fusion in both guaianes was
not that found in Umbelliferae guaianes (see Fig. 1), suggesting
a UD-conformation for the parent epoxyalcohol 20. Mono- and
bidimensional low temperature 1H NMR experiments and NOE
study of 20 confirmed effectively the occurrence of two conformers
at room temperature: UD (78% population) and DD (22%
population).
O
H
O
H
O
H
(a)
H
O
H
H
H
H
(b)
Figure 2. Observed NOEs in 6-epi-costunolide 8 (a) and eudesmanolide 9 (b).
p-TsOH
TBHP
+
VO(acac)2
CH2Cl2
rt, 1h
H
CH2Cl2
0 ºC, 1h
75%
H
O
O
O
O
OH
19
OH
8
O
9
10
O
O
OTBDMS
OTBDMS
20
70%
unable to purify
upon standing
on CDCl3
m-CPBA
pyridine
CH2Cl2
OH
OH
O
H
SiO2
H
+
+
H
12
O
O
O
11
HO
H
HO
H
O
13+14
O
O
HO
21
HO
22
64 %
identified as a mixture
OTBDMS
OTBDMS
decomposes on
silica gel
60%
38%
Scheme 7. Sharpless epoxidation of alcohol 19.
Scheme 5. Synthesis of steiractinolides 9 and 10 and 12–14 from 6-epi-costunolide.
In view that the presence of a b-oriented hydroxyl group at C-6
did not exert enough influence as to induce the DD-conformer to be
predominant, we rationalize that the presence of a lactone ring
attached to the cyclodecadiene ring could effectively induce the
change in the conformation. Compound 19 was then deprotected
with TBAF in dichloromethane, affording diol 23 in 92% yield
(Scheme 8).
Epoxidation of 23 with tert-butyl hydroperoxide and VO(acac)2
afforded the epoxydiol 24 (75% yield). The oxidation of the primary
hydroxyl group resulted to be troublesome, leading to a complex
mixture under several conditions. Surprisingly, it was discovered,
that the use of TPAP20 and NMO for 6 h led to melampolide 25 in
which the isomerization of the C-1–C-10 double bond had taken
place. We have found precedents in which Ru(III), produced in the
TPAP catalytic cycle, is able to promote double bonds isomeriza-
tions but not a change in their configuration.21 Treatment of 25
with p-TsOH did not lead to a cyclization product but to the
formation of the allylic alcohol 26. A careful optimization of the
TPAP oxidation conditions of 24, allowed us to prepare epoxy-
lactone 27 only after 2 h of reaction in 76% yield. When 27 was
We wondered next whether it was possible to access to
Umbelliferae-type guaianolides through this method as they share
with eudesmanolides a common biogenetic pathway. The prepa-
ration of guaianolides from 4,5-epoxygermacranes is well docu-
mented.18 The most direct way consists in the epoxidation of the
C-4–C-5 double bond of a germacrane, and further treatment with
acid to promote the cyclization to the guaiane framework.
As suspected, epoxidation of 6 with m-CPBA was far to be
regioselective and a mixture of epoxides 15 (5%), 16 (34%), and 17
(9%) was formed (Scheme 6). The allylic epoxidation with tert-butyl
hydroperoxide and VO(acac)2 did not show regioselection either
and both C-4–C-5 and C-11–C-13 double bonds were simulta-
neously epoxidated, affording 15 and 18 in 9% and 88% yields,
respectively.19
We realize that the selective epoxidation of the C-4–C-5
double bond in the presence of an additional C-11–C-13 double
bond would be very difficult in compound 6, so we decided as
an alternative to employ its congener 19 where the exo-meth-
ylene group was reduced to a methyl group. This compound was
O
O
m-CPBA
+
+
O
15
O
CH2Cl2, py
O
16
OH
OH
OH
OH
OTBDMS
OTBDMS
OTBDMS
OTBDMS
17
rt, 3h
6
5 %
9 %
34 %
TBHP
VO(acac)2
CH2Cl2
O
+
O
O
OH
OH
OTBDMS
OTBDMS
15
18
9%
88%
Scheme 6. Epoxidation of alcohol 6.

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R. Azarken et al. / Tetrahedron 64 (2008) 10896–10905
TBHP
purification by flash chromatography (1:4 EtOAc/hexanes) the in-
separable mixture of anomeric lactols 2 (386 mg, 76%) was
VO(acac)2
obtained.
CH2Cl2
0 ºC, 1h
75%
O
OH
OH
24
OR
OH
3.2. Lactols 2 (as a mixture of anomers)
TBAF
19 R = OTBDMS
23 R = H
TPAP
CH2Cl2
rt, 6 h
70%
NMO
Yellow oil; 1H NMR (400 MHz, CDCl3)
d 5.72 (1H, s, H-12, major
CH2Cl2
4A ms
0 ºC
15 min
isom.), 5.52 (1H, s, H-12, minor isom.), 5.32 (1H, dd, J¼3.1, 1.2 Hz, H-
13, major isom.), 5.25 (1H, dd, J¼3.2, 1.2 Hz, H-13, minor isom.), 5.11
(1H, br s, H-130, major isom.), 5.04 (1H, br s, H-130, minor isom.),
4.78 (1H, m, H-1), 4.66 (1H, d, J¼10.4 Hz, H-5), 4.36 (1H, dd,
J¼9.2 Hz, H-6, major isom.), 4.09 (1H, dd, J¼7.1 Hz, H-6, minor
isom.), 1.66 (3H, s, 3H-15), 1.36 (3H, s, 3H-14); 13C NMR (CDCl3,
100 MHz): 155.2, 136.7, 131.4, 130.6, 126.9, 126.7, 108.1, 106.9, 98.8,
97.8, 81.1, 79.7, 53.2, 50.6, 41.6, 41.5, 39.7, 39.6, 27.5, 26.7, 26.6, 17.1,
17.0, 16.1; IR nmax (cmꢂ1): 3403, 2927, 1763, 1642, 1219, 1011, 898,
754; EM m/z (rel int.): 234 (8), 217 (12), 213 (26), 207 (28), 185 (30),
175 (31), 161 (62), 159 (78), 83 (100).
92%
p-TsOH
CH2Cl2
rt, 12 h
35%
O
25
HO
O
O
26
O
O
Scheme 8. Synthesis of melampolide 26.
treated with p-TsOH in dichloromethane, guaianolides 28 and 29
were formed in 30% and 60% yields, respectively (Scheme 9). The
Umbelliferae stereochemistry of 28 and 29 was confirmed by NOE
studies. Closely related guaianolides have been isolated from Ferula
oopoda22 and Ferula koso-poljanskyi23 (Umbelliferae).
3.3. Reduction of lactol 2 with sodium borohydride
A solution of the mixture of lactols 2 (158 mg, 0.68 mmol) in
methanol (5 mL) was cooled to 0 ꢀC and treated with NaBH4
(25.5 mg, 0.68 mmol). The mixture was stirred for 3 h, after which
time brine (10 mL) was added. Methanol was reduced to a half of
the volume under vacuum. The remaining aqueous solution was
extracted with EtOAc (3ꢁ25 mL) and the organic layer was dried
over anhydrous sodium sulfate. Removal of the solvent and puri-
fication by column chromatography (3:7 EtOAc/hexanes) led to diol
3 (131 mg, 82%) as a colorless oil.
TPAP
NMO
CH2Cl2
4A ms
rt, 2 h
76%
O
O
OH
24
O
OH
27
O
p-TsOH
CH2Cl2
rt, 1h
3.4. Diol 3
H
H
20
þ109.4 (c 1.6, CHCl3); 1H NMR (400 MHz,
+
Colorless oil; [
C6D6)
a
]
D
d
5.19 (1H, s, H-13), 4.95 (1H, s, H-130), 4.68 (1H, br d,
H
HO
HO
O
O
J¼10.4 Hz, H-1), 4.61 (1H, br d, 10.0 Hz, H-5), 4.13 (3H, m, H-6, 2H-
12), 2.17 (1H, m, H-7), 2.10–1.77 (7H, m, 2H-3, 2H-2, 2H-9, H-8 ),
1.55 (1H, m, H-8
), 1.48 (3H, s, 3H-15), 1.24 (3H, s, 3H-14); 13C NMR
28
29
a
O
O
30%
60%
b
(C6D6, 100 MHz): 153.8, 137.7, 134.0, 133.4, 126.9, 111.8, 71.5, 65.1,
55.6, 41.8, 39.7, 32.5, 26.1, 16.8, 16.3; IR nmax (cmꢂ1): 3370, 2929,
2858, 1646, 1439, 1383, 1014, 899; EM m/z (rel int.): 236 (1), 218 (9),
203 (10), 185 (11), 149 (29), 121 (47), 107 (78), 93 (82), 84 (98), 81
(100).
Scheme 9. Synthesis of guaianolides 28 and 29.
The syntheses of 9, 10, 12–14, 28, and 29 demonstrate that
conformational changes in the structure of germacranolides can be
induced by setting an oxygenated functionality at carbon C-6 with
the appropriate orientation. In some cases, the presence of a hy-
droxyl group is not enough to lock the cyclodecadiene ring in the
3.5. Protection of diol 3 with tert-butyldimethylsilyl chloride
DD-conformation and it is necessary to set a g-lactone ring, which
provides more important steric constraints, obliging the confor-
mational flipping to occur. Finally, the methodology described
herein seems suitable for the preparation of eudesmanolides and
guaianolides from umbelliferous plants. Promising results have
been obtained by using cnicin, an easily available 8-acyloxy-
germacranolide, as starting material en route to thapsigargin. Re-
sults of these efforts will be reported in due course.
A solution of compound 3 (972 mg, 4.12 mmol), catalytic DMAP
(50 mg, 041 mmol), and Et3N (1 mL) in dry dichloromethane
(20 mL) was cooled to 0 ꢀC and TBDMSCl (1 M in dichloromethane,
4.6 mL, 4.6 mmol). The mixture was stirred for 4 h, after which time
brine (20 mL) was added. The aqueous layer was extracted with
dichloromethane (3ꢁ25 mL) and the resulting organic layer was
dried over anhydrous sodium sulfate. After removal of solvent, the
resulting crude mixture was purified by column chromatography
(1:9 EtOAc/hexanes), affording pure 4 (1196 mg, 83%).
3. Experimental part
3.1. Reduction of costunolide 1 with DIBAL
3.6. Alcohol 4
20
Costunolide
1
(500 mg, 2.16 mmol) was dissolved in dry
Colorless oil; [
CDCl3) d
a]
þ43.3 (c 0.6, CHCl3); 1H NMR (400 MHz,
D
dichloromethane (25 mL) under argon atmosphere and a 1.5 M
solution of DIBAL (1.6 mL, 2.4 mmol) was added at 0 ꢀC. The re-
action mixture was stirred for 2 h, after which time aqueous satu-
rated NH4Cl (25 mL) was added. The crude mixture was filtered off
through a Celite path and then extracted with dichloromethane
(3ꢁ25 mL). The organic layers were washed with brine (25 mL) and
dried over sodium sulfate. After removal of the solvent and
5.15 (1H, s, H-13), 4.99 (1H, s, H-130), 4.79 (1H, br d,
J¼10.0 Hz, H-1), 4.63 (1H, br d, J¼9.2 Hz, H-5), 4.12 (3H, m, H-6, 2H-
12), 2.33 (1H, m, H-7), 2.28–1.83 (7H, m, 2H-3, 2H-2, 2H-9, H-8 ),
), 1.64 (3H, s, 3H-15), 1.40 (3H, s, 3H-14), 0.92 (9H,
a
1.67 (1H, m, H-8
b
s, –OSitBuMe2), 0.10 (6H, s, –OSitBuMe2); 13C NMR (CDCl3,
100 MHz): 152.0, 137.6, 134.2, 132.9, 126.9, 112.3, 70.6, 65.3, 55.8,
41.7, 39.5, 32.0, 25.9, 25.8, 18.3, 16.9, 16.3, ꢂ5.5; IR nmax (cmꢂ1):

R. Azarken et al. / Tetrahedron 64 (2008) 10896–10905
10901
3461, 2927, 1458, 1253, 1105, 1005, 835, 776; MS (CI) m/z (rel int.):
350 (13), 293 (4), 275 (5), 218 (12), 201 (32), 159 (46), 145 (83), 119
(55), 105 (82), 81 (78), 75 (100); HRMS (CI) calcd for C21H39O2Si
351.2719, found 351.2722.
organic layers were combined and dried over anhydrous sodium
sulfate and the solvent was removed under vacuum. Purification by
column chromatography (3:7 EtOAc/hexanes) afforded diol 7
(60 mg, 0.25 mmol, 95%).
3.7. Oxidation of 4 with Dess–Martin periodinane
3.12. Diol 7
A solution of alcohol 4 (100 mg, 0.29 mmol) and pyridine (10
mL)
Colorless oil; 1H NMR (400 MHz, CDCl3)
d 5.12 (1H, br s, H-5),
in dichloromethane (5 mL) was treated at room temperature with
DMP (243 mg, 0.572 mmol). After stirring for 15 min, aqueous
saturated NaHCO3 (5 mL) was added and the resulting aqueous
layer was extracted with dichloromethane (3ꢁ25 mL). Drying over
sodium sulfate and removal of the solvent under vacuum, afforded
pure germacranone 5 (80 mg, 0.23 mmol, 80%).
5.06 (1H, br s, H-13), 4.97 (3H, m, H-1, H-5, H-13), 4.41 (1H, d,
J¼7.3 Hz, 1H, H-6), 4.20 (1H, br d, J¼12.9 Hz, H-12), 4.08 (1H, d,
J¼12.8 Hz, H-120), 2.68 (1H, m, H-2
a), 2.36 (1H, m, H-3a), 2.12–1.82
(4H, m, H-30,H-9, H-90, H-20), 1.64 (1H, m, H-7), 1.56 (3H, s, 3H-15),
1.49 (3H, s, 3H-14), 1.30 (1H, m, H-8
b
), 0.90 (1H, ddd, J¼14.8, 7.4,
7.3 Hz, H-8
a
); 13C NMR (100 MHz, CDCl3)
d
129.9, 121.6, 114.7, 113.8,
71.3, 71.1, 64.9, 52.3, 51.6, 49.4, 44.3, 40.6, 38.9, 36.9, 33.4, 29.7, 28.3,
26.7, 24.1, 20.5, 19.9, 16.6; IR nmax (cmꢂ1): 3305, 2924, 2853, 1449,
1383, 1087, 1030, 908, 848; MS (CI) m/z (rel int.) 237 [Mþ1]þ (14.6),
219 (100), 189 (22), 175 (20), 163 (39), 121 (60), 95 (47), 80 (37);
HRMS (CI): calcd for C15H25O2[Mþ1]þ 237.1854, found 237.1852.
3.8. Germacranone 5
Colorless oil; 1H NMR (400 MHz, CDCl3)
d 5.55 (1H, s, H-5), 5.34
(1H, dd, J¼1.4 Hz, H-13), 5.18 (1H, s, H-130), 4.64 (1H, dd, J¼10.1,
4.7 Hz, H-1), 4.43 (1H, d, J¼13.6 Hz, H-12), 4.20 (1H, d, J¼13.6 Hz, H-
120), 1.4 (3H, s, 3H-15), 1.08 (3H, s, 3H-14), 0.99 (9H, s, –OSitBuMe2),
0.28 (6H, s, –OSitBuMe2), 0.10 (s, 3H, –OSitBuMe2); 13C NMR
3.13. Oxidation of diol 7 with manganese dioxide
(100 MHz, CDCl3)
d
200.3, 150.0, 149.6, 140.3, 133.5, 125.9, 110.3,
Diol 7 (40 mg, 0.17 mmol) was dissolved in diethyl ether (10 mL)
and MnO2/C24 (148 mg, 1.71 mmol) was added. The mixture was
stirred for 48 h, after which time it was filtered off through a Celite
path, giving a crude mixture. Purification by HPLC (1:9, EtOAc/
hexanes) afforded 6-epi-costunolide 8 (35.5 mg, 0.153 mmol, 90%).
66.1, 57.7, 42.0, 41.1, 32.4, 30.0, 25.9, 19.1, 14.8, 1.8, ꢂ5.4; IR nmax
(cmꢂ1): 2954, 2928, 2856, 1677, 1604, 1461, 1256, 1096, 835, 800;
MS (CI) m/z (rel int.): 349 [Mþ1]þ (31), 331 (22), 217 (42), 211 (12),
199 (100), 143 (18.2), 80 (28.0); HRMS (CI) calcd for C21H37O2Si
[Mþ1]þ 349.2562, found 349.2557.
3.14. 6-epi-Costunolide 8
3.9. Reduction of germacranone 5 with LiAlH4
Colorless oil; 1H NMR (400 MHz, CDCl3)
d
6.24 (1H, d, J¼2.8 Hz,
A suspension of LiAlH4 (4.6 mg, 12 mmol) in diethyl ether (5 mL)
was cooled to ꢂ78 ꢀC and a solution of germacranone 5 (35 mg,
0.10 mmol) in diethyl ether (5 mL) was added. The mixture was
stirred at ꢂ78 ꢀC for 2 h, after which time aqueous saturated am-
monium chloride (5 mL) was added. The aqueous layer was
extracted with diethyl ether (3ꢁ25 mL) and the organic layer was
washed with brine (25 mL). Drying with anhydrous sodium sulfate
and removal of the solvent afforded a crude mixture, which was
purified by column chromatography (1:9 EtOAc/hexanes), affording
pure 6 (21 mg, 0.060 mmol, 60%).
H-13a), 5.61 (1H, d, J¼2.8 Hz, H-13b), 5.20 (1H, dd, J¼10.4, 6.8 Hz,
H-6), 4.96 (1H, dd, J¼8.8 Hz, H-1), 4.87 (1H, d, J¼10.4 Hz, H-5), 3.08
(1H, dd, J¼8.4 Hz, H-7), 2.54 (1H, dt, J¼13.6 Hz, H-9), 2.28 (1H, dt,
J¼14.8, 3.6 Hz, H-3
ddd, J¼13.2, 8.8, 3.2 Hz, H-8
), 1.70 (3H, s, H-15), 1.45 (3H, s, 3H, H-14); 13C NMR (100 MHz,
a), 2.21–2.18 (4H, m, H-9, H-3b, 2H-2), 2.16 (1H,
b), 1.90 (1H, ddd, J¼13.2, 8.8, 4.4 Hz, H-
8a
CDCl3)
d 164.1, 141.6, 138.6, 137.3, 126.7, 124.4, 122.9, 77.2, 44.3, 40.1,
37.5, 34.7, 25.5, 21.0, 17.9; IR nmax (cmꢂ1): 2920, 2850, 1764, 1450,
1409, 1260, 1060, 800; MS (CI) m/z (rel int.): 233 [Mþ1]þ (79), 213
(15), 189 (17), 187 (100), 121 (36), 109 (37), 95 (59), 80(80); HRMS
(CI): calcd for C15H21O2 [Mþ1]þ 233.1541, found 233.1537.
3.10. Alcohol 6
3.15. Cyclization of 6-epi-costunolide 8 with p-TsOH
Colorless oil; 1H NMR (400 MHz, CDCl3)
d 5.14 (1H, br s, H-5),
5.11 (1H, br s, H-13), 5.05 (1H, br s, 1H, H-13), 4.97 (3H, m, H-1, H-5,
6-epi-Costunolide 8 (20 mg, 0.086 mmol) was dissolved in
dichloromethane (2 mL) and p-TsOH (1 mg) was added. The re-
action mixture was stirred for 1 h. Aqueous saturated sodium bi-
carbonate (5 mL) was added and the aqueous layer was extracted
with brine (3ꢁ5 mL). The organic layer was dried over anhydrous
sodium sulfate and the solvent was removed under vacuum. Puri-
fication by column chromatography (1:19 EtOAc/hexanes) afforded
eudesmanolide 9 (14 mg, 0.06 mmol, 70%) and a minor amount of
impure eudesmanolide 10 that was identified by comparison of the
1H NMR spectrum with reported data.
H-13), 4.36 (1H, br s, H-6), 4.24 (1H, br d, J¼12.4 Hz, H-12), 4.07 (1H,
d, J¼12.4 Hz, H-120), 2.35 (1H, m, H-2
a), 2.30 (1H, m, H-3a), 2.17
(1H, m, H-3
b
), 1.96–2.14 (3H, m, H-7, H-9
b
, H-2
), 1.56 (3H, s, 3H-15),
), 0.91 (9H, s, –OSitBuMe2), 0.11
a), 1.90 (1H, dd,
J¼12.7 Hz, H-8
a
), 1.78 (1H, dd, J¼12.6 Hz, H-9
a
1.50 (3H, s, 3H-14), 1.41 (1H, m, H-8
b
(3H, s, –OSitBuMe2), 0.10 (3H, s, –OSitBuMe2); 13C NMR (CDCl3,
100 MHz, conformers mixture): 132.3, 130.1, 129.1, 121.6, 114.4,
113.3, 72.4, 70.6, 66.9, 65.6, 51.4, 49.3, 40.7, 39.0, 37.0, 33.6, 29.7,
28.3, 25.9, 24.4, 24.1, 16.8, 16.6, ꢂ5.3, ꢂ5.4; IR nmax (cmꢂ1): 3472,
2923, 2852, 1463, 1260, 1091, 801; MS (CI) m/z (rel int.): 350 (0.1),
293 (3), 267 (4), 237 (5), 219 (4), 221 (12), 159 (22), 145 (46), 119
(32), 105 (46), 93 (54), 75 (100); HRMS (CI) calcd for C21H39O2Si
[Mþ1]þ 351.2719, found 351.2711.
3.16. Eudesmanolide 9
Colorless oil; 1H NMR (400 MHz, CDCl3)
d
6.28 (1H, d, J¼3.6 Hz,
H-13a), 5.51 (1H, d, J¼3.3 Hz, H-13b), 4.4 (1H, d, J¼1.28 Hz, H-15a),
3.11. Deprotection of 6 with TBAF
4.80 (1H, dd, J¼7.8, 10.5 Hz, H-6), 4.78 (1H, d, J¼1.28 Hz, H-15b),
3.28 (1H, m, H-7), 2.33 (1H, dddd, J¼13.2, 5.7, 3.9, 1.8 Hz, H-3
b
),
), 1.65 (1H, d, J¼10.7 Hz,
H-5), 1.61–1.55 (2H, m, 2H-2), 1.40 (1H, dddd, J¼13.3, 6.5, 3.2,
1.7 Hz, H-1 ), 1.32–1.27 (2H, m, 2H-9), 1.24 (1H, m, H-1 ), 0.77 (3H,
s, Me-14); 13C NMR (100 MHz, CDCl3)
170.4 (C-12), 144.3 (C-4),
A solution of alcohol 6 (95 mg, 0.27 mmol) in THF (15 mL) was
treated with TBAF (1 M in THF, 0.5 mL) at 0 ꢀC. After stirring for
15 min, aqueous saturated ammonium chloride (20 mL) was added.
The aqueous layer was extracted with EtOAc (3ꢁ10 mL). The
2.84–1.97 (2H, m, 2H-8), 1.87 (1H, m, H-3a
a
b
d

10902
R. Azarken et al. / Tetrahedron 64 (2008) 10896–10905
137.5 (C-11), 119.3 (C-13), 108.4 (C-15), 76.3 (C-6), 52.8 (C-5), 41.3
(C-1), 39.4 (C-7), 36.2 (C-10),35.9 (C-3), 34.7 (C-9), 23.1 (C-2), 19.8
(C-8), 16.3 (C-14); IR nmax (cmꢂ1): 2930, 2853, 1773, 1458, 1256,
1126, 1005, 965, 892; MS (CI) m/z (rel int.) 233 [Mþ1]þ (100), 213
(6.5), 189 (16.0), 187 (75.2), 121 (11.6), 109 (13.8), 95 (31.8), 80
(38.9); HRMS (CI): calcd for C15H21O2 [Mþ1]þ 233.1541, found
233.1537.
73.7, 67.7, 65.4, 59.6, 46.2, 37.2, 36.6, 31.8, 31.7, 29.6, 25.8, 18.3, 16.5,
ꢂ5.3; IR nmax (cmꢂ1): 3440, 2953, 2928, 2856, 1463, 1387, 1253, 1098,
837, 779; MS (CI) m/z (rel int.) 367 [Mþ1]þ (11), 349 (43), 331 (18), 309
(8), 291 (14), 275(7), 251 (9), 235 (34), 217 (100),199(74),189(30),175
(26),159 (66),145 (26),133 (43),121 (27),109 (38), 95 (50); HRMS (CI):
calcd for C15H39O3Si [Mþ1]þ 367.2668, found 367.2657.
3.21. Diepoxide 16
3.17. Epoxidation of 6-epi-costunolide 8 with m-CPBA
Colorless oil; 1H NMR (400 MHz, CDCl3)
d
5.03 (1H, d, J¼1.1 Hz,
A solution of 6-epi-costunolide 8 (30 mg, 0.12 mmol) and pyri-
dine (0.5 mL) in dichloromethane (5 mL) was treated with m-CPBA
at room temperature. The reaction mixture was stirred for 3 h, after
which time it was diluted with dichloromethane (25 mL). The or-
ganic layer was washed with aqueous saturated sodium sulfite and
then with brine. The organic layer was dried over anhydrous so-
dium sulfate and the solvent was removed under vacuum, giving
rise to impure epoxide 11 (as shown by the 1H NMR analysis of the
crude mixture). Flash chromatography of the crude mixture gave
rise to a mixture of steiractinolides 12–14 that was submitted to
HPLC chromatography affording 12 (19 mg, 0.076 mmol, 64%).
Steiractinolides 13 and 14 could not be purified and they have been
identified in the mixtures by comparison with the spectroscopic
reported data.
H-13a), 4.94 (1H, br s, H-13b), 4.22 (1H, dd, J¼12.5, 1.0 Hz, H-12a),
4.02 (1H, dd, J¼12.5, 1.0 Hz, H-12b), 3.47 (1H, d, J¼8.1 Hz, H-6), 3.05
(1H, dd, J¼9.0, 5.7 Hz, H-1), 2.85 (1H, d, J¼8.4 Hz, H-5), 2.28 (1H, m,
H-2
(1H, m, H-3), 2.07 (1H, m, H-8
), 1.40 (3H, s, H-15), 1.33 (3H, s, H-14), 1.23 (1H, m, H-30), 1.03 (1H,
dd, J¼13.0 Hz, H-9
), 0.89 (9H, s, –OSitBuMe2), 0.08 (3H, s, –OSit-
BuMe2), 0.09 (3H, s, –OSitBuMe2); 13C NMR (100 MHz, CDCl3)
150.4, 114.5, 72.4, 67.2, 65.0, 60.3, 59.9, 58.9, 48.6, 39.7, 34.3, 25.8,
a
), 2.27 (1H, br s, H-7), 2.19 (1H, dd, J¼13.4, 7.0 Hz, H-9
a
), 2.14
b), 1.60 (1H, m, H-8a), 1.52 (1H, m, H-
2b
b
d
24.6, 21.8, 18.3, 16.9, 16.6, ꢂ5.2; IR nmax (cmꢂ1): 3437, 2955, 2928,
2856, 1462, 1389, 1253, 1068, 836, 777; MS (CI) m/z (rel int.) 383
[Mþ1]þ (4), 365 (21), 349 (10), 307 (6), 251 (30), 233 (100), 215 (68),
205 (74), 187 (28), 175 (46), 161 (32), 145 (35), 133 (66), 115 (73), 109
(70), 95 (62); HRMS (CI): calcd for C15H39O4Si [Mþ1]þ 383.2676,
found 383.2613.
3.18. Steiractinolide 12
3.22. Diepoxide 17
Colorless oil; 1H NMR (400 MHz, CDCl3)
d
6.28 (1H, dd, J¼3.4,
0.5 Hz, H-13a), 5.54 (1H, d, J¼3.1 Hz, H-13b), 5.35 (1H, m, H-3),
1H NMR (400 MHz, CDCl3)
d 5.13 (1H, s, H-13a), 5.00 (1H, s, H-
4.65 (1H, dd, J¼10.3, 7.5 Hz, H-6), 3.50 (1H, dd, J¼9.6, 6.5 Hz, H-1),
13b), 4.25 (1H, d, J¼12.2 Hz, H-12a), 4.05 (1H, d, J¼12.2 Hz, H-12b),
3.52 (1 Hz, dd, J¼7.0, 1.2 Hz, H-6), 3.03 (1H, d, J¼7.1 Hz, H-5), 3.00
(1H, br d, J¼10.7 Hz, H-1), 2.49 (1H, d, J¼8.3 Hz, H-7), 2.20 (1H, ddd,
´
3.27 (1H, m, H-7), 2.30 (1H, m, H-2), 2.02 (3H, m, H-2, 2H-8), 1.86–
1.83 (4H, m, H-5, 3H-15), 1.76 (1H, dt, J¼13.1, 4.6 Hz, H-9
(1H, m, H-9
), 0.82 (3H, s, H-14); 13C NMR (100 MHz, CDCl3)
172.8 (C-12), 135.4 (C-11), 125.0 (C-4), 121.2 (C-3), 119.3 (C-13),
a), 1.26
b
J¼13.3, 9.5, 3.1 Hz, H-2
2.03 (1H, m, H-3
1.50 (2H, m, H-2
(3H, s, H-14), 1.24 (1H, m, H-9
s, –OSitBuMe2), 0.09 (3H, s, –OSitBuMe2); 13C NMR (100 MHz, CDCl3)
150.3, 115.9, 72.6, 67.9, 65.2, 61.5, 60.9, 57.6, 45.8, 40.2, 36.6, 25.8,
a
), 2.07 (1H, ddd, J¼14.3, 10.4, 3.5 Hz, H-9
a
),
), 1.66–
), 1.45 (3H, s, H-15), 1.33 (1H, m, H-3 ), 1.31
), 0.90 (9H, s, –OSitBuMe2), 0.10 (3H,
d
b
), 1.91 (1H, ddd, J¼14.1, 10.1, 3.2 Hz, H-8
b
78.8 (C-6), 76.6 (C-1), 49.1 (C-7), 39.5 (C-5), 32.5 (C-10), 29.8 (C-9),
26.7 (C-2), 23.6 (C-8), 20.9 (C-15), 10.3 (C-14); IR nmax (cmꢂ1):
3443, 2923, 2852, 1747, 1454, 1260, 1106, 965, 817; MS (CI) m/z (rel
int.) 249 [Mþ1]þ (26), 231 (77), 213 (100), 185 (70), 157 (29), 119
(10), 95 (16), 80 (16); HRMS (CI): calcd for C15H21O3 [Mþ1]
249.1490, found 249.1483.
b
, H-8 a
a
b
d
23.9, 23.6, 23.2, 18.3, 16.7, ꢂ5.3; IR nmax (cmꢂ1): 3437, 2955, 2928,
2856, 1463, 1388, 1253, 1070, 836, 778; MS (CI) m/z (rel int.) 383
[Mþ1]þ (5), 365 (20), 349 (6), 307 (6), 251 (27), 233 (100), 215 (67),
205 (27), 187 (41), 175 (50), 161 (25), 145 (30), 133 (45), 115 (39), 109
(76), 95 (56); HRMS (CI): calcd for C15H39O4Si [Mþ1]þ 383.2617,
found 383.2618.
3.19. Epoxidation of alcohol 6 with m-CPBA
A solution of alcohol 6 (30 mg, 0.086 mmol) and pyridine
(0.5 mL) in dichloromethane (5 mL) was treated with m-CPBA
(30 mg, 0.12 mmol) at room temperature. After 3 h, the reaction
mixture was diluted with dichloromethane (20 mL) and the organic
layer was washed with aqueous saturated sodium sulfite, and then
washed with brine. The organic layer was dried over anhydrous
sodium sulfate and the solvent was removed under vacuum. Con-
secutive purification by column chromatography (2:3 EtOAc/hex-
anes) and HPLC (1:1 EtOAc/hexanes) led to compounds 15 (1.5 mg,
0.004 mmol, 5%), 16 (11 mg, 0.028 mmol, 34%), and 17 (3.0 mg,
0.008 mmol, 9%).
3.23. Epoxidation of alcohol 6 with TBHP and VO(acac)2
A solution of alcohol 6 (62 mg, 0.17 mmol) and VO(acac)2
(12 mg, 0.034 mmol) in dichloromethane (4 mL) was cooled to 0 ꢀC
and TBHP (0.55 M in nonane, 0.68 mL, 0.37 mmol) was added. After
stirring for 1 h, aqueous saturated sodium sulfite (5 mL) was added
and the aqueous layer was extracted with dichloromethane
(3ꢁ5 mL). The organic layer was washed with brine and dried over
anhydrous sodium sulfate. Removal of the solvent and purification
by column chromatography (3:7 EtOAc/hexanes) afforded 15 (6 mg,
0.016 mmol, 9%) and 18 (57 mg, 0.15 mmol, 88%).
3.20. Epoxide 15
Yellow oil; 1H NMR (400 MHz, CDCl3, mixture of conformers)
3.24. Diepoxide 18
d
5.30 (m, 1H, H-1), 5.05 (d, J¼0.9 Hz, 1H, H-13a), 4.96 (s,1H, H-13b),
4.23 (dd, J¼1, 12.6 Hz, 1H, H-12a), 4.06 (dd, J¼1, 12.6 Hz, 1H, H-12b),
Colorless oil; 1H NMR (300 MHz, CDCl3, mixture of conformers)
3.42 (d, J¼8 Hz,1H, H-6), 2.60 (m, 1H, H-5), 2.31–2.35 (m, 1H, H-2
2.28 (br s,1H, H-7), 2.22–2.11 (m,1H, H-9 ), 2.08–2.01 (m,1H, H-2
1.96 (dt, J¼2.9, 13.5 Hz, H-8 ), 1.78 (m, 1H, H-9
1.50–1.58(m,1H,H-8 ),1.27–1.32 (m, 2H, 2H-3),1.23(s, 3H, H-15), 0.90
(s, 9H, –OSitBuMe2), 0.09 (3H, s, –OSitBuMe2), 0.08 (3H, s, –OSitBuMe2);
13C NMR (100 MHz, CDCl3, mixture of conformers)
151.2,123.5,113.9,
a
),
d
5.27 (1H, m, H-1), 3.98 (1H, d, J¼11.4 Hz, H-12a), 3.65 (1H, d,
b
b),
J¼8.0 Hz, H-6), 3.40 (1H, d, J¼11.2 Hz, H-12b), 2.73 (1H, d, J¼4.2 Hz,
a
a), 1.66 (s, 3H, H-14),
H-13), 2.64 (1H, d, J¼4.2 Hz, H-130), 2.55 (1H, m, H-5), 2.34 (1H, m,
b
H-2
H-2
a
b
), 2.22 (1H, m, H-9
), 1.90 (1H, ddd, J¼10.9, 2.7 Hz, H-8
a
), 2.05 (1H, m, H-7), 1.96 (1H, dd, J¼8.7 Hz,
a
), 1.66 (1H, m, H-9
b), 1.63
d
(3H, s, H-14),1.57 (3H, s, H-140),1.55 (1H, m, H-8
a),1.24 (2H, m, 2H-3),

R. Azarken et al. / Tetrahedron 64 (2008) 10896–10905
10903
1.19 (3H, s, H-15), 0.90 (9H, s, –OSitBuMe2), 0.08 (3H, s, –OSitBuMe2),
0.06 (3H, s, –OSitBuMe2); 13C NMR (75 MHz, CDCl3)
143.5, 77.2,
–OSitBuMe2), 0.09 (3H, s, –OSitBuMe2), 0.07 (3H, s, –OSitBuMe2); 13
C
d
NMR (100 MHz, CDCl3)
d
125.4, 117.5, 77.4, 68.0, 65.3, 57.4, 56.0,
71.7, 67.5, 65.8, 59.6, 51.5, 44.1, 37.0, 29.7, 25.8, 22.5, 18.2, 16.5, ꢂ5.4;
IR nmax (cmꢂ1): 3439, 2953, 2928, 2856, 1463, 1387, 1253, 1098, 837,
779; MS (CI) m/z (rel int.) 383 [Mþ1]þ (3), 365 (16), 347 (18), 307
(7), 267 (5), 251 (16), 233 (95), 215 (100),187 (64),159 (85),133 (74),
115 (66), 95 (62); HRMS (CI): calcd for C21H39O4Si [Mþ1]þ 383.2617,
found 383.2615.
42.5, 39.1, 36.5, 29.7, 26.1, 25.8, 24.5, 23.1, 18.2, 17.0, ꢂ5.5; IR nmax
(cmꢂ1): 3420, 2955, 2928, 2856, 1464, 1387, 1255, 1077, 837, 777;
MS (CI) m/z (rel int.) 369 [Mþ1]þ 369 [Mþ1]þ (8), 333 (13), 293
(13), 235 (14), 219 (92), 201 (100), 161 (32), 145.1 (18), 119 (10), 95
(14); HRMS (CI): calcd for C21H41O3Si [Mþ1]þ 369.2825, found
369.2824.
3.25. Epoxidation of alcohol 19 with TBHP and VO(acac)2
3.29. Deprotection of alcohol 19 with TBAF
A solution of alcohol 19 (78 mg, 0.22 mmol) and VO(acac)2
(16 mg, 0.036 mmol) in dichloromethane (5 mL) was cooled to 0 ꢀC
and TBHP (0.55 M in nonane, 2.6 mL, 0.01 mmol) was added. The
reaction was worked up as in the formation of diepoxide 18,
affording epoxide 20 (61 mg, 0.16 mmol, 75%). Compound 20 was
allowed to stand on deuterochloroform for 2 days, affording
a mixture of compounds, which was purified by column chroma-
tography (2:3 EtOAc/hexanes) giving rise to pure 21 (36 mg,
0.09 mmol 60%) and 22 (23 mg, 0.06, 38%).
A solution of alcohol 19 (100 mg, 0.28 mmol) in THF (15 mL) was
treated with TBAF (1 M in THF, 0.5 mL) at 0 ꢀC. The reaction mixture
was stirred for 15 min, after which time aqueous saturated am-
monium chloride (20 mL) was added. The aqueous layer was
extracted with EtOAc (3ꢁ10 mL) and the organic layers were
combined, dried over sodium sulfate, and the solvent was removed
under vacuum. The resulting residue was purified by column
chromatography (3:7 EtOAc/hexanes) giving rise to diol 23 (61 mg,
0.26 mmol, 92%).
3.26. Epoxide 20
3.30. Diol 23
20
Colorless oil; [
a]
þ27.7 (c 0.007, CHCl3); 1H NMR (400 MHz,
D
ꢂ35.7 (c 0.002, CHCl3); 1H NMR (400 MHz,
20
CDCl3, mixture of conformers)
J¼10.6, 2.5 Hz, H-12
J¼10.5, 5.0 Hz, H-12
(1H, ddd, J¼12.2, 9.9, 7.1, 2.5 Hz, H-11), 1.64 (3H, s, H-14), 1.34 (1H,
d
5.25 (1H, m, H-1), 3.77 (1H, dd,
Colorless oil; [
a
]
D
b
), 3.59 (1H, d, J¼8.0 Hz, H-6), 3.50 (1H, dd,
CDCl3, mixture of conformers) d 5.09 (1H, m, H-5), 4.98 (1H, d,
a
), 2.60 (1H, m, H-5), 2.33 (1H, m, H-3 ), 1.69
a
J¼7.8 Hz, H-50), 4.96 (1H, m, H-1), 4.65 (1H, d, J¼7.8 Hz, H-6), 3.75
(1H, dd, J¼11.8, 2.6 Hz, H-12a), 3.57 (1H, m, H-12b), 2.34 (1H, m, H-
br d, J¼6.7 Hz, H-7),1.25 (1H, m, H-3
b),1.24 (3H, s, H-15),1.20 (3H, s,
2
a
b
), 2.20–2.00 (2H, m, H-2b, H-9a), 1.99–1.52 (4H, m, H-11, 2H-3, H-
H-150), 0.98 (1H, d, J¼7 Hz, H-13), 0.88 (9H, s, –OSitBuMe2), 0.86
9
), 1.60 (3H, s, H-14), 1.55 (3H, s, H-140), 1.46 (3H, br s, H-15), 1.31
), 1.24 (1H, m, H-7), 1.05 (1H, d, J¼7.1 Hz, H-13), 0.90
(1H, ddd, J¼2.6, 9 Hz, H-8
), 0.87 (1H, m, H-11); 13C NMR (100 MHz,
CDCl3, mixture of conformers) 138.7, 133.5, 132.8, 130.83, 128.7,
(1H, m, H-8
a
), 0.08 (3H, s, –OSitBuMe2), 0.07 (3H, s, –OSitBuMe2);
(1H, m, H-8a
13C NMR (75 MHz, CDCl3)
d
153.4, 137.2, 125.3, 125.0, 108.3, 70.2,
b
68.1, 65.2, 59.7, 44.5, 44.4, 44.1, 42.5, 39.4, 37.2, 31.9, 31.6, 29.6, 25.8,
22.8, 18.3, 16.5, 16.1, ꢂ5.5; IR nmax (cmꢂ1): 3440, 2953, 2928, 2856,
1463, 1388, 1253, 1098, 838, 779; MS (CI) m/z (rel int.) 369 [Mþ1]þ
(35), 351 (94), 333 (64), 311 (24), 293 (41), 237 (65), 219 (100), 201
(99), 161 (90), 145 (42), 121 (39), 95 (41); HRMS (CI): calcd for
C21H41O3Si [Mþ1]þ 369.2824, found 369.2828.
d
121.5, 110.4, 106.37, 77.2, 69.9, 67.7, 67.0, 65.5, 64.9, 60.8, 60.3, 58.2,
49.9, 47.3, 45.3, 41.7, 40.9, 40.3, 39.0, 36.9, 34.8, 30.1, 29.6, 25.9, 24.5,
21.5, 21.0, 16.4, 16.1; IR nmax (cmꢂ1): 3314, 2927, 1455, 1255, 1019,
835, 774; MS (CI) m/z (rel int.) 239 [Mþ1]þ (22), 221 (98), 203 (94),
189 (26), 163 (100), 147 (53), 137 (43), 121 (77), 109 (71), 95 (67);
HRMS (CI): calcd for C15H27O2 [Mþ1]þ 239.2011, found 239.2011.
3.27. Guaiane 21
3.31. Epoxidation of diol 23 with TBHP and VO(acac)2
20
Colorless oil; [
CDCl3)
a]
ꢂ78.0 (c 0.01, CHCl3); 1H NMR (400 MHz,
D
d
4.77 (1H, s, H-14a), 4.71 (1H, s, H-14b), 3.98 (1H, dd, J¼10.2,
Compound 16 was treated with TBHP and VO(acac)2 following
the same experimental procedure followed in the synthesis of 20
with the following amounts: alcohol 23 (100 mg, 0.42 mmol),
VO(acac)2 (20 mg, 0.04 mmol), dichloromethane (5 mL), and TBHP
(0.03 mL). Compound 24 (81 mg, 0.31 mmol) was thus obtained in
75% yield.
6.9 Hz, H-6), 3.72 (1H, dd, J¼10.4, 2.4 Hz, H-12a), 3.52 (1H, dd,
J¼10.4, 6.6 Hz, H-12b), 2.52 (1H, m, H-9 ), 2.28 (1H, m, H-1), 2.18
(1H, m, H-9
), 1.90 (1H, dd, J¼11.7, 10.1 Hz, H-5), 1.82–1.86 (1H, m,
H-2 ), 1.71–1.80 (2H, m, H-11, H-8 ), 1.65 (1H, m, H-2 ), 1.45–1.53
(2H, m, H-7, H-8
a
b
a
a
b
b
), 1.27 (3H, s, H-15), 0.93 (3H, d, J¼6.8 Hz, H-13),
0.90 (2H, m, 2H-3), 0.89 (9H, s, –OSitBuMe2), 0.08 (3H, s, –OSit-
BuMe2), 0.06 (3H, s, –OSitBuMe2); 13C NMR (100 MHz, CDCl3)
d
152.4, 108.3, 76.5, 72.5, 67.6, 58.4, 47.0, 42.9, 39.6, 36.4, 34.5, 27.4,
3.32. Epoxide 24
25.8, 24.5, 24.3, 18.2, 17.2, ꢂ5.6; IR nmax (cmꢂ1): 3422, 2955, 2928,
2856, 1464, 1387, 1254, 1077, 837, 776; MS (CI) m/z (rel int.) 369
[Mþ1]þ (5), 333 (11), 293 (14), 235 (8), 219 (100), 201 (99.9), 161
(21), 145.1 (15), 115 (12), 95 (9); HRMS (CI): calcd for C21H41O3Si
[Mþ1]þ 369.2825, found 369.2822.
20
Colorless oil; [
a
]
þ21.2 (c 0.01, CHCl3); 1H NMR (400 MHz,
D
CDCl3, mixture of conformers)
J¼11.2, 3.0 Hz, H-12
J¼11.1, 5.6 Hz, H-12
(1H, m, H-9 ), 2.06 (1H, m, H-9
11), 1.64 (3H, s, 3H-14), 1.39 (1H, m, H-7), 1.25 (1H, m, H-3
(3H, s, H-15), 1.02 (1H, d, J¼7.0 Hz, H-13), 0.89 (1H, m, H-8
NMR (100 MHz, CDCl3, mixture of conformers) 137.7, 122.9, 77.2,
d 5.27 (1H, m, H-1), 3.76 (1H, dd,
b
a
), 3.66 (1H, d, J¼8.1 Hz, H-6), 3.54 (1H, dd,
), 2.63 (1H, m, H-5), 2.36 (1H, m, H-2 ), 2.16
), 2.00–1.70 (3H, m, H-8 , H-3 , H-
), 1.21
). 13C
b
b
a
b
a
3.28. Guaiane 22
b
a
Colorless oil; [
a
]
ꢂ62.2 (c 0.02, CHCl3); 1H NMR (400 MHz,
d
20
D
CDCl3)
d
5.46 (1H, m, H-9), 4.08 (1H, dd, J¼10.1, 6.9 Hz, H-6), 3.67
70.0, 69.1, 68.4, 64.4, 60.7, 60.1, 46.8, 44.5, 37.1, 26.5, 24.6, 16.6, 16.4,
16.3, 16.0, 15.9; IR nmax (cmꢂ1): 3439, 2953, 2928, 2856, 1463, 1386,
1252, 1098, 838, 778; MS (CI) m/z (rel int.) 255 [Mþ1]þ (4), 237 (55),
219 (100), 189 (26), 201 (45), 191 (16), 161 (62), 149 (30), 135 (32),
123 (24), 109 (37), 95 (45); HRMS (CI): calcd for C15H27O2 [Mþ1]þ
255.1960, found 255.1955.
(1H, dd, J¼10.4, 2.5 Hz, H-12a), 3.52 (1H, dd, J¼10.3, 7.4 Hz, H-12b),
2.25–2.44 (2H, m, H-1, H-8
), 2.10 (1H, dd, J¼11.9, 10.1 Hz, H-5),
2.01 (1H, m, H-8 ), 1.67–1.81 (2H, m, 2H-2), 1.65 (1H, m, H-11), 1.54
(3H, s, H-14),1.52 (1H, m, H-7),1.42 (1H, m, H-3 ),1.27 (3H, s, H-15),
0.98 (3H, d, J¼7 Hz, H-13), 0.90 (1H, m, H-3 ), 0.89 (9H, s,
a
b
a
b

10904
R. Azarken et al. / Tetrahedron 64 (2008) 10896–10905
3.33. Oxidation of diol 24 with TPAP and NMO
J¼9.1, 5.1 Hz, H-6), 2.78 (1H, m, H-5), 2.43 (1H, dddd, J¼7.5, 7.4, 7.4,
2.7 Hz, H-11), 2.33 (1H, m, H-2 ), 2.08 (1H, m, H-2 , H-9 ), 2.03
(2H, m, H-7, H-3 ), 2.00 (2H, m, H-8 , H-9 ), 1.68 (3H, br s, 3H-14),
1.52 (1H, m, H-8
), 1.30 (1H, d, J¼7.4 Hz, H-13), 1.28 (3H, br s, 3H-
15), 1.25 (1H, m, H-3
); 13C NMR (150 MHz, CDCl3, mixture of
conformers) 178.8, 130.8, 125.1, 80.1, 79.1, 62.1, 61.2, 60.5, 60.3,
48.4, 47.2, 47.1, 46.1, 41.0, 38.6, 36.7, 35.7, 33.9, 32.2, 31.7, 29.6, 26.5,
24.4, 23.1, 16.7, 15.2; IR nmax (cmꢂ1): 2930, 2873, 1771, 1458, 1380,
1186, 1072, 965, 807; MS (CI) m/z (rel int.) 251 [Mþ1]þ (10), 233
(100), 215 (10), 205 (37), 187 (28), 159 (49), 147 (22), 133 (13), 119
(18), 107 (11), 81 (11); HRMS (CI): calcd for C15H23O3 [Mþ1]þ
251.1647, found 251.1644.
b
a
b
A
solution of diol 24 (34 mg, 0.12 mmol), NMO (30 mg,
b
a
b
a
0.26 mmol), and 4 Å molecular sieves (30 mg) were treated with
TPAP (7 mg, 0.02 mmol). After stirring for 6 h, the reaction mix-
ture was filtered with EtOAc through a silica pad. After removal
of the solvent, the crude mixture was purified by column chro-
matography (2:3 EtOAc/hexanes), affording melampolide 25
(21 mg, 0.084 mmol, 70%).
a
d
3.34. Melampolide 25
20
Amorphous solid;
(300 MHz, CDCl3)
[
a]
þ12.4 (c 0.008, CHCl3); 1H NMR
D
d
5.25 (1H, t, J¼7.1 Hz, H-1), 4.25 (1H, dd, J¼8.2,
3.39. Treatment of lactone 27 with p-TsOH
6.3 Hz, H-6), 3.08 (1H, d, J¼8.3 Hz, H-5), 2.42 (1H, m, H-9
(1H, m, H-11), 2.21 (1H, m, H-9 ), 2.14–1.99 (5H, m, 2H-2, H-3
, H-7), 1.65 (3H, br s, H-14), 1.60 (1H, m, H-8 ), 1.41 (3H, s, H-15),
1.29 (3H, dd, J¼7.4, 2.0 Hz, H-13), 1.22 (1H, m, H-3
); 13C NMR
(75 MHz, CDCl3) 178.9, 136.8, 121.8, 81.8, 62.2, 53.4, 46.1, 42.3,
b
), 2.30
a
b
, H-
A solution of lactone 27 (10 mg, 0.04 mmol) and p-TsOH (1 mg)
in dichloromethane (5 mL) was stirred at room temperature for
12 h. Aqueous saturated NaHCO3 (5 mL) was added and the mixture
was extracted with dichloromethane (3ꢁ10 mL). The organic layer
was dried over sodium sulfate and the solvent was removed under
vacuum. Purification of the crude mixture by HPLC (2:3 EtOAc/
hexanes) afforded guaianolide 28 (3 mg, 0.012 mmol, 30%) and 29
(6 mg, 0.024 mmol, 60%).
8
a
b
a
d
38.6, 29.6, 28.5, 26.6, 23.1, 22.1, 15.2; IR nmax (cmꢂ1): 2930, 2873,
1771, 1458, 1380, 1186, 1072, 962, 811; MS (CI) m/z (rel int.) 251
[Mþ1]þ (14), 233 (100), 215 (9), 205 (64), 177 (53), 159 (73), 147
(26), 135 (32), 133 (14), 119 (23),107 (14), 81 (7); HRMS (CI): calcd
for C15H23O3 [Mþ1]þ 251.1647, found 251.1650.
3.40. Guaianolide 28
3.35. Treatment of lactone 25 with p-TsOH
Amorphous solid. [
CDCl3)
a]
þ8.1 (c 0.1, CHCl3); 1H NMR (400 MHz,
20
D
A solution of alcohol 25 (20 mg, 0.08 mmol) in dichloromethane
(5 mL) was treated with p-TsOH (1 mg) at room temperature. After
stirring for 12 h, aqueous saturated NaHCO3 (5 mL) was added and
the resulting mixture was extracted with dichloromethane
(3ꢁ10 mL). The organic layer was dried over sodium sulfate and the
solvent was removed under vacuum. Purification of the crude
mixture by HPLC (2:3 EtOAc/hexanes) afforded melampolide 26
(7 mg, 0.028 mmol, 35%).
d
4.78 (1H, br s, H-14a), 4.77 (1H, d, J¼1.8 Hz, H-14b), 4.66
(1H, dd, J¼11.4, 7.6 Hz, H-6), 2.51 (1H, dd, J¼13.8, 7.6 Hz, H-1), 2.42–
2.21 (3H, m, H-7, H-11, H-9 ), 2.14 (1H, m, H-8 ), 2.02 (1H, t,
), 1.51 (1H, m, H-
a
b
J¼11.1 Hz, H-5), 1.98–1.65 (5H, m, 2H-2, 2H-3, H-9
b
8a
), 1.38 (3H, s, 3H-15), 1.27 (3H, d, J¼7.0 Hz, 3H-13); 13C NMR
(150 MHz, CDCl3)
d 178.6, 150.9, 108.8, 82.7, 80.1, 54.7, 46.1, 44.6,
40.5, 35.3, 32.2, 28.8, 26.4, 23.4, 14.6; IR nmax (cmꢂ1): 3340, 2930,
2873,1770,1170, 892, 807; MS (CI) m/z (rel int.) 251 [Mþ1]þ (6), 233
(100), 215 (11), 205 (35), 187 (30), 159 (68), 119 (12), 107 (6), 81 (11);
HRMS (CI): calcd for C15H23O3 [Mþ1]þ 251.1647, found 251.1643.
3.36. Melampolide 26
20
Colorless oil; [
a
]
þ51.0 (c 0.02, CHCl3); 1H NMR (600 MHz,
D
3.41. Guaianolide 29
CDCl3)
d
5.61 (1H, dd, J¼11.7, 1.8 Hz, H-3), 5.29 (1H, d, J¼8.8 Hz, H-
1), 4.48 (1H, dd, J¼10.4, 7.9 Hz, H-6), 4.27 (1H, d, J¼10.4 Hz, H-5),
3.02 (1H, br t, J¼13.6 Hz, H-2 ), 2.53 (1H, m, H-2 ), 2.28 (1H, dt,
J¼13.0, 6.9 Hz, H-11), 2.19 (1H, ddd, J¼13.0, 7.8, 4.1 Hz, H-7), 2.18–
20
Amorphous solid. [
CDCl3)
5), 2.33 (3H, m, H-7, H-11, H-2
, H-9 ), 1.95 (2H, m, 2H-8), 1.78 (1H, m, H-3
a
]
þ11.3 (c 0.15, CHCl3); 1H NMR (400 MHz,
D
a
b
d
4.61 (1H, dd, J¼11.6, 8.4 Hz, H-6), 2.82 (1H, d, J¼11.6 Hz, H-
a
), 2.25 (1H, m, H-9a), 2.13 (2H, m, H-
), 1.69 (1H, ddd,
2.13 (2H, m, 2H-9), 1.93 (1H, m, H-8a), 1.80 (3H, s, 3H, H-15), 1.68
2b
b
a
(3H, s, H-14), 1.47 (1H, m, H-8
NMR (150 MHz, CDCl3)
b
), 1.23 (3H, d, J¼7.0 Hz, 3H-13); 13C
J¼12.0, 7.6,1.5 Hz, H-3
b), 1.56 (3H, s, 3H-14),1.29 (3H, s, 3H-15),1.24
d
171.7, 140.7, 130.1, 120.0, 94.7, 79.8, 75.6,
(1H, d, J¼6.7 Hz, 3H-13); 13C NMR (100 MHz, CDCl3)
d 178.6, 130.9,
45.6, 39.3, 30.8, 29.9, 29.6, 25.2, 13.7, 11.3; IR nmax (cmꢂ1): 3610,
2930, 2873, 1770, 1458, 1189, 1070, 964, 809; MS (CI) m/z (rel int.)
251 [Mþ1]þ (18), 233 (95), 219 (47), 203 (51), 175 (54), 159 (100),
147 (39), 135 (25), 133 (31), 119 (34), 107 (35), 81 (38); HRMS (CI):
calcd for C15H23O3 [Mþ1]þ 251.1647, found 251.1648.
130.7, 82.2, 80.3, 51.6, 46.1, 39.7, 38.1, 33.5, 29.0, 26.6, 22.3, 21.4,
13.7; IR nmax (cmꢂ1): 3344, 2930, 2873, 1175, 1182, 987, 811; MS (CI)
m/z (rel int.) 251 [Mþ1]þ (34), 233 (100), 215 (10), 205 (43), 187
(53), 159 (80), 119 (27),107 (10), 81 (9); HRMS (CI): calcd for
C15H23O3 [Mþ1]þ 251.1647, found 251.1649.
3.37. Oxidation of diol 24 with TPAP and NMO
Acknowledgements
A
solution of diol 24 (34 mg, 0.12 mmol), NMO (30 mg,
´
We thank Ministerio de Educacion y Cultura (CTQ2007-0585)
0.26 mmol), and 4 Å molecular sieves (30 mg) were treated with
TPAP (7 mg, 0.02 mmol). After stirring for 2 h, the reaction
mixture was filtered with EtOAc through a silica pad. After re-
moval of the solvent, the crude mixture was purified by column
chromatography (3:7 EtOAc/hexanes), affording lactone 27
(24 mg, 0.096 mmol, 76%).
´
and Junta de Andalucıa (P06-FQM-01590) for financial support. R.A.
is grateful to Agencia Espan˜ola de Cooperacion Internacional (AECI)
for a fellowship. We also are grateful to Professor Antonio J. Macıas
and Professor J. Alberto Marco for their helpful comments.
´
´
References and notes
3.38. Lactone 27
1. Picman, A. K. Biochem. Syst. Ecol. 1986, 14, 255–281.
2. (a) Fischer, H. N.; Oliver, E. J.; Fischer, H. D. Fortschr. Chem. Org. Naturst. 1979, 38,
47–390; (b) Fraga, B. M. Nat. Prod. Rep. 2007, 24, 1350–1381 and previous ref-
erences of this series.
20
Amorphous solid; [
CDCl3, mixture of conformers)
a
]
þ16.0 (c 0.01, CHCl3); 1H NMR (400 MHz,
D
d 5.26 (1H, m, H-1), 4.18 (1H, dd,

R. Azarken et al. / Tetrahedron 64 (2008) 10896–10905
10905
3. (a) Treiman, M.; Caspersen, C.; Christensen, S. B. Trends Pharmacol. Sci. 1998, 19,
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Kashyap, R. P. J. Org. Chem. 1986, 51, 2521–2524.
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Angew. Chem., Int. Ed. 2003, 42, 5996–6000; (b) Ball, M.; Andrews, S. P.;
Wierschem, F.; Cleator, E.; Smith, M. D.; Ley, S. V. Org. Lett. 2007, 9, 663–666.
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13. Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1983, 48, 4155–4156.
14. At this point, we observed that in some runs, partial racemization of germa-
cranone 5 could occur. The presence of pyridine is necessary to avoid the cy-
clization to the corresponding eudesmanes, but at the same time it may
provoke the racemization through inversion of the configuration of C-7. For this
reason, from 5 to 18 the values of the optical rotations are not supplied. This
fact is not observed in the synthesis of 19 (vide infra), since C-7 is not allylic.
15. Zdero, C.; Bohlmann, F. Phytochemistry 1989, 28, 3105–3120.
16. A steiractinolide is a 5
bH,10aMe-eudesmanolide.
17. Compounds 9 and 10 are first described in Bohlmann, F.; Jakupovic, J.; Lonitz, M.
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