11,16 Oxetane lactones. Spectroscopic evidences and conformational analysis

Article abstract of DOI:10.1016/j.tet.2006.05.058

Sesquiterpene lactones constitute a wide group of compounds with several biological activities, including allelopathic. The naturally occurring sesquiterpene lactones dehydrocostuslactone and cynaropicrin have been modified in three different ways: preparation of 11,13-oxetane lactones, addition of a second Michael acceptor and reduction of the α-methylene-γ-lactone in order to future structure-activity relationship (SAR) studies. We have obtained all oxetane lactones stereoisomers at C-11 and C-16 positions. This fact has allowed us to establish some correlations between experimental data, derived by NMR and X-ray analysis, and the configuration at C-11 and C-16, which could be a useful tool to establish the stereochemistry as well as to confirm the presence of an oxetane ring on similar compounds. Comparative conformational analyses as a key aspect in the biological behaviour of those compounds in future structure-activity relationship (SAR) studies are presented.

Full text of DOI:10.1016/j.tet.2006.05.058

Tetrahedron 62 (2006) 7747–7755
11,16 Oxetane lactones. Spectroscopic evidences
and conformational analysis
a,
Francisco A. Macıas, Victor M. I. Vinolo, Frank R. Fronczek, Guillermo M. Massanet
a
b
a
*
´
˜
and Jose M. G. Molinillo
a
´
a
´
Grupo de Alelopatıa, Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Cadiz, Avda. Republica Saharaui,
´
ꢀ
ꢀ
ꢀ
s/n, 11510 Puerto Real, Caꢀdiz, Spain
bDepartment of Chemistry, Louisiana State University, Baton Rouge Louisiana, 70803 USA
Received 2 May 2006; revised 20 May 2006; accepted 24 May 2006
Available online 16 June 2006
Abstract—Sesquiterpene lactones constitute a wide group of compounds with several biological activities, including allelopathic. The
naturally occurring sesquiterpene lactones dehydrocostuslactone and cynaropicrin have been modified in three different ways: preparation
of 11,13-oxetane lactones, addition of a second Michael acceptor and reduction of the a-methylene-g-lactone in order to future structure–
activity relationship (SAR) studies. We have obtained all oxetane lactones stereoisomers at C-11 and C-16 positions. This fact has allowed
us to establish some correlations between experimental data, derived by NMR and X-ray analysis, and the configuration at C-11 and C-16,
which could be a useful tool to establish the stereochemistry as well as to confirm the presence of an oxetane ring on similar compounds.
Comparative conformational analyses as a key aspect in the biological behaviour of those compounds in future structure–activity relationship
(SAR) studies are presented.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
methods.3 Oxetane ring containing compounds have been
reported to display a wide range of biological activities
and this structural feature is regarded to be essential for their
bioactivity.4–6 However, despite the efforts, in many cases
the biochemical behaviour of the oxetane ring remains
unclear and more research on both conformational and elec-
tronic effects needs to be done. In this way, we have achieved
Five natural oxetane lactones, clementein, clementein B,
clementein C, subexpinnatin B and subexpinnatin C, were
isolated from Centaurea clementei Boiss,1 and Centaurea
canariensis Brous. Var. subexpinnata Burchd (Fig. 1),2 and
some of them have been obtained later by hemi-synthetic
H
H
H
O
OH
H
H
H
O
O
O
O
O
O
2
3 (a-b)
1
14
H
2
1
5
H
9
10
C11
R
C16
R
C11
R
C16
S
3
4
8
6
7
8
9
14
6
7
R
S
15
16
17
R
R
OH
OH
H
S
S
S
R
15
11
H
O
S
R
S
S
16
O
13
12O
17
O
O
Figure 1. Natural oxetane lactones and synthetic intermediates.
* Corresponding author. Tel.: +34 956 016370; fax: +34 956 016295; e-mail: famacias@uca.es
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.058

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F. A. Macıas et al. / Tetrahedron 62 (2006) 7747–7755
7748
the preparation of four new oxetane lactones (compounds
14–17) from (1) as starting material. The accomplished
semi-synthesis also yielded six other derivatives (com-
pounds 2, 3(a–b) and 6–9), which present different stereo-
chemistries and have been afforded for first time in this
study (Fig. 1). The fact that we have obtained all oxetane lac-
tones stereoisomers at C-11 and C-16 positions has allowed
us to establish some correlations between experimental data,
derived by NMR and X-ray analysis, and the configuration at
C-11 and C-16, that could be a useful tool in proposing the
stereochemistry as well as in confirming the presence of
an oxetane ring on similar compounds. Moreover, we carried
out a comparative conformational analysis as a key aspect in
the biological behaviour of those compounds in future struc-
ture–activity relationship (SAR) studies.
yield) (step a). Reduction of compound (2) with sodium
borohydride at 0 ꢀC afforded the 1:1 mixture of epimers at
C-16, 3 (a–b) in 98% yield (step b). The new hydroxyl group
formed is protected with DHP and p-toluenesulfonic acid as
catalyst, yielding an epimeric mixture of diastereoisomers 4
(step c).
The a-hydroxylation of 4 to obtain the mixture of diastereo-
isomers 5 was carried out under the specific conditions as
shown below. First, the enolate at C-11 of 4 is generated at
ꢁ73 ꢀC in THF by deprotonation with potassium hexa-
methyldisilazide (KHMDS) under a restricted dry argon
atmosphere. Then, dry oxygen is bubbled through the solu-
tion for an hour in order to achieve the corresponding hydro-
peroxide ion. The latter treatment with triethylphosphite as
‘in situ’ reducing agent afforded the mixture 5 (step d).
Both the 11R and the 11S configurations were obtained as
it was deduced after step 5.
Herein, we present the methodology, which has been accom-
plished to obtain the new oxetane lactones as well as the
prior results derived from their spectroscopic and conforma-
tional analysis.
Mild acid treatment of 5 (p-TsOH, ethyl acetate) provided
the diols 6, 7, 8 and 9 and not the oxetane lactones as we ex-
pected (step e). Thus, it was necessary to include two more
steps into the sequence. The above four diols were isolated in
20% yield each as crystalline compounds, allowing us to
establish the structures of compounds 6 and 7 by X-ray anal-
ysis. The absolute configuration of compound 7 was also
determined using Cu Ka radiation, establishing the absolute
configuration of the entire series.
2. Results and discussion
In order to perform the hemi-synthesis, we employed the
previously reported methodology7 for the formation of an
oxetane ring at C-11 and C-13 positions from the corre-
sponding a-methylene-g-lactone using dehydrocostuslac-
tone (1) as starting material. This natural product in one of
the major constituents obtained from the root of the Chinese
plant Saussurea lappa and, therefore, it is readily available
in the amounts needed to accomplish the synthesis in seven
steps as shown in Scheme 1.
The introduction of the mesyl moiety as leaving group at
C-16 to afford compounds 10, 11, 12 and 13 (90%) was ac-
complished by the reactions of diols with mesyl chloride in
pyridine at 0 ꢀC (step f). Basic treatment of mesylated com-
pounds 10, 11, 12 and 13 with butyllithium in THF led to the
ring closure with inversion in the configuration at C-16
yielding the oxetane lactones 14, 15, 16 and 17 (step g)
The first step was the photoaddition of acetaldehyde to de-
hydrocostuslactone (1) providing the methylketone (2) (66%
H
H
H
H
c
b
a
H
H
H
H
O
O
O
O
O
O
OH
OTHP
O
O
O
3
2
4
1
H
H
d
e
H
H
O
O
OH
OH
OTHP
OH
O
O
6-9
5
H
H
g
f
H
H
O
O
O
OH
OMs
O
O
14-17
10-13
Scheme 1. (a) CH3CHO, hn; (b) NaBH4, MeOH, 0 ꢀC; (c) DHP, p-Toluenesulfonic acid, THF; (d) KHMDS, THF, ꢁ73 ꢀC; (e) p-Toluenesulfonic acid, AcOEt;
(f) MesCl, py, 0 ꢀC and (g) BuLi, THF.

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F. A. Macıas et al. / Tetrahedron 62 (2006) 7747–7755
7749
Table 1
Compounds
d H-5
d H-6
d H-7
d H-13
d H-130
d H-16
d H-17
C-11
C-16
14
15
16
17
1
2.69
2.68
2.80
2.83
2.78
4.05
4.05
3.78
3.78
3.92
2.01
1.93
2.35
2.26
—
2.71
2.96
2.84
2.56
—
2.61
2.22
2.24
2.44
—
5.10
4.75
4.84
5.24
—
1.35
1.50
1.60
1.39
—
R
R
S
S
—
S
R
R
S
—
with an overall yield of 21%. Since compounds 15 and 16
were crystalline, we confirmed the proposed mechanism of
the step g based on their X-ray analyses and, consequently,
we established the stereochemistry of compounds 14 and 17.
It is interesting to note the large downfield for the H-13 and
H-130 signals when the ring closure occurs. Following with
the analysis of these signals, it is relevant the JH13–H16 and
0
JH13 –H16 coupling constants, which are similar on the oxe-
tane lactones whereas the differences among them are far
longer on the corresponding diols. These results are consis-
tent with the relative angle formed between protons H-13
and H-130 with proton H-16 at the oxetane moiety. With re-
spect to the 13C NMR spectra, we emphasize the shift down-
field for C-11 and C-16 signals as well as the contrary effect
for C-13 as a result of the ring closure in compounds 14, 15,
16 and 17.
Once we obtained the four oxetane lactones their configura-
tions at C-11 and C-16 were assigned, a depth analysis of
their 1H NMR and 13C NMR spectra revealed some interest-
ing relationships, especially for the NMR data correspond-
ing to the nucleus found in the area close to the oxetane ring.
In Table 1, we present the 1H NMR chemical shifts for H-5,
H-6, H-7, H-13, H-130, H-16 and H-17, as well as the
assigned configuration at C-11 and C-16 for the compounds
14, 15, 16 and 17.
Regardless, it is well established that conformational aspects
are a keystone for the biological activity; little has been done
about the conformational changes that the oxetane ring
induces on the guaianolide backbone. Following this way,
we have carried out a comparative structural study of the ox-
etane lactones 15 and 16 with the corresponding a-methyl-
ene-g-lactone, dehydrocostuslactone (1). To perform that,
we used the experimental data obtained from the X-ray anal-
ysis of the crystalline compounds 1,8 15 and 16, which are
shown in Figure 2.
A slight shift downfield is observed for H-6 signals when the
configuration at C-11 is R (compounds 14 and 15), which
may be due to the paramagnetic effect that the oxygen
nucleus of the oxetane rings induce over those signals. On
the other hand, a similar effect occurs for the H-5 and H-7
signals in case of the (S)-configuration at C-11 (compounds
16 and 17). With respect to the configuration at C-16, for
oxetane lactones 15 and 16 (16S) a shift downfield is also
observed for the H-17 signals and, it is worth noting that,
in the latter compounds, the difference between the chemical
shifts for H-13 and H-130 is 0.68ꢂ0.08 ppm, being
0.11ꢂ0.01 ppm for the oxetane lactones 14 and 17 (16R).
Furthermore, these results show how it may be possible to
make the C-11 and C-16 configuration assignments in other
oxetane lactones using their experimental data derived from
1H NMR. In Table 1, the chemical shifts for H-5 and H-6 of
dehydrocostuslactone (1) is also included, because com-
paring those with the respective signals of the lactones can
be an interesting clue for C-11 configuration assignment,
to determine whether we obtained one of the possible dia-
stereoisomers.
Comparing the resultant geometries reveals that the essential
difference appears to be the conformation of the cyclohep-
tane ring. Whereas in compound 1 the cycloheptane presents
the theoretical lowest energy conformer (twist-chair), in
both oxetane lactones (15 and 16) the heptane ring is in a
chair conformation.9 Those preferential conformations are
in good agreement with the coupling constants JH9b–H8b
,
JH9b–H8a, JH9a–H8b and JH9a–H8a derived from 1H NMR anal-
ysis of 15 and 16 (see Table 3).10
In Figure 2, the modification of the relative positions of C-2,
C-9, C-10 and C-14 with respect to the guaianolide back-
bone, as a result of the different seven-membered ring con-
formations is shown. With regard to this matter, we have
prepared other guaianolide-type sesquiterpene lactones,
both natural and semi-synthetic (18, 19,11 20, 21 and 2212)
and revised other published results (2313 and 2414). Different
behaviours have been observed in guaianolides with a methyl-
ene at C-10 (Fig. 3). Thus, 1, 20 and 24 possess an a-methyl-
ene-g-lactone moiety twist-chair conformation, whereas 6,
Determining the presence of the oxetane ring moiety can
be difficult, so a comparative NMR spectroscopic study
between the oxetane lactones and the corresponding diols
was undertaken to provide evidence, which may be useful
to overcome the problem. The most significant results de-
rived from this comparative analysis are shown in Table 2.
Table 2
6
14
2.71
2.61
6.4
7.8
81.7
32.5
75.3
7
15
2.84
2.24
7.7
6.5
82.9
32.4
75.3
8
16
2.96
2.22
7.0
7.3
82.3
32.4
75.3
9
17
2.56
2.44
7.6
7.5
82.8
32.3
75.2
d H-13
d H-130
J13–16
1.89
1.65
10.8
2.7
75.7
41.4
64.9
1.73
1.55
11.2
2.2
76.4
37.8
65.7
1.94
1.79
10.3
3.0
76.4
43.1
64.7
1.76
1.68
8.5
0
J13 –16
2.7
d C-11
d C-13
d C-16
76.4
43.3
64.7

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F. A. Macıas et al. / Tetrahedron 62 (2006) 7747–7755
7750
Figure 2. Conformations of 1, 15 and 16 obtained by X-ray analysis.
Table 3
3. Experimental
Compound JH9b–H8b JH9b–H8a JH9a–H8b JH9a–H8a Conformations
3.1. General
1
15
16
4.9
7.0
7.3
5.8
6.8
7.5
5.9
10.1
11.3
4.4
4.0
4.0
Twist-chair
Chair
Chair
1H NMR and 13C NMR spectra were recorded at 399.952
and 100.577 MHz, respectively, on a Varian UNITY-400
spectrometer using CDCl3 as solvent. The resonances of
1
residual chloroform at dH 7.25 ppm in the H spectra and
of dC at 77.00 ppm in the 13C spectra were used as internal
references. Mass spectra were obtained by using a VG 1250
or a Kratos MS-80-RFA instrument at 70 eV. The infrared
(IR) spectra were recorded on a PERKIN Elmer Spectrum
BX. Column chromatography (CC) was performed on silica
gel (35–75 mesh). For HPLC, LiChrosorb silica 60 was used
in the normal-phase mode using differential LaChrom RI
L-7490 refractometer and UV–vis LaChrom L-7420 detec-
tors, with an HPLC MERCK HITACHI instrument. All sol-
vents were of spectral grade or distilled from glass prior to
use. The diffraction data were collected at low temperature
7, 15, 16, 18, 19 and 23 lacking that functionalization
showed chair conformation in the seven-membered ring.
Nevertheless, the influence of the functionalization of the
other five-membered ring is also important (Fig. 4). Thus,
21 and 22 that have the a-methylene-g-lactone and a car-
bonyl group at C-3 showed a chair conformation. So, the
functionalization and hybridization of both five-membered
rings of guaianolides do influence the conformation of the
seven-membered group ring and, probably, their biological
activities. So, any structure–activity relationship study of
this type of compounds should consider this parameter.
H
H
H
H
H
HO
HO
HO
OH
OH
OH
OH
OH
H
H
H
H
H
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
O
O
O
6
7
18
19
20
H
H
H
H
O
O
O
O
HO
OH
OH
OH
OAc
O
HO
Cl
H
H
H
H
OH
O
O
O
O
OH
O
O
O
O
21
22
23
24
Figure 3. Natural and semi-synthetic guaianolides to be studied.

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F. A. Macıas et al. / Tetrahedron 62 (2006) 7747–7755
7751
Figure 4. Conformations obtained for 6, 7, 18, 19, 20, 22 and 21 by X-ray analysis.
on a KappaCCD diffractometer equipped with Mo Ka radi-
ation and an Oxford Cryosteam sample chiller. Room-T Cu
Ka was also collected for 7 in order to determine its absolute
configuration.
and 2.3, H-150), 4.86 (1H, s, H-14), 4.76 (1H, s, H-140),
4.20a and 4.00b (1H, m, H-16), 4.00a and 3.95 (1H, dd,
J¼9.7 and 9.3, H-6), 2.84 (1H, m, H-1), 2.82 (1H, m,
H-5), 2.51 (1H, m, H-3a), 2.47 (1H, ddd, J¼12.6, 8.9 and
3.8, H-11b), 2.38 (1H, ddd, J¼11.6, 8.5 and 4.4, H-9a),
2.11 (1H, m, H-8a), 2.10 (1H, m, H-7), 1.99 (1H, m,
H-9b), 1.95 (1H, m, H-2a), 1.93 (1H, m, H-3b), 1.86 (1H,
m, H-2b), 1.84 (1H, ddd, J¼14.5, 9.0 and 3.7, H-13), 1.66
(1H, ddd, J¼14.5, 8.9 and 3.1, H-130), 1.34 (1H, m, H-8b),
1.22a and 1.20 (3H, d, J¼6.2, H-17). 13C NMR (100 MHz,
CDCl3) d 180.1 and 179.4 (C-12), 151.6 and 151.5 (C-10),
149.8 and 149.6 (C-4), 112.1 and 111.9 (C-14), 109.3 and
109.1 (C-15), 86.4 and 85.9 (C-6), 67.1 and 64.8 (C-16),
51.9 and 51.8 (C-5), 48.4 and 47.4 (C-7), 47.1 and 46.4
(C-1), 43.4 and 43.3 (C-11), 38.3 and 38.2 (C-13), 38.2
and 37.5 (C-9), 32.6 and 32.5 (C-3), 32.3 and 32.2 (C-2),
30.1 and 29.7 (C-8) 24.2 and 23.8 (C-17).
3.2. Starting material
Dehydrocostuslactone (1) was obtained from crude costus-
resin oil (S. lappa) by previous column chromatography
(CC) separation and then purified by crystallization from
hexane/ethyl acetate mixtures.
3.3. 13-Acetylmokkolactone (2)
Photochemical reactions were carried out in a modified
Hanovia reactor equipped with a Pyrex jacket as filter and
a 125 W Hg/medium pressure lamp. The filter solution
contained NiSO4$6H2O (46 g) and CoSO4$7H2O (14 g)
per 100 mL of water. Compound 1 (250 mg, 1.08 mmol) in
freshly distilled acetaldehyde (100 mL) was irradiated for
1 h with stirring. The reaction was kept fresh by a water re-
circulation device. The reaction mixture was concentrated
under reduced pressure with the addition of small amounts
of cyclohexane. This procedure was repeated ten times.
The reaction mixtures were purified by means of CC
(Hexane–EtOAc 9:1) to afford 13-acetylmokkolactone 2
3.5. 13-[10-(200-Tetrahydropyranyloxy)-ethyl]-
mokkolactone (4)
To a solution of 3 (a–b) (6.96 mmol) in dry THF (50 mL),
fresh distilled DHP (500 mL) and a few crystals of p-toluene-
sulfonic acid were added. After 3 h, anhydrous potassium
carbonate was added and the mixture is kept during an
hour. The salts were separated by filtration and the mixture
was purified by means of CC (Hexane–Et2O 9:1) to give
the mixture of diastereoisomers 4. Compound 4: IR (neat,
KBr) nmax, 1746 (carbonyl group) cmꢁ1; EIMS m/z (rel
int.) 360 [M]+ (2), 85 [C5H9O]+ (100); HREIMS (M+) found
360.2354, C22H32O4 requires 360.2301. 1H NMR
(400 MHz, CDCl3) d 5.18 (1H, s, H-15), 5.03 (1H, s,
H-150), 4.85 (1H, s, H-14), 4.75 (1H, s, H-140), 4.49 (1H,
m, H-2-THP), 4.20a and 4.13 (1H, ddq, J¼9.8, 6.1 and
3.3, H-16), 3.91a and 3.90b (1H, dd, J¼9.2 and 9.1, H-6),
3.43 (2H, m, H-6-THP), 2.84 (1H, m, H-1), 2.79 (1H, m,
H-5), 2.47 (1H, m, H-3), 2.43 (1H, ddd, J¼11.6, 8.5 and
4.4, H-9), 2.32 (1H, ddd, J¼12.0, 8.6 and 3.5, H-11b),
2.11 (1H, m, H-7), 1.99 (1H, m, H-90), 1.98 (1H, m, H-8),
1.95 (1H, m, H-2), 1.93 (1H, m, H-30), 1.86 (1H, m, H-20),
1.75 (1H, ddd, J¼14.5, 9.8 and 3.5, H-13), 1.66 (1H, ddd,
J¼14.5, 8.6 and 3.3, H-130), 1.63–1.45 (6H, m, H-3-THP,
H-4-THP, H-5-THP), 1.28 (1H, m, H-80), 1.26a and 1.13b
(3H, d, J¼6.2, H-17). 13C NMR (100 MHz, CDCl3)
d 179.6 and 179.0 (C-12), 150.8 and 149.9 (C-10), 147.6
and 146.6 (C-4), 111.5 and 111.3 (C-14), 108.8 and 108.1
(7.17 mmol, 66%). Colourless oil. IR (neat, KBr) nmax
,
1719 (carbonyl group) cmꢁ1; EIMS m/z (rel int.) 274 [M]+
1
(25), 232 [MꢁC2H6O]+ (15). H NMR, see Table 4. 13C
NMR, see Table 5; HREIMS (M+) found 274.1571,
C17H22O3 requires 274.1568.
3.4. 13-(10-Hydroxyethyl)-mokkolactone (3)
A 2 mL methanolic solution with 7.1 mmol of compound 2
was kept in a Dewar glass at 0 ꢀC. While the solution was
stirring, NaBH4 (1.4 equiv) was added during the first
5 min of reaction. After 1 h, the reaction was stopped by
addition of 2 mL of distilled water. Extraction with AcOEt
yielded the mixture 1:1 of epimers at C-16, 3 (a–b) in
98% yield (6.96 mmol). Compound 3: colourless oil. IR
(neat, KBr) nmax 3670 (hydroxyl group), 1750 (carbonyl
group) cmꢁ1; EIMS m/z (rel int.) 276 [M]+ (10), 258
[MꢁH2O]+ (10); HREIMS (M+) found 276.1746,
1
C17H24O3 requires 274.1725. H NMR (400 MHz, CDCl3)
d 5.17 (1H, dd, J¼2.2 and 2.2, H-15), 5.03 (1H, dd, J¼2.3

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F. A. Macıas et al. / Tetrahedron 62 (2006) 7747–7755
7752
Table 4. 1H NMR data for compounds 2, 6–9 and 14–17 (400 MHz in CDCl3, signal of residual CHCl3 centred at d 7.25 ppm)
2
6
7
8
9
14
15
16
17
1
2.81 m
2.15 m
1.84 m
2.43 m
1.93 m
2.82 m
3.92 dd
2.13 m
1.95 m
1.29 m
2.41 m
1.97 m
2.64 ddd
2.88 dd
2.65 dd
4.81 s
2.84 ddd
2.00 m
1.86 m
2.54 ddd
1.79 m
2.69 ddd
4.21 dd
1.87 ddd
2.45 m
1.79 m
2.47 ddd
2.01 m
2.86 m
1.92 m
1.81 m
2.48 m
1.95 m
2.85 m
3.86 dd
2.36 ddd
2.08 m
1.31 m
2.52 m
1.96 m
2.86 ddd
2.00 m
1.86 m
2.55 m
1.73 m
2.69 ddd
4.24 dd
2.07 ddd
1.87 m
1.77 m
2.47 m
2.01 m
2.84 m
1.81 m
1.75 m
2.48 m
1.95 m
2.87 m
3.96 dd
2.37 ddd
1.97 m
1.31 m
2.51 m
2.08 m
2.85 ddd
2.03 m
1.88 m
2.54 m
2.20 m
2.69 m
4.05 dd
2.01 ddd
2.45 m
1.79 m
2.48 ddd
2.24 ddd
2.85 ddd
1.88 m
1.82 m
2.48 m
2.13 m
2.68 m
4.05 dd
1.93 ddd
2.45 m
1.78 m
2.54 ddd
2.09 ddd
2.88 m
1.95 m
1.82 m
2.47 m
2.42 m
2.80 m
3.78 dd
2.35 ddd
2.45 m
1.57 m
2.58 ddd
2.08 ddd
2.86 m
2.23 m
2.00 m
2.49 m
2.22 m
2.83 m
3.78 dd
2.26 ddd
1.95 m
1.82 m
2.46 ddd
2.24 ddd
2a
2b
3a
3b
5
6
7
8a
8b
9a
9b
11
13
130
14
140
15
150
16
17
1.89 dd
1.65 dd
4.97 s
4.86 s
5.18 d
5.03 dd
4.97 ddq
1.23 d
1.73 dd
1.55 dd
4.86 s
1.94 dd
1.79 dd
4.87 s
4.79 s
5.18 d
5.03 dd
4.16 ddq
1.27 d
1.76 dd
1.68 dd
4.88 s
4.79 s
5.16 d
5.06 dd
4.27 ddq
1.21 d
2.71 dd
2.61 dd
4.87 s
2.96 dd
2.22 dd
4.88 s
2.89 dd
2.24 dd
4.89 s
2.56 dd
2.44 dd
4.89 s
4.72 s
4.75 s
4.79 s
4.79 s
4.77 s
4.77 s
5.15 d
5.00 dd
—
5.18 d
5.03 d
4.27 ddq
1.21 d
5.17 d
5.03 d
4.75 ddq
1.50 d
5.17 d
5.03 d
5.10 ddq
1.35 d
5.14 d
5.03 d
4.84 ddq
1.59 d
5.16 d
5.04 d
5.24 ddq
1.39 d
2.17 s
J (Hz): (2) 6,7¼9.5; 6,5¼9.3; 11,7¼11.8; 11,13¼6.3; 11,130¼5.7; 13,130¼16.8; 15,3¼1.0; 150,3¼1.9; 150,5¼0.8. (6) 1,2b¼14.7; 1,5¼8.0; 1,2a¼7.5;
3a,3b¼11.3; 3a,2a¼8.9; 3a,2b¼1.86; 5,6¼9.7; 5,15¼2.2; 6,7¼9.5; 7,8b¼12.7; 7,8a¼3.9; 9a,9b¼12.9; 9a,8a¼4.6; 9a,8b¼9.6; 13,130¼14.5;
13,16¼10.8; 130,16¼2.7; 16,17¼6.2; 15,3¼1.3; 150,3¼0.9. (7) 6,7¼10.2; 6,5¼8.7; 7,8b¼12.4; 7,8a¼3.0; 13,130¼14.7; 13,16¼11.2; 130,16¼2.2;
16,17¼6.1; 15,3¼2.0; 150,5¼2.0. (8) 1,2b¼15.0; 1,5¼8.0; 1,2a¼6.7; 5,6¼9.6; 5,15¼2.2; 6,7¼9.8; 7,8b¼13.0; 7,8a¼3.7; 13,130¼15.0; 13,16¼10.3;
130,16¼3.0; 16,17¼6.2; 15,3¼2.0; 150,3¼0.7. (9) 6,7¼10.2; 6,5¼8.9; 7,8b¼12.6; 7,8a¼3.3; 13,130¼14.7; 13,16¼8.5; 130,16¼2.7; 16,17¼6.2; 15,3¼3.0;
150,5¼2.1; 150,5¼0.6. (14) 1,2b¼14.6; 1,5¼7.4; 1,2a¼7.2; 6,7¼9.5; 6,5¼9.6; 7,8b¼11.5; 7,8a¼3.4; 9a,9b¼13.2; 9a,8a¼4.6; 9a,8b¼10.6; 9b,8a¼7.3;
9b,8b¼7.6; 13,130¼11.7; 13,16¼6.4; 130,16¼7.8; 16,17¼6.1; 15,3¼2.0; 150,5¼2.1. (15) 1,2b¼15.0; 1,5¼7.7; 1,2a¼6.6; 5,6¼9.6; 5,150¼1.5; 6,7¼9.6;
7,8b¼12.6; 7,8a¼3.6; 9a,9b¼13.0; 9a,8a¼4.0; 9a,8b¼10.1; 9b,8a¼6.8; 9b,8b¼7.0; 13,130¼11.5; 13,16¼7.0; 130,16¼7.3; 16,17¼6.0; 15,3¼1.9. (16)
6,7¼9.8; 6,5¼9.0; 7,8b¼12.6; 7,8a¼3.6; 9a,9b¼12.9; 9a,8a¼4.0; 9a,8b¼11.3; 9b,8a¼7.5; 9b,8b¼7.3; 13,130¼11.5; 13,16¼7.7; 130,16¼6.5; 16,17¼6.2;
15,3¼2.3; 150,5¼1.7. (17) 6,7¼8.9; 6,5¼9.9; 7,8b¼12.8; 7,8a¼3.2; 9a,9b¼12.8; 9a,8a¼4.2; 9a,8b¼11.1; 9b,8a¼7.2; 9b,8b¼6.9; 13,130¼11.4;
13,16¼7.6; 130,16¼7.5; 16,17¼6.1; 15,3¼2.2; 150,5¼2.0.
(C-15), 84.8 (C-6), 72.5 (C-2-THP), 68.2 (C-16), 63.4 (C-6-
THP), 51.7 (C-5), 47.2 (C-7), 46.8 (C-1), 42.9 and 42.7 (C-
11), 37.4 and 37.3 (C-13), 36.4 and 36.1 (C-9), 32.1 (C-8),
32.0 (C-3), 31.1 and 29.8 (C-2), 25.1 (C-17), 22.2 (C-3-
THP), 20.1 (C-5-THP), 19.5 (C-4-THP).
oxygen was bubbled for 1 h. At this point, treatment with
triethylphosphite (50 mL) as a reducing agent took place.
Then, the mixture was warmed to ꢁ20 ꢀC and a buffer solu-
tion (pH¼7) was added (20 mL). Extractive workup with
Et2O and CC separation (Hexane–EtOAc 9:1) gave the dia-
stereoisomers 5. This procedure was repeated with different
3.6. 11-Hydroxy-13-[10-(200-tetrahydropyranyloxy)-
ethyl]-mokkolactone (5)
amounts of the mixture 4. Compound 5: IR (neat, KBr) nmax,
3540 (hydroxyl group), 1763 (carbonyl group) cmꢁ1; EIMS
m/z (rel int.) 376 [M]+ (2), 85 [C5H9O]+ (100); HREIMS
(M+) found 376.2215, C22H32O5 requires 376.2250. 1H
NMR (400 MHz, CDCl3) d 5.17 (1H, d, J¼2.4, H-15),
5.05 (1H, dd, J¼2.8 and 0.8, H-150), 4.86 (1H, s, H-14),
To a solution of 4 (100 mg) in dry THF (25 mL) at ꢁ73 ꢀC
a 0.4 M solution of KHMDS (8 mL) in dry THF was added
under Ar. After 30 min of stirring at ꢁ73 ꢀC a current of dry
Table 5. 13C NMR data for compounds 2, 6–9 and 14–17 (400 MHz in CDCl3, signal of residual CHCl3 centred at d 77.0 ppm)
14 15 16
47.8 47.6 46.9
2
6
7
8
9
17
46.6
30.1
31.2
1
47.0
30.0
32.3
47.6
30.0
32.1
46.8
30.0
32.4
47.5
30.1
32.2
47.6
30.0
32.2
2
30.1
32.1
30.1
32.2
30.1
31.2
3
4
5
6
149.6
51.8
85.5
149.8
52.3
83.4
150.3
52.3
82.7
149.5
52.1
84.7
149.2
52.3
83.4
148.4
52.1
83.8
149.4
52.2
83.5
149.9
52.4
82.2
150.0
52.2
82.4
7
8
47.3
32.4
52.2
25.1
52.2
27.1
51.4
25.7
52.1
25.1
50.2
25.7
50.3
25.7
50.2
29.2
50.3
29.2
9
37.3
151.5
42.4
177.4
41.6
111.9
109.1
205.3
30.1
35.8
151.3
75.7
177.5
41.4
112.1
109.7
64.9
37.6
151.5
76.4
178.3
37.8
111.7
109.4
65.7
35.8
151.2
76.4
178.1
43.1
112.3
109.8
64.7
36.3
151.6
76.5
178.1
41.3
112.0
109.6
65.3
35.6
151.1
81.7
174.7
32.5
111.8
109.6
75.3
35.8
151.0
82.3
175.7
32.4
112.4
109.8
75.3
37.5
151.2
82.9
177.4
32.4
111.9
109.4
75.3
37.5
151.0
82.8
177.3
32.3
111.7
109.3
75.2
10
11
12
13
14
15
16
17
25.0
24.6
24.8
24.5
23.6
23.5
23.8
23.7

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F. A. Macıas et al. / Tetrahedron 62 (2006) 7747–7755
7753
4.77 (1H, s, H-140), 4.57 (1H, m, H-2-THP), 4.25 (1H, ddq,
J¼7.4, 6.2 and 4.1, H-16), 3.89 (1H, dd, J¼10.2 and 8.2, H-
6), 3.48 (2H, m, H-6-THP), 2.87 (1H, br dd, J¼11.0 and 8.2,
H-5), 2.84 (1H, ddd, J¼11.0, 10.3 and 8.7, H-1), 2.50 (1H,
m, H-3), 2.48 (1H, m, H-9), 2.37 (1H, ddd, J¼12.3, 10.2
and 3.2, H-7), 1.98 (1H, m, H-90), 1.96 (1H, m, H-8), 1.95
(1H, m, H-30), 1.93 (1H, m, H-2), 1.93 (1H, dd, J¼14.9
and 4.1, H-13), 1.82 (1H, dd, J¼14.8 and 7.4, H-130), 1.83
(1H, m, H-20), 1.65–1.40 (6H, m, H-3-THP, H-4-THP, H-
5-THP), 1.36 (1H, dddd, J¼16.7, 12.4, 12.0 and 4.10, H-
8), 1.21 (3H, d, J¼6.2, H-17). 13C NMR (100 MHz,
CDCl3) d 180.0 (C-12), 150.3 (C-10), 148.0 (C-4), 111.5
(C-14), 109.3 (C-15), 83.9 (C-6), 76.2 (C-11), 72.4 (C-2-
THP), 67.9 (C-16), 63.3 (C-6-THP), 52.0 (C-5), 47.6 (C-
7), 47.2 (C-1), 38.3 (C-13), 37.9 (C-9), 33.0 (C-8), 32.8
(C-3), 31.1 (C-2), 26.0 (C-17), 22.8 (C-3-THP), 21.1 (C-5-
THP), 19.7 (C-4-THP).
compounds (11R,16R) 11-hydroxy-13-(10-(methylsulfonyl-
oxy)-ethyl)-mokkolactone (10) (1.36 mmol, 98%), (11R,
16S) 11-hydroxy-13-(10-(methylsulfonyloxy)-ethyl)-mok-
kolactone (11) (1.49 mmol, 98%), 11-hydroxy-13-(10-
(methylsulfonyloxy)-ethyl)-mokkolactone (12) (1.29 mmol,
98%) and (11S,16R) 11-hydroxy-13-(10-(methylsulfonyl-
oxy)-ethyl)-mokkolactone (13) (1.36 mmol, 98%). Com-
pound 10: colourless oil. IR (neat, KBr) nmax, 3440
(hydroxyl group), 1770 (carbonyl group) cmꢁ1; EIMS m/z
(rel int.) 370 [M]+ (10), 275 [MꢁOMs]+ (12); HREIMS
1
(M+) found 370.4410, C18H26O6S requires 370.1450. H
NMR (400 MHz, CDCl3) d 5.45 (1H, ddq, J¼9.8, 6.2 and
3.2, H-16), 5.17 (1H, d, J¼1.2, H-15), 5.05 (1H, d, J¼2.0,
H-150), 4.88 (1H, s, H-14), 4.79 (1H, s, H-140), 4.21 (1H,
dd, J¼10.0 and 9.7, H-6), 3.02 (3H, s, H-Ms), 2.88 (1H,
ddd, J¼14.3, 8.1 and 7.3, H-1), 2.80 (1H, dd, J¼9.7 and
8.1, H-5), 2.50 (1H, ddd, J¼11.3, 8.9 and 4.5, H-3), 2.46
(1H, ddd, J¼12.7, 9.3 and 4.2, H-9), 2.45 (1H, m, H-8),
2.33 (1H, dd, J¼14.5 and 9.8, H-13), 2.01 (1H, ddd,
J¼12.7, 10.1 and 4.8, H-90), 2.01 (1H, m, H-2), 1.85 (1H,
ddd, J¼12.7, 10.0 and 3.9, H-7), 1.86 (1H, m, H-20), 1.79
(1H, m, H-80), 1.86 (1H, dd, J¼14.5 and 3.2, H-130), 1.78
(1H, ddd, J¼11.3, 5.1 and 2.0, H-30), 1.52 (3H, d, J¼6.2,
H-17). 13C NMR (100 MHz, CDCl3) d 177.5 (C-12), 151.3
(C-10), 149.8 (C-4), 112.1 (C-14), 109.7 (C-15), 83.4
(C-6), 75.7 (C-11), 63.0 (C-16), 52.3 (C-5), 52.2 (C-7),
47.6 (C-1), 41.6 (C-13), 38.2 (C-Ms), 35.8 (C-9), 32.1
(C-3), 30.0 (C-2), 25.1 (C-8), 23.2 (C-17). Compound 11:
colourless oil. IR (neat, KBr) nmax, 3434 (hydroxyl group),
1774 (carbonyl group) cmꢁ1; EIMS m/z (rel int.) 370 [M]+
(7), 275 [MꢁOMs]+ (15); HREIMS (M+) found 370.4411,
C18H26O6S requires 370.1450. 1H NMR (400 MHz,
CDCl3) d 5.18 (1H, d, J¼1.2, H-15), 5.10 (1H, ddq,
J¼9.7, 6.1 and 3.3, H-16), 5.03 (1H, d, J¼2.0, H-150),
4.86 (1H, s, H-14), 4.76 (1H, s, H-140), 3.87 (1H, dd,
J¼10.1 and 8.9, H-6), 3.02 (3H, s, H-Ms), 2.84 (1H, m,
H-1), 2.83 (1H, m, H-5), 2.52 (1H, ddd, J¼15.3, 8.5 and
4.5, H-3), 2.48 (1H, m, H-9), 2.28 (1H, ddd, J¼12.7,
10.1 and 3.9, H-7), 2.15 (1H, dd, J¼14.7 and 9.7, H-13),
2.00 (1H, m, H-8), 1.99 (1H, m, H-90), 1.93 (1H, m, H-2),
1.92 (1H, m, H-30), 1.86 (1H, dd, J¼14.7 and 3.3, H-130),
1.83 (1H, m, H-20), 1.46 (3H, d, J¼6.1, H-17), 1.35 (1H,
m, H-80). 13C NMR (100 MHz, CDCl3) d 178.3 (C-12),
151.4 (C-10), 150.3 (C-4), 111.8 (C-14), 109.4 (C-15),
83.4 (C-6), 76.4 (C-11), 63.1 (C-16), 52.3 (C-5), 52.2
(C-7), 46.8 (C-1), 42.1 (C-13), 38.1 (C-Ms), 37.8 (C-9),
32.1 (C-3), 30.1 (C-2), 27.2 (C-8), 22.8 (C-17). Compound
12: colourless oil. IR (neat, KBr) nmax, 3456 (hydroxyl
group), 1768 (carbonyl group) cmꢁ1; EIMS m/z (rel int.)
370 [M]+ (10), 275 [MꢁOMs]+ (18); HREIMS (M+) found
370.4409, C18H26O6S requires 370.1450. 1H NMR
(400 MHz, CDCl3) d 5.18 (1H, d, J¼1.2, H-15), 5.12 (1H,
ddq, J¼9.9, 6.2 and 3.5, H-16), 5.03 (1H, d, J¼2.0,
H-150), 4.88 (1H, s, H-14), 4.80 (1H, s, H-140), 4.26 (1H,
dd, J¼10.1 and 9.6, H-6), 3.02 (3H, s, H-Ms), 2.84 (1H,
ddd, J¼14.3, 8.1 and 7.3, H-1), 2.68 (1H, dd, J¼9.7 and
8.1, H-5), 2.51 (1H, m, H-3), 2.48 (1H, m, H-9), 2.23 (1H,
dd, J¼14.8 and 9.9, H-13), 2.03 (1H, ddd, J¼12.7, 10.1
and 3.9, H-7), 2.01 (1H, m, H-90), 1.99 (1H, m, H-2), 1.85
(1H, m, H-8), 1.84 (1H, m, H-20), 1.83 (1H, dd, J¼14.8
and 3.5, H-130), 1.73 (1H, m, H-80), 1.72 (1H, m, H-30),
1.45 (3H, d, J¼6.2, H-17). 13C NMR (100 MHz, CDCl3)
d 178.1 (C-12), 151.2 (C-10), 149.5 (C-4), 112.8 (C-14),
3.7. Diols 6, 7, 8 and 9
The mixture 4 was dissolved in EtOAc (25 mL) with a few
crystal of p-toluenesulfonic acid. After 24 h potassium
carbonate was added and the mixture stirred for several
minutes. The salts were removed by filtration and the puri-
fication was accomplished by CC (Hexane–EtOAc 8:2) to
yield diols (11R,16R) 11-hydroxy-13-(10-hydroxyethyl)-
mokkolactone (6) (1.39 mmol, 20%), (11R,16S) 11-hy-
droxy-13-(10-hydroxyethyl)-mokkolactone (7) (1.53 mmol,
22%), (11S,16S) 11-hydroxy-13-(10-hydroxyethyl)-mokko-
lactone (8) (1.32 mmol, 19%) and (11S,16R) 11-hydroxy-
13-(10-hydroxyethyl)-mokkolactone (9) (1.39 mmol, 20%).
Compound 5: colourless crystal. IR (neat, KBr) nmax, 3490
(hydroxyl group), 1765 (carbonyl group) cmꢁ1; EIMS m/z
(rel int.) 292 [M]+ (9), 274 [MꢁH2O]+ (38); HREIMS
(M+) found 292.1620, C17H24O4 requires 292.1675.1H
NMR, see Table 1. 13C NMR, see Table 2. Compound 6: col-
ourless crystal. IR (neat, KBr) nmax, 3450 (hydroxyl group),
1770 (carbonyl group) cmꢁ1; EIMS m/z (rel int.) 292 [M]+
(7), 274 [MꢁH2O]+ (14); HREIMS (M+) found 292.1677,
C17H24O4 requires 292.1675.1H NMR, see Table 4. 13C
NMR, see Table 5. Compound 7: colourless crystal. IR
(neat, KBr) nmax, 3460 (hydroxyl group), 1772 (carbonyl
group) cmꢁ1; EIMS m/z (rel int.) 292 [M]+ (3), 274
[MꢁH2O]+ (4); HREIMS (M+) found 292.1703, C17H24O4
1
requires 292.1675. H NMR, see Table 4. 13C NMR, see
Table 5. Compound 8: colourless crystal. IR (neat, KBr)
nmax, 3460 (hydroxyl group), 1772 (carbonyl group) cmꢁ1
;
EIMS m/z (rel int.) 292 [M]+ (3), 274 [MꢁH2O]+ (4);
HREIMS (M+) found 292.1703, C17H24O4 requires
292.1675. 1H NMR, see Table 4. 13C NMR, see Table 5.
3.8. Reaction of mesylation
Diols 6–9, separately, were dissolved in pyridine (15 mL)
and 1.5 equiv of mesyl chloride was added at 0 ꢀC with stir-
ring. After 24 h the reaction was stopped by addition of 2 mL
of distilled water. The reaction mixture was extracted with
AcOEt (5ꢃ), and the combined organic phases were washed
with aq saturated CuSO4 (3ꢃ). The organic phase was dried
over anhydrous sodium sulfate, the solvent evaporated under
vacuum, and the crude product of the reaction purified by CC
(Hexane–EtOAc 8:2), yielding the corresponding mesylated

´
F. A. Macıas et al. / Tetrahedron 62 (2006) 7747–7755
7754
109.7 (C-15), 84.4 (C-6), 76.4 (C-11), 62.9 (C-16), 52.1
(C-5), 51.0 (C-7), 47.8 (C-1), 42.6 (C-13), 38.2 (C-Ms),
35.7 (C-9), 32.1 (C-3), 30.1 (C-2), 25.2 (C-8), 23.6 (C-17).
Compound 13: colourless oil. IR (neat, KBr) nmax, 3448 (hy-
droxyl group), 1763 (carbonyl group) cmꢁ1; EIMS m/z (rel
int.) 370 [M]+ (8), 275 [MꢁOMs]+ (9); HREIMS (M+) found
370.4406, C18H26O6S requires 370.1450. 1H NMR
(400 MHz, CDCl3) d 5.26 (1H, ddq, J¼8.4, 6.2 and 3.2,
H-16), 5.16 (1H, d, J¼2.0), 5.04 (H-150, d, J¼2.1, H-15),
4.88 (1H, s, H-14), 4.80 (1H, s, H-140), 3.95 (1H, dd,
J¼10.3 and 8.9, H-6), 3.02 (3H, s, H-Ms), 2.84 (1H, m,
H-1), 2.83 (1H, m, H-5), 2.51 (1H, m, H-9), 2.49 (1H, m,
H-3), 2.33 (1H, ddd, J¼12.7, 10.1 and 3.9, H-7), 2.30 (1H,
dd, J¼14.7 and 8.4, H-13), 2.04 (1H, m, H-90), 2.02 (1H,
m, H-8), 1.95 (1H, m, H-30), 1.82 (1H, m, H-2), 1.77 (1H,
m, H-20), 1.74 (1H, dd, J¼14.7 and 3.2, H-130), 1.48 (3H,
d, J¼6.2, H-17), 1.35 (1H, m, H-80). 13C NMR (100 MHz,
CDCl3) d 178.1 (C-12), 151.4 (C-10), 149.8 (C-4), 112.6
(C-14), 109.4 (C-15), 84.4 (C-6), 76.6 (C-11), 63.0 (C-16),
52.3 (C-5), 51.2 (C-7), 47.8 (C-1), 40.1 (C-13), 38.2
(C-Ms), 36.3 (C-9), 32.1 (C-3), 30.2 (C-2), 25.8 (C-8),
23.2 (C-17).
with diluted HCl, the mixture was extracted with ethyl ace-
tate. The organic solution was washed with water, dried and
the solvent evaporated. The reaction mixture was chromato-
graphed on silica gel using hexane/AcOEt (3:2) as eluent
yielding 94 mg of 18 (60%, 0.69 mmol) and 182 mg of 20
(29%, 0.34 mmol). Compound 18: colourless crystal. IR
(neat, KBr) nmax, 3548 (hydroxyl group), 1772 (carbonyl
group) cmꢁ1; EIMS m/z (rel int.) 280.1310 [M]+ (18),
272.1519 [Mꢁ18]+ (21); 1H NMR (400 MHz, CDCl3)
d 5.19 (1H, br s, H-15), 5.17 (1H, br s, H-150), 4.92 (1H, s,
H-14), 4.85 (1H, s, H-140), 4.34 (1H, br dd, J¼8.1 and 7.4,
H-3), 3.96 (1H, dd, J¼9.8 and 9.7, H-6), 3.95 (1H, dd,
J¼11.0 and 3.7, H-13), 3.54 (1H, dd, J¼11.0 and 8.2,
H-130), 3.53 (1H, ddd, J¼9.0, 7.6 and 5.0, H-8), 2.73 (1H,
ddd, J¼9.1, 9.0 and 8.4, H-1), 2.64 (1H, dd, J¼9.8 and
9.1, H-5), 2.60 (1H, ddd, J¼11.0, 9.7 and 7.6, H-7), 2.57
(1H, dd, J¼12.2 and 5.0, H-9), 2.12 (1H, ddd, J¼11.0, 8.2
and 3.7, H-11), 2.11 (1H, ddd, J¼13.1, 8.4 and 7.4, H-2),
2.08 (1H, dd, J¼12.2 and 7.6, H-90), 1.58 (1H, ddd,
J¼13.1, 9.0 and 8.1, H-20). 13C NMR (100 MHz, CDCl3)
d 73.8 (C-8), 73.2 (C-3), 62.1 (C-13), 54.7 (C-11), 50.3
(C-5), 50.1 (C-7), 44.1 (C-1), 43.7 (C-9), 39.0 (C-2), 175.6
(C-12), 153.2 (C-10), 143.6 (C-4), 116.1 (C-14), 111.6
(C-15), 79.6 (C-6). Compound 20: colourless crystal. IR
(neat, KBr) nmax, 3427 (hydroxyl group), 1754 (carbonyl
group) cmꢁ1; EIMS m/z (rel int.) 262.1198 [M]+ (30),
3.9. Oxetane lactones 14, 15, 16 and 17
The mesylated compounds 10, 11, 12 and 13, separately,
were dissolved in dry THF (20 mL). While the solution
was stirring, BuLi (1.5 equiv) was added dropwise at 0 ꢀC.
After 12 min the mixture was warmed up to 55 ꢀC and main-
tained for 2 h. The reaction was quenched by addition of
2 mL of distilled water and was extracted with AcOEt
(5ꢃ). The organic phase was dried over anhydrous sodium
sulfate, the solvent evaporated under vacuum, and the crude
product of the reaction purified by CC (Hexane–EtOAc 9:1),
yielding the oxetane lactones (11R,16S) 11,16-epoxy-
13-ethylmokkolactone (14) (0.27 mmol, 20%), (11R,16R)
11,16-epoxy-13-ethylmokkolactone (15) (0.31 mmol,
21%), (11S,16R) 11,16-epoxy-13-ethylmokkolactone (16)
(0.24 mmol, 19%) and (11S,16S) 11,16-epoxy-13-ethyl-
mokkolactone (17) (0.29 mmol, 22%). Compound 14: col-
ourless crystal. IR (neat, KBr) nmax, 1782 (carbonyl group)
cmꢁ1; EIMS m/z (rel int.) 274 [M]+ (15), 248 [Mꢁ44]+
(36); HREIMS (M+) found 274.1619, C17H22O3 requires
1
244.1096 [Mꢁ18]+; H NMR (400 MHz, CDCl3) d 6.25
(1H, dd, J¼3.3 and 0.7, H-13), 6.13 (1H, dd, J¼3.1 and
0.8, H-130), 5.47(1H, dd, J¼1.9 and 1.6, H-15), 5.31 (1H,
dd, J¼1.7 and 1.4, H-150), 4.97 (1H, dd, J¼0.6 and 0.4, H-
14), 4.94 (1H, dd, J¼0.6 and 0.4, H-140), 4.54 (1H, br dd,
J¼7.4 and 2.1, H-3), 4.14 (1H, dd, J¼10.6 and 9.1, H-6),
3.96 (1H, br ddd, J¼9.1, 5.0 and 4.0, H-8), 3.10 (1H, br
ddd, J¼10.0, 9.1, 3.3 and 3.1, H-7), 2.96 (1H, br ddd,
J¼11.0, 9.4 and 8.0, H-1), 2.79 (1H, br dd, J¼10.5 and
9.7, H-5), 2.69 (1H, dd, J¼14.1 and 5.1, H-9b), 2.28 (1H,
dd, J¼14.1 and 3.9, H-9a), 2.22 (1H, ddd, J¼13.2, 7.6
and 7.4, H-2b), 1.72 (1H, ddd, J¼13.2, 11.0 and 7.6,
H-2a). 13C NMR (100 MHz, CDCl3) d 183.5 (C-12),
152.4 (C-10), 142.7 (C-4), 138.1 (C-11), 123.2 (C-13),
117.4 (C-14), 113.1 (C-15), 78.8 (C-6), 73.7 (C-3), 70.9
(C-8), 51.2 (C-7), 50.9 (C-5), 45.1 (C-1), 41.3 (C-9), 39.2
(C-2).
1
274.1569. H NMR, see Table 4. 13C NMR, see Table 5.
Compound 15: colourless crystal. IR (neat, KBr) nmax
,
3.11. 8a-Hydroxy-dehydrozaluzanin C (21)
1766 (carbonyl group) cmꢁ1; EIMS m/z (rel int.) 274 [M]+
(12), 248 [Mꢁ44]+ (39); HREIMS (M+) found 274.1656,
Compound 20 (100 mg, 0.38 mmol) was dissolved in dried
CH2Cl2 (20 mL). SeO2 (45 mg, 0.40 mmol) was added
over the stirred solution, and allowed to react for 24 h. Filter-
ing the reaction mixture through silica gel stopped the reac-
tion, the solvent was then evaporated under vacuum. The
crude product was purified by CC using hexane/ethyl acetate
mixtures as eluent, yielding 78 mg of 21 (79%, 30 mmol).
1
C17H22O3 requires 274.1569. H NMR, see Table 4. 13C
NMR, see Table 5. Compound 16: colourless crystal. IR
(neat, KBr) nmax, 1766 (carbonyl group) cmꢁ1; EIMS m/z
(rel int.) 274 [M]+ (11), 248 [Mꢁ44]+ (38); HREIMS (M+)
1
found 274.1586, C17H22O3 requires 274.1569. H NMR,
see Table 4. 13C NMR, see Table 5. Compound 17: colour-
less crystal. IR (neat, KBr) nmax, 1766 (carbonyl group)
cmꢁ1; EIMS m/z (rel int.) 274 [M]+ (9), 248 [Mꢁ44]+
(42); 1H NMR, see Table 4. 13C NMR see Table 5.
Compound 21: colourless crystal. IR (neat, KBr) nmax
3430 (hydroxyl group), 1762 (carbonyl group) cmꢁ1
,
;
EIMS m/z (rel int.) 260.1098 [M]+ (21), 242.1069
1
[Mꢁ18]+; H NMR (400 MHz, CDCl3) d 6.36 (1H, dd,
3.10. 11,13-Dihydro-13-hydroxy-deacylcynaropicrin
(18) and deacylcynaropicrin (20)
J¼3.4 and 0.9, H-13), 6.30 (1H, dd, J¼3.0 and 0.9, H-130),
6.26 (1H, d, J¼2.5, H-15), 5.87 (1H, d, J¼2.2, H-150),
5.03 (1H, s, H-14), 4.83, (1H, s, H-140), 3.98 (1H, dd,
J¼9.5 and 9.2, H-6), 3.96 (1H, br ddd, J¼9.1, 5.0 and 4.0,
H-8), 3.25 (1H, ddd, J¼9.5, 8.6 and 2.5, H-5a), 3.11 (1H,
br ddd, J¼8.2, 8.6 and 5.2, H-1a), 3.06 (1H, dddd, J¼9.3,
Cynaropicrin was isolated from Cynara scolimus.15 Cynaro-
picrin (400 mg, 1.15 mmol) was mixed with aq 10% K2CO3
(200 mL) and stirred for 24 h at 50 ꢀC. After acidification

´
F. A. Macıas et al. / Tetrahedron 62 (2006) 7747–7755
7755
9.2, 3.4 and 3.0, H-7), 2.79 (1H, dd, J¼13.1 and 5.6, H-9b),
Acknowledgements
2.60 (1H, dd, J¼13.2 and 8.2, H-2b), 2.49 (1H, dd, J¼18.5
and 5.2, H-2a), 2.30 (1H, dd, J¼3.1 and 7.0, H-9a). 13C
NMR (100 MHz, CDCl3) d 204.2 (C-3), 169.5 (C-12),
143.1 (C-11), 136.5 (C-10), 130.1 (C-4), 125.9 (C-13),
123.5 (C-15), 117.1 (C-14), 80.0 (C-6), 73.2 (C-8), 49.6
(C-7), 49.3 (C-5), 46.5 (C-9), 43.7 (C-2), 40.6 (C-1).
´
This research was supported by the Ministerio de Educacion
y Ciencia, Spain (MEC; Project No. AGL2004-08357-C04-
04/AGR and AGL2005-05190/AGR).
References and notes
CCDC 602144-602148 and CCDC 605928-605933 contain
the supplementary crystallographic data for this paper.
These data can be obtained free of charge at www.ccdc.
cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0)1223 336033; email:
deposit@ccdc.cam.ac.uk].
´
1. (a) Massanet, G. M.; Collado, I. G.; Macıas, F. A.; Bohlmann,
F.; Jakupovic, J. Tetrahedron Lett. 1983, 24, 1641–1642; (b)
´
Collado, I. G.; Macıas, F. A.; Massanet, G. M.; Luis, F. R.
Tetrahedron 1986, 42, 3611–3622.
´
´
2. Collado, I. G.; Macıas, F. A.; Massanet, G. M.; Rodrıguez-Luis,
F. Phytochemistry 1985, 24, 2107–2109.
´
3. Macıas, F. A.; Molinillo, J. M. G.; Massanet, G. M. Tetrahedron
1993, 49, 2499–2508.
4. Wang, M.; Cornett, B.; Nettles, J.; Liotta, D.; Zinder, J. J. Org.
Chem. 2000, 65, 1059–1068.
5. Hosono, F.; Nishiyama, S.; Yamamura, S.; Izawa, T.; Kato, K.
Bioorg. Med. Chem. Lett. 1994, 4, 2083–2086.
6. Fried, J.; Zhou, Z.; Chen, C. K. Tetrahedron Lett. 1984, 25,
3271–3272.
4. Conclusions
The achievement of the four oxetane lactones using de-
hydrocostuslactone as starting material has provided some
correlations, which can be useful tools in future researches
with this type of molecules. Thus, a deep analysis of the
NMR and X-ray derived data of the obtained oxetane
lactones has allowed us to find some relationships that can
be helpful in order to detect the presence of the oxetane
ring as well as to establish its stereochemistry on similar
compounds.
´
7. Collado, I. G.; Macıas, F. A.; Massanet, G. M.; Molinillo,
J. M. G.;Rodrıguez-Luis, F. J. Org. Chem. 1987, 52, 3323–3326.
´
8. Fronczek, F. R.; Vargas, D.; Parodi, F. J.; Fischer, N. H. Acta
Crystallogr. 1989, C45, 1829–1831.
9. Wiberg, K. B. J. Org. Chem. 2003, 68, 9322–9329.
´
10. Milosavljevic, S.; Juranic, I.; Bulatovic, V.; Macura, S.;
Juranic, M.; Limbach, H.; Weisz, K.; Vajs, V.; Todorovic, N.
´
´
´
´
Struct. Chem. 2004, 15, 237–245.
´
11. Macıas, F. A.; Molinillo, J. M. G.; Massanet, G. M.
Tetrahedron 1993, 49, 2499–2508.
Furthermore, the results of the conformational analysis may
also be important findings due to the key aspect that the
molecular conformations play on the biological activity.
We have found that guaianolides having the a-methylene-
g-lactone moiety and non-bulky substituents prefer
a twist-chair conformation at the cycloheptane ring, whereas
a chair conformation occurs when the lack of the a-methyl-
ene-g-lactone group takes place.
12. Samek, Z.; Holub, M.; Drozdz, B.; Iommi, G.; Corbella, A.;
Gariboldi, P. Tetrahedron Lett. 1971, 4775–4778.
¨
13. Oks€uz, S.; Clark, R. J.; Herz, W. Phytochemistry 1993, 33,
1267–1268.
14. Mattern, G.; Weckert, E.; Youssef, D.; Frahm, A. W. Acta
Crystallogr. 1996, C52, 1791–1793.
15. Berhard, H. O. Pharm. Acta Helv. 1982, 57, 179–180.