Synthesis of (+)-leopersin D

Article abstract of DOI:10.1016/j.tet.2009.09.010

This paper describes the use of (-)-sclareol in the first synthesis of the spirolabdanolide (+)-leopersin D, which also establishes the absolute configuration of the product. The reversibility of conjugate addition/elimination of oxaspirolabdanolide forma

Full text of DOI:10.1016/j.tet.2009.09.010

Tetrahedron 65 (2009) 9256–9263
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of (þ)-leopersin D
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 2 July 2009
Received in revised form 10 August 2009
Accepted 3 September 2009
Available online 9 September 2009
This paper describes the use of (ꢀ)-sclareol in the first synthesis of the spirolabdanolide (þ)-leopersin D,
which also establishes the absolute configuration of the product. The reversibility of conjugate addition/
elimination of oxaspirolabdanolide formation is demonstrated.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Labdanes
Diterpenes
Leopersin
Sclareol
Oxo-Michael
1. Introduction
Our group is studying the synthesis of highly functionalized B
ring diterpenes, such as labdanes,6 furolabdanes7 and labdeno-
Labdane diterpenes with highly functionalized B rings consti-
tute an interesting class of natural products with important bio-
logical activities.1
Labdanes bearing a dioxaspiro group with oxygen at C-9 rep-
resent a group of natural products that are sufficiently significant
from a structural point of view.
lides7 beginning with (ꢀ)-sclareol. In this paper we communicate
the first synthesis of the spirolabdanolide (þ)-leopersin D, starting
from commercial (ꢀ)-sclareol. The pivotal step of the synthesis was
an intramolecular conjugate addition to make the spirolabdane. As
(þ)-leopersin D was synthesized from a diterpene of known con-
figuration, its absolute configuration was established, Figure 3.
Currently, 29 natural spirolabdanes with a highly functionalized
B ring are known, some of which are shown in Figure 1. All of these
compounds have been isolated from plants of the genus Leonorus,2
Otostegia3 or Ballota.4 The genus Leonorus is a widely distributed,
medicinally important member of the Lamiaceae family that
comprises more than 20 species. Preparations from some of the
plants of this genus are utilized in the treatment of cardiovascular
diseases, as sedatives, antitumor and for their uterotonic effects.2b
(þ)-Leopersin D is an example of a natural spirolabdanolide
with a highly functionalized B ring. It was first isolated and char-
acterized by Tasdermir and co-workers in 1996 from the aerial
parts of Leonorus persicus.2a
Surprisingly, there are few publications on the synthesis of
spirolabdanes. The only example in the literature was the synthesis
of prehispanolone reported by Wong,5 Figure 2. The spirolabdane
prehispanolone was found to be unstable under acidic conditions
providing the corresponding furolabdane, hispanolone.5c
2. Results and discussion
The syntheses of the spirolabdanolides (þ)-leopersin D 1, and
13-epi-leopersin D 2 were planned according to the following ret-
rosynthetic scheme, Scheme 1.
The key intermediate for the elaboration of the target com-
pounds 1 and 2 is the butenolide 7, which by intramolecular con-
jugate addition generates the oxaspiro group. The butenolide 7 can
be accessed from 4 by functionalization of the side chain and fitting
the B ring functionality. The triol 4 obtained from (ꢀ)-sclareol 3 has
been used before in the synthesis of natural compounds by our
group.6,7
Initially the synthesis of 7 will be described, followed by that of
1 and 2.
2.1. Synthesis of intermediate 7
The synthesis of 7 from triol 4 is carried out according to Scheme 2,
by protecting the diol at C-6 and C-7 and subsequently altering the
side chain.
* Corresponding author. Tel.: þ34 923 294474; fax: þ34 923 294574.
E-mail address: ismarcos@usal.es (I.S. Marcos).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.010

I.S. Marcos et al. / Tetrahedron 65 (2009) 9256–9263
9257
O
15
O
13
16
20
O
O
O
1
4
O
O
O
O
17
9
10
8
5
O
OH
OH
OH
H
H
H
H
OH
O
O
O
19
18
iso-preleoheterin
leopersin D
preleoheterin
epi-preleoheterin
O
OH
OH
O
O
O
O
OMe
O
O
O
O
O
H
O
OH
O
H
H
H
OH
O
OH
OH
leopersin K
sibiricinone E
leopersin J
leopersin C
Figure 1.
2.2. Synthesis of (D)-leopersin D, 1 and (D)-13-epi-
leopersin D, 2
O
O
O
OH
Ref. 5
HCl
The structures of 1 and 2 differ in the configuration of C-13,
being R in 1 and S in 2.
O
O
H
H
The intramolecular conjugate addition of 7, shown in Scheme 3,
provides an inseparable mixture of the spirolabdanolides 8 and 9.
This reaction was carried out in various conditions. When DBU/
Et3N5 (a) was used, a mixture of 8/9 (1:1) was obtained and when
R-(-)-1,10-binaphthyl-2,20-diyl hydrogenophosphate10 (b), S-(þ)-1,10-bi-
naphthyl-2,20-diyl hydrogenophosphate10 (c) or S-(þ)-1-(2-pyrroli-
dinylmethyl)pyrrolidine (d) were used, a mixture of 8/9 (3:7) was
obtained.
The different proportion of 8 and 9 obtained can be explained as
the thermodynamic equilibrium is only reached with DBU/Et3N; in
the other cases the major product 9 obtained, corresponded to the
addition of the more stable conformer of 7, Figure 4.
Hydrolysis with K2CO3 in MeOH of the mixture 8/9 (1:1)
obtained from the reaction using DBU/Et3N led to another in-
separable mixture 10/11 (1:1) in quantitatively yield, Scheme 4. The
acetylation of this mixture followed by the oxidation with TPAP11
was shown to afford 12/13 (1:1). Finally the hydrolysis of 12/13
(1:1) with K2CO3 in MeOH provided a mixture (1:1) of compounds
1 and 2.
hispanolone
prehispanolone
Figure 2.
HO
O
13S
O
13R
O
O
O
O
OH
+
H
OH
OH
H
H
O
(+)-leopersin D, 1
O
(-)-sclareol, 3
2
Figure 3.
The reaction of 4 with triphosgene8 was found to give the car-
bonate 5 quantitatively. The ulterior oxidation of 5 with 1O2 using
Faulkner methodology9 afforded the
g-hydroxybutenolide 6. Fi-
nally 7 was obtained by the reduction of 6 with NaBH4, with an
overall yield from 4 of 54%.
When the mixture 8/9 (3:7) was hydrolyzed with K2CO3 in the
conditions used before, the same mixture as before 10/11 (1:1) was
O
13R
O
O
O
O
O
15
HO
OH
H
13
O
16
20
(+)-leopersin D, 1
17
OH
OH
1
9
10
8
OH
5
4
OH
O
H
H
H
18
OH
O
19
O
13S
O
4
(-)-sclareol, 3
7
O
O
OH
H
O
2
Scheme 1.

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I.S. Marcos et al. / Tetrahedron 65 (2009) 9256–9263
O
O
HO
OH
OH
a
b
OH
7
6
O
OH
H
H
H
O
OH
O
5
4
sclareol, 3
c
O
O
O
O
HO
OH
OH
d
O
O
H
H
O
O
O
O
6
7
Scheme 2. Reagents and conditions: a) 16 steps, 5% global yield,6,7; b) (Cl3CO)2CO, DCM, Py, ꢀ78 ꢁC, 40 min, (100%); c) 1O2, Rose Bengal, DIPEA, DCM, ꢀ78 ꢁC, 12 h, (95%); d) NaBH4,
EtOH, rt, 20 min, (57%).
O
Reagent
8/9 Yield (%)
13R
a
b
DBU
1:1
3:7
74
80
O
O
O
O
O
O
P
O
H
OH
O
O
O
OH
8
a, b, c or d
+
13S
O
O
O
OH
O
O
H
P
O
3:7
3:7
83
79
c
O
O
O
7
O
N
H
d
N
H
O
H
O
9
Scheme 3. Reagents and conditions: a) DBU, Et3N, 90 ꢁC, 1 h, (74%, 8/9: 1/1); b) R-(-)-1,10-binaphthyl-2,20-diyl hydrogenophosphate, toluene, 80 ꢁC, 72 h, (80%, 8/9: 3/7);
c) S-(þ)-1,10-binaphthyl-2,20-diyl hydrogenophosphate, toluene, 80 ꢁC, 82 h, (83%, 8/9: 3/7); d) S-(þ)-1-(2-pyrrolidinylmethyl)pyrrolidine, toluene, 80 ꢁC, 22 h, (79%, 8/9: 3/7).
To separate these epimers, the mixture 10/11 was treated with
(R)-C6H5C(OMe)(CF3)COOH12 and 14/15 were obtained. Fortunately
these compounds could be separated by column chromatography
and the relative configurations of C-13 were established by 2D
ROESY, Figure 5. 14 was shown to have 13R configuration, as the
NOE between Me-17 and H-16 was observed, and 15 was shown to
have 13S configuration, as the NOE between Me-17 and H-14 was
observed.
O
O
OH
Once the epimers at C-13 were separated, the synthesis of 1
and 2 was attempted by oxidation of 14 as described pre-
viously; this was unsuccessful, presumably due to steric or
electronic interactions with the Mosher ester. However the
oxidation of 14 with CrO3/py13 at 45 ꢁC gives 16 and in the same
way 15 is transformed into 17, as shown in Scheme 5. When 16
was treated with KOH/MeOH a mixture of 1/2 was obtained
identical to the mixture found when 17 was subjected to the
same conditions, and also similar to the mixture when 12/13
was hydrolyzed to give 1/2. This corroborates that in basic
conditions a retro-Michael reaction occurs and an ulterior cyc-
lisation takes place with both conformers of the open side
chain.
O
H
O
O
7
Figure 4. Molecular model made by ChemBioOfficeÒ and is included for better un-
derstanding of the structure.
obtained, Scheme 5. This supports the view that the products are in
equilibrium. An attempt to separate the C-13 epimers was made,
through the preparation of derivatives as shown in Scheme 5.

I.S. Marcos et al. / Tetrahedron 65 (2009) 9256–9263
9259
O
O
13S
13R
O
O
O
O
a
8 / 9
+
1:1
OH
OH
H
H
OH
OH
10
1:1
11
b
O
O
O
13R
13S
O
O
O
O
O
O
O
O
O
c
+
+
OAc
OAc
OH
OH
H
H
H
H
O
O
O
O
12
13
1
2
1:1
Scheme 4. Reagents and conditions: a) K2CO3, MeOH, rt, 22 h, (99%; 10/11: 1/1); b) i) Ac2O, Py, rt, 18 h; ii) TPAP, NMO, sieves, DCM, rt, 4 h, (85%; 12/13: 1:1); c) K2CO3, MeOH, rt,
90 min, (1, 47%; 2, 47%).
O
13R
13S
O
O
O
O
O
a
8 / 9
+
3:7
OH
OH
H
H
OH
10
OH
1:1
b
11
O
O
O
13R
O
O
O
O
O
O
c
+
Ph CF3
OMe
Ph CF3
OMe
Ph CF3
OMe
O
O
O
H
H
H
OH
O
OH
O
O
O
15
16
14
e
d
O
13S
O
13S
O
13R
O
O
O
O
f
O
O
+
Ph CF3
OMe
O
O
OH
H
OH
H
H
O
O
O
17
2
1
Scheme 5. Reagents and conditions: a) K2CO3, MeOH, rt, 22 h, (99%, 10/11: 1/1); b) C6H5C(OMe)(CF3)COOH, DCC, DMAP, DCM, rt, 16 h (14, 39%; 15, 42%); c) CrO3, Py, DCM, 45 ꢁC, 1 h,
(81%); d) CrO3, Py, DCM, 45 ꢁC, 1 h, (89%); e) K2CO3, MeOH, rt, 15 h, (1, 47%; 2, 47%);f) K2CO3, MeOH, rt, 15 h, (1, 47%; 2, 47%).
Luckily 1/2 could be separated by column chromatography using
DCM and Et2O as solvents. The ROESY experiment shows NOEs
between Me-17 and H-16 for 1 (13R) and between Me-17 and H-14
for 2 (13S), Figure 6. The physical properties of the natural com-
pound, isolated from Leonorus persicus, ½a D22
þ26.3 (c 0.18, CHCl3),
ꢂ
are coincident with the ones of 1, ½a D22
þ25.4 (c 0.14, CHCl3); so the
ꢂ

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I.S. Marcos et al. / Tetrahedron 65 (2009) 9256–9263
O
13R
13S
O
O
O
16
17
O
O
14
17
Ph CF3
Ph CF3
O
H
OMe
O
OH
14
H
OMe
O
OH
15
O
Figure 5. Molecular model made by ChemBioOfficeÒ and is included for better understanding of the structures and the NOEs experiments.
O
13S
O
13R
O
O
O
14
17
16
17
O
OH
H
OH
H
O
O
1
2
Figure 6. Molecular model made by ChemBioOfficeÒ and is included for better understanding of the structures and the NOEs experiments.
structure and absolute configuration for the natural compound is
established, as shown in Figure 6.
(ESI). Optical rotations were determined on a Perkin–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.
3. Conclusions
Starting from (ꢀ)-sclareol the syntheses of two spirolab-
danolides, 1 and 2, have been carried out for the first time. Com-
pound 1 has been shown to have identical properties to the
natural product (þ)-leopersin D, the structure of the natural
compound has been corroborated and the absolute configuration
established. In addition it has been reported that when the oxo-
spirolabdanolides are subjected to basic conditions a retro-Mi-
chael/Michael addition occurs, the first case described for this
type of compounds.
4.2. Reaction of 4 with triphosgene to yield 5
To a solution of triphosgene (14 mg, 0.048 mmol) in pyridine
(0.04 mL) and CH2Cl2 (0.2 mL) cooled at ꢀ78 ꢁC was added a solu-
tion of 4 (16 mg, 0.048 mmol) in CH2Cl2 (0.6 mL). The reaction
mixture was stirred until it warmed up to room temperature and
then saturated NH4Cl solution (1 mL) was added. The mixture was
extracted with Et2O and washed with 2 M HCl, aqueous 6% NaHCO3
and brine. The organic layer was dried over Na2SO4, filtered and
evaporated to afford 5 (17 mg, 100%).
4. Experimental
4.1. General
4.2.1. (8R)-6b,7b-Carbonyldioxy-15,16-epoxy-labda-13(16),14-dien-
9
a
-ol (5). Rf (Hex/EtOAc 6/4)¼0.55; ½a D22
þ15.8 (c 0.79, CHCl3); IR
ꢂ
(film): 3435, 1786, 1459, 1383, 1262, 1149, 1096, 1033, 943, 874, 799,
739; 1H NMR (200 MHz)
d: 7.37 (1H, br s, H-16), 7.24 (1H, br s, H-15),
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
the residual peak of CHCl3 at
13C, respectively, using Varian 200 VX and Bruker DRX 400 in-
struments. Chemical shifts are reported in ppm and coupling
constants (J) are given in hertz. MS were performed at 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 (ammonia as gas) or Fast
Atom Bombardment (FAB) technique. For some of the samples,
QSTAR XL spectrometer was employed for electrospray ionization
6.27 (1H, br s, H-14), 4.96 (1H, dd, J¼6.2 and 3.0 Hz, H-7), 4.32 (1H,
dd, J¼9.8 and 6.2 Hz, H-6), 2.80–0.80 (12H, m), 1.25 (3H, s, Me-20),
1.21 (3H, d, J¼6.6 Hz, Me-17), 1.18 (3H, s, Me-19), 1.05 (3H, s, Me-18);
13C NMR (50 MHz)
d: 156.0 (OCOO), 143.5 (C-15), 138.9 (C-16), 124.9
d 7.26 ppm and d
77.0 ppm, for 1H and
(C-13), 110.9 (C-14), 82.1 (C-7), 78.0 (C-9), 77.6 (C-6), 48.5 (C-5), 43.0
(C-3), 42.5 (C-10), 38.8 (C-8), 34.4 (C-4), 33.8 (C-1), 32.8 (C-18), 32.8
(C-12), 24.0 (C-19), 21.4 (C-11), 18.6 (C-2), 18.2 (C-20), 12.7 (C-17);
EIHRMS: calcd for C21H30O5Na: 385.1985, found 385.1977.
d
4.3. Oxidation of 5 with 1O2 to yield 6
Rose Bengal (1.1 mg) was added to a solution of 5 (160 mg,
0.442 mmol) and DIPEA (diisopropylethylamine) (0.79 mL) in

I.S. Marcos et al. / Tetrahedron 65 (2009) 9256–9263
9261
and concentrated to give a crude oil, which was chromato-
graphed on silica gel to afford 8/9 (3:7) (4 mg, 83%).
CH2Cl2 (39 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 lamp.
After 12 h, irradiation was stopped and the pink solution was
allowed to warm to room temperature and saturated oxalic acid
solution (50 mL) and H2O were added. After 30 min of vigorous
stirring the mixture was extracted with CH2Cl2 and the combined
organic extracts were washed with H2O, dried over Na2SO4, filtered
and evaporated to afford 6 (166 mg, 95%).
d) To a solution of 7 (5 mg, 0.015 mmol) in toluene (0.5 mL) is added
S-(þ)-1-(2-pyrrolidinylmethyl)pyrrolidine (4 mg, 0.029 mmol)
and the mixture is heated at 80 ꢁC for 22 h. After that time, H2O
(1 mL) is added, the mixture is extracted with EtOAc and the or-
ganic layer washed successively with 2 M HCl, aqueous 6%
NaHCO3 and H2O, dried over Na2SO4 filtered and concentrated to
give a crude oil, which was chromatographed on silica gel to af-
ford 8/9 (3:7) (4 mg, 79%).
4.3.1. (8R)-6b,7b-Carbonyldioxy-9a,16-dihydroxy-labd-13-en-15,16-
olide (6). Rf (Hex/EtOAc 4/6)¼0.40; ½a D22
ꢀ93.5 (c 0.90, CHCl3); IR
ꢂ
4.5.1. (8R)-6b,7b-Carbonyldioxy-9R,13R/S-epoxy-labdan-15,16-olide
(film): 3399,1786,1763, 1648,1461, 1379, 1263,1112,1034, 945, 800,
(8/9). 8/9 (1:1): Rf (Hex/EtOAc 4/6)¼0.57; ½a D22
þ13.9 (c 0.54,
ꢂ
737; 1H NMR (200 MHz)
d: 6.02 (1H, br s, H-16), 5.86 (1H, br s, H-
CHCl3); IR (film): 3399, 1792, 1716, 1459, 1377, 1167, 1096, 1031,
1020; EIHRMS: calcd for C21H30O6Na: 401.1935, found 401.1946.
14), 4.97 (1H, dd, J¼6.2 and 3.0 Hz, H-7), 4.32 (1H, dd, J¼9.4 and
6.2 Hz, H-6), 2.60–0.80 (12H, m),1.25 (3H, s, Me-20),1.19 (3H, s, Me-
19), 1.17 (3H, d, J¼6.6 Hz, Me-17), 1.06 (3H, s, Me-18); 13C NMR
8: 1H NMR (200 MHz)
d
: 4.95 (1H, dd, J¼6.2 and 3.2 Hz, H-7),
4.33 (1H, d, J¼9.2 Hz, H-16), 4.21 (1H, d, J¼9.2 Hz, H-16), 4.20 (1H,
dd, J¼10.0 and 6.2 Hz, H-6), 2.86 (1H, d, J¼17.4 Hz, H-14), 2.55 (1H,
d, J¼17.2 Hz, H-14), 2.40–0.80 (12H, m), 1.18 (3H, s, Me-20),1.15 (3H,
s, Me-19),1.11 (3H, d, J¼6.6 Hz, Me-17),1.06 (3H, s, Me-18); 13C NMR
(50 MHz) d: 171.4 (C-15), 169.7 (C-13), 156.0 (OCOO), 117.6 (C-14),
99.3 (C-16), 82.0 (C-7), 77.9 (C-9), 77.6 (C-6), 45.8 (C-5), 42.9 (C-3),
42.7 (C-10), 38.7 (C-8), 34.5 (C-4), 33.0 (C-18), 32.9 (C-1), 29.9 (C-
12), 24.0 (C-19), 23.6 (C-11), 18.6 (C-2), 18.3 (C-20), 12.6 (C-17);
EIHRMS: calcd for C21H30O7Na: 417.1884, found 417.1885.
(50 MHz) d: 174.3 (C-15), 155.6 (OCOO), 94.0 (C-9), 87.0 (C-13), 81.7
(C-7), 78.4 (C-16), 77.9 (C-6), 46.7 (C-5), 43.3 (C-3), 42.7 (C-14), 41.9
(C-10), 37.9 (C-8), 37.3 (C-12), 34.7 (C-4), 33.7 (C-1), 32.6 (C-18),
28.7 (C-11), 23.9 (C-19), 19.8 (C-20), 18.7 (C-2), 13.3 (C-17).
4.4. Reduction of 6 with NaBH4 to yield 7
9: 1H NMR (200 MHz)
d: 4.95 (1H, dd, J¼6.2 and 3.2 Hz, H-7),
To a solution of 6 (165 mg, 0.420 mmol) in EtOH (14 mL) cooled
at 0 ꢁC was added NaBH4 (25 mg, 0.671 mmol). After stirring for
20 min at room temperature 2 M HCl (6 mL) and H2O (6 mL) were
added. The solution was then extracted with Et2O and the organic
phase was washed with H2O, dried over Na2SO4, filtered and
evaporated to give a crude oil, which was chromatographed on
silica gel to afford 7 (91 mg, 57%).
4.29 (1H, d, J¼8.0 Hz, H-16), 4.20 (1H, dd, J¼10.0 and 6.2 Hz, H-6),
4.11 (1H, d, J¼9.0 Hz, H-16), 2.89 (1H, d, J¼17.2 Hz, H-14), 2.59 (1H,
d, J¼17.2 Hz, H-14), 2.40–0.80 (12H, m), 1.18 (3H, s, Me-20),1.15 (3H,
s, Me-19),1.11 (3H, d, J¼6.6 Hz, Me-17),1.06 (3H, s, Me-18); 13C NMR
(50 MHz) d: 174.2 (C-15), 155.6 (OCOO), 93.9 (C-9), 87.0 (C-13), 81.7
(C-7), 78.2 (C-16), 77.9 (C-6), 46.8 (C-5), 43.3 (C-3), 42.3 (C-14), 42.0
(C-10), 38.0 (C-8), 37.3 (C-12), 34.7 (C-4), 33.4 (C-1), 32.6 (C-18),
28.7 (C-11), 23.9 (C-19), 19.8 (C-20), 18.7 (C-2), 13.3 (C-17).
4.4.1. (8S)-6
b
,7
b
-Carbonyldioxy-9
a
-hydroxy-labd-13-en-15,16-olide
þ28.4 (c 0.32, CHCl3); IR (film):
(7). Rf (Hex/EtOAc 4/6)¼0.41; ½a D22
ꢂ
3468, 1783, 1745, 1461, 1446, 1378, 1172, 1149, 1112, 1034, 781; 1H
NMR (200 MHz)
d
: 5.86 (1H, s, H-14), 4.98 (1H, dd, J¼6.2 and 3.4 Hz,
4.6. Reaction of 8/9 with K2CO3/MeOH to yield 10/11
H-7), 4.76 (2H, s, H-16), 4.32 (1H, dd, J¼10.0 and 6.2 Hz, H-6), 2.60–
0.80 (12H, m), 1.21 (3H, s, Me-20), 1.20 (3H, s, Me-19), 1.17 (3H, d,
Compounds 8/9 (38 mg, 0.100 mmol) were treated with K2CO3
in MeOH (4%, 5 mL) and the mixture was stirred at room temper-
ature for 22 h. After that time, the reaction mixture was diluted
with H2O (5 mL) and 2 M HCl (5 mL) 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 affording
10/11 (1:1) (35 mg, 99%).
J¼6.6 Hz, Me-17), 1.07 (3H, s, Me-18); 13C NMR (50 MHz)
d: 173.9
(C-15), 170.0 (C-13), 155.7 (OCOO), 115.6 (C-14), 81.7 (C-7), 77.9 (C-
9), 77.6 (C-6), 73.2 (C-16), 45.9 (C-5), 42.9 (C-3), 42.6 (C-10), 38.7 (C-
8), 34.5 (C-4), 33.0 (C-18), 32.9 (C-1), 31.0 (C-12), 25.3 (C-11), 24.0
(C-19), 18.6 (C-2), 18.3 (C-20), 12.6 (C-17); EIHRMS: calcd for
C21H30O6Na: 401.1935, found 401.1947.
4.5. Reactions of 7 to yield 8/9
4.6.1. (8R)-6b,7b-Dihydroxy-9R,13R/S-epoxy-labdan-15,16-olide (10/
11). Rf (Hex/EtOAc 3/7)¼0.54; ½a D22
þ18.1 (c 0.37, CHCl3); IR (film):
ꢂ
a) To a solution of 7 (69 mg, 0.183 mmol) in Et3N (15 mL) was
added DBU (0.054 mL, 0.366 mmol). After heating at 90 ꢁC for
1 h the solvent was removed to give a crude oil, which was
chromatographed on silica gel to afford 8/9 (1:1) (51 mg, 74%).
b) To a solution of 7 (6 mg, 0.017 mmol) in toluene (0.5 mL) is
added R-(-)-1,10-binaphthyl-2,20-diyl hydrogenophosphate
(6 mg, 0.017 mmol) and the mixture is heated at 80 ꢁC for 72 h.
After that time, H2O (1 mL) is added, the mixture is extracted
with EtOAc and the organic layer washed successively with 2 M
HCl, aqueous 6% NaHCO3 and H2O, dried over Na2SO4 filtered
and concentrated to give a crude oil, which was chromato-
graphed on silica gel to afford 8/9 (3:7) (4 mg, 80%).
c) To a solution of 7 (5 mg, 0.014 mmol) in toluene (0.5 mL) is
added S-(þ)-1,10-binaphthyl-2,20-diyl hydrogenophosphate
(5 mg, 0.014 mmol) and the mixture is heated at 80 ꢁC for 82 h.
After that time, H2O (1 mL) is added, the mixture is extracted
with EtOAc and the organic layer washed successively with 2 M
HCl, aqueous 6% NaHCO3 and H2O, dried over Na2SO4 filtered
3453, 1784, 1716, 1465, 1384, 1365, 1266, 1169, 1098, 1023, 737;
EIHRMS: calcd for C20H32O5Na: 375.2142, found 375.2153.
10: 1H NMR (200 MHz)
d
: 4.36 (1H, d, J¼8.8 Hz, H-16), 4.23 (1H,
br s, H-6), 4.21 (1H, d, J¼8.8 Hz, H-16), 3.40 (1H, dd, J¼9.2 and
2.6 Hz, H-7), 2.86 (1H, d, J¼17.0 Hz, H-14), 2.49 (1H, d, J¼17.0 Hz, H-
14), 2.20–0.80 (12H, m), 1.24 (6H, s, Me-20 and Me-19), 1.23 (3H, d,
J¼6.6 Hz, Me-17),1.00 (3H, s, Me-18); 13C NMR (50 MHz)
d: 174.1 (C-
15), 95.5 (C-9), 86.4 (C-13), 78.7 (C-16), 74.3 (C-6), 70.7 (C-7), 48.7
(C-5), 44.0 (C-3), 43.1 (C-14), 42.7 (C-10), 37.9 (C-8), 37.8 (C-12),
34.8 (C-4), 34.8 (C-1), 33.5 (C-18), 29.9 (C-11), 25.1 (C-19), 20.2 (C-
20), 18.9 (C-2), 12.3 (C-17).
11: 1H NMR (200 MHz)
d
: 4.28 (1H, d, J¼8.8 Hz, H-16), 4.23 (1H,
br s, H-6), 4.06 (1H, d, J¼8.8 Hz, H-16), 3.40 (1H, dd, J¼9.2 and
2.6 Hz, H-7), 2.92 (1H, d, J¼17.0 Hz, H-14), 2.58 (1H, d, J¼17.0 Hz, H-
14), 2.20–0.80 (12H, m), 1.24 (6H, s, Me-20 and Me-19), 1.23 (3H, d,
J¼6.6 Hz, Me-17), 1.00 (3H, s, Me-18); 13C NMR (50 MHz)
d: 174.0
(C-15), 94.0 (C-9), 86.4 (C-13), 78.5 (C-16), 74.3 (C-6), 70.7 (C-7),
48.7 (C-5), 44.0 (C-3), 42.7 (C-10), 42.6 (C-14), 38.0 (C-8), 37.8

9262
I.S. Marcos et al. / Tetrahedron 65 (2009) 9256–9263
(C-12), 34.8 (C-4), 34.3 (C-1), 33.5 (C-18), 29.9 (C-11), 25.1 (C-19),
20.2 (C-20), 18.9 (C-2), 12.3 (C-17).
32.5 (C-1), 32.4 (C-4), 32.3 (C-18), 29.1 (C-11). 22.1 (C-19), 19.6 (C-
20), 18.1 (C-2), 13.2 (C-17); EIHRMS: calcd for
373.1985, found 373.1967.
C20H30O5Na:
4.7. Acetylation and oxidation of 10/11 to yield 12/13
4.8.2. 13-Epi-leopersin D (2). Rf (DCM/Et2O 9/1)¼0.32; ½a D22
þ27.5 (c
ꢂ
To a solution of 10/11 (1:1) (9 mg, 0.026 mmol) in dry pyridine
(0.50 mL), acetic anhydride (0.50 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 a crude oil that together with
N-methylmorpholine N-oxide (NMO) (11 mg, 0.078 mmol) and
molecular sieves (100 mg) were dissolved in dry DCM (1 mL) and
then TPAP (1 mg, 0.003 mmol) was added. The reaction mixture
was stirred at room temperature for 4 h under argon and then was
filtered through silica gel and celite eluting with EtOAc and DCM.
The solvent was evaporated to give a crude oil, which was chro-
matographed on silica gel to afford 12/13 (1:1) (8 mg, 85%).
0.33, CHCl3); IR (film): 3465, 1788, 1707, 1463, 1385, 1364, 1264 1166,
1127, 1092, 1028; 1H NMR (400 MHz)
d
: 4.38 (1H, d, J¼8.9 Hz, H-16),
4.18 (1H, d, J¼8.9 Hz, H-16), 3.81 (1H, dd, J¼11.0 and 3.6 Hz, H-7), 3.70
(1H, d, J¼3.6 Hz, OH-7), 3.02 (1H, d, J¼17.1 Hz, H-14), 2.66 (1H, d,
J¼17.1 Hz, H-14), 2.65 (1H, s, H-5), 2.25–2.15 (1H, m, H-11), 2.20–2.10
(2H, m, H-12), 1.90–1.80 (2H, m, H-8 and H-11), 1.60–1.45 (2H, m, H-
2),1.50–1.35 (2H, m, H-1),1.40–1.30 (1H, m, H-3),1.28 (3H, s, Me-19),
1.17 (3H, d, J¼6.5 Hz, Me-17), 1.15–0.95 (1H, m, H-3), 0.98 (3H, s, Me-
18), 0.87 (3H, s, Me-20); 13C NMR (100 MHz)
d: 211.2 (C-6), 174.1 (C-
15), 93.5 (C-9), 86.9 (C-13), 78.0 (C-16), 77.3 (C-7), 57.0 (C-5), 48.0
(C-10), 46.9 (C-8), 42.2 (C-14), 42.2 (C-3), 37.7 (C-12), 32.4 (C-18), 32.3
(C-4), 32.2 (C-1), 29.1 (C-11). 22.2 (C-19), 19.6 (C-20), 18.1 (C-2), 13.3
(C-17); EIHRMS: calcd for C20H30O5Na: 373.1985, found 373.1967.
4.7.1. (8R)-7
b
-Acetoxy-9R,13R/S-epoxy-6-oxo-labdan-15,16-olide
4.9. Reaction of 10/11 with (R)-C6H5C(OMe)(CF3)COOH to yield
14 and 15
a 22
(12/13). Rf (Hex/EtOAc 1/1)¼0.38; ½ ꢂD þ26.4 (c 0.69, CHCl3); IR
(film): 1788, 1745, 1727, 1462, 1383, 1229, 1166, 1092, 1031; EIHRMS:
calcd for C22H32O6Na: 415.2091, found 415.2102.
To a mixture of 10/11 (36 mg, 0.102 mmol), DCC 1 M in DCM
(0.2 mL, 0.2 mmol) and DMAP (0.5 mg, 0.005 mmol) in DCM
(010 mL) at 0 ꢁC and under inert atmosphere, was added (R)-
C6H5C(OMe)(CF3)COOH (48 mg, 0.204 mmol) and the solution was
stirred for 16 h at room temperature. Then the white solid was fil-
tered, the solution was extracted with EtOAc and the organic layer
was washed successively with 2 M HCl, aqueous 6% NaHCO3 and
H2O, dried over Na2SO4 filtered and concentrated to give a crude oil,
which was chromatographed on silica gel to afford 14 (23 mg, 39%)
and 15 (25 mg, 42%).
12: 1H NMR (200 MHz)
d: 4.94 (1H, d, J¼12.0 Hz, H-7), 4.42 (1H, d,
J¼8.8 Hz, H-16), 4.24 (1H, d, J¼8.8 Hz, H-16), 2.99 (1H, d, J¼16.8 Hz,
H-14), 2.63 (1H, s, H-5), 2.61 (1H, d, J¼16.8 Hz, H-14), 2.30–0.70 (12H,
m), 2.18 (3H, s, MeCOO),1.24 (3H, s, Me-18),1.00 (3H, d, J¼7.0 Hz, Me-
17), 0.97 (3H, s, Me-19), 0.91 (3H, s, Me-20); 13C NMR (50 MHz)
d:
204.4 (C-6),174.0 (C-15),170.4 (OCO), 93.8 (C-9), 87.2 (C-13), 79.5 (C-
7), 78.3 (C-16), 57.4 (C-5), 47.8 (C-10), 47.7 (C-8), 43.2 (C-14), 42.5
(C-3), 38.3 (C-12), 32.7 (C-1), 32.4 (C-4), 32.1 (C-18), 29.6 (C-11), 22.3
(C-19), 20.9 (MeCOO), 19.7 (C-20), 18.4 (C-2), 14.3 (C-17).
13: 1H NMR (200 MHz)
d: 4.94 (1H, d, J¼12.0 Hz, H-7), 4.37 (1H, d,
J¼8.8 Hz, H-16), 4.20 (1H, d, J¼8.8 Hz, H-16), 3.04 (1H, d, J¼16.8 Hz,
H-14), 2.65 (1H, s, H-5), 2.64 (1H, d, J¼16.8 Hz, H-14), 2.30–0.70 (12H,
m), 2.18 (3H, s, MeCOO),1.24 (3H, s, Me-18),1.04 (3H, d, J¼7.0 Hz, Me-
4.9.1. (8R)-6b-Hydroxy-7b-[R-(3,3,3-trifluoro-2-methoxy-2-phenyl)-
propionoxy]-9R,13R-epoxy-labdan-15,16-olide (14). Rf (Hex/EtOAc
7/3)¼0.43; ½a 2D2
þ46.5 (c 0.38, CHCl3); IR (film): 3546, 1785, 1744,
ꢂ
17), 0.97 (3H, s, Me-19), 0.91 (3H, s, Me-20); 13C NMR (50 MHz)
d:
1464, 1452, 1365, 1270, 1169, 1123, 1022, 993, 873, 737; 1H NMR
204.4 (C-6),174.2 (C-15),170.4 (OCO), 93.8 (C-9), 87.2 (C-13), 79.5 (C-
7), 78.3 (C-16), 57.5 (C-5), 47.8 (C-10), 47.7 (C-8), 43.0 (C-14), 42.5
(C-3), 38.3 (C-12), 32.7 (C-1), 32.4 (C-4), 32.1 (C-18), 29.6 (C-11), 22.3
(C-19), 20.9 (MeCOO), 19.7 (C-20), 18.4 (C-2), 14.3 (C-17).
(400 MHz) d: 7.56–7.52 (2H, m, Ph), 7.45–7.40 (3H, m, Ph), 5.02 (1H,
dd, J¼11.6 and 3.0 Hz, H-7), 4.43 (1H, d, J¼9.1, H-16), 4.34 (1H, br s,
H-6), 4.20 (1H, d, J¼9.1 Hz, H-16), 3.55 (3H, s, MeO), 2.90 (1H, d,
J¼17.0 Hz, H-14), 2.54 (1H, d, J¼17.0 Hz, H-14), 2.50–0.70 (12H, m),
1.24 (3H, s, Me-20), 1.22 (3H, s, Me-19), 1.00 (3H, s, Me-18), 0.74 (3H,
4.8. Reaction of 12/13 with K2CO3/MeOH to yield 1 and 2
d, J¼6.8 Hz, Me-17); 13C NMR (50 MHz)
d: 174.7 (C-15), 166.0 (OCO),
132.2 (C-10), 130.1 (C-40), 128.8 (C-30 and C-50), 127.5 (C-20 and C-60),
123.6 (q, J¼287.5 Hz, CF3), 95.3 (C-9), 86.6 (C-13), 84.3 (q, J¼27.5 Hz,
CCF3), 80.9 (C-7), 78.5 (C-16), 68.8 (C-6), 55.7 (MeO), 48.6 (C-5), 43.8
(C-3), 43.1 (C-14), 42.8 (C-10), 38.1 (C-8), 38.1 (C-12), 34.7 (C-1), 34.7
(C-4), 33.4 (C-18), 29.8 (C-11). 24.7 (C-19), 20.1 (C-20),18.8 (C-2),11.7
(C-17); EIHRMS: calcd for C30H39O7F3Na: 591.2540, found 591.2550.
Compounds 12/13 (5 mg, 0.013 mmol) were treated with K2CO3
in MeOH (2%, 1 mL) and the mixture was stirred at room temper-
ature for 90 min. After that time, the reaction mixture was diluted
with H2O (1 mL) and 2 M HCl (1 mL) 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 eluting with
DCM/Et2O (95/5) to afford 1 (2.3 mg, 47%) and 2 (2.3 mg, 47%).
4.9.2. (8R)-6b-Hydroxy-7b-[R-(3,3,3-trifluoro-2-methoxy-2-phenyl)-
propionoxy]-9R,13S-epoxy-labdan-15,16-olide (15). Rf (Hex/EtOAc
7/3)¼0.46; ½a 2D2
þ51.9 (c 0.48, CHCl3); IR (film): 3545, 1786, 1743,
ꢂ
4.8.1. Leopersin D (1). Rf (DCM/Et2O 9/1)¼0.38; ½a D22
ꢂ
þ25.4 (c 0.14,
1663, 1452, 1364,1262, 1168,1122,1022, 929, 873, 801, 736; 1H NMR
CHCl3); IR (film): 3465, 1788, 1707, 1463, 1385, 1364, 1264, 1166,
(400 MHz) d: 7.55–7.53 (2H, m, Ph), 7.45–7.41 (3H, m, Ph), 5.01 (1H,
1127, 1092, 1028; 1H NMR (400 MHz)
d
: 4.44 (1H, d, J¼9.1 Hz, H-16),
dd, J¼11.6 and 3.0 Hz, H-7), 4.35 (1H, br s, H-6), 4.28 (1H, d,
J¼8.8 Hz, H-16), 4.05 (1H, d, J¼8.8 Hz, H-16), 3.55 (3H, s, MeO), 3.02
(1H, d, J¼17.1 Hz, H-14), 2.54 (1H, d, J¼17.1 Hz, H-14), 2.50–0.70
(12H, m),1.26 (3H, s, Me-20),1.23 (3H, s, Me-19),1.00 (3H, s, Me-18),
4.27 (1H, d, J¼9.1 Hz, H-16), 3.81 (1H, dd, J¼11.1 and 3.6 Hz, H-7),
3.71 (1H, d, J¼3.6 Hz, OH-7), 2.98 (1H, d, J¼17.0 Hz, H-14), 2.67 (1H,
s, H-5), 2.62 (1H, d, J¼17.0 Hz, H-14), 2.25–2.15 (1H, m, H-11), 2.20–
2.10 (2H, m, H-12), 1.90–1.80 (2H, m, H-8 and H-11), 1.60–1.45 (2H,
m, H-2), 1.50–1.35 (2H, m, H-1), 1.40–1.30 (1H, m, H-3), 1.28 (3H, s,
Me-19), 1.14 (3H, d, J¼6.5 Hz, Me-17), 1.15–0.95 (1H, m, H-3), 0.98
0.75 (3H, d, J¼6.7 Hz, Me-17); 13C NMR (50 MHz)
d: 174.5 (C-15),
166.0 (OCO), 132.2 (C-10), 130.1 (C-40), 128.8 (C-30 and C-50),127.5 (C-
20 and C-60), 123.6 (q, J¼287.5 Hz, CF3), 95.2 (C-9), 86.6 (C-13), 84.3
(q, J¼27.5 Hz, CCF3), 80.9 (C-7), 78.3 (C-16), 68.7 (C-6), 55.7 (MeO),
48.7 (C-5), 43.8 (C-3), 42.7 (C-10), 42.2 (C-14), 38.0 (C-8), 38.0 (C-
12), 34.7 (C-4), 34.3 (C-1), 33.4 (C-18), 29.8 (C-11). 24.7 (C-19), 20.1
(3H, s, Me-18), 0.87 (3H, s, Me-20); 13C NMR (100 MHz)
d: 211.2 (C-
6), 174.0 (C-15), 93.6 (C-9), 86.9 (C-13), 78.0 (C-16), 77.3 (C-7), 56.9
(C-5), 48.1 (C-10), 46.6 (C-8), 42.6 (C-14), 42.3 (C-3), 37.8 (C-12),

I.S. Marcos et al. / Tetrahedron 65 (2009) 9256–9263
9263
(C-20), 18.8 (C-2), 11.7 (C-17); EIHRMS: calcd for C30H39O7F3Na:
4.12. Reaction of 16 or 17 with KOH/MeOH to yield 1 and 2
591.2540, found 591.2550.
a) Compound 16 (5 mg, 0.010 mmol) was treated with KOH in
MeOH (10%, 0.5 mL) and the mixture was stirred at room
temperature for 15 h. After that time, the reaction mixture was
diluted with H2O (1 mL) and 2 M HCl (1 mL) was added. The
solution was then extracted with EtOAc and the organic phase
was washed successively with aqueous 6% NaHCO3 and brine,
dried over Na2SO4, filtered and concentrated to afford 1/2
(3.7 mg, 99%).
b) Compound 17 (7 mg, 0.012 mmol) was treated with KOH in
MeOH (10%, 0.5 mL) and the mixture was stirred at room
temperature for 15 h. After that time, the reaction mixture was
diluted with H2O (1 mL) and 2 M HCl (1 mL) was added. The
solution was then extracted with EtOAc and the organic phase
was washed successively with aqueous 6% NaHCO3 and brine,
dried over Na2SO4, filtered and concentrated to afford 1/2
(4.4 mg, 99%).
4.10. Oxidation of 14 with CrO3/py to yield 16
To a solution of CrO3 (40 mg, 0.400 mmol) in DCM (0.2 mL) and
pyridine (0.066 mL) was added 14 (6 mg, 0.010 mmol) in DCM
(0.4 mL) and the solution was heated at 45 ꢁC for 1 h. After that, the
mixture was filtered eluting with EtOAc and then, the organic phase
obtained was washed successively with 2 M HCl, aqueous 6% NaHCO3
and brine, dried over Na2SO4 filtered and concentrated to give a crude
oil, which was chromatographed on silica gel to afford 16 (5 mg, 89%).
4.10.1. (8R)-6b-Oxo-7b-[R-(3,3,3-trifluoro-2-methoxy-2-phenyl)-
propionoxy]-9R,13R-epoxy-labdan-15,16-olide (16). Rf (Hex/EtOAc
6/4)¼0.38; ½a 2D2
þ56.0 (c 0.49, CHCl3); IR (film): 1787, 1755, 1728,
ꢂ
1463, 1452, 1365, 1267, 1169, 1111, 1028, 737; 1H NMR (200 MHz)
d:
7.75–7.68 (2H, m, Ph), 7.44–7.40 (3H, m, Ph), 5.03 (1H, d, J¼11.8 Hz,
H-7), 4.43 (1H, d, J¼9.0 Hz, H-16), 4.21 (1H, d, J¼9.0 Hz, H-16), 3.75
(3H, s, MeO), 3.00 (1H, d, J¼16.9 Hz, H-14), 2.68 (1H, s, H-5), 2.63
(1H, d, J¼16.9 Hz, H-14), 2.30–0.70 (12H, m), 1.26 (3H, s, Me-19),
1.01 (3H, s, Me-18), 0.90 (3H, s, Me-20), 0.75 (3H, d, J¼6.2 Hz, Me-
Acknowledgements
The authors gratefully acknowledge the help of A. Lithgow
(NMR) and C. Raposo (MS) of Universidad de Salamanca and
MICINN CTQ2009-11557BQU, Junta de Castilla y Leon (SA063A07)
17); 13C NMR (50 MHz)
d: 202.6 (C-6), 174.0 (C-15), 166.1 (OCO),
132.7 (C-10), 129.8 (C-40), 128.5 (C-30 and C-50).127.7 (C-20 and C-60),
123.2 (q, J¼316.5 Hz, CF3), 93.8 (C-9), 87.4 (C-13), 84.7 (q, J¼27,1 Hz,
CCF3), 81.3 (C-7), 78.2 (C-16), 57.4 (C-5), 56.3 (MeO), 47.8 (C-10),
47.7 (C-8), 43.2 (C-14), 42.6 (C-3), 38.2 (C-12), 32.8 (C-1), 32.5 (C-4),
33.5 (C-18), 29.6 (C-11). 22.4 (C-19), 19.7 (C-20), 18.3 (C-2),
12.8 (C-17); EIHRMS: calcd for C30H37O7F3Na: 589.2384, found
589.2393.
´
for financial support. L.C.G. is grateful to the Junta de Castilla
´
y Leon for a fellowship. Simon Richards helped with proof
reading.
References and notes
1. Hanson, J. R. Nat. Prod. Rep. 2007, 24, 1332.
2. (a) Tasdermir, D.; Wright, A. D.; Sticher, O.; Calis, I. J. Nat. Prod. 1996, 59, 131;
(b) Boalino, D. M.; McLean, S.; Reynolds, W. F.; Tinto, W. F. J. Nat. Prod. 2004, 67,
714; (c) Hon, P. M.; Wang, E. S.; Lam, S. K. M.; Choy, Y. M.; Lee, C. M.; Wong, H.
4.11. Oxidation of 15 with CrO3/py to yield 17
´
N. C. Phytochemistry 1993, 33, 639; (d) Romero-Gonza´lez, R. R.; Avila-Nu´ n˜ez, J.
To a solution of CrO3 (40 mg, 0.400 mmol) in DCM (0.2 mL) and
pyridine (0.066 mL) was added 15 (7 mg, 0.012 mmol) in DCM
(0.4 mL) and the solution was heated at 45 ꢁC for 1 h. After that, the
mixture was filtered eluting with EtOAc and then, the organic phase
obtained was washed successively with 2 M HCl, aqueous 6% NaHCO3
and brine, dried over Na2SO4 filtered and concentrated to give a crude
oil, which was chromatographed on silica gel to afford 17 (6 mg, 81%).
L.; Aubert, L.; Alonso-Amelot, M. E. Phytochemistry 2006, 67, 965; (e) Giang, P.
M.; Son, P. T.; Matsunami, K.; Otsuka, H. Chem. Pharm. Bull. 2005, 53, 1475;
(f) Agnihotri, V. K.; Elsohly, H. N.; Smillie, T. J.; Khan, I. A.; Walker, L. A. Planta
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64, 8815.
4.11.1. (8R)-6b-Oxo-7b-[R-(3,3,3-trifluoro-2-methoxy-2-phenyl)-
propionoxy]-9R,13S-epoxy-labdan-15,16-olide (17). Rf (Hex/EtOAc
6/4)¼0.39; ½a 2D2
þ58.4 (c 0.64, CHCl3); IR (film): 1788, 1755, 1728,
ꢂ
´
7. Marcos, I. S.; Castan˜eda, L.; Basabe, P.; Dıez, D.; Urones, J. G. Tetrahedron 2008,
1451, 1364, 1262, 1230, 1169, 1109, 1028, 803; 1H NMR (200 MHz)
d:
64, 10860.
´
8. (a) Buro, R. M.; Roof, M. B. Tetrahedron Lett. 1993, 34, 395; (b) Kang, S.-K.; Jeon,
7.75–7.68 (2H, m, Ph), 7.45–7.40 (3H, m, Ph), 5.03 (1H, d, J¼12.2 Hz,
H-7), 4.39 (1H, d, J¼8.8 Hz, H-16), 4.19 (1H, d, J¼8.8 Hz, H-16), 3.76
(3H, s, MeO), 3.05 (1H, d, J¼17.1 Hz, H-14), 2.67 (1H, s, H-5), 2.61 (1H,
d, J¼17.1 Hz, H-14), 2.30–0.70 (12H, m), 1.26 (3H, s, Me-19), 1.00 (3H,
s, Me-18), 0.89 (3H, s, Me-20), 0.76 (3H, d, J¼6.2 Hz, Me-17); 13C
J.-H.; Nam, K.-S.; Park, C.-H.; Lee, H.-W. Synth. Commun. 1994, 24, 305;
(c) Greene, T.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.; Wiley:
New York, NY, 1999; p 241.
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NMR (50 MHz) d
: 202.6 (C-6), 174.0 (C-15), 166.1 (OCO), 132.7 (C-10),
129.8 (C-40), 128.5 (C-30 and C-50).127.7 (C-20and C-60), 123.2 (q,
J¼316.5 Hz, CF3), 93.8 (C-9), 87.4 (C-13), 84.7 (q, J¼27,1 Hz, CCF3),
81.3 (C-7), 78.3 (C-16), 57.5 (C-5), 56.3 (MeO), 47.8 (C-10), 47.7 (C-8),
42.9 (C-14), 42.6 (C-3), 38.2 (C-12), 32.7 (C-1), 33.5 (C-18), 32.5 (C-4),
29.6 (C-11). 22.4 (C-19), 19.7 (C-20), 18.3 (C-2), 12.9 (C-17); EIHRMS:
calcd for C30H37O7F3Na: 589.2384, found 589.2393.
´
˜
Garcıa, I.; Sierra, M. A. J. Nat. Prod. 2002, 65, 66; (e) Seco, J. M.; Quinoa, E.;
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