Synthesis of sibiricinone A, sibiricinone B and leoheterin

Article abstract of DOI:10.1016/j.tet.2008.09.007

Two labdenolides, sibiricinone A and sibericinone B, and a furo-labdane leoheterin have been synthesized from sclareol, for the first time, establishing in this manner the absolute configuration for these compounds.

Full text of DOI:10.1016/j.tet.2008.09.007

Tetrahedron 64 (2008) 10860–10866
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of sibiricinone A, sibiricinone B and leoheterin
*
´
I.S. Marcos , L. Castan˜eda, P. Basabe, D. Dıez, J.G. Urones
´
´
Departamento de Qu´ımica Organica, Facultad de Ciencias Quımicas, Universidad de Salamanca, Plaza de los Caidos 1-5, 37008 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 16 July 2008
Received in revised form 1 September 2008
Accepted 3 September 2008
Available online 17 September 2008
Two labdenolides, sibiricinone A and sibericinone B, and a furo-labdane leoheterin have been synthe-
sized from sclareol, for the first time, establishing in this manner the absolute configuration for these
compounds.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Labdanes
Diterpenes
Sibiricinone A
Sibiricinone B
Leoheterin
Sclareol
O
1. Introduction
O
O
O
HO
H
HO
H
Labdane diterpenes with a highly functionalised ring B that
present important biological activities are very commom.1 Among
them, forskolin 1, is one of the most representative as it has car-
dioactive, adenylate cyclase stimulant and hypotensive properties.2
Recently our group has carried out a study on the synthesis of
highly functionalised ring B labdanes3 introducing a new strategy
O
H
HO
OH
O
OH
OH
OAc
OH
O
O
OH
for the synthesis of a-cis, b-cis or trans diols in that ring. Now we
forskolin, 1
sibiricinone A, 2
sibiricinone B, 3
put in practice this methodology for the synthesis of sibiricinone A
2,4 sibiricinone B 34 and leoheterin 45 (Fig. 1).
O
O
The plants from genus Leonorus are widely distributed and
medicinally important members of Lamiaceae. Preparations of
some of them have been used for the treatment of cardiovascular
diseases and for their sedative as well as uterotonic effects. Sibir-
icinone A 2 and sibiricinone B 3 are two labdanes isolated from
Leonorus sibericus L., which is commonly referred to as ‘mother-
wort’ in the West Indies, where it is utilized as a cough syrup and
antipyretic for malaria.4 The juice of the fresh plant is used to treat
haemoptysis, oedema, gout and arthritis. Both compounds show
oxygenated functionalities at C-6 and C-7 and a hydroxyl group at
C-9, for sibiricinone A 2, or a double bond in C-8 sibiricinone B 3. In
HO
OH
OH
OH
OH
OH
H
H
H
O
O
(+)-leoheterin, 4
(-)-leoheterin, 5
sclareol, 6
Figure 1.
the side chain appears a
hydroxyketone on ring B appears alternatively in one and another
g-hydroxybutenolide for both. The a-
molecule, that is, the carbonyl group and the hydroxyl group are in
C-6 and C-7 or in C-7 and C-6, respectively.
22
Leoheterin 4, [
a
]
D
þ47.7 (c 0.65, EtOH), is a furo-labdane iso-
lated from Leonorus heterophyllus.5 These kind of compounds are
very abundant in plants of this genus.6 From Ballota aucheri was
22
isolated compound 5,7
[
a
]
ꢀ48 (c 0.78, CHCl3), with the same
* Corresponding author. Tel.: þ34 923 294474; fax: þ34 923 294574.
E-mail address: ismarcos@usal.es (I.S. Marcos).
D
physical properties as the ones of leoheterin 4 with the only
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.007

I.S. Marcos et al. / Tetrahedron 64 (2008) 10860–10866
10861
O
O
O
O
O
HO
H
HO
OH
OH
OH
O
OH
H
H
O
O
OH
15
HO
16
leoheterin, 4
sibiricinone A, 2
sibiricinone B, 3
13
17
20
1
9
8
10
4
OH
5
O
O
O
H
O
18
19
sclareol, 6
OH
O
H
O
OH
H
H
O
O
O
OH
O
9
8
7
Scheme 1.
difference in the sign of the rotation value. So both compounds are
enantiomers, although the absolute configuration for both remains
undisclosed. To the best of our knowledge these compounds have
not been synthesized until now. The synthesis of 2, 3 and 4 will
corroborate the structure and establish the absolute configuration
for all of them.
The starting material for the synthesis was sclareol 6, a com-
mercial compound that our group has used for the synthesis of
natural products as luffolide,8 subersic acid,9 hyrtiosal,10 chrysolic
acid,11 nimbiol12 and others.3
OR
HO
O
O
a
b
OH
O
O
O
O
H
O
H
sclareol
H
O
R
10 Ac
11 Me
7
2. Results and discussion
The synthesis of the diterpenes 2, 3 and 4 was planned
according to the following retrosynthetic scheme (Scheme 1).
The key compound is ketone 7,3 previously obtained by us from
sclareol 6. The methylketone of 7 permit us to have access
to the butenolide 8. This compound could be transformed into
c
O
O
R
O
a g-hydroxybutenolide and by control of the functionality at C-6
and C-7 in ring B to obtain sibiricinone B 3. The synthesis of sibir-
icinone A 2 and leoheterin 4 will require the use of triol 9 as
intermediate, that can be accessible from lactone 8. Lactone 8 will
be obtained from methylketone 7 after C-16 functionalization and
the introduction of the two remaining carbons in the side chain.
In summary compound 7 shows a carbonate function that could
be transformed into hydroxyketones at C-6 and C-7 or C-7 and C-6,
respectively, as well as to a hydroxy group at C-9 in ring B of the
labdane skeleton. The methylketone in the side chain of compound
d
O
O
O
H
H
O
O
O
R
8
12 CH2OH
13
OH
Scheme 2. Reagents and conditions: (a) Ref. 3; (b) Pb(OAc)4, BF3$Et2O, MeOH, C6H6, rt,
50 min (10, 60%; 11, 21%); (c) K2CO3, MeOH, rt, 20 min (12, 81%; 13, 13% from 10); (d)
Ph3P]C]C]O, C6H6, 85 ꢁC, 40 min (84% from 12).
7 is the starting point for the synthesis of furane or
g-hydroxy-
butenolide, making this compound a reference for the control of
the functionality in ring B and functionalization of the side chain for
these kind of compounds.
functionalization was achieved and later on the
g-butenolide
function of the side chain was installed.
13
2.1. Synthesis of intermediate 8
Reaction of 7 with Pb(OAc)4 in presence of BF3$Et2O gave
a mixture of 10 and 11, 10 being the major compound. Alkaline
hydrolysis of 10 gives hydroxyketone 12 and a small proportion of
acid 13. Compound 12 was transformed, in good yield, into 8 by
reaction with Bestmann ketene Ph3P]C]C]O.14
As described in Scheme 1, lactone 8 is the key intermediate for
the synthesis of 2, 3 and 4. The synthesis of 8 from methylketone 7
was carried out according to Scheme 2. First of all C-16

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I.S. Marcos et al. / Tetrahedron 64 (2008) 10860–10866
2.2. Synthesis of 2, 3 and 4
The synthesis of 9 (69%) from 8 was carried out through
epoxide 16. Epoxidation of 8 was achieved quantitatively with
total stereoselection from the side of the molecule, due to the
steric hindrance that Me-20 and carbonate at C-6 and C-7 exert
on the side to give 16. DIBAL-H reduction of the latter com-
pound installed the furane ring in the side chain, as was done
for the synthesis of 3, to give an epoxyfuro-labdane intermediate
that without isolation was submitted to LAH reduction in hot
THF of the epoxide group, to obtain the desired triol 9. In this
manner, considering the trans-diaxial opening of the epoxide,
and entry of the hydride at C-8, the required triol 9 was
The synthesis of sibiricinone A 2 sibiricinone B 3 and leoheterin
4 was achieved according to Scheme 3.
The synthesis of sibiricinone B 3 (Scheme 3) was done in three
steps from 8. DIBAL-H15 reduction of 8 and after filtration on silica
gel gave a furo-labdane derivative that without purification was
reduced with LAH to give diol 14, with both hydroxyl groups at C-6
a
b
and C-7 b, from which 15 was obtained by allylic oxidation with
MnO2, with the required hydroxyketone functionality in ring B, in
a 81% yield from 8. Compound 15 has been recently synthesized by
Davies-Coleman et al. from hispanolone, showing that it is the
enantiomer of the natural compound isolated from Ballota
obtained with a
required.
a-hydroxy group at C-9 and Me-17 equatorial as
aucheri.16 The oxidation of 15 with 1O2 using Faulkner17 method-
Chemoselective acetylation of 9 gave quantitatively the mono-
22
ology gave sibiricinone B 3, [
a
]
þ7.5 (c 0.42, CHCl3), in excellent
acetyl derivative 17 needed for the synthesis of the a-hydroxy-
D
yield. The physical properties of 3 are coincident with the ones
ketone at C-6 and C-7 group. TPAP18 oxidation of 17 gave 18 that by
20
22
described by Tinto et al.4 for sibiricinone B, [
CHCl3).
a
]
þ4.4 (c 0.18,
hydrolysis led quantitatively to leoheterin 4, [
a
]
D
þ46.0 (c 0.37,
D
CHCl3). The physical properties of 4 are coincident with the ones of
O
O
O
O
O
HO
c
a
R
O
H
H
O
H
OH
O
O
OH
sibiricinone B, 3
R
8
14
β OH
b
=O
15
d
O
O
O
O
O
OH
OH
g
e
O
H
OR
OAc
H
H
O
O
OH
R
O
16
18
9
H
f
17 Ac
i
h
O
O
O
O
O
HO
HO
OH
OH
OH
j
OH
H
OAc
OH
H
H
O
O
O
leoheterin, 4
sibiricinone A, 2
19
1
Scheme 3. Reagents and conditions: (a) (i) DIBAL-H, DCM, ꢀ78 ꢁC, 30 min; (ii) LAH, Et2O, rt, 1 h (91%); (b) MnO2, DCM, rt, 2.5 h (89%); (c) O2, Rose Bengal, DIPEA, DCM, ꢀ78 ꢁC,
2.5 h (85%); (d) m-CPBA, DCM, rt, 40 h (98%); (e) (i) DIBAL-H, DCM, ꢀ78 ꢁC, 30 min; (ii) LAH, THF, 50 ꢁC, 24 h (70%); (f) Ac2O, Py, rt, 18 h (98%); (g) TPAP, NMO, sieves, DCM, rt, 3 h
1
(86%); (h) K2CO3, MeOH, rt, 50 min (99%); (i) O2, Rose Bengal, DIPEA, DCM, ꢀ78 ꢁC, 5 h (92%); (j) K2CO3, MeOH, rt, 1 h (97%).
22
For the synthesis of sibiricinone A 2 and leoheterin 4 (Scheme 3),
besides the adequate functionalization at C-6 and C-7 positions, it
was necessary to introduce an hydroxy group in C-9a (symbol) of B
ring and finally in the case of 2 to oxidize the side chain and to
the compound described by Wong et al., [
a
]
þ47.7 (c 0.65, EtOH),
D
so leoheterin has the structure and absolute configuration of 4.
24
Consequently, the compound described by Zdero et al.,7
[
a]
ꢀ48
D
(c 0.78, CHCl3), is the enantiomer of 4 and corresponds to the
structure of (ꢀ)-leoheterin 5.
achieve the g-hydroxybutenolide function.

I.S. Marcos et al. / Tetrahedron 64 (2008) 10860–10866
10863
Oxidation of 18 with 1O2 gave the
by alkaline hydrolysis rendered sibiricinone A 2, [
g
-hydroxybutenolide 19, that
4.2.2. 6
one (11)
Rf (hexane/OAcEt 4:6)¼0.39; [
(film): 1794, 1718, 1459, 1374, 1319, 1170, 1137, 1117, 1082, 1018; 1H
NMR
b,7b-Carbonyldioxy-16-methoxy-14,15-dinor-labd-8-en-13-
22
a
]
D
þ20.2 (c 0.27,
22
CHCl3). The physical properties of 2 are coincident with the ones
a
]
þ32.4 (c 0.76, CHCl3); IR
D
20
described by Tinto et al.4 for sibiricinone A, [
CHCl3).
a]
þ18.4 (c 0.64,
D
d
: 5.17 (1H, dd, J¼8.0 and 1.4 Hz, H-6), 4.90 (1H, d, J¼8.0 Hz, H-
7), 3.98 (2H, s, CH2OMe), 3.42 (3H, s, CH2OMe), 2.60–0.80 (11H, m),
1.72 (3H, s, Me-17), 1.24 (3H, s, Me-20), 1.19 (3H, s, Me-19), 1.03 (3H,
3. Conclusions
s, Me-18); 13C NMR
d: 208.1 (C-13), 155.4 (OCOO), 148.8 (C-9), 122.0
(C-8), 78.9 (C-7), 77.9 (C-16), 75.1 (C-6), 59.6 (OMe), 51.9 (C-5), 42.7
(C-3), 39.1 (C-10), 38.9 (C-1), 38.7 (C-12), 34.2 (C-4), 33.0 (C-18),
23.7 (C-19), 22.5 (C-20), 21.1 (C-11), 18.8 (C-2), 16.5 (C-17); EIHRMS
calcd for C20H30O5Na (MþNaþ): 373.195, found: 373.1958.
Starting from sclareol 6, has been carried out the synthesis of
two natural -hydroxybutenolides sibiricinone A 2 and sibir-
g
icinone B 3, and one natural furo-labdane leoheterin 4, from a very
valuable common intermediate 7. The synthesis of these com-
pounds has permitted us to establish unequivocally the structure
and absolute configuration of all of them. Currently these and
other dioxygenated labdanes at C-6 and C-7 are being biologically
evaluated.
4.3. Reaction of 10 with K2CO3/MeOH to yield 12 and 13
Compound 10 (110 mg, 0.291 mmol) was treated with K2CO3 in
MeOH (1%, 6 mL) and the mixture was stirred at room temperature
for 20 min. After that time, the reaction mixture was diluted with
H2O and 2 M HCl was added. The solution was then extracted with
EtOAc and the organic phase was washed with H2O and brine, dried
over Na2SO4, filtered and evaporated to give a crude oil, which was
chromatographed on silica gel to afford 12 (79 mg, 81%) and 13
(12 mg, 13%).
4. Experimental
4.1. General
Unless otherwise stated, all chemicals were purchased as the
highest purity commercially available and were used without fur-
ther purification. IR spectra were recorded on a BOMEM 100 FT-IR
or an AVATAR 370 FT-IR Thermo Nicolet spectrophotometers. 1H
and 13C NMR spectra were performed in CDCl3 and referenced to
4.3.1. 6
one (12)
Rf (hexane/OAcEt 4:6)¼0.53; [
b
,7
b
-Carbonyldioxy-16-hydroxy-14,15-dinor-labd-8-en-13-
22
a
]
þ46.5 (c 0.97, CHCl3); IR
D
the residual peak of CHCl3 at
13C, respectively, using Varian 200 VX and Bruker DRX 400 in-
struments. Chemical shifts are reported in parts per million and
d 7.26 ppm and d
77.0 ppm, for 1H and
(film): 3447,1793,1718,1458,1374,1174,1118,1076,1018; 1H NMR
d:
5.18 (1H, dd, J¼8.0 and 1.8 Hz, H-6), 4.90 (1H, d, J¼8.0 Hz, H-7), 4.25
d
(2H, s, CH2OH), 2.60–0.80 (11H, m), 1.73 (3H, s, Me-17), 1.24 (3H, s,
Me-20), 1.19 (3H, s, Me-19), 1.03 (3H, s, Me-18); 13C NMR
d: 208.6
coupling constants (J) are given in hertz. MS were performed using
a VG-TS 250 spectrometer at 70 eV ionizing voltage. Mass spectra
are presented as m/z (% rel int.). HRMS were recorded on a VG
Platform (Fisons) spectrometer using chemical ionization (ammo-
nia as gas) or Fast Atom Bombardment (FAB) technique. For some of
the samples, QSTAR XL spectrometer was employed for electro-
spray ionization (ESI). Optical rotations were determined on a Per-
kin–Elmer 241 polarimeter in 1 dm cells. Diethyl ether and THF
were distilled from sodium, and dichloromethane was distilled
from calcium hydride under argon atmosphere.
(C-13), 155.3 (OCOO), 148.3 (C-9), 122.4 (C-8), 78.8 (C-7), 75.0 (C-6),
68.2 (C-16), 51.9 (C-5), 42.7 (C-3), 39.2 (C-10), 38.8 (C-1), 38.3
(C-12), 34.2 (C-4), 33.0 (C-18), 23.7 (C-19), 22.6 (C-20), 21.3 (C-11),
18.8 (C-2), 16.5 (C-17); EIHRMS calcd for C19H28O5Na (MþNaþ):
359.1829, found: 359.1815.
4.3.2. 6
Rf (hexane/OAcEt 4:6)¼0.18; [
3600–300, 1793, 1716, 1458, 1374, 1171, 1138; 1H NMR
b,7b-Carbonyldioxy-14,15-dinor-labd-8-en-13-oic acid (13)
22
a
]
þ37.9 (c 0.99, CHCl3); IR (film):
D
d
: 5.18 (1H,
dd, J¼8.0 and 2.0 Hz, H-6), 4.91 (1H, d, J¼8.0 Hz, H-7), 2.60–0.80
4.2.
a
-Acetoxylation of 7 with LTA/BF3$Et2O to yield 10 and 11
(11H, m), 1.77 (3H, s, Me-17), 1.25 (3H, s, Me-20), 1.19 (3H, s, Me-19),
1.04 (3H, s, Me-18); 13C NMR
d: 180.6 (C-13),155.3 (OCOO),148.0 (C-
To a solution of 7 (163 mg, 0.508 mmol) in benzene (6.5 mL) and
MeOH (0.025 mL), Pb(OAc)4 (308 mg, 0.712 mmol) was added and
this mixture was treated under argon with BF3$Et2O (1 mL) and
stirred at room temperature for 50 min. Then the solution was di-
luted with Et2O and H2O was added. The mixture was extracted
with Et2O and washed with H2O and brine, the organic layer was
dried over Na2SO4, filtered and evaporated to give a crude oil,
which was chromatographed on silica gel to afford 7 (22 mg, 14%),
10 (115 mg, 60%) and 11 (37 mg, 21%).
9), 122.5 (C-8), 78.8 (C-7), 75.1 (C-6), 51.9 (C-5), 42.7 (C-3), 39.1 (C-
10), 38.7 (C-1), 34.2 (C-4), 33.7 (C-12), 33.0 (C-18), 23.7 (C-19), 23.0
(C-11), 22.5 (C-20), 18.8 (C-2), 16.4 (C-17); EIHRMS (Mþ) calcd for
C18H26O5: 322.1780, found: 322.1785.
4.4. Reaction of 12 with the Bestmann ketene to yield 8
To a solution of 12 (71 mg, 0.211 mmol) in dry benzene (9 mL),
Bestmann ketene (Ph3P]C]C]O)14 (133 mg, 0.423 mmol) was
added and the mixture was stirred 40 min at 85 ꢁC under argon.
Then the solution was cooled down to room temperature and
AcOEt was added. The resulting organic layer was washed with
H2O, dried over Na2SO4, filtered and evaporated to give a crude oil,
which was chromatographed on silica gel to afford 8 (64 mg, 84%).
4.2.1. 16-Acetoxy-6
b,7
b-carbonyldioxy-14,15-dinor-labd-8-en-13-
one (10)
22
Rf (hexane/OAcEt 1:1)¼0.39; [
a]
þ43.1 (c 1.09, CHCl3); IR
D
(film): 1795, 1740, 1732, 1463, 1417, 1375, 1323, 1233, 1171, 1118,
1077, 1018, 960, 781; 1H NMR
d
: 5.17 (1H, dd, J¼8.0 and 1.4 Hz, H-6),
4.90 (1H, d, J¼8.0 Hz, H-7), 4.63 (2H, s, CH2OAc), 2.60–0.80 (11H, m),
4.4.1. 6
Rf (hexane/OAcEt 4:6)¼0.37; [
(film): 1791,1746,1637,1458,1374,1324,1171,1140,1118,1081,1036,
1018; 1H NMR
b,7b-Carbonyldioxy-labd-8,13-dien-16,15-olide (8)
22
2.17 (3H, s, –OAc),1.72 (3H, s, Me-17), 1.23 (3H, s, Me-20),1.18 (3H, s,
a
]
þ48.7 (c 0.75, CHCl3); IR
D
Me-19), 1.03 (3H, s, Me-18); 13C NMR
d: 203.0 (C-13), 170.5
(OCOMe), 155.3 (OCOO), 148.5 (C-9), 122.2 (C-8), 78.8 (C-7), 75.1 (C-
6), 68.0 (C-16), 51.9 (C-5), 42.7 (C-3), 39.1 (C-10), 38.8 (C-1), 38.7 (C-
12), 34.2 (C-4), 33.0 (C-18), 23.7 (C-19), 22.6 (C-20), 21.0 (C-11), 20.7
(OCOMe), 18.8 (C-2), 16.5 (C-17); EIHRMS calcd for C21H30O6Na
(MþNaþ): 401.1935, found: 401.1940.
d
: 5.89 (1H, s, H-14), 5.21 (1H, dd, J¼8.4 and 1.0 Hz,
H-6), 4.92 (1H, d, J¼8.4 Hz, H-7), 4.75 (2H, br s, H-16), 2.60–0.80
(11H, m), 1.76 (3H, s, Me-17), 1.26 (3H, s, Me-20),1.20 (3H, s, Me-19),
1.05 (3H, s, Me-18); 13C NMR
d
: 173.8 (C-15), 169.3 (C-13), 155.2
(OCOO), 147.8 (C-9), 122.8 (C-8), 115.7 (C-14), 78.6 (C-7), 75.0 (C-6),

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I.S. Marcos et al. / Tetrahedron 64 (2008) 10860–10866
73.0 (C-16), 51.9 (C-5), 42.6 (C-3), 39.1 (C-10), 38.9 (C-1), 34.3 (C-4),
33.0 (C-18), 28.7 (C-12), 25.5 (C-11), 23.7 (C-19), 22.7 (C-20), 18.8
(C-2), 16.6 (C-17); EIHRMS calcd for C21H28O5Na (MþNaþ):
383.1907, found: 383.1859.
give a crude oil, which was chromatographed on silica gel to afford
3 (13 mg, 85%).
4.7.1. Sibiricinone B (3)
22
Rf (hexane/OAcEt 6/4)¼0.17; [
a
]
þ7.5 (c 0.42, CHCl3); IR (film):
D
3384, 1753, 1736, 1648,1624, 1604, 1459, 1378, 1332, 1121,1038, 948,
4.5. Reaction of 8 with DIBAL-H and LiAlH4 to yield 14
755; 1H NMR : 6.06 (1H, s, H-16), 6.05 (1H, s, H0-16), 5.95 (1H, s,
d
H-14), 4.34 (1H, d, J¼3.6 Hz, H-6), 2.70–0.80 (11H, m), 1.84 (3H, s,
To a solution of 8 (56 mg, 0.155 mmol) in CH2Cl2 (4 mL) at
ꢀ78 ꢁC, DIBAL-H (0.31 mL of solution 1.5 M in toluene, 0.466 mmol)
was added under argon. After 30 min the mixture was warmed up
to 0 ꢁC, quenched with wet Et2O and at room temperature, Et2O,
Na2SO4 (1.0 g) and NaHCO3 (0.8 g) were added. The solution was
stirred for 1 h, filtered through silica gel eluting with Et2O and
EtOAc, and concentrated to afford a crude oil, which was dissolved
in dry Et2O (5 mL) cooled at 0 ꢁC, treated with LiAlH4 (12 mg,
0.320 mmol) and stirred at room temperature for 1 h. Then, the
solution was cooled back to 0 ꢁC, wet EtOAc was added and the
mixture was filtered. The resulting organic phase was dried over
Na2SO4, filtered and evaporated affording 14 (45 mg, 91%).
Me-17), 1.41 (3H, s, Me-20), 1.31 (3H, s, Me-19), 1.06 (3H, s, Me-18);
13C NMR
d: 199.1 (C-7), 170.2 (C-15), 167.6 (C-13), 167.5 (C-9), 129.0
(C-8),118.0 (C-14), 98.3 (C-16), 70.9 (C-6), 53.3 (C-5), 43.2 (C-3), 41.1
(C-10), 37.5 (C-1), 34.1 (C-4), 32.4 (C-18), 26.8 (C-12), 26.7 (C-11),
23.9 (C-19), 22.1 (C-20), 18.6 (C-2), 11.7 (C-17); EIHRMS calcd for
C20H28O5Na (MþNaþ): 371.1829, found: 371.1840.
4.8. Epoxidation of 8 with m-CPBA to yield 16
To a solution of 8 (42 mg, 0.117 mmol) in dry CH2Cl2 (1 mL)
cooled at 0 ꢁC was added another solution of m-CPBA (31 mg,
0.175 mmol) in CH2Cl2 (1 mL). The reaction mixture was stirred at
room temperature for 40 h and then aqueous 10% NaHSO3 was
added. The mixture was extracted with EtOAc, washed with
aqueous 6% NaHCO3 and brine, and the organic layer was dried over
Na2SO4, filtered and evaporated to afford 16 (43 mg, 98%).
4.5.1. 15,16-Epoxy-labd-8,13(16),14-trien-6
b b-diol (14)
,7
22
Rf (hexane/OAcEt 6:4)¼0.47; [
a]
D
þ13.0 (c 0.67, CHCl3); IR (film):
3405, 1465, 1378, 1265, 1121, 1066, 1025, 929, 901, 874, 778, 739; 1H
NMR : 7.36 (1H, br s, H-15), 7.24 (1H, br s, H-16), 6.30 (1H, br s,
d
H-14), 4.33 (1H, d, J¼4.4 Hz, H-7), 4.00 (1H, dd, J¼4.4 and 1.0 Hz,
4.8.1. 6
en-16,15-olide (16)
Rf (hexane/OAcEt 4:6)¼0.51; [
b
,7
b
-Carbonyldioxy-8
a
,9
a
-epoxy-labd-13-
H-6), 2.60–0.80 (11H, m), 1.76 (3H, s, Me-17), 1.36 (3H, s, Me-20),
1.22 (3H, s, Me-19), 0.97 (3H, s, Me-18); 13C NMR
d: 143.9 (C-9),
22
a
]
þ28.8 (c 0.94, CHCl3); IR
D
143.0 (C-15), 138.7 (C-16), 125.8 (C-8), 125.6 (C-13), 111.0 (C-14),
73.5 (C-7), 68.0 (C-6), 53.2 (C-5), 43.0 (C-3), 40.1 (C-1), 40.1 (C-10),
34.0 (C-4), 33.8 (C-18), 28.2 (C-12), 25.3 (C-11), 24.2 (C-19), 22.1
(C-20), 19.2 (C-2), 15.1 (C-17); EIHRMS calcd for C20H30O3Na
(MþNaþ): 341.2087, found: 341.2086.
(film): 1802, 1736, 1636, 1449, 1375, 1325, 1260, 1167, 1130, 1077,
1044, 894, 851, 776; 1H NMR
d: 5.85 (1H, s, H-14), 5.02 (1H, dd,
J¼8.8 and 2.2 Hz, H-6), 4.78 (1H, d, J¼8.8 Hz, H-7), 4.73 (2H, br s,
H-16), 2.50–0.80 (11H, m), 1.41 (3H, s, Me-17), 1.28 (3H, s, Me-20),
1.18 (3H, s, Me-19), 1.02 (3H, s, Me-18); 13C NMR
d: 173.9 (C-15),
169.3 (C-13), 154.2 (OCOO), 115.7 (C-14), 75.8 (C-7), 74.4 (C-6), 73.2
(C-16), 70.6 (C-9), 60.8 (C-8), 42.9 (C-5), 42.8 (C-3), 37.8 (C-10), 36.8
(C-1), 34.0 (C-4), 33.1 (C-18), 25.5 (C-12), 24.0 (C-19), 23.5 (C-11),
20.1 (C-20), 18.3 (C-2), 17.3 (C-17); EIHRMS calcd for C21H28O6Na
(MþNaþ): 399.1778, found: 399.1766.
4.6. Reaction of 14 with MnO2 to yield 15
To a solution of 14 (38 mg, 0.119 mmol) in dry CH2Cl2 (3 mL) was
added MnO2 (519 mg, 5.975 mmol). The reaction mixture was
stirred at room temperature for 2.5 h and then was filtered through
CeliteÒ eluting with CH2Cl2 and AcOEt. The solvent was evaporated
to afford 15 (34 mg, 89%).
4.9. Reduction of 16 with DIBAL-H and LiAlH4 to yield 9
To a solution of 16 (39 mg, 0.104 mmol) in CH2Cl2 (3.8 mL) at
ꢀ78 ꢁC, DIBAL-H (0.21 mL of solution 1.5 M in toluene, 0.32 mmol)
was added under argon. After 30 min the mixture was warm up to
0 ꢁC, quenched with wet Et2O and at room temperature, Et2O,
Na2SO4 (1.0 g) and NaHCO3 (1.0 g) were added and the solution was
stirred for 1 h, filtered through silica gel eluting with Et2O and
EtOAc, and concentrated to afford a crude oil, which was dissolved
in dry THF (2 mL) cooled at 0 ꢁC and treated with LiAlH4 (8 mg,
0.250 mmol) and stirred at 50 ꢁC for 24 h under argon. Then, the
solution was cooled back to 0 ꢁC, wet EtOAc was added and the
mixture filtered. The resulting organic phase was dried over
Na2SO4, filtered and evaporated affording 9 (24 mg, 70%).
4.6.1. 6
Rf (hexane/OAcEt 6:4)¼0.62; [
3406, 1651, 1604, 1462, 1378, 1157, 1121, 1067, 1026, 872, 784; 1H
NMR : 7.38 (1H, br s, H-15), 7.28 (1H, br s, H-16), 6.32 (1H, br s,
b-Hydroxy-15,16-epoxy-labd-8,13(16),14-trien-7-one (15)
22
a]
þ16.3 (c 0.91, CHCl3); IR (film):
D
d
H-14), 4.33 (1H, br s, H-6), 2.70–0.70 (11H, m), 1.86 (3H, s, Me-17),
1.39 (3H, s, Me-20),1.30 (3H, s, Me-19), 1.06 (3H, s, Me-18); 13C NMR
d: 199.6 (C-7), 170.0 (C-9), 143.3 (C-15), 138.9 (C-16), 128.7 (C-8),
124.7 (C-13), 110.8 (C-14), 71.3 (C-6), 53.4 (C-5), 43.6 (C-3), 41.3
(C-10), 37.7 (C-1), 34.4 (C-4), 32.6 (C-18), 30.9 (C-12), 24.6 (C-11),
24.2 (C-19), 22.4 (C-20), 19.0 (C-2), 11.9 (C-17); EIHRMS calcd for
C20H28O3Na (MþNaþ): 339.1931, found: 339.1931.
4.7. Oxidation of 15 with 1O2 to yield 3
4.9.1. 15,16-Epoxy-labda-13(16),14-dieno-6b b a-triol (9)
,7
,9
22
Rf (hexane/OAcEt 4:6)¼0.59; [
a]
þ7.4 (c 0.50, CHCl3); IR (film):
D
Rose Begal (1.5 mg) was added to a solution of 15 (14 mg,
0.044 mmol) and DIPEA (0.085 mL, 0.488 mmol) in CH2Cl2 (4.5 mL)
at room temperature. Anhydrous oxygen was bubbled in for 2 min,
and after that the solution was placed under oxygen atmosphere at
ꢀ78 ꢁC and irradiated with a 200 W lamp. After 2.5 h irradiation
was stopped, the pink solution was allowed to warm to room
temperature, and saturated oxalic acid solution (7 mL) and H2O
were added. After 30 min of vigorous stirring the mixture was
extracted with CH2Cl2 and the combined organics extracts were
washed with H2O, dried over Na2SO4, filtered and evaporated to
3405, 1459, 1383, 1239, 1156, 1126, 1025, 938, 874, 777; 1H NMR
d:
7.34 (1H, br s, H-15), 7.22 (1H, br s, H-16), 6.27 (1H, br s, H-14), 4.23
(1H, br s, H-6), 3.46 (1H, d, J¼10.6 and 3.6 Hz, H-7), 2.60–0.80 (12H,
m), 1.26 (3H, s, Me-20), 1.12 (3H, d, J¼7.0 Hz, Me-17), 0.99 (3H, s,
Me-19), 0.99 (3H, s, Me-18); 13C NMR
d: 143.2 (C-15), 138.7 (C-16),
125.5 (C-13), 111.0 (C-14), 78.8 (C-9), 74.2 (C-7), 70.6 (C-6), 47.6
(C-5), 43.7 (C-3), 43.4 (C-10), 38.3 (C-8), 35.3 (C-1), 34.4 (C-4), 34.0
(C-18), 30.0 (C-12), 25.0 (C-19), 21.7 (C-11), 19.9 (C-20), 18.9 (C-2),
11.5 (C-17); EIHRMS calcd for C20H32O4Na (MþNaþ): 359.2193,
found: 359.2186.

I.S. Marcos et al. / Tetrahedron 64 (2008) 10860–10866
10865
4.10. Acetylation of 9 to yield 17
12.4 (C-17); EIHRMS calcd for C20H30O4Na (MþNaþ): 357.2036,
found: 357.2052.
To a solution of 9 (24 mg, 0.071 mmol) in dry pyridine (0.70 mL),
acetic anhydride (0.70 mL) was added and the mixture was stirred
at room temperature for 18 h. The reaction mixture was poured into
ice-water and extracted with EtOAc. The organic layer was washed
successively with aqueous 2 M HCl, aqueous 6% NaHCO3 and water.
The resulting solution was then dried over Na2SO4 and evaporated
to afford 17 (27 mg, 69%).
4.13. Oxidation of 18 with 1O2 to yield 19
Rose Bengal (1.1 mg) was added to a solution of 18 (8.8 mg,
0.023 mmol) and DIPEA (0.042 mL, 0.241 mmol) in CH2Cl2 (2.2 mL)
at room temperature. Anhydrous oxygen was bubbled in for 10 min,
and after that the solution was placed under oxygen atmosphere at
ꢀ78 ꢁC and irradiated with a 200 W tungsten incandescent lamp.
After 5 h irradiation was stopped, the pink solution was allowed to
warm to room temperature, and saturated oxalic acid solution
(5 mL) and H2O were added. After 30 min of vigorous stirring the
mixture was extracted with CH2Cl2 and the combined organics
extracts were washed with H2O, dried over Na2SO4, filtered and
evaporated to afford 19 (8.6 mg, 92%).
4.10.1. 7
diene-6
Rf (hexane/OAcEt 6:4)¼0.74; [
1368, 1237, 1129, 1025, 971, 873, 775; 1H NMR
b
-Acetoxy-15,16-epoxy-labda-13(16),14-
b
,9 -diol (17)
a
a]
22; IR (film): 3539, 1737, 1462,
D
d
: 7.35 (1H, br s,
H-15), 7.22 (1H, br s, H-16), 6.27 (1H, br s, H-14), 4.92 (1H, dd, J¼11.2
and 3.4 Hz, H-7), 4.29 (1H, br s, H-6), 2.60–0.80 (12H, m), 2.12 (3H,
s, MeCOO), 1.29 (3H, s, Me-20), 1.25 (3H, s, Me-19), 0.97 (3H, d,
J¼6.2 Hz, Me-17), 0.97 (3H, s, Me-18); EIHRMS calcd for C22H34O5Na
(MþNaþ): 401.2298, found: 401.2288.
4.13.1. 7
en-16,15-olide (19)
Rf (hexane/OAcEt 4:6)¼0.48; [
b
-Acetoxy-9
a
,16-dihydroxy-6-oxo-labd-13-
22
a]
þ55.3 (c 0.39, CHCl3); IR
D
(film): 3398, 1736, 1648, 1460, 1373, 1259, 1128, 1042, 949, 910, 742;
4.11. Oxidation of 17 with TPAP to yield 18
1H NMR
d
: 6.04 (1H, br s, H-16), 5.88 (1H, br s, H-14), 5.04 (1H, d,
J¼11.4 Hz, H-7), 2.89 (1H, s, H-5), 2.60–0.80 (11H, m), 2.18 (3H, s,
MeCOO), 1.25 (3H, s, Me-18), 1.09 (3H, d, J¼6.6 Hz, Me-17), 0.96 (3H,
To a mixture of 17 (33 mg, 0.087 mmol), N-methylmorpholine
N-oxide (NMO) (50 mg, 0.370 mmol) and molecular sieves
(120 mg) in dry CH2Cl2 (2 mL) was added TPAP (3 mg, 0.009 mmol).
The reaction mixture was stirred at room temperature for 3 h under
argon and then was filtered through silica gel and CeliteÒ eluting
with AcOEt. The solvent was evaporated to give a crude oil, which
was chromatographed on silica gel to afford 18 (28 mg, 86%).
s, Me-19), 0.94 (3H, s, Me-20); 13C NMR
d: 204.9 (C-6), 171.3 (C-15),
170.9 (MeCOO), 169.3 (C-13), 117.8 (C-14), 99.2 (C-16), 79.4 (C-7),
77.3 (C-9), 56.4 (C-5), 48.7 (C-10), 47.6 (C-8), 42.3 (C-3), 32.8 (C-18),
32.6 (C-4), 31.8 (C-1), 31.1 (C-11), 24.4 (C-12), 22.4 (C-19), 21.0
(MeCOO), 18.3 (C-2), 18.2 (C-20), 12.4 (C-17); EIHRMS calcd for
C22H32O7Na (MþNaþ): 431.2040, found: 431.2036.
4.11.1. 7
6-one (18)
Rf (hexane/OAcEt 8:2)¼0.55; [
b
-Acetoxy-9
a
-hydroxy-15,16-epoxy-labda-13(16),14-dien-
4.14. Reaction of 19 with K2CO3/MeOH to yield 2
22
a
]
þ71.3 (c 0.64, CHCl3); IR
D
Compound 19 (6.0 mg, 0.015 mmol) was treated with K2CO3 in
MeOH (2%, 1.5 mL) and the mixture was stirred at room tempera-
ture for 1 h. After that time, the reaction mixture was diluted with
H2O and 2 M HCl was added. The solution was then extracted with
EtOAc and the organic phase was washed with water and brine,
dried over Na2SO4, filtered and evaporated to give a crude oil,
which was chromatographed on silica gel to afford 2 (6 mg, 97%).
(film): 3531,1740, 1710,1461, 1370,1241, 1158, 1103, 1042, 1025, 966,
908, 782; 1H NMR
d: 7.38 (1H, br s, H-15), 7.26 (1H, br s, H-16), 6.28
(1H, br s, H-14), 5.05 (1H, d, J¼11.6 Hz, H-7), 2.91 (1H, s, H-5), 2.60–
0.80 (11H, m), 2.18 (3H, s, MeCOO), 1.27 (3H, s, Me-18), 1.12 (3H, d,
J¼6.6 Hz, Me-17), 0.96 (3H, s, Me-19), 0.93 (3H, s, Me-20); 13C NMR
d: 205.2 (C-6), 170.6 (MeCOO), 143.5 (C-15), 138.9 (C-16), 124.8
(C-13), 110.9 (C-14), 79.5 (C-7), 77.6 (C-9), 56.5 (C-5), 48.6 (C-10),
43.9 (C-8), 42.4 (C-3), 34.6 (C-1), 32.8 (C-18), 32.5 (C-4), 31.8 (C-12),
22.4 (C-19), 21.6 (C-11), 21.0 (MeCOO), 18.4 (C-2), 18.2 (C-20), 12.4
(C-17); EIHRMS calcd for C22H32O5Na (MþNaþ): 399.2142, found:
399.2160.
4.14.1. Sibiricinone A (2)
22
Rf (hexane/OAcEt 4:6)¼0.30; [
a]
þ20.2 (c 0.27, CHCl3); IR
D
(film): 3406, 1740, 1647, 1461, 1384, 1263, 1127, 1042, 951, 907, 737;
1H NMR
d: 6.03 (1H, br s, H-16), 5.90 (1H, br s, H-14), 3.86 (1H, d,
J¼11.4 Hz, H-7), 2.91 (1H, s, H-5), 2.70–0.80 (11H, m), 1.30 (3H, s,
Me-18), 1.24 (3H, d, J¼6.6 Hz, Me-17), 0.98 (3H, s, Me-19), 0.91 (3H,
4.12. Reaction of 18 with K2CO3/MeOH to yield 4
s, Me-20); 13C NMR
d: 211.5 (C-6), 170.5 (C-15), 169.3 (C-13), 118.2
Compound 18 (4.2 mg, 0.011 mmol) was treated with K2CO3 in
MeOH (2%, 0.7 mL) and the mixture was stirred at room tempera-
ture for 50 min. After that time, the reaction mixture was diluted
with H2O and 2 M HCl was added. The solution was then extracted
with EtOAc and the organic phase was washed with water and
brine, dried over Na2SO4, filtered and evaporated to afford 4
(3.7 mg, 99%).
(C-14), 98.7 (C-16), 77.4 (C-9), 77.2 (C-7), 56.5 (C-5), 49.3 (C-10), 47.7
(C-8), 42.1 (C-3), 32.9 (C-18), 32.5 (C-4), 31.9 (C-1), 31.2 (C-11), 22.5
(C-19), 21.7 (C-12), 18.3 (C-20), 18.2 (C-2), 12.7 (C-17); EIHRMS calcd
for C20H30O6Na (MþNaþ): 389.1935, found: 389.1950.
Acknowledgements
The authors are gratefully acknowledged to Dr. A. Lithgow and
Dr. C. Raposo, from the NMR and Mass Spectrometry Services, re-
spectively, of Universidad de Salamanca and to the CICYT
(CTQ2005-04406) for financial support. L.C.G. is grateful to Junta de
4.12.1. Leoheterin (4)
22
Rf (hexane/OAcEt 8:2)¼0.47; [
a
]
þ46.0 (c 0.37, CHCl3); IR
D
(film): 3464, 1706, 1461, 1384, 1258, 1161, 1126, 1096, 1046, 967, 906,
873; 1H NMR
d
: 7.37 (1H, br s, H-15), 7.26 (1H, br s, H-16), 6.28 (1H,
´
Castilla y Leon for a fellowship.
br s, H-14), 3.89 (1H, d, J¼10.6 Hz, H-7), 2.95 (1H, s, H-5), 2.60–0.80
(11H, m), 1.31 (3H, s, Me-18), 1.26 (3H, d, J¼6.4 Hz, Me-17), 0.97 (3H,
s, Me-19), 0.90 (3H, s, Me-20); 13C NMR
d: 211.9 (C-6), 143.2 (C-15),
References and notes
138.6 (C-16), 124.8 (C-13), 110.6 (C-14), 77.2 (C-9), 77.0 (C-7), 55.9
(C-5), 49.0 (C-10), 47.6 (C-8), 42.0 (C-3), 34.3 (C-1), 32.6 (C-18), 32.1
(C-4), 31.6 (C-12), 22.2 (C-19), 21.3 (C-11), 18.1 (C-2), 18.0 (C-20),
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