An easy access to bioactive 13-hydroxylated and 11,13-dihydroxylated sesquiterpene lactones (SLs) through Michael addition of a nucleophilic hydroxyl group

Article abstract of DOI:10.1016/j.tet.2008.09.024

The addition of a hydroxyl group to α,β-unsaturated carbonyl systems provides a new and easy access to bioactive difunctionalized sesquiterpene lactones (SLs) through a Michael addition to the α-methylene-γ-lactone system. The use of HMPA to enhance the nucleophilic properties of the hydroxyl groups and to stabilize the enolate is discussed. Also, we present a proposal for the mechanism based on the experimental data obtained. The scope and usefulness of the reaction are explored with other substrates and is limited by the need for a certain level of steric hindrance to avoid chain polycondensations. Nevertheless, the reaction works with esters, ketones and aldehydes. The absolute stereochemistry of some products has been elucidated by X-ray diffraction analysis. The synthesis of a natural SL using this methodology and the correction of the structure of another illustrate the usefulness of this reaction.

Full text of DOI:10.1016/j.tet.2008.09.024

Tetrahedron 64 (2008) 10996–11006
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An easy access to bioactive 13-hydroxylated and 11,13-dihydroxylated
sesquiterpene lactones (SLs) through Michael addition
of a nucleophilic hydroxyl group
a
,
a
a
a
*
´
´
´
´
´
´
Francisco A. Macıas , Marıa D. Garcıa-Dıaz , Guillermo M. Massanet , Jose F. Gomez-Madero ,
Frank R. Fronczek b, Juan C.G. Galindo a
a
´
´
´
´
´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad de Cadiz, c/Republica Saharaui s/n, 11510 Puerto Real, Cadiz, Spain
b Department of Chemistry, Louisiana State University, Baton Rouge, LS 78083-1804, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The addition of a hydroxyl group to
bioactive difunctionalized sesquiterpene lactones (SLs) through a Michael addition to the
g
stabilize the enolate is discussed. Also, we present a proposal for the mechanism based on the experi-
mental data obtained. The scope and usefulness of the reaction are explored with other substrates and is
limited by the need for a certain level of steric hindrance to avoid chain polycondensations. Nevertheless,
the reaction works with esters, ketones and aldehydes. The absolute stereochemistry of some products
has been elucidated by X-ray diffraction analysis. The synthesis of a natural SL using this methodology
and the correction of the structure of another illustrate the usefulness of this reaction.
Ó 2008 Elsevier Ltd. All rights reserved.
a
,
b
-unsaturated carbonyl systems provides a new and easy access to
-methylene-
-lactone system. The use of HMPA to enhance the nucleophilic properties of the hydroxyl groups and to
Received 12 August 2008
Accepted 3 September 2008
Available online 17 September 2008
a
Keywords:
Sesquiterpene lactones
Enolates
Michael addition
Peroxide intermediate
Solvent effect
HMPA
1. Introduction
Hence, it is of interest to look for synthetic routes to access the
lactone ring and the nearby positions. However, the total synthesis
Sesquiterpene lactones (SLs) constitute a large group of natural
products1 with a wide range of biological activities.2 Though the
number of different skeletons is not particularly high, SLs contain
a wide variety of functional groups. Nevertheless, the biological
activity profiles have usually been related with the presence of an
of SLs is expensive and time consuming and hemisynthesis using
naturally abundant SLs with an exocyclic double bond at the lac-
tone ring (e.g., dehydrocostuslactone or cynaropicrin) can be en-
visaged as a feasible alternative. Notwithstanding, the D
11,13 double
bond present in most guaianolides and pseudoguaianolides is
electron-deficient, making reactions such as epoxidations or allylic
oxidations in the lactone ring difficult or impossible. Other poten-
tial methods to introduce an oxygen atom in the lactone ring could
a
-methylene-g
-lactone group,3 which is very common in these
compounds. However, the number of known bioactive SLs without
such a feature is increasing.4 Among them, we have focused our
attention on those examples in which the lactone ring has different
degrees of oxidation, carrying either one or two hydroxyl groups at
positions C-11 and C-13. Other minor modifications include the
presence of epoxide or oxetane rings. Most of the 13-hydroxyl or
11,13-dihydroxyl-SLs reported to date are guaianolides (compounds
1–26) or pseudoguaianolides (27–33). In addition, hydroxy-
methylene groups attached to a lactone ring are present in the
monoterpene lactones the iridoids (34–36) (Fig. 1, Table 1). In many
cases these compounds have proven to be bioactive in a wide array
of situations.
exploit the a,b-unsaturated carbonyl system through Michael ad-
dition reactions. This approach is challenged by the fact that nu-
cleophilic oxygen species that can be smoothly converted into free
hydroxyl groups are not easy to obtain. Our previous results30 show
that magnesium methoxide [(MeO)2Mg] can act as a good nucle-
ophile and undergoes Michael addition to the exocyclic double
bond of the lactone. Unfortunately, demethylation needs to be
carried out under strongly acidic conditions with Lewis acids such
as BBr3.31 All attempts to demethylate the hydroxyl group in the
adduct of dehydrocostuslactone and magnesium methoxide
resulted in isomerization of the exocyclic double bonds to give
unstable azulene-like compounds (unpublished results).
The most direct access to 13-hydroxylated SLs should be the
synthetic equivalent of a Michael addition where a hydroxyl group
* Corresponding author. Tel.: þ34 956 016 370; fax: þ34 956 016 193.
´
E-mail address: famacias@uca.es (F.A. Macıas).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.024

F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
10997
Refs.
Table 1
Sources of compounds named in Figure 1
GUAIANOLIDES
Source
Compound
14
Ambrosia maritime
Centaurea clementei
Centaurea imperialis
Centaurea behen
Centaurea musimomum
Centaurea solstitialis
Cymbaria mongolica
Cynara cardunculus
Cynara humilis
32
24, 25, 26
11, 16, 17
20, 21
20, 21
11, 14, 17
35
11, 12
5
6
1
HO
7,8
9,10
11
12,13
14
OH
5
11 13
12
O
O
O
O
15
OR
OH
O
O
15,16
17
R = H, 7,11-dehydro (1)
(3)
(4)
R = Me (2)
15, 16, 18
Cynara scolymus
11, 19, 20, 22, 23
11, 13
9: corrected as 11(S)
5, 7
33
27, 28, 29
31
1, 3
2
18,19
7
20
21
22
23
24
25
26
27
Cynara sibthorpiana
Helianthus petiolaris
Hemisteptia lyrata
Hymenoxis grandiflora
Parthenium hysterophorus
Parthenium tomentosum
Podachaenium eminens
Saussurea lappa
R1O
R2 AcO
OMe
OAc
OMe
R
O
O
O
OH
R3
OH
O
O
O
R1 = H, R2 = αOH, R3 = αH (5)
R1 = H, R2 = βOH, R3 = βH (6)
(8)
R = CH2 (9)
R = αMe, βH (10)
Saussurea amara
6
R1 = H, R2 = αOCOC(=CH2)CH2OH, R3 = αH (7)
Scorzonera austriaca
Verbena littoralis
4
34
28
29
R1 = H, R2 = Cl (15)
R1 = Ac, R2 = Cl (16)
R1
R1O
R
1 = H, R2 = OAc (17)
attacks the
a,b-unsaturated carbonyl system. However, the hy-
R2
O
O
OH
R2
droxyl group usually acts as a base and not as a nucleophile. Con-
sequently, methods to increase the nucleophilicity of the hydroxyl
group should be used to achieve this aim. Indeed, there is only one
previous report that describes nucleophilic additions of hydroxyl
groups to unsaturated carbonyl systems.32 Herein, a Michael ad-
OH
OH
O
O
HO
R1 = βOH, R2 = αMe, βH solstitialin A (11)
R
R
R
1 = βOGlu, R2 = αMe, βH cynaroside A (12)
1 = αOH, R2 = αMe, βH sibthorpin (13)
1 = βOAc, R2 = αMe, βH (14)
O
O
O
(18)
O
dition reaction between a hydroxyl group and the
a-methylene
group of a SL is presented. In this reaction the generation of the
corresponding stabilized enolate at high temperature leads to the
corresponding 13-hydroxyl-derivatives and an unexpected 11,13-
dihydroxylated compound. The use of the aprotic solvent HMPA is
crucial to enhance the nucleophilic properties of the hydroxyl
group and to stabilize the enolate at high temperature. There are no
previous reports of the use of HMPA as a solvent to allow the 1,4-
O
O
R1
R2
HO
SO2Me
OR1
O
O
R2
R3
O
OH
O
O
O
R1 = H, R2 = OH (20)
(19)
R1 = COC(=CH2)CH2OH, R2 = Me, R3 = H
R1 = H, R2 = OAc (21)
clementein A (24)
nucleophilic addition of hydroxyl groups to
a,b-unsaturated car-
R1 = αH, R2 = OH cynarinin A (22)
R1 = COC(=CH2)CH2OH, R2 = H, R3 = Me
clementein B (25)
R1 = H, R2 = Cl (23)
bonyl systems at such temperatures. In SLs the reaction proceeds
with high regioselectivity. However, the scope of the reaction in
other systems is challenged by the possibility of chain reactions,
which can be avoided only with high levels of steric hindrance.
R1 = H, R2 = Me, R3 = H clementein C (26)
PSEUDOGUAIANOLIDES
R
2. Results and discussion
O
O
O
O
O
O
Treatment of a solution of dehydrocostuslactone (DHC, 37) in
HMPA with an aqueous solution of Na2CO3 at 90–95 ꢀC (7 days)
yielded the hydroxylated compounds 38, 39 and 40 (Fig. 2), with
some starting material remaining (30%).
Compounds 38 and 39 correspond to the Michael addition of the
hydroxyl group to the unsaturated carbonyl system of the lactone
ring. The relative stereochemistry of compound 39 at C-11 was
initially assigned through NOESY experiments and was un-
equivocally established by X-ray diffraction as 11(R) (Fig. 3).
Moreover, the allylic oxidation of 39 using SeO2/TBTHP yielded, in
OMe
OH
OH
O
O
O
O
hymenoflorin (30)
stramonin B (31)
R = H (27)
2,3-dihydrostramonin B (32)
R = OH (28)
R = OMe (29)
IRIDOIDS
O
O
OH
H
H
H
O
O
O
O
O
HO
O
H
OH
OMe
OH
O
addition to the 3
a-hydroxyl derivative 41, the crystalline
HO
HO
1
a,3a-trihydroxylderivative 42, which again confirmed the pro-
gelsemiol (34)
HO
(35)
OH
posed absolute stereochemistry as 11(R). The absolute stereo-
chemistry of 38 was established as 11(S) by comparison of the
respective 1H NMR and EIMS data of 38 and 39.
The absolute stereochemistry at C-11 of compound 40 was ini-
tially established as 11(R) through NOE experiments (Fig. 4) and
was further confirmed by derivatization with tosyl chloride.
The reaction of 40 with tosyl chloride in pyridine afforded the
H
florigrandin (33)
O
O
H
(36)
Figure 1. Natural SLs and iridoids with a hydroxymethylene group.
expected 13
b-tosyl derivative 43 and the 11b-chloro-13-tosyl
derivative 44, obtained by the nucleophilic substitution of the

10998
F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
HMPA
Na2CO3 aq. 20%
80-90 °C, 7 d.
+
+
O
O
O
O
OH
OH
OH
OH
O
O
O
O
DHC (37)
38
39
40
Figure 2. Michael addition of a nucleophilic hydroxyl group to the lactone 37.
11,13-ditosyl intermediate (Fig. 5). X-ray diffraction of 44 showed
the stereochemistry at C-11 to be 11(S), thus confirming the initial
assignment for 40. The chloride derivative 44 can be obtained ei-
ther through an SN1 or an SN2 mechanism, with the SN1 option
being more likely when good tertiary leaving groups are involved,
particularly in polar aprotic solvents such as pyridine. In this case,
deprotonated alkoxide that finally renders compound 40. This re-
action has some novel aspects that require further discussion.
There is only one previous report of a hydroxyl group acting
as a nucleophile and not as a base: treatment of DHC (37) with
an aqueous solution of K2CO3 at 50 ꢀC over 5 days yielded 38 as
the only product,32 and this is a unique example of an enantio-
selective Michael addition. The use of HMPA changes the situa-
tion drastically. It has been reported that polar aprotic solvents
with low levels of proton exchange by hydrogen bonds (e.g.,
HMPA, DMSO) allow a better equilibrium between an enolate and
its corresponding ketone, thus prolonging the life of these very
reactive species. The chelating effect of HMPA on metallic cations
has also been reported to enhance the nucleophilic properties of
the counter ion.33 This is the reason why HMPA is so valuable for
SN2 displacement reactions with anionic nucleophiles.34 More-
over, there is an enhanced regioselectivity in the addition of
organolithium reagents to enones in the presence of HMPA,33c
with 1,4-additions favoured in comparison to 1,2-additions. In
this particular case, we tried to obtain the same results with
other aprotic polar solvents like DMSO or DMF, but in these cases
reaction products were not formed. DMSO is not able to chelate
metallic cations or to enhance the nucleophilic properties of the
hydroxyl group. In the case of DMF, its chelating properties are
probably not strong enough. Our previous results32 show that the
use of an aqueous solution of K2CO3 only leads to the 11(S) en-
antiomer 38. Curiously, traces of the 11(R) epimer were not
obtained. When the reaction is carried out in an HMPA/water
mixture, the protonation of the enolate leads to a mixture of
molecular calculations of the
possibilities (11 - and 11 -chloro) show the difference to be too
D
H# and the Hfo values for both
D
a
b
small (ca. ꢁ2.7 kcal/mol, Fig. 5) to explain the enantioselectivity
obtained for 44. Consequently, if a racemic mixture is not obtained,
the reaction must proceed mainly through an SN2 pathway, thus
supporting the stereochemistry of the diol 40.
The characterization of compound 9 from Helianthus petio-
laris20 has previously been reported and this has the same
structure as compound 40. However, the spectroscopic data
supporting the structure are not fully consistent with those
presented here. The main differences concern the chemical shift
of H-6:
d
4.31 (t, J¼9.4 Hz) for the natural product 9 and
d 4.06
(dd, J¼8.9, 9.9 Hz) for the synthetic compound 40. Since the
relative stereochemistry at C-11 is unequivocally assigned in the
synthetic compound, the stereochemistry at this centre must be
corrected in the natural product 9 as 11(S). This is in good
agreement with the deshielding effect observed in the signal
corresponding to H-6 in the natural product due to the effect of
the
b-oriented hydroxyl group (Fig. 6).
2.1. Mechanism and scope of the reaction
a
and
b enantiomers.
The mechanism proposed for this reaction is depicted in Fig-
ure 7. The initial Michael addition of the hydroxyl group to the
Regarding the dihydroxyl-derivative 40, there are some pre-
vious reports concerning effective auto-oxidation of
a large
a
-methylene-g-lactone group yields compounds 38 and 39. Fur-
number of compounds including ketones35 and the possibility of
peroxy-radical formation in HMPA. It is also important to note
that HMPA does not undergo auto-oxidation as DMSO does.36 The
high stereoselectivity obtained in this reaction, where only
thermore, trapping of molecular oxygen leads to a peroxyadduct
that, after dismutation with the enolate intermediate, gives the
the 11a-hydroxy-11b-hydroxymethylene enantiomer is obtained,
comes from the necessary face-to-back approach (Fig. 7) to give
attack of the enolate to the peroxyadduct. The formation of
the 11a-peroxy-derivative 43 as the sole product is crucial
to explain the stereochemical path of the reaction. In this case,
MOPAC molecular modelling using the PM3 algorithm showed
the 11
than the 11
a
-peroxyl enantiomer to be more stable (ca. ꢁ5 kcal/mol)
b
-peroxy adduct
(
D
Hfo ¼ ꢁ241:64 kcal=mol and
H
14
H
8%
2%
5%
H
6%
2 %
11
H
H
15
H
H
H
6
H
13
OH
5
O
OH
O
Figure 3. X-ray structure of compound 39 showing the absolute stereochemistry at C-
11 to be 11(R).
Figure 4. NOE effects observed for compound 40.

F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
10999
6
Cl
OTs
7
ClTs, py
11S
Cl
11
13
+
OTs
+
OTs
12
O
O
O
O
O
OTs
OH
OH
OH
s
OT
OH
O
O
O
O
O
40
43
44
ΔH º = -27.10184
f
O
OTs
O
O
OTs
Cl
O
ΔH º = -198.97423
ΔHfº = -201.68659
f
O
OTs
OTs
O
Cl
OTs
O
O
ΔH º = -304.98694
f
reaction path
Figure 5. PM3 calculations supporting the stereochemistry assigned for 40.
D
Hfo ¼ ꢁ236:85 kcal=mol, respectively), thus supporting the
In the case of the 4-methoxychalcone (51) the steric hindrance
becomes sufficient to allow the isolation of the dihydroxyl-de-
mechanism proposed.37
An increase in the reaction yield and the speed of the reaction is
observed if vigorous stirring is used or if oxygen is bubbled
through. In both cases a larger amount of oxygen in solution is
available, thus substantiating the mechanism proposed. We also
need to highlight the fact that the reaction reaches equilibrium at
a point where the starting material 37 and the three end-products
(38–40) co-exist and no further evolution can be observed. More-
over, similar proportions of compounds 38–39 are obtained if any
of them are used as starting materials under the same conditions as
for compound 37.
In order to explore the scope of this reaction we tested
several Michael acceptors, including different types of SL back-
bones. The results obtained show that this reaction is general to
any type of unsaturated carbonyl system, but a certain degree of
steric hindrance is needed to avoid multiple Michael additions of
the enolate to the remaining starting material, as can be ob-
served in Table 2.
These results show that the hydroxyl group effectively acts as
a nucleophile under aqueous HMPA basic conditions with a variety
of unsaturated carbonyl systems (ketones, aldehydes and lactones),
but the evolution of the reactiondand thus its usefulnessdis
limited by the need to avoid chain reactions. If such a condition
fails, autocondensation of the enolate intermediate leads to high
molecular weight adducts, which is the case for mesityl oxide (49)
and cinnamaldehyde (50) (Table 2). Attempts to perform the re-
action at room temperature or lower with 49 and 50 resulted in no
reaction, even after several days.
rivative. However, the high acidity of H
a in the Michael mono-
hydroxylated adduct, caused by the conjugation of the aromatic
ring, makes it a very reactive species that easily undergoes oxidation
to yield the dihydroxylated compound 54 and the mixture of di-
astereomeric epoxides 55a and 55b. This is not unexpected, since
the peroxide intermediate proposed in the general mechanism
(Fig. 7) may undergo intramolecular nucleophilic substitution by
the hydroxyl group to yield the epoxide with a superoxide anion as
a leaving group. Such epoxides could not be detected with sesqui-
terpene lactones. In any case, the major products are still those
resulting from polycondensation of the enol intermediate with
OH
O
O
O
OH
O
OH
O2
O
O
O
O
45
37
H
+
OH
O
O
OH
O
38
O
39
H
2
+
2
O
O
O
O
OH
OH
OH
OH
OH
O
O
O
O
O
O
O
40
45
OH
O
O
O
O
O
O
OH
OH
O
OH
OH
O
O
O
40
9: new structure proposed
synthetic compound
(Helianthus petiolaris)
Figure 6. Corrected structure for the 11,13-dihydroxylactone isolated from Helianthus
petiolaris, compound 9.
Figure 7. Proposed mechanism for the generation of the dihydroxyl-derivative.

11000
F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
Table 2
Scope of the reaction: entries 1 and 2, SLs; entries 3 and 5, unsaturated ketones; entry 4, unsaturated aldehyde
Starting material
Final products
Conditions
Yield (%)
H
H
H
R = H, 38
38: 21%
39: 30%
40: 6%
R = OH, 40
20% aq CaCO3, HMPA, 90 ꢀC, 5 days
H
O
H
H
O
O
OH
OH
R
39
O
O
O
37
OH
O
OH
R = H, 47
R = OH, 48
47: 22%
48: 5%
20% aq CaCO3, HMPA, 90 ꢀC, 5 days
OH
R
O
O
O
46
(a) 100 mmol, 5 mL HMPA, 20% aq CaCO3,
110 ꢀC, 2 days
(b) 4 mmol, 3 mL HMPA, 20% aq CaCO3,
80 ꢀC, 1 day
O
Complex mixture
of polymers
d
49
O
OH
O
H
O
(a) 80 mmol, 4 mL HMPA, 20% aq Na2CO3,
80 ꢀC, 1 day
(b) 4 mmol, 3 mL HMPA, 20% aq Na2CO3,
80 ꢀC, 90 min
H
Traces of the low mol.
wt. compounds 51 and 52
H
OH
51
52
50
+ benzaldehyde (53) + high molecular weight adducts
Traces of 54, 55a and 55b
53: 28%
56: 20%
57: 14%
58: 10%
HO
Φ'
Φ'
O
Φ
Φ
Φ
Φ
Φ
OMe
OH
O
Φ'
O
O
O
54
O
56
55a
59: 21%
400 mmol, 2 mL HMPA, CaCO3,
100 ꢀC, 20 h
55b
HO
Φ'
φ'
Φ'
Φ
H
O
Φ
Φ'
Φ'
φ
53
O
O
Φ
Φ'
O
57
O
58
59
another molecule of starting material through successive Michael
additions, as occurred with cinnamaldehyde. Compounds 57, 58 and
59 could be isolated and identified as the major compounds from
the reaction mixture. Benzaldehyde (53) and p-methoxy-
benzaldehyde (59) are the result of a McLafferty rearrangement
(Fig. 8), which takes place under high temperature conditions. Fi-
nally, compound 58, obtained through a [2þ2] cycloaddition, was an
unexpected final product that was not detected in the other re-
actions (Table 2).
and 62 with lithium carbonate led to the dehydrohalogenated
compounds 63 and 64, respectively. Finally, reduction of 64 with
TBTH/AIBN led to the natural guaianolide 65. The spectroscopic
data for the synthetic compound 65 are in full agreement with
those previously reported for the natural product.25a,38
Some carbon and proton values reported in the literature for
compound 65 must be corrected since their assignment has been
unequivocally made here by high resolution 1H and 13C NMR cor-
relation techniques (COSY and HSQC) (see Section 4 and Table 3). In
the case of compound 63, only the 1H NMR spectroscopic data of
the acetylated derivative have been published (Table 3). The syn-
thesis of these bioactive natural products illustrates the usefulness
of this method.
2.2. Synthesis of natural SLs
In order to illustrate the utility of this new route to access
functionalized lactone rings in SLs, we achieved the synthesis of the
SLs 63 and 65 (Fig. 9). On using compound 40 as the starting ma-
terial, treatment with thionyl chloride in dry pyridine led to
a mixture of compounds 60–62, which have a similar polarity to 40.
The presence of the chlorine atom was confirmed by the EIMS
spectra. The absolute stereochemistry was unequivocally estab-
lished by the deshielding effect observed in the 1H NMR signal
3. Conclusions
We report the effective Michael addition of a hydroxyl group to
a,b-unsaturated carbonyl systems in a biphasic solvent system
(HMPA/water). The mechanism proceeds through a 1,4-Michael
addition of the hydroxyl group to yield the corresponding mono-
hydroxylated derivatives. The formation of the dihydroxylated ad-
duct is explained through the generation of a hydroperoxide
corresponding to H-6 in compounds 60 and 62 (d 4.15 ppm), in
comparison with that of 61 ( 4.07 ppm). Further treatment of 60
d

F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
11001
H
OH
O
O
O
O
OH
H
McLafferty's
rearrangement
Ph
H
Ph
H
Ph
HO
H
O
50
Ph
OH
H
Ph
O
OH
OH
OH
O
-H2O
+
H
H
Ph
Ph
Ph
H
+H
53
O
O
O
OH
OH
OH
OH
O2
H
Ph
1,4-add.
H
Ph
H
Ph
51
OH
OH
O
O
O
O
OH
H
Ph
H
2
H
Ph
H
H
Ph
Ph
O
O2
OH
52
Figure 8.
intermediate obtained by trapping of molecular oxygen by the enol
intermediate and dismutation. The role of HMPA as an effective
chelator of the cationic counter ion is crucial to enhance the nucle-
ophilicityof thehydroxylgroup. Theadditionproceeds withall types
of unsaturated carbonyl systems (lactones, ketones and aldehydes)
but the scope of the reaction is challenged by the possibility of side
polycondensations. Thus, its applicability is limited to substrates
where the hydroxyl intermediates have the necessary level of steric
hindrance to avoid the nucleophilic addition of the enolate with the
remaining starting material or with other carbonyl intermediates.
HPLC instrument. 1H and 13C NMR spectra were recorded using
a Varian UNITY-400 spectrometer (at 400 MHz and 100 MHz,
respectively) and a Varian INOVA-200 spectrometer (at 200 MHz
and 50 MHz, respectively) using CDCl3 as solvent. The resonance
of residual chloroform at dH 7.25 ppm in the 1H and dC
77.00 ppm for CDCl3 in the 13C spectra was used as internal
references. Mass spectra were obtained using a VG 1250 or a VG
AUTOSPEC instruments at 70 eV. IR spectra were recorded on
a Mattson 5020 spectrophotometer.
4. Experimental
4.2. Hydroxylation of 37 with HMPA/Na2CO3 aq: general
procedure
4.1. General
An aqueous solution of Na2CO3 (20%) was added dropwise to
a solution of 37 (150 mg, 0.619 mmol) in HMPA (15 mL) until it
remained turbid (15 mL). The reaction mixture was vigorously
stirred and heated at 90–95 ꢀC for 7 days, after which the
equilibrium was established (as shown by TLC). Work up: the
reaction mixture was extracted with AcOEt (5ꢂ) and the com-
bined organic phases washed successively with 1 N aq HCl (3ꢂ),
Na2CO3 (w/v, 3ꢂ) and brine (3ꢂ). The organic phase was dried
over anhydrous Na2SO4, concentrated under vacuum and puri-
fied by column chromatography (CC, hexane/EtOAc 3:2), yielding
37 (30%), 38 (21%), 39 (30%) and 40 (6%).
All reagents and solvents were used as obtained from com-
mercial
suppliers,
apart
from
compound
37.
Dehy-
drocostuslactone (37) was isolated by column chromatography
from Costus Resin Oil (Pierre Chauvet, S.A.) and purified by re-
crystallization from hexane/ethyl acetate mixtures. Solvents were
distilled from glass prior to use. Column chromatography was
performed on silica gel (35–75 mesh) and TLC analysis was
carried out using aluminium-packed precoated silica gel plates.
For HPLC, LiChrosorb silica 60 was used in the normal-phase
mode with a differential refractometer (RI) in a Hitachi
L-6020
H
H
H
H
H
a)
H
H
H
OH
OH
Cl
Cl
O
O
O
O
OH
Cl
OH
Cl
O
O
O
O
40
60
61
62
b)
b)
H
H
H
c)
H
H
H
OH
Cl
O
O
O
O
O
O
63
64
65
Figure 9. Key: (a) SO2Cl, dry py, 70 ꢀC, 24 h; (b) Li2CO3/LiCl, DMF, reflux; (c) TBTH, AIBN, toluene.

11002
F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
Table 3
158.8(1); C6–C7–C8: 112.9(1); C1–C10–C15: 123.4(2); O1–C12–C11
110.6(1); C2–C3–C4: 105.7(2); C4–C5–C6: 114.4(1); C6–C7–C11
101.4(1); C9–C10–C15: 121.2(2); O3–C13–C11: 109.2(2).
:
:
13C NMR chemical shifts of compounds 38–40, 43 and 71–73. (50.3 MHz, CDCl3,
signal of residual CHCl3 centred at
d
77.0 ppm)a
C
38
39
52.1
23.1
30.6
152.0
14.3
85.6
48.0
23.0
38.0
150.1
43.7
176.5
67.8
40
43
71
49.0
30.0
30.6
148.0
51.2
72
48.7
73
48.9
28.9
30.4
149.3
51.6
80.6
162.8
29.7
30.7
149.3
123.0
174.1
8.6
113.1
112.2
1
2
3
4
5
6
7
8
51.8 d
32.7 t
30.2 t
152.0 s
47.0 d
85.6 d
49.6 d
32.6 t
37.7 t
149.5 s
43.1 d
177.5 s
59.2 t
109.1 t
112.0 t
52.5
32.4
26.7
152.0
48.1
83.9
50.8
29.9
37.5
146.5
77.0 s
177.5
63.2
109.8
112.0
47.1b
32.4
29.9
150.8
51.0
83.4
47.3b
27.9
35.9
149
66.3
183.3
67.4
4.2.3. (11R)-11,13-Dihydroxy-guaian-4(15),10(14)-diene-
28.8
29.9
6,12-olide (40)
C15O4H20; amorphous white solid; IR nnmeaaxt, KBr cmꢁ1: 3382 (OH,
148.7b
51.0
st), 3085 (C–H, st), 2932 (C–H), 1748 (g-lactone), 1642 (C]C). HRMS
calcd for C15O4H20 264.1362, found 264.1364; EIMS (70 eV) m/z (rel
81.1
80.8
int.): 264 [M]þ (3), 246 [MꢁH2O]þ (1), 233 [MꢁCH3O]þ (18). 1H
30.0
31.0
148.0
124.6
164.8
55.0
29.7
30.3
NMR (200 MHz):
d
5.18 (1H, br d, J¼1.8 Hz, H-15), 5.07 (1H, br d,
9
J¼2.1 Hz, H-150), 4.89 (1H, br s, H-14), 4.79 (1H, br s, H-140), 4.06
(1H, dd, J¼8.9, 9.9 Hz, H-6), 3.80 (1H, d, J¼11.4 Hz, H-13), 3.72 (1H,
d, J¼11.4 Hz, H-130), 3.35 (1H, s, –OH), 2.88 (1H, ddd, J¼8.9, 4.8 Hz,
10
11
12
13
14
15
148.5b
123.0
168.8
33.1
H-1), 2.83 (1H, dd, J¼8.9 Hz, H-5), 2.51 (4H, m, H-3
a
, H-3
), 1.84 (1H, m, H-2
). 13C NMR: see Table 3.
b
, H-7, H-
109.2
112.2
110.2
112.7
112.9
112.0
113.7
112.7
9
b
), 2.10 (1H, ddd, J¼4.4, 7.5, 11.9 Hz, H-8
a
b), 1.41
(1H, ddd, J¼4.6, 12.6 Hz, H-8
b
Compound 41:
d
128.1 (C-20, C-60);
d
130.1 (C-30, C-50);
d
145.9 (C-40);
d
21.7 (Me–Ar).
a
Degree of protonation and assignments were established by APT, HETCOR and
HMQC experiments; multiplicities are not repeated if identical with those in the
preceding column.
4.3. Hydroxylation of 39 with SeO2/TBTPH
b
May be interchanged within the same column.
Treatment of 39 with SeO2 (0.5 equiv) and tert-butylhydroperoxide
(TBTPH) (2 equiv) in DCM (0.01 M) according to the previously repor-
ted conditions4c yielded after 1 h compounds 41 (63%) and 42 (12%).
4.2.1. (11S)-13-Hydroxy-guaian-4(15),10(14)-diene-6,12-olide (38)
C15O3H20; amorphous white solid; IR nnmeaaxt, KBr cmꢁ1: 3425 (OH,
st), 2929 (C–H), 1766 (
g
-lactone), 1640 (C]C). HRMS calcd for
4.3.1. (3R,11R)-3,13-Dihydroxy-guaian-4(15),10(14)-diene-
6,12-olide (41)
C15O3H20 248.1412, found 248.1399; EIMS (70 eV) m/z (rel int.): 248
[M]þ (2), 230 [MꢁH2O]þ (3), 218 [MꢁCH2O]þ (17). 1H NMR
C15O4H20; amorphous white solid; IR nnmeaaxt, KBr cmꢁ1: 3450 (OH,
(200 MHz):
d
5.19 (1H, br d, J¼1.9 Hz, H-15), 5.04 (1H, dd, J¼2.1,
st), 2930 (C–H), 1746 (g-lactone), 1651 (C]C). HRMS calcd for
0.8 Hz, H-150), 4.87 (1H, s, H-14), 4.76 (1H, s, H-140), 3.95 (1H, dd,
J¼9.3 Hz, H-6), 3.86 (1H, dd, J¼3.3, 9.7 Hz, H-13), 3.69 (1H, dd,
J¼9.7, 2.8 Hz, H-130), 2.90 (1H, ddd, J¼4.8, 7.1, 11.6 Hz, H-1), 2.76
C15O4H20 248.1412, found 248.1895; EIMS (70 eV) m/z (rel int.): 264
[M]þ (2), 246 [MꢁH2O]þ (5), 228 [Mꢁ2H2O]þ (4). 1H NMR
(400 MHz):
d
5.35 (1H, dd, J¼1.9 Hz, H-15), 5.29 (1H, dd, J¼1.9 Hz,
(1H, br dd, J¼8.9 Hz, H-5), 2.16 (1H, m, H-8
a
), 1.88 (1H, m, H-2
b
),
H-150), 4.86 (1H, s, H-14), 4.68 (1H, s, H-140), 4.63 (1H, dd, J¼6.9 Hz,
H-3), 3.96 (1H, dd, J¼11.8, 3.3 Hz, H-13), 3.88 (1H, dd, J¼9.3 Hz, H-
6), 3.68 (1H, dd, J¼11.8, 4.4 Hz, H-13), 3.06 (1H, m, H-5), 3.01 (1H, m,
1.33 (1H, ddd, J¼2.9, 11.7 Hz, H-8
b
). 13C NMR: see Table 3.
4.2.2. (11R)-13-Hydroxy-guaian-4(15),10(14)-diene-6,12-olide (39)
H-1), 2.45 (1H, ddd, J¼12.9, 11.8, 4.1 Hz, H-9
a
), 2.37 (1H, m, H-7),
), 2.10 (1H, m, H-8 ), 1.99 (1H,
), 1.83 (1H, ddd, J¼13.2, 7.3, 6.9 Hz, H-
), 1.27 (1H, dddd, J¼12.6, 11.8, 4.6, 4.1 Hz, H-8
). 13C NMR
(100 MHz): 177.4 (C-12), 154.4 (C-4), 149.1 (C-10), 112.4 (C-14, C-
C15O3H20; white crystals; mp (CHCl3, uncorrected) 148–150 ꢀC;
2.33 (1H, m, H-11), 2.15 (1H, m, H-2
ddd, J¼12.9, 4.6, 4.1 Hz, H-9
a
a
IR nnmeaaxt, KBr cmꢁ1: 3390 (OH, st), 2931 (C–H), 1769 (
g
-lactone), 1642
b
(C]C). HRMS calcd for C15O3H20 248.1412, found 248.1423; EIMS
(70 eV) m/z (rel int.): 248 [M]þ (3), 230 [MꢁH2O]þ (6), 218
2b
b
d
[MꢁCH2O]þ (22). 1H NMR (200 MHz):
d
5.16 (1H, br dd, J¼1.9,
15 overlapped), 85.9 (C-6), 7.4 (C-3), 58.6 (C-13), 49.6 (C-1), 49.3 (C-
4.1 Hz, H-15), 5.03 (1H, br dd, J¼2.1, 3.6 Hz, H-150), 4.88 (1H, s, H-
14), 4.78 (1H, s, H-140), 4.00 (1H, dd, J¼9 Hz, H-6), 4.00 (1H, br d,
J¼11.5 Hz, H-13), 3.73 (1H, dd, J¼11.5, 4.5 Hz, H-130), 2.88 (1H, ddd,
J¼8.0, 4.4 Hz, H-1), 2.82 (1H, dd, J¼9.0 Hz, H-5), 2.51 (1H, m, H-3),
5), 43.6 (C-7)*, 43.1 (C-11)*, 39.7 (C-9), 38.0 (C-2), 32.4 (C-8).
values may be interchanged.
*
: these
4.3.2. (3R,11R)-1,3,13-Trihydroxy-guaian-4(15),10(14)-diene-
2.48 (1H, m, H-3), 2.44 (1H, br dd, J¼4.2,12.3 Hz, H-9
b), 2.38 (1H, m,
6,12-olide (42)
H-11), 2.33 (1H, dddd, J¼4.9, 9.0, 12.1 Hz, H-7), 2.10 (1H, m, H-8
a
),
C
C15O4H20; white crystals; IR nnmeaaxt, KBr cmꢁ1: 3280 (OH, st), 2932 (C–
2.01 (1H, m, H-9
a), 1.34 (1H, dddd, J¼12.1, 10.9, 4.2 Hz, H-8
b
). 13
H), 1754 (g-lactone), 1650 (C]C). HRMS calcd for C15O5H20 280.1311,
NMR: see Table 3. X-ray analysis: complete tables of distances,
angles, torsion angles, least-square planes, anisotropic thermal
parameters and structure factors have been deposited with the
Cambridge Crystallographic Data Centre (deposition number CCDC
667537). Copies may be obtained through the Executive Secretary.
Bond lengths (Å) with e.s.d. values in parenthesis: O1–C6: 1.473(1);
C1–C2: 1.541(3); C3–C4: 1.499(2); C6–C7: 1.522(2); C9–C10: 1.505(3);
O1–C12: 1.334(2); C1–C5: 1.556(2); C4–C5: 1.520(2); C7–C8: 1.529(2);
found 280.1401; EIMS (70 eV) m/z (rel int.): 280 [M]þ (1), 262
[MꢁH2O]þ (7), 244 [Mꢁ2H2O]þ (4).1H NMR(200 MHz):
d5.53(1H, dd,
J¼2.1,1.2 Hz, H-15), 5.50 (1H, dd, J¼2.1, 1.2 Hz, H-150), 5.12 (1H, br s, H-
14), 5.07 (1H, br s, H-140), 4.60 (1H, br s, H-3
b
), 3.98(1H, brd,J¼11.3 Hz,
H-13), 3.79 (1H, dd, J¼10.0 Hz, H-6), 3.74 (1H, br dd, J¼11.3, 4.5 Hz, H-
130), 3.02 (1H, d, J¼10.0 Hz, H-5), 2.54 (1H, m, H-9
a), 2.48 (1H, m, H-7),
2.40 (1H, m, H-2
a
), 2.38 (1H, m, H-9
b
), 2.15 (1H, dddd, J¼13.3, 4.6 Hz,
H-8 ), 1.32 (1H, dddd, J¼13.3,
11.4, 4.6 Hz, H-8b). X-rayanalysis: complete tables of distances, angles,
a
), 2.04 (1H, ddd, J¼14.3, 6.3, 1.2 Hz, H-2
b
C10–C15
:
1.332(3); O2–C12: 1.217(2); C1–C10
:
1.521(3); C4–C14
:
1.317(3); C7–C11: 1.534(2); C11–C12: 1.508(2); O3–C13: 1.411(4); C2–
C3: 1.533(4); C5–C6: 1.514(2); C8–C9: 1.541(3); C11–C13: 1.511(3).
torsion angles, least-square planes, anisotropic thermal parameters
and structure factors have been deposited with the Cambridge Crys-
tallographic Data Centre (deposition number CCDC 697081). Copies
may be obtained through the Executive Secretary.
Bond angles (ꢀ) with e.s.d. values in parenthesis: C6–O1–C12
109.9(1); C3–C4–C5: 109.0(2); O1–C6–C5: 107.1(1); C8–O7–C11
113.5(2); C7–C11–C12: 102.2(1); C2–C1–C5: 102.3(1); C3–C4–C14
125.0(2); O1–C6–C7: 104.3(1); C7–C8–C9: 114.1(2); C7–C11–C13
116.9(2); C2–C1–C10: 115.6(2); C5–C4–C15: 126.0(1); O2–C12–C11
128.5(1); C8–C9–C10: 115.1(2); C11–C12–C13: 114.1(2); C5–C1–C10
:
:
:
:
:
:
4.4. Hydroxylation of 46
Compound 46 was obtained from costunolide as previously
described.39 Then, 46 was treated as 37, yielding 47 (22%) and 48
(5%).
114.5(1); C1–C5–C4: 104.0(1); C5–C6–C7: 108.5(1); C1–C10–C9:
115.3(2); O1–C12–O2: 121.0(1); C1–C2–C3: 106.5(2); C1–C5–C6:

F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
11003
4.4.1. (11R)-(1E,4E)-13,14-Dihydroxy-germacrane-1(10),4(5)-
4.6.1. 2,3-Dihydroxy-3-(4-methoxy-phenyl)-1-phenyl-1-oxa-
propane (54)
diene-6,12-olide (47)
neat, KBr
C15O4H22; colourless oil; IR
n
cmꢁ1: 3518 (OH, st), 2927
C16O4H16; white powder; IR nnmeaaxt, KBr cmꢁ1: 3480 (O–H, st), 2918
(C–H), 1700 (C]O). HRMS calcd for C11O3H12 272.1049, found
272.1495; EIMS (70 eV) m/z (rel int.): 254 [MꢁH2O]þ (4), 238
[MꢁH2OꢁOꢃ]þ (6), 149 [p-MeO–Ph–CO–CH2]þ (25), 135 [p-MeO–
Ph–CO]þ (51), 105 [Ph–CO]þ (100), 77 [Ph]þ (84). 1H NMR
max
(C–H, st), 2851 (C–H), 1754 (
g-lactone). HRMS calcd for C15O4H22
248.1412, found 248.1895; EIMS (70 eV) m/z (rel int.): 266 [M]þ (1),
248 [MꢁH2O]þ (4), 230 [Mꢁ2H2O]þ (4). 1H NMR (400 MHz):
d 5.47
(1H, dd, J¼7.8 Hz, H-1), 5.00 (1H, br d, J¼9.9 Hz, H-5), 4.68 (1H, dd,
J¼9.9 Hz, H-6), 4.13 (1H, d, J¼12.5 Hz, H-14), 4.03 (1H, d, J¼12.5 Hz,
H-140), 3.98 (1H, dd, J¼3.7, 11.6 Hz, H-13), 3.74 (1H, dd, J¼5.2,
11.6 Hz, H-130), 2.38 (1H, ddd, J¼12.5, 5.2, 3.7 Hz, H-11), 1.85 (1H, d,
(400 MHz):
d
7.91 (2H, dd, J¼8.5, 1.5 Hz, H-20, H-60), 7.66 (1H, tt,
J¼7.6, 2.2 Hz, H-40), 7.52 (2H, t, J¼7.6 Hz, H-30, H-50), 7.47 (2H, d,
J¼8.8 Hz, H-200, H-600), 6.88 (2H, d, J¼8.8 Hz, H-300, H-500), 5.37 (1H,
dd, J¼7.1, 2.2 Hz, H-3), 5.21 (1H, d, J¼2.2 Hz, C3–OH), 4.08 (1H, d,
J¼1.1 Hz, H-15), 1.51 (1H, m, H-8
b d 177.7 (C-
). 13C NMR (100 MHz):
12),140.9 (C-4),137.4 (C-10),126.5 (C-1),125.4 (C-5), 81.1 (C-6), 66.6
(C-14), 59.1 (C-13), 49.0 (C-11), 42.8 (C-7), 38.4 (C-9), 26.3 (C-8),
24.7 (C-3), 21.1 (C-2), 17.1 (C-15).
J¼7.3 Hz, H-2), 3.80 (3H, s, –OMe). 13C NMR (100 MHz):
d 198.0 (C-
1), 134.2 (C-40), 133.8 (C-100), 130.4 (C-10), 129.3 (C-200, C-600), 129.1
(C-30, C-50), 128.6 (C-20, C-60), 113.9 (C-300, C-500), 76.3 (C-3), 63.7 (C-
2), 55.3 (–OMe).
4.4.2. (11R)-(1E,4E)-11,13,14-Trihydroxy-germacrane-1(10),4(5)-
diene-6,12-olide (48)
4.6.2. [3-(4-Methoxy-phenyl)-oxiranyl]-phenyl-methanone (55a)
C16O3H14; white powder; IR nnmeaaxt, KBr cmꢁ1: 2931 (C–H, st), 2864
(C–H), 1700 (C]O), 1275 (epox., C–O–C). HRMS calcd for C11O3H12
254.0943, found 254.1112; EIMS (70 eV) m/z (rel int.): 254 [M]þ (4),
238 [MꢁOꢃ]þ (6), 149 [p-MeO–Ph–CO–CH2]þ (25), 135 [p-MeO–Ph–
CO]þ (51), 105 [Ph–CO]þ (100), 77 [Ph]þ (84). 1H NMR (400 MHz):
neat, KBr
C15O5H22; colourless oil; IR
n
cmꢁ1: 3468 (OH, st), 2931
max
(C–H, st), 2864 (C–H), 1755 (g-lactone). HRMS calcd for C15O4H22
248.1412, found 248.1895; EIMS (70 eV) m/z (rel int.): 282 [M]þ (1),
264 [MꢁH2O]þ (1), 250 [MꢁCH3OH]þ (3). 1H NMR (400 MHz):
d
5.47 (1H, dd, J¼4.2 Hz, H-1), 4.95 (1H, br d, J¼10.0 Hz, H-5), 4.83
(1H, dd, J¼10.0 Hz, H-6), 4.14 (1H, d, J¼12.8 Hz, H-13), 4.03 (1H, d,
J¼12.8 Hz, H-130), 3.81 (1H, d, J¼11.5 Hz, H-14), 3.77 (1H, d,
J¼11.5 Hz, H-130), 1.92 (3H, s, H-15).
d
7.80 (2H, d, J¼8.2, 1.3 Hz, H-20, H-60), 7.46 (1H, br t, J¼8.2 Hz, H-40),
7.35 (2H, t, J¼8.2 Hz, H-30, H-50), 6.94 (2H, d, J¼8.7 Hz, H-200, H-600),
6.72 (2H, d, J¼8.7 Hz, H-300, H-500), 4.68 (1H, br d, J¼6.1 Hz, H-2),
4.34 (1H, br d, J¼6.1 Hz, H-3), 3.74 (3H, s, –OMe). 13C NMR
(100 MHz):
d
198.0 (C-1), 158.1 (C-400), 136.0 (C-100), 132.8 (C-40),
4.5. Hydroxylation of cinnamaldehyde (50)
131.3 (C-10), 129.1 (C-200, C-600), 128.6 (C-30, C-50), 128.0 (C-20, C-60),
113.7 (C-300, C-500), 55.2 (–OMe), 49.5 (C-2), 44.2 (C-3).
The reaction was carried out as described above for the other SLs
under various conditions (see Table 2), yielding in all cases a com-
plex mixture of high molecular weight products. The major com-
pound isolated was benzaldehyde 53. Compounds 51 and 52 could
be isolated as minor compounds after several tedious purifications
by HPLC.
4.6.3. [3-(4-Methoxy-phenyl)-oxiranyl]-phenyl-methanone (55b)
C16O3H14; white powder; IR nnmeaaxt, KBr cmꢁ1: 2931 (C–H, st), 2864
(C–H), 1700 (C]O), 1275 (epox., C–O–C). HRMS calcd for C11O3H12
254.0943, found 254.1024; EIMS (70 eV) m/z (rel int.): 254 [M]þ (6),
238 [MꢁOꢃ]þ (19), 149 [p-MeO–Ph–CO–CH2]þ (23), 135 [p-MeO–
Ph–CO]þ (87), 105 [Ph–CO]þ (93), 77 [Ph]þ (100). 1H NMR
4.5.1. (2E,4E)-5-Phenyl-penta-2,4-diene-1-al (51)
(400 MHz):
d
7.77 (2H, d, J¼7.1, 1.5 Hz, H-20, H-60), 7.46 (1H, br t,
neat, KBr
C11OH10; colourless oil; IR
n
cmꢁ1: 2864 (C–H), 1680
max
J¼7.3 Hz, H-40), 7.30 (2H, t, J¼7.7 Hz, H-30, H-50), 7.21 (2H, d,
J¼8.8 Hz, H-200, H-600), 6.82 (2H, d, J¼8.8 Hz, H-300, H-500), 4.53 (1H,
dd, J¼5.6 Hz, J2,OH¼3.4 Hz, H-2), 3.82 (1H, br d, J¼5.7 Hz, H-3), 3.74
(C]O). HRMS calcd for C11OH10 158.3702, found 158.3895; EIMS
(70 eV) m/z (rel int.): 158 [M]þ (88), 129 [Mꢁ:COH]þ (100), 128
[Mꢁ:CHOH]þ (94). 1H NMR (400 MHz):
9.61 (1H, d, J¼7.9 Hz, H-1),
d
(3H, s, –OMe). 13C NMR (100yMHz):
d
135.7 (C-100)
*
, 133.6 (C-10)y
*
,
7.51 (2H, dd, J¼7.9, 1.7 Hz, H-20, H-60), 7.37 (3H, H-30, H-40, H-50),
7.26 (1H, ddd, J¼15.1, 7.9, 3.0 Hz, H-3), 7.00 (1H, dd, J¼15.1 Hz, H-4),
7.00 (1H, d, J¼7.3 Hz, H-5), 6.26 (1H, dd, J¼15.1, 7.9 Hz, H-2). 13C
133.3 (C-40), 128.8 (C-200, C-600) , 128.5 (C-30, C-50), 128.5 (C-20, C-60) ,
114.1 (C-300, C-500), 55.3 (–OMe), 48.0 (C-2), 48.8 (C-3). ,y: these
*
values may be interchanged.
NMR (100 MHz): d
193.4 (C-1), 151.9 (C-3), 142.3 (C-5), 135.5 (C-10),
132.6 (C-2), 129.7 (C-4), 128.9 (C-30, C-50), 127.5 (C-20, C-60), 126.1
(C-40).
4.6.4. 3-(4-Methoxy-phenyl)-1,5-diphenyl-pentane-1,5-dione (56)
C24O3H22; colourless oil; IR nnmeaaxt, KBr cmꢁ1: 2931 (C–H, st), 1700
(C]O). HRMS calcd for C24O3H22 358.1569, found 358.1589; EIMS
(70 eV) m/z (rel int.): 358 [M]þ (2), 239 [MꢁPh–CO–CHꢃ2]þ (96), 105
4.5.2. (2E)-2,4-Dihydroxy-5-phenyl-hepta-2-ene-1-al (52)
C11O3H12; colourless oil; IR nnmeaaxt, KBr cmꢁ1: 2931 (C–H, st), 2864
(C–H), 1685 (C]O). HRMS calcd for C11O3H12 192.0786, found
192.0618; EIMS (70 eV) m/z (rel int.): 174 [MꢁH2O]þ (15), 158
[Ph–CO]þ (100), 77 [Ph]þ (70). 1H NMR (400 MHz):
d 7.93 (4H, dd,
J¼8.6, 1.2 Hz, H-20, H-200, H-60, H-600), 7.53 (2H, tt, J¼8.6, 1.2 Hz, H-40,
H-400), 7.43 (4H, dd, J¼8.6 Hz, H-30, H-300, H-50, H-500), 7.18 (2H, d,
J¼8.8 Hz, H-20, H-60), 6.80 (2H, d, J¼8.8 Hz, H-30, H-50), 4.01 (1H, tt,
J¼7.0 Hz, H-3), 3.75 (3H, s, –OMe), 3.45 (2H, ddd, J¼16.6, 6.8 Hz, H-
2a, H-4a), 3.31 (2H, ddd, J¼16.6, 7.2 Hz, H-2b, H-4b). 13C NMR
[Mꢁ2H2O]þ (22), 129 (100), 128 (81). 1H NMR (400 MHz):
d 9.61
(1H, d, J¼7.6 Hz, H-1), 7.37 (3H, m, H-30, H-40, H-50), 7.30 (2H, dd,
J¼7, 1.5 Hz, H-20, H-60), 6.67 (1H, dd, J¼15.9, 6.7 Hz, H-3), 6.44 (1H,
dd, J¼15.8, 7.7 Hz, H-2), 3.89 (1H, s, J¼1.4 Hz, H-5), 3.58 (1H, dd,
J¼6.8, 1.8 Hz, H-2).
(100 MHz):
100)
60), 128.1 (C-30, C-300, C-50, C-500), 127.6 (C-10), 114.0 (C-300, C-500), 55.2
d
198.7 (C-1, C-5), 158.3 (C-40), 137.1 (C-10)
*
, 135.8 (C-
*
, 133.0 (C-40, C.400), 128.6 (C-20, C-200, C-60, C-600), 128.4 (C-20, C-
4.6. Hydroxylation of 53
(–OMe), 45.2 (C-2, C-4), 36.6 (C-3).
*
: these values may be
interchanged.
4-Methoxychalcone 53 was purchased from Lancaster and
treated according to the general methodology under conditions
described in Table 3. Compounds 54, 55a and 55b were obtained
only in traces. Benzaldehyde 53 (28%) and p-methoxybenzaldehyde
59 (31%) were the major compounds, followed by 56 (20%), 57 (14%)
and 58 (10%).
4.6.5. 2-[Hydroxy-(4-methoxy-phenyl)-methylene]-3-(4-methoxy-
phenyl)-1,5-diphenyl-pentane-1,5-dione (57)
neat, KBr
C32O5H28; colourless oil; IR
n
cmꢁ1: 3180 (HO–C]C, st),
max
2980 (C–H, st), 2892 (C–H), 1700 (C]O), 1612 (Ph–C]O–C]C–OH).
HRMS calcd for C32O5H28 492.1937, found 374.1843C24O4H2þ1

11004
F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
[MꢁPh–CO–CH2]; EIMS (70 eV) m/z (rel int.): 374 [MꢁPh–CO–
CH2]þ (7), 239 [MꢁPh–CO–CHꢃ2ꢁp-MeO–Ph–CO]þ (96), 135 [p-
MeO–Ph–CO]þ (100), 105 [Ph–CO]þ (37), 77 [Ph]þ (36). 1H NMR
[M]þ (18), 401 [MꢁCl]þ (2), 281 [MꢁC7O2SH7]þ (2), 264
[MꢁC7O3SH8]þ (3), 229 [MꢁC7O3SH8ꢁCl]þ (55). 1H NMR
(200 MHz):
d
7.78 (2H, d, J¼8.3 Hz, H-30, H-50), 7.37 (2H, d,
(400 MHz):
d
8.0 (2H, d, J¼9.0 Hz, H-2IV, H-6IV), 8.0 (2H, d, J¼9.0 Hz,
J¼8.2 Hz, H-20, H-60), 5.15 (1H, br d, J¼1.8 Hz, H-15), 5.06 (1H, br
d, J¼1.8 Hz, H-150), 4.91 (1H, br s, H-14), 4.81 (1H, br s, H-140),
4.25 (1H, d, J¼10.6 Hz, H-13), 4.22 (1H, d, J¼10.6 Hz, H-130), 4.13
(1H, dd, J¼9.3 Hz, H-6), 2.89 (1H, br dd, J¼7.24 Hz, H-1), 2.83
(1H, dd, J¼8.9 Hz, H-5), 2.62 (1H, ddd, J¼3.6, 9.5, 11.2 Hz, H-7),
2.45 (3H, s, Me–Ar), 2.04 (1H, ddd, J¼4.3, 12.3 Hz, H-9), 1.97 (2H,
H-2IV, H-6IV), 7.96 (4H, d, J¼7.8 Hz, H-20, H-200, H-60, H-600), 7.53 (2H,
tt, J¼7.2, 1.2 Hz, H-40, H-400), 7.42 (4H, br t, J¼7.3 Hz, H-30, H-300, H-50,
H-500), 6.86 (2H, d, J¼8.8 Hz, H-30, H-50), 6.82 (2H, d, J¼8.6 Hz, H-3IV,
H-5IV), 5.23 (1H, dd, J¼9.8, 3.9 Hz, H-3), 4.13 (1H, dd, J¼18.1, 9.4 Hz,
H-4a), 3.81 (3H, s, –OMe), 3.74 (3H, s, –OMe), 3.24 (1H, dd, J¼17.9,
3.9 Hz, H-3b).
m, H-2
b
*
, H-8
a
), 1.82 (1H, ddd, J¼6.4, 8.7, 13.0 Hz, H-2
a
*
), 1.61
(1H, ddd, J¼4.4, 11.6 Hz, H-8
b
). 13C NMR: see Table 3. Complete
4.6.6. 2,4-Bis-(4-methoxy-phenyl)-1,3-bis-benzoyl-
cyclobutane (66)
tables of distances, angles, torsion angles, least-square planes,
anisotropic thermal parameters and structure factors have been
deposited with the Cambridge Crystallographic Data Centre
(deposition number CCDC 667538). Copies may be obtained
through the Executive Secretary. Bond lengths (Å) with e.s.d.
values in parenthesis: Cl–C11: 1.802(1); O2–C12: 1.192(2); C4–C5:
1.516(2); C9–C10: 1.506(3); C16–C21: 1.379(3); S–O3: 1.588(1); O3–
C32O4H28; colourless oil; IR nnmeaaxt, KBr cmꢁ1: 2995 (C–H, st), 1700
(C]O). HRMS calcd for C32O4H28 476.1988, found 476.21805; EIMS
(70 eV) m/z (rel int.): 476 [M]þ (1), 370 [MꢁPh–CO]þ (3), 265
[Mꢁ2Ph–CO]þ (3), 238 [p-MeO–Ph–C]C–CO–Ph]þ (100), 108 [p-
MeO–Ph]þ (23), 105 [Ph–CO]þ (48), 77 [Ph]þ00 (40). 1H NMR
(400 MHz):
d
8.30 (2H, d, J¼7.0 Hz, H-200, H-6 ), 7.68 (2H, d,
C13
:
1.444(4); C4–C14
:
1.308(3); C10–C15
:
1.327(3); C17–C18
:
J¼7.1 Hz, H-20, H-60), 7.58 (2H, tt, J¼7.5, 1.8 Hz, H-400), 7.48 (4H, br t,
J¼7.1 Hz, H-300, H-500), 7.41 (1H, br t, J¼7.3 Hz, H-40), 7.29 (2H, t, J¼
6.1 Hz, H-30, H-50), 6.78 (2H, d, J¼7.7 Hz, H-2IV, H-6IV), 6.76 (2H, d,
J¼8.5 Hz, H-20, H-60), 6.62 (2H, d, J¼8.6 Hz, H-3IV, H-5IV), 6.44 (2H,
d, J¼8.8 Hz, H-300, H-500), 5.43 (1H, dd, J¼9.6 Hz, H-1), 4.71 (1H, dd,
J¼9.5 Hz, H-2), 4.68 (1H, dd, J¼9.8 Hz, H-4), 4.49 (1H, dd, J¼10.0 Hz,
H-3), 3.68 (3H, s, –OMe), 3.60 (3H, s, –OMe). 13C NMR (100 MHz):
1.380(3); S–O4: 1.420(2); C1–C2: 1.543(3); C5–C6: 1.513(2); C11
–
C12: 1.528(2); C19–C22: 1.501(3); S–O5: 1.413(2); C1–C5: 1.554(2);
C6–C7: 1.523(2); C11–C13 1.508(2); C20–C21 1.371(3); S–C16
1.753(2); C1–C10: 1.512(2); C7–C8: 1.524(2); C18–C19: 1.370(3);
:
:
:
O1–C6: 1.473(2); C2–C3: 1.509(3); C7–C11
:
1.530(2); C19–C20
:
1.384(3); O1–C12: 1.340(2); C3–C4: 1.505(2); C8–C9: 1.528(3); C16
–
C17: 1.373(3).
d
200.8 (2C]O), 157.9 (C-4IV)a, 157.8 (C-40)a, 136.5 (C-10)b, 136.1 (C-
Bond angles (ꢀ) with e.s.d. values in parenthesis: C6–O1–C12
:
100)b, 133.4 (C-40)c, 132.9 (C.400)c, 130.9 (C-10)d, 128.7 (C-300, C-500)e,
128.6 (C-1IV)d, 128.4 (C-200, C-600)e, 128.3 (C-20, C-60)e, 128.1 (C-2IV, C-
6IV)e, 113.4 (C-3IV, C-5IV)f, 113.0 (C-30, C-50)f, 55.1 (–OMe), 54.9
(–OMe), 47.9 (C-3)g, 47.9 (C-1)g, 44.2 (C-4)h, 42.7 (C-2)h. a, b, c, d, e, f,
g, h: values with the same superscript may be interchanged.
111.3(1); C1–C5–C6: 115.7(1); C1–C10–C9: 115.3(2); O3–S–O4:
103.8(2); Cl–C11–C12 104.3(1); C2–C1–C5: 101.9(2); C4–C5–C6:
:
114.8(1); C1–C10–C15: 123.1(2); O3–S–O5: 108.63(9); Cl–C11–C13
106.5(1); C2–C1–C10: 116.6(2); O1–C6–C5: 107.2(1); C9–C10–C15
121.6(2); O3–S–C16: 102.65(7); C17–C16–C21: 120.0(2); C5–C1–C10
:
:
:
112.1(1); O1–C6–C7: 104.9(1); C7–C11–C12
121.0(1); C16–C17–C18 119.1(1); C1–C2–C3: 107.7(2); C5–C6–C7:
: 103.7(1); O4–S–O5:
4.7. Tosylation of 40
:
116.8(1); C7–C11–C13: 116.8(1); O4–S–C16: 109.8(1); C17–C18–C19
121.8(2); C2–C3–C4: 105.9(2); C6–C7–C8: 114.2(1); C11–C12–C13
112.5(1); O5–S–C16: 109.3(1); C18–C19–C20: 118.2(2); C3–C4–C5:
108.4(2); C6–C7–C11: 102.7(1); O1–C12–O2: 122.8(1); S–O3–C13
120.2(1); C18–C19–C22: 121.1(2); C3–C4–C14: 125.6(2); C8–C7–C11
116.0(1); O1–C12–C11: 109.4(1); S–C16–C17: 121.2(1); C19–C20–C21
120.9(2); C5–C4–C14: 125.9(1); C7–C8–C9: 115.3(2); O2–C12–C11
127.8(1); S–C16–C21: 118.8(2); C20–C19–C22: 120.8(2); C1–C5–C4:
104.0(1); C8–C9–C10: 115.2(2); O3–C13–C11: 106.7(1); Cl–C11–C7:
112.5(1); C16–C17–C18: 120.0(2).
:
:
p-Toluensulfonyl chloride (500 mg, 2.623 mmol) was added to
a solution of 40 (200 mg, 0.758 mmol) in dry pyridine. The reaction
mixture was stirred at room temperature over 3 days. Work-up was
as follows: the crude mixture was dissolved in ethyl acetate and
washed with aqueous solutions of 1 N hydrochloric acid (3ꢂ), so-
dium hydrogen carbonate (10% w/v, 3ꢂ) and brine (3ꢂ). The or-
ganic layer was dried over anhydrous sodium sulfate and
evaporated under reduced pressure. The crude mixture chromato-
graphed by CC yielding 180 mg of 41 (57%) and a 20 mg of 43 (6%).
Compound 44 was recrystallized from hexane/AcOEt.
:
:
:
:
4.8. Chlorination of 40
4.7.1. (11R)-11-Hydroxy-13-(p-toluensulfonate)-guaian-
4(15),10(14)-diene-6,12-olide (43)
C22O6SH26; white crystals; IR
(C–H, st), 1761 (g-lactone), 1344, 1170 (–SO2 st. as., st. s.), 749 (C–C
Compound 40 (150 mg, 0.568 mmol) was dissolved in dry
pyridine (25 mL) and the mixture was vigorously stirred. A so-
lution of SOCl2 in dry pyridine (10% v/v) (1 mL) was added
dropwise during 1 h. The reaction mixture was heated at 70 ꢀC for
24 h. The work up was carried out as for the tosylation of 36.
Purification of the crude mixture by CC yielded 68 (8%), 69 (12%)
and 70 (3%).
neat, KBr
n
cmꢁ1: 3453 (OH), 2928
max
ar). HRMS calcd for C22O6SH26 418.1450, found 246.1518C15O3H18
according to [MꢁC7O3SH8]þ; EIMS (70 eV) m/z (rel int.): 246
[MꢁC7O3SH8]þ (10), 228 [MꢁC7O3SH8ꢁH2O]þ (2). 1H NMR
(200 MHz):
d
7.75 (2H, d, J¼8.5 Hz, H-30, H-50), 7.35 (2H, d, J¼8.1 Hz,
H-20, H-60), 5.09 (1H, br d, J¼1.8 Hz, H-15), 5.04 (1H, br d, J¼1.8 Hz,
H-150), 4.88 (1H, br s, H-14), 4.79 (1H, br s, H-140), 4.14 (1H, d,
J¼10.1 Hz, H-13), 4.00 (1H, d, J¼10.0 Hz, H-130), 4.00 (1H, dd, J¼8.8,
9.7 Hz, H-6), 2.87 (1H, br dd, J¼6.4 Hz, H-1), 2.76 (1H, dd, J¼8.9 Hz,
4.8.1. (11S)-11-Chloro-13-hydroxy-guian-4(15),10(14)-
diene-6,12-olide (68)
neat, KBr
C15ClO3H19; amorphous solid; IR
n
cmꢁ1: 3450 (OH, st),
max
H-5), 1.44 (1H, dddd, J¼3.3, 11.4 Hz, H-8
b).
2945 (C–H, st), 1765 (g-lactone), 1636 (C]C), 775 (C–Cl). HRMS
calcd for C15ClO3H19 282.1023, found 282.0995; EIMS (70 eV) m/z
4.7.2. (11S)-11-Chloro-13-(p-toluensulphonate)-guaian-
4(15),10(14)-diene-6,12-olide (44)
C22ClO5SH25; white crystals; IR
1773 (g-lactone), 1358, 1172 (–SO2 st. as., st. s.), 805 (C–Cl), 742
(rel int.): 282 [M]þ (1), 264 [MꢁH2O]þ (5), 229 [MꢁH2OꢁCl]þ
(92). 1H NMR (200 MHz):
d 5.13 (1H, br s, H-15), 5.02 (1H, br s, H-
neat, KBr
n
cmꢁ1: 2932 (C–H, st),
150), 4.83 (1H, br s, H-14), 4.75 (1H, br s, H-140), 4.15 (1H, dd,
J¼9.4 Hz, H-6), 3.68 (1H, d, J¼11.2 Hz, H-13), 3.56 (1H, d, J¼
11.2 Hz, H-130), 2.85 (1H, dd, J¼9.4, 14.7 Hz, H-5), 2.71 (1H, dd,
J¼14.7 Hz, H-1).
max
(C–C ar). HRMS calcd for C22ClO5SH25 436.1111, found 436.1495;
EIMS (70 eV) m/z (rel int.): 438 [Mþ2]þ (2), 437 [Mþ1]þ (7), 436

F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
11005
4.8.2. (11R)-11-Hydroxy-13-chloro-guian-4(15),10(14)-diene-6,12-
Work up was as follows: the solvent was evaporated under vacuum
and the residue was diluted with acetonitrile; the solution was
washed twice with light petroleum and the final acetonitrile phase
was evaporated under reduced pressure. The crude product was
chromatographed by CC (hexane/AcOEt) yielding 85% of 73.
olide (69)
neat, KBr
C15ClO3H19; amorphous solid; IR
n
cmꢁ1: 3429 (OH, st),
max
2939 (C–H, st), 1756 (g-lactone), 1635 (C]C), 782 (C–Cl). HRMS
calcd for C15ClO3H19 282.1023, found 282.1395; EIMS (70 eV) m/z
(rel int.): 284 [Mþ2]þ (3), 282 [M]þ (9), 254 [MꢁCO]þ (23), 246
[MꢁHCl]þ (4), 233 [MꢁCH2Cl]þ (10). 1H NMR (200 MHz):
d
5.12
4.10.1. Guaian-4(15),7(11),10(14)-triene-6,12-olide (73)
neat, KBr
(1H, br s, H-15), 5.00 (1H, br s, H-150), 4.83 (1H, br s, H-14), 4.74 (1H,
C15O2H18; amorphous solid; IR
n
cmꢁ1: 2948 (C–H, st),
max
br s, H-140), 4.07 (1H, dd, J¼9.9 Hz, H-6), 3.56 (2H, s, H-13, H-130),
1727 (
g-lactone), 1644 (C]C). HRMS calcd for C15O2H18 230.1307,
2.80 (2H, m, H-1, H-5), 2.56 (3H, m, H-2
a, H-7, H-9a), 2.52 (1H, m,
found 230.1518; EIMS (70 eV) m/z (rel int.): 230 [M]þ (4). 1H NMR
H-3
a
), 1.67 (1H, dddd, J¼4.6, 12.6 Hz, H-8
b
).
(200 MHz):
d
5.17 (1H, ddd, J¼1.2, 2.3, 3.5 Hz, H-15), 5.10 (1H, br s,
J¼1.1, 2.1, 3.2 Hz, H-150), 4.94 (1H, br s, H-14), 4.91 (1H, dd, J¼1.4 Hz,
4.8.3. (11R)-11,13-Dichloro-guian-4(15),10(14)-diene-
H-140), 4.62 (1H, br d, J¼11.1 Hz, H-6), 2.89 (1H, m, H-1), 2.84 (1H,
6,12-olide (70)
m, H-8
(3H, m, H-5, H-8
2.21 (1H, dddd, J¼3.7, 11.9 Hz, H-9
b), 2.60 (1H, ddddd, J¼1.2, 2.5, 4.9, 9.6, 17.1 Hz, H-3
b
), 2.50
),
), 1.99 (1H, dddd, J¼2.7, 6.6, 9.4,
), 1.78 (3H,
C15Cl2O2H18; amorphous solid; IR nnmeaaxt, KBr cmꢁ1: 2949 (C–H, st),
a
, H-9
b
), 2.43 (1H, ddddd, J¼2.5, 8.6,10.0 Hz, H-3
a
1779
(
g-lactone), 1637 (C]C), 731 (C–Cl). HRMS calcd for
a
C15Cl2O2H18 300.0684, found 300.0817; EIMS (70 eV) m/z (rel int.):
12.9 Hz, H-2
a
), 1.84 (1H, dddd, J¼9.9, 11.4, 12.8 Hz, H-2
b
302 [Mþ2]þ (28), 300 [M]þ (38), 264 [MꢁCl]þ (30), 229
br s, H-13). 13C NMR: see Table 3.
[MꢁClꢁHCl]þ (16). 1H NMR (200 MHz):
d 5.19 (1H, br s, H-15), 5.07
(1H, br s, H-150), 4.90 (1H, br s, H-14), 4.81 (1H, br s, H-140), 4.15 (1H,
4.11. Molecular modelling
dd, J¼8.9, 10.0 Hz, H-6), 3.64 (2H, s, H-13, H-130), 2.86 (2H, m, H-1,
H-5), 2.60 (1H, m, H-3a), 2.50 (3H, m, H-2a, H-7, H-9a), 1.60 (1H, m,
Minimum energy conformations and molecular properties were
obtained using MM2 and MOPAC calculations (Chem3D ULTRA ver.
7.0Ó, 2001 Cambridge Soft, Cambridge, MA, USA; MOPAC, ver. 6.00).
Spatial geometry was optimized using MM2 calculations. Heats of
formation were obtained by semiempiric minimization with
MOPAC using the PM3 method. For semiempiric calculations the
parameters PRECISE, GEO-OK, and T¼86,400 were used.
H-8
b).
4.9. Dehydrohalogenation of 68 and 70
Each compound (50 mmol) was dissolved in dry DMF (5 mL)
and the solution was vigorously stirred. The Li2CO3/LiCl (100 mg)
was added and the mixture was heated at 120 ꢀC for 1 h. Purifica-
tion of the crude product yielded 71 (84%) and 72 (96%),
respectively.
Acknowledgements
This research was supported by the Ministerio de Ciencia y
4.9.1. 13-Hydroxy-guaian-4(15),7(11),10(14)-triene-6,12-olide (71)
´
Tecnologıa, Spain (MCYT; Project No. AGL2005-05190).
neat, KBr
C15O3H18; amorphous solid; IR
2926 (C–H, st), 1725 (
n
cmꢁ1: 3196 (OH, st),
max
g
-lactone), 1650 (C]C). HRMS calcd for
Supplementary data
C15O3H18 246.1256, found 246.1149; EIMS (70 eV) m/z (rel int.): 247
[Mþ1]þ (32), 246 [M]þ (10), 228 [MꢁH2O]þ (100). 1H NMR
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.09.024.
(200 MHz): d
5.19 (1H, br s, H-15), 5.13 (1H, br s, H-150), 4.98 (1H, br
s, H-14), 4.94 (1H, br s, H-140), 4.69 (1H, dd, J¼11.2 Hz, H-6), 4.52
(1H, d, J¼16.1 Hz, H-13), 4.37 (1H, d, J¼16.1 Hz, H-130), 3.01 (1H,
References and notes
ddd, J¼3.7, 7.2, 17.1 Hz, H-8 ), 2.91 (1H, ddd, J¼7.4, 12.0 Hz, H-1),
b
2.43 (1H, dddd, J¼2.4, 8.3, 10.5 Hz, H-3
14.0 Hz, H-9
), 2.03 (1H, dddd, J¼2.6, 9.0, 12.0 Hz, H-2
dddd, J¼9.7, 10.9, 12.6 Hz, H-2
). 13C NMR: see Table 3.
a
), 2.23 (1H, ddd, J¼8.2, 10.2,
1. Fraga, B. M. J. Nat. Prod. Rep. 2005, 22, 465–486 And previous reports in the
same journal.
2. (a) Datta, S.; Saxena, D. B. Pest Manag. Sci. 2001, 57, 95–101; (b) Castillo, M.;
a
a
), 1.85 (1H,
b
´
Martınez-Pardo, R.; Garcera, M. D.; Couillaud, F. J. Agric. Food Chem. 1998, 46,
2030–2035; (c) Saroglou, V.; Karioti, A.; Demetzos, C.; Dimas, K.; Skaltsa, H.
J. Nat. Prod. 2005, 68, 1404–1407; (d) Wedge, D. E.; Galindo, J. C. G.; Macı´as, F. A.
Phytochemistry 2000, 53, 747–757; (e) Li-Weber, M.; Palfi, K.; Giaisi, M.;
Krammer, P. H. Cell Death Differ. 2005, 12, 408–409; (f) Zhang, S.; Won, Y.-K.;
Ong, C.-N.; Shen, H.-M. Curr. Med. Chem.: Anti-Cancer Agents 2005, 5, 239–249;
(g) Bremner, P.; Heinrich, M. Phytochem. Rev. 2005, 4, 27–37.
3. Dirsch, V. M.; Stuppner, H.; Ellmerer-Muller, E. P.; Vollmar, A. M. Bioorg. Med.
Chem. 2000, 8, 2747–2753.
4. (a) Wang, Y.; Hamburger, M.; Cheng, C. H. K.; Costall, B.; Naylor, R. J.; Jenner, P.;
Hostettman, K. Helv. Chim. Acta 1991, 74, 117–123; (b) Rugutt, K. J. J. Agric. Food
Chem. 1997, 45, 4845–4849; (c) Macı´as, F. A.; Galindo, J. C. G.; Velasco, R.;
Castellano, D. J. Agric. Food Chem. 2000, 48, 5288–5296; (d) Gertsch, J.; Sticher,
O.; Schmidt, T.; Heilmann, J. Biochem. Pharmacol. 2003, 66, 2141–2153.
5. Jakupovic, J.; Sun, H.; Geerts, S.; Bohlmann, F. Planta Med. 1987, 53, 49–51.
6. Massanet, G. M.; Collado, I. G.; Macias, F. A.; Bohlmann, F.; Jakupovic, J. Tetra-
hedron Lett. 1983, 24, 1641–1642.
4.9.2. 13-Chloro-guaian-4(15),7(11),10(14)-triene-6,12-olide (72)
C15ClO2H17; amorphous solid; IR nnmeaaxt, KBr cmꢁ1: 2947 (C–H, st),
1737
(g-lactone), 1645 (C]C), 778 (C–Cl). HRMS calcd for
C15ClO2H17 264.0917, found 264.1122; EIMS (70 eV) m/z (rel int.):
266 [Mþ2]þ (32), 264 [M]þ (4), 229 [MꢁCl]þ (15), 236 [MꢁCO]þ
(13). 1H NMR (200 MHz):
d 5.18 (1H, br s, H-15), 5.12 (1H, br s, H-
150), 4.98 (1H, br s, H-14), 4.95 (1H, br s, H-140), 4.71 (1H, d,
J¼10.2 Hz, H-6), 4.24 (1H, d, J¼11.8 Hz, H-13), 4.20 (1H, d, J¼12.0 Hz,
H-130), 3.03 (1H, ddd, J¼3.6, 7.6, 17.5 Hz, H-8
), 2.91 (1H, ddd, J¼7.1,
b
12.8 Hz, H-1), 2.64 (1H, ddd, J¼4.5, 9.7, 17.5 Hz, H-8
a
), 2.59 (1H, m,
), 2.44 (1H, ddddd, J¼2.4,
), 2.26 (1H, ddd, J¼3.6, 9.4, 13.2 Hz, H-9 ), 2.02
(1H, dddd, J¼2.7, 6.3, 8.9, 12.5 Hz, H-2 ), 1.84 (1H, dddd, J¼9.9, 11.5,
12.9 Hz, H-2
). 13C NMR: see Table 3.
H-3
b), 2.56 (1H, m, H-5), 2.52 (1H, m, H-9b
8.2, 10.6 Hz, H-3
a
a
7. Omar, A. A.; Sarg, T. M.; Khafagy, S. M.; Ibrahim, Y. E.; Grenz, M. Phytochemistry
1984, 23, 2381–2382.
8. Rustaiyan, A.; Sharif, Z.; Tajarodi, A.; Ziesche, J.; Bohlmann, F. Planta Med. 1984,
50, 193–194.
a
b
9. Rustaiyan, A.; Niknejad, A.; Zdero, C.; Bohlmann, F. Phytochemistry 1981, 20,
2427–2429.
10. Oksuz, S.; Ulubelen, A.; Aynechi, Y.; Wagner, H. Phytochemistry 1982, 21, 2747–
2749.
11. (a) Medjroubi, K.; Benayache, F.; Benayache, S.; Akkal, S.; Khalfallah, N.; Aclinou,
P. Phytochemistry 1997, 45, 1449–1451; (b) Gonzalez-Platas, J.; Ruiz-Perez, C.;
Gonzalez, A. G.; Bermejo, J.; Medjroubi, K. Acta Crystallogr., Sect. C 1999, C55,
1837–1839.
4.10. Reduction of 72 with TBTH
A 1 M solution of tributyltin hydride (TBTH, 0.4 mmol) (400
in toluene and a catalytic amount of azaisobutyronitrile (AIBN)
were added to a solution of 72 (100 mg, 0.379 mmol) in dry toluene
(15 mL). The reaction mixture was heated under reflux for 2 h.
mL)

11006
F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 10996–11006
12. (a) Thiessen, W. E.; Hope, H.; Zarghami, N.; Heinz, D. E.; Deuel, P.; Hahn, E. A.
Chem. Ind. 1969, 14, 460–461; (b) Thiessen, W. E.; Hope, H. Acta Crystallogr., Sect.
B 1970, 26, 554–562.
13. Zarghami, N.; Heinz, D. E. Chem. Ind. 1969, 43, 1556–1557.
14. Dai, J.-Q.; Liu, Z.-L.; Yang, L. Phytochemistry 2002, 59, 537–542.
15. Bernhard, H. O.; Thiele, K.; Pretsch, E. Helv. Chim. Acta 1979, 62, 1288–1297.
16. Shimizu, S.; Ishihara, N.; Umehara, K.; Miyase, T.; Ueno, A. Chem. Pharm. Bull.
1988, 36, 2466–2474.
28. Li, J.; Wu, Q. X.; Shi, Y. P.; Zhu, Y. Chin. Chem. Lett. 2004, 15, 1309–1310.
29. Yushan, L.; Masami, I.; Masayuki, S.; Yasukatsu, O.; Yasushi, O. Chem. Pharm.
Bull. 2003, 51, 1103–1105.
´
´
30. Macıas, F. A.; Velasco, R.; Alvarez, J. A.; Castellano, D.; Galindo, J. C. G. Tetra-
hedron 2004, 60, 8477–8488.
31. Demuynck, M.; De Clercq, P.; Vandewalle, M. J. Org. Chem. 1979, 44, 4863–4866.
´
´
32. Collado, I. G.; Macıas, F. A.; Massanet, G. M.; Rodrıguez-Luis, F. Tetrahedron
1986, 42, 3611–3622.
17. Reis, L. V.; Tavares, M. R.; Palma, F. M. S. B.; Marcelo-Curto, M. J. Phytochemistry
1992, 31, 1285–1287.
18. Barbetti, P., Menghini, A., Casinovi, C. G., Santurbano, B. Studi Carciofo, [Congr. Int.],
3rd.; Marzi, V., Lattanzio, V., Eds.; Ind. Grafica Laterza, Bari, Italy, 1981; pp 77–86.
19. Li, X.; Qian, P.; Liu, Z.; Zhao, Y.; Xu, G.; Tao, D.; Zhao, Q.; Sun, H. Heterocycles
2005, 65, 287–291.
33. (a) Wartski, L.; El Boutz, M.; Seyden-Penne, J.; Dumont, W.; Krief, A. Tetrahedron
Lett. 1979, 17, 1543–1546; (b) Tiecco, M.; Testaferri, L.; Tingoli, M.; Chianelli, D.;
Montanucci, M. J. Org. Chem. 1983, 48, 4795–4800; (c) Reich, H. J.; Sikorski, W.
H. J. Org. Chem. 1999, 64, 14–15; (d) Sikorski, W. H.; Reich, H. J. J. Am. Chem. Soc.
2001, 123, 6527–6535.
´
34. (a) Stephenson, B.; Solladie, G.; Mosher, H. S. J. Am. Chem. Soc. 1972, 94, 4184–
20. Meragelman, K. M.; Ariza Espinar, L.; Sosa, V. E. J. Nat. Prod. 1998, 61, 105–107.
21. Ha, T. J.; Park, K. H.; Jang, D. S.; Lee, J. R.; Park, K. M.; Yang, M. S. Heterocycles
2003, 60, 623–629.
22. Herz, W.; Watanabe, K.; Blount, J. F. J. Org. Chem. 1982, 47, 3011–3012.
23. (a) Chhabra, B. R.; Jain, M.; Bhullar, M. K. Indian J. Chem., Sect. B 1999, 38B, 1090–
1092; (b) Bhullar, M. K.; Kalsi, P. S.; Chhabra, B. R. Fitoterapia 1997, 68, 91–92; (c)
Kalsi, P. S.; Mittal, V.; Singh, I. P.; Chhabra, B. R. Fitoterapia 1995, 66, 191.
24. Grieco, P. A.; Oguri, T.; Burke, S.; Rodriguez, E.; DeTitta, G. T.; Fortier, S. J. Org.
Chem. 1978, 43, 4552–4554.
25. (a) Bohlmann, F.; Le-Van, N. Phytochemistry 1977, 16, 1304–1306; (b) Fronczek,
F. R.; Vargas, D.; Fischer, N. H.; Hostettmann, K. J. Nat. Prod. 1984, 47, 1036–1039.
26. Dhillon, R. S.; Kalsi, P. S.; Singh, W. P.; Gautam, V. K.; Chhabra, B. R. Phyto-
chemistry 1987, 26, 1209–1210.
27. Modonova, L. D.; Semenov, A. A.; Zhapova, Ts.; Ivanova, N. D.; Dzhaparova, A. K.;
Fedoseev, A. P.; Kirdei, E. G.; Malkova, T. I. Khimiko-Farm. Zh.1986, 20, 1472–1475.
4188; (b) Schlessinger, R. H.; Richman, J. E.; Lee, C. S.; Hermann, J. L.; Cregge, R.
J. Tetrahedron Lett. 1973, 2425–2428.
35. Wallace, T. J.; Pobiner, H.; Schriesheim, A.; Baron, F. A. Chem. & Industry (London
United Kingdom) 1965, 22, 945–946.
36. Hofmann, J. E.; Schriesheim, A.; Ronsenfeld, D. D. J. Am. Chem. Soc. 1965, 11,
2523–2524.
37. Chem3D UltraÒ
. Molecular modelling and analysis. 2001 Cambridge Soft.
Cambridge, MA, USA. Molecular modelling was performed as follows. Mole-
cules were first minimized using an mm2 algorithm to optimize geometry.
Then, MOPAC semiempirical calculations using a pm3 algorithm and the key-
words precise and geo-ok gave the heat of formation and other molecular
parameters.
38. Yuuya, S.; Hagiwara, H.; Suzuki, T.; Ando, M.; Yamada, A.; Suda, K.; Kataoka, T.;
Nagai, K. J. Nat. Prod. 1977, 62, 22–30.
39. Haruna, M.; Ito, K. J. Chem. Soc., Chem. Commun. 1981, 483–485.