Bismuth triflate-catalyzed Wagner-Meerwein rearrangement in terpenes. Application to the synthesis of the 18α-oleanane core and A-neo-18α-oleanene compounds from lupanes

Article abstract of DOI:10.1039/b814448f

The use of bismuth(III) salts as catalysts for the Wagner-Meerwein rearrangement of lupane derivatives with expansion of ring E and formation of an additional O-containing ring is reported. This process has also been extended to other terpenes, such as the sesquiterpene (-)-caryophyllene oxide. When the reaction was performed with oleanonic acid, 28,13β-lactonization occurred, without Wagner-Meerwein rearrangement. Under more vigorous reaction conditions, dehydration of the 3β-hydroxyl group and subsequent additional Wagner-Meerwein rearrangement led to the selective synthesis of A-neo-18α-oleanene compounds, in very high yields. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b814448f

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Bismuth triflate-catalyzed Wagner-Meerwein rearrangement in terpenes.
Application to the synthesis of the 18a-oleanane core and A-neo-18a-oleanene
compounds from lupanes†
a,b
a
a
c
d
Jorge A. R. Salvador,* Rui M. A. Pinto, Rita C. Santos, Christophe Le Roux, Ana Matos Beja and
Jos e´ A. Paix a˜ o
d
Received 20th August 2008, Accepted 3rd November 2008
First published as an Advance Article on the web 9th December 2008
DOI: 10.1039/b814448f
The use of bismuth(III) salts as catalysts for the Wagner-Meerwein rearrangement of lupane derivatives
with expansion of ring E and formation of an additional O-containing ring is reported. This process
has also been extended to other terpenes, such as the sesquiterpene (-)-caryophyllene oxide. When the
reaction was performed with oleanonic acid, 28,13b-lactonization occurred, without Wagner-Meerwein
rearrangement. Under more vigorous reaction conditions, dehydration of the 3b-hydroxyl group and
subsequent additional Wagner-Meerwein rearrangement led to the selective synthesis of
A-neo-18a-oleanene compounds, in very high yields.
Introduction
1
Terpenes were among those natural products wherein rear-
2
rangements were earliest detected and studied. Rearrangements
involving the formation of a carbocation and 1,2-migrations of
hydrogen or alkyl groups from one carbon to a neighboring carbon
3
are designated as Wagner-Meerwein rearrangements. This group
of transformations constitutes a particularly important field of
research in organic chemistry and has been widely reported in
2,3
terpenoid chemistry.
One such well-known transformation involves the acid catalyzed
ring E rearrangement of betulin 1 and important related triter-
4
pene derivatives, to 18a-oleanane compounds bearing a 19b,28-
epoxide or 28,19b-lactone ring, and is commonly referred to
2
“
betulin-allobetulin rearrangement” (Fig. 1).
The “betulin-allobetulin rearrangement” was first reported by
5
Schulze and Pieroh by the use of formic acid. The reaction
involves the formation and hydrolysis of allobetulin formate,
6
,7
and was later applied by other authors. A variety of acidic
reagents has been employed to promote the one-step conversion of
betulin and betulinic acid to the corresponding ring E expanded
Fig. 1 Acid-catalyzed Wagner-Meerwein rearrangement of ring E of
betulin 1 to allobetulin 2.
13
silica, as well as ferric nitrate or ferric chloride adsorbed on silica
7–11
products.
In addition, Linkowska used dimethyl sulfate as a
14
gel or alumina have been reported in the high yield synthesis of
12
catalyst, for the same conversion. Later, the use of solid acids,
such as sulfuric acid on silica, montmorillonite clays (both K10
and KSF), kaolinite, bleaching clay and p-toluenesulfonic acid on
allobetulin and other 18a-oleanane derivatives.
More recently, a new process for the isomerisation of betulin to
allobetulin using orthophosphoric acid in either homogeneous or
15
heterogeneous reaction conditions, has been patented, whereas
the use of trifluoroacetic acid has been reported by Medvedeva and
a
Laborat o´ rio de Qu ´ı mica Farmac eˆ utica, Faculdade de Farm a´ cia, Universi-
dade de Coimbra, 3000-295 Coimbra, Portugal. E-mail: salvador@ci.uc.pt;
Fax: +351 239 827126; Tel: +351 239 859950
16
co-workers. The bromination of betulin with molecular bromine
afforded 29,30-dibromoallobetulin in high yields, with rearrange-
b
Instituto Pedro Nunes-Labpharm, Rua Pedro Nunes, 3030-199 Coimbra,
Portugal
17
ment of the starting material leading to ring E expansion.
c
Laboratoire H e´ t e´ rochimie Fondamentale et Appliqu e´ e, Universit e´ Paul
Sabatier, 118, route de Narbonne, 31062 Toulouse Cedex 9, France
CEMDRX, Departamento de F ´ı sica, Faculdade de Ci eˆ ncias e Tecnologia,
Universidade de Coimbra, 3004-516 Coimbra, Portugal
Allobetulin and related ring E rearranged compounds have
been prepared and tested for biological activity. Antifeedant
d
6
properties have been found for some of these compounds
whereas others have been used as biomarkers.
13,18
†
Electronic supplementary information (ESI) available: 1D and 2D NMR
Allobetulin
data for compounds 7, 11, 14 and 16, colour images of the ORTEP dia-
grams and crystallographic data as cif files for compounds 5 and 17. CCDC
reference numbers 699289 and 699290. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b814448f
and its 3-oxo derivatives have been used as starting materials
in the synthesis of compounds that have been tested for anti-
19
20
21
inflammatory, cytotoxic and immunotropic activities. Quite
5
08 | Org. Biomol. Chem., 2009, 7, 508–517
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recently, moderate cytotoxicity has been found in A-549, DLD-
Table 1 Catalyst screening for the Wagner-Meerwein rearrangement of
a
betulin 1 to allobetulin 2
1 and WSI cell lines for some derivatives of allobetulin and
8-oxoallobetulin, which have been prepared and evaluated by
2
b
Entry
Catalyst (mol%)
Time (h)
Yield (%)
22
Thibeault and co-workers. The same group described a useful
synthetic route to obtain germanicanes (e.g. machaeroceric acid
and 19b-machaerocerol) from betulinic acid, which involved
Wagner-Meerwein rearrangement with formation of the typical
ring E of both 18a-oleanane- and germanicane-type compounds,
1
2
3
4
5
6
7
8
9
Bi(OTf) ·xH O (5)
3
2
3
24
24
24
3
24
48
4
95
–
Bi(OAc)
3
(10)
BiCl
BiBr
BiBr
3
(10)
(10)
(20)
traces
c
3
3
45
23
97c
and subsequent lactone ring-opening.
Bi(NO
Bi(NO
Sc(OTf)
Yb(OTf)
La(OTf) (10)
3
)
)
3
·5H
2
2
O (10)
O (20)
32
3
3
·5H
97
The generality of the methods reported in the literature for the
synthesis of the referred compounds present drawbacks, such as
the use of toxic, corrosive and/or expensive reagents, as well as the
fact that most of them are non-catalytic. Thus, the development of
new catalytic processes using environmentally friendly, cheap and
easily available reactants would be of considerable interest in this
area.
3
(10)
94c
3
(10)
7
4
20
10
3
–
a
b
Reaction conditions: 0.10 mmol of 1, 5 mL of CH
2
Cl
2
, reflux; Isolated
c
yield; The yield was determined by integration of the 19a-H signals of 1
1
and 2 on the H NMR spectrum of the crude mixture.
Bismuth(III) salts emerged in the past few years as “eco-
Table 2 Wagner-Meerwein rearrangement of betulin 1 to allobetulin 2 in
24,25
friendly” reagents suitable for green chemistry.
As part of
a
different solvents
our current interest on the development of new bismuth-based
26
27–29
◦
processes applied to natural product chemistry,
we herein
Entry
Solvent
Temp. ( C)
Time (h)
Yield (%)
report the use of bismuth(III) salts as catalysts for the Wagner-
Meerwein rearrangement of both betulin and betulinic acid as
well as their derivatives, which occurs with expansion of ring E
and formation of an additional O-containing ring. We found that
under more vigorous reaction conditions, A-neo-18a-oleanene
compounds can be selectively obtained in very high yields, from
the above mentioned lupanes, in a one-pot procedure. The scope
of this procedure has been extended by the use of other terpenic
compounds, such as the sesquiterpene (-)-caryophyllene oxide and
the 3-oxo derivative of oleanolic acid.
b
1
2
3
4
5
6
CH
MeNO
Toluene
t-BuOMe
MeOH
EtOH
2
Cl
2
rt
50
50
50
50
50
24
24
24
24
24
24
90c
2
50
c
40
traces
–
–
a
Reaction conditions: 0.10 mmol of 1, 5 mol% of Bi(OTf)
3
·xH
2
O, 5 mL of
b
c
solvent; Isolated yield; The yield was determined by integration of the
9a-H signals of 1 and 2 on the H NMR spectrum of the crude mixture.
1
1
with Bi(OAc)
the reaction with BiBr
However, a loading amount of 20 mol% of these catalysts was
needed to obtain full conversion (Table 1, entries 5 and 7). Among
the other metal triflates screened for this reaction (Table 1, entries
3
and BiCl
3
(Table 1, entries 2 and 3), as opposed to
O (Table 1, entries 4–7).
3
and Bi(NO
3
)
3
·5H
2
Results and discussion
Catalyst and solvent screening
We have recently reported the use of bismuth(III) salts as catalysts
for the Westphalen and “backbone” rearrangements of 5b,6b-
epoxysteroids. These reactions involve the migration of one or
two of the angular C18 and C19 methyl groups with the formation
8–10), only Sc(OTf)
high yield, after a relatively short reaction time. Thus, we chose
Bi(OTf) O as the optimal catalyst for the study of Wagner-
Meerwein rearrangements.
Further optimization of the reaction conditions using various
3
(10 mol%) afforded allobetulin 2 in very
3
·xH
2
29
of a double bond on ring B or D of the steroid nucleus.
The interesting results achieved with those reactions in par-
ticular, have turned our attention to the study of the Wagner-
Meerwein rearrangement in terpenes. Screening assays for catalyst
solvents was undertaken (Scheme 1, Table 2). The Bi(OTf)
3
·xH
2
O-
catalyzed reaction of betulin 1 in CH Cl was performed at room
2
2
temperature, and allobetulin 2 was afforded in 90% yield, after
24 h (Table 2, entry 1). The use of other solvents led to poorer
results (Table 2, entries 2–6).
Low yields were achieved in the reactions carried out in MeNO
and toluene (Table 2, entries 2 and 3), and no reaction was observed
choice using betulin 1 in refluxing CH
Scheme 1, Table 1). These results were promising, as the expected
product 2 was obtained in very high yield using 5 mol% of
Bi(OTf) O (Table 1, entry 1). Almost no reaction occured
·xH
2
Cl
2
are depicted on Table 1
(
2
3
2
Scheme 1 Wagner-Meerwein rearrangement of betulin 1 to allobetulin 2.
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Scheme 2 Bi(OTf)
of the 19b-H signals of 1 and 2 on the H NMR of the crude mixture.
3
·xH
2
O-catalyzed reaction of betulin 1 in ethyl acetate. The allobetulin 2:betulin-28-yl acetate 3 ratio was determined by integration
1
in MeOH or EtOH (Table 2, entries 5 and 6) while only trace
amounts of product were seen on the TLC plate using methyl
tert-butyl ether as the solvent (Table 2, entry 4).
(Fig. 2).‡ Starting from betulonic acid 6, the Wagner-Meerwein
rearrangement of ring E resulted in the high yielding preparation
of the 18a-oleanane compound 7,† bearing an 28,19b-lactone
function (Table 3, entry 2).
Interestingly, whenthe reactionwas performed in ethyl acetate at
◦
30
5
0 C, 3b-hydroxylup-20(29)-en-28-yl acetate 3 was found to be
the major reaction product and allobetulin 2 was obtained as by-
product (Scheme 2). This result, shows that Bi(OTf) O is an
3
·xH
2
effective and selective catalyst for the transesterification reaction
of the primary hydroxyl group of betulin 1, in the presence of ethyl
acetate.
The acid protons derived from the hydrolysis of bismuth(III)
salts have been identified as the true catalytic species in some
31,32
reactions.
carried out to determine whether the observed reactivity in the
betulin-allobetulin rearrangement” is due to Lewis or Brønsted
In the light of this fact, a set of experiments has been
“
acid catalysis. Thus, when the reaction was performed in the
presence of 2,6-di-tert-butylpyridine, a known proton scavenger
which binds to protons only and is unable to coordinate to metal
Fig. 2 ORTEP diagram of compound 5 (50% probability level, H atoms
of arbitrary sizes).
32
ions due to the bulky tert-butyl groups, no reaction was observed
0.1 mmol of betulin 1, 5 mol% of Bi(OTf) O and 15 mol%
·xH
of 2,6-di-tert-butylpyridine in CH Cl at reflux, 4 h, no reaction).
BiPh was also used as a proton scavenger for the first time, due to
(
3
2
When the reaction was performed with betulinic acid 8, a
slower conversion rate was observed along with formation of a
trace amount of an apolar side product, as observed on TLC
plates. NMR analysis of the crude mixture, after 30 h of reaction,
showed a 79% conversion of 8. Thus, the 18a-oleanan-28,19b-
olide compound 9 was isolated by flash column chromatography in
2
2
3
24
the high lability of the Bi-Ph bond under acidic conditions. As
expected, only traces of product 2 were observed on the TLC
plate (0.1 mmol of betulin 1, 5 mol% of Bi(OTf)
3
·xH
at reflux, 4 h, traces of allobetulin
). The confirmation that the true catalytic species is a Brønsted
2
O and
1
5 mol% of BiPh
3
in CH
2
Cl
2
66% yield. A lower reactivity and selectivity for the acid-catalyzed
2
Wagner-Meerwein rearrangement of betulinic acid had already
acid generated in situ, was unequivocally demonstrated by the
isomerisation of betulin 1 to allobetulin 2, which was efficiently
achieved in the presence of TfOH (0.1 mmol of betulin 1, 15 mol%
11,13
been reported by other authors.
The Bi(OTf)
3
·xH
2
O-catalyzed Wagner-Meerwein rearrange-
ment was further studied using the sesquiterpene (-)-caryo-
phyllene oxide 10. The reaction was completed in 10 minutes,
and after purification by flash column chromatography, the
clovane-type compound 11 was isolated in 60% yield (Table 3,
entry 4). Analytical data of clov-2-en-9a-ol 11† was in accordance
of TfOH in CH
These results indicate that Bi(OTf)
the reaction conditions, affording a Brønsted acid species in situ,
2
Cl
2
at reflux, 1 h, 95% yield of allobetulin 2).
3
·xH O is hydrolyzed under
2
33
which is the real catalyst.
34
with literature. However, 2D NMR spectroscopy was performed
in order to unequivocally assign the orientation of the 9a-
hydroxyl group. The “caryophyllene-clovane rearrangement” has
Wagner-Meerwein rearrangement in terpenes
This new bismuth triflate-based process was then applied to other
terpenic substrates, showing good versatility, as both lupane-,
35
previously been reported under acid conditions, and it has been
found that 2-substituted clovane-type compounds may be formed
when a nucleophilic species is present.
1
8a-oleanane- and caryophyllene-type compounds rearranged,
under the optimized reaction conditions (Table 3). Thus, in the
presence of 5 mol% of Bi(OTf) O in refluxing CH Cl , betulin-
·xH
b-yl acetate 4 afforded the corresponding 19b,28-epoxy-18a-
28,36
3
2
2
2
3
‡ Crystal data for compound 5. C32
H
52
O
3
, M = 484.76, monoclinic, a =
3
1
2
3.3520(2), b = 6.54000(10), c = 32.4439(5) A˚ , V = 2798.13(7) A˚ , T =
oleanane product 5, in 96% yield, after 1 h of reaction (Table 3,
entry 1). In addition to spectroscopic evidence, the structure
of compound 5 was confirmed by single crystal X-ray analysis
93(2) K, space group C2, Z = 4, 26879 reflections measured, 3074 unique
(
R
int = 0.027) which were used in all calculations. Final R indices: R1 =
2
0.036 for 2759 reflections with I> 2s(I), wR(F ) was 0.099 (all data).
5
10 | Org. Biomol. Chem., 2009, 7, 508–517
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a
Table 3 Wagner-Meerwein rearrangement in triterpenes 2, 4, 6 and 8 and (-)-caryophyllene oxide 10 catalyzed by Bi(OTf)
3
·xH
2
O
b
Entry
Substrate
Time (h)
Product
Yield (%)
1
1
96
2
3
97
c,d
3
30
66
e
4
10 min
60
f
5
21
94
a
b
c
Reactions conditions: 5 mol% of Bi(OTf)
3
·xH
2
O, CH
2
Cl
2
(5 mL/0.10 mmol of substrate), reflux; Isolated yield; There was 79% conversion of betulinic
1
d
acid 8, as calculated by integration of the 29-Ha and 19a-H signals of 8 and 9, respectively, on the H NMR spectrum of the crude mixture; Purification
by flash column chromatography on SiO
using toluene/diethyl ether 95:5 (v:v) as eluent; The reaction was performed with 20 mol% of Bi(OTf)
◦
e
2
using CHCl
3
/petroleum ether 40–60 C 80:20 (v:v) as eluent; After flash column chromatography on SiO
·xH O.
2
f
3
2
When oleanonic acid 13 was used as substrate in the presence
of 5 mol% of Bi(OTf) O, a single product was detected
·xH
on the TLC plate, however low conversion was observed after
4 h. By increasing the amount of bismuth(III) salt to 20 mol%,
quantitative formation of the 3-oxo-18a-olean-28,13b-olide 14†
occurred (Scheme 3). This lactonization reaction of triterpenoids
with a C12=C13 double bond has already been reported under
37
3
2
acid conditions. Thus, whereas in lupanes the formation of
the additional O-containing ring occurs along with a Wagner-
Meerwein rearrangement that causes ring E expansion, in the
oleanolic acid derivative 13 only 28,13b-lactonization with 18-H
inversion of orientation is observed.
2
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Scheme 3 Bi(OTf)
3
·xH
2
O-promoted lactonization of oleanonic acid 13.
3
9
The Wagner-Meerwein rearrangement has also been applied to
the construction of cyclopentyl units by ring contraction of six-
membered carbocyclic compounds during the total synthesis of
group, which is designated as the A-neo ring. The formation
of these A-neo-18a-oleanene compounds as by-products of the
“betulin-allobetulin rearrangement” has been reported, and the
location of the double bond has been found to be dependent
38
natural products. The presence of the 3b-hydroxyl group is a
typical feature of triterpenic compounds. The loss of this function
is often associated with a Wagner-Meerwein rearrangement of ring
A, with contraction and formation of a double bond, that may be
11,13,14
on the reaction conditions employed.
This transformation
has also been described through the use of typical dehydration
and Fuller’s earth, and by solvolysis
of the corresponding 3b-tosyl derivatives. A-neo-18a-oleanene
9,40
agents, such as PCl
5
, P
2
O
5
2
40
located at C3=C4, C3=C5 or C9=C10 (Fig. 3).
compounds bearing a double bond on rings A or B have been used
13,18
both as biomarkers in geochemical studies
and as synthetic
intermediates, due to the presence of the highly versatile alkene
41
group.
The fact that these compounds are interesting and the lack of
selective high yielding methods for their synthesis, have prompted
us to investigate whether Bi(OTf)
promote these transformations. Thus, reaction of allobetulin 2 in
the presence of 5 and 10 mol% of Bi(OTf) O afforded a highly
3
·xH
2
O was a suitable reagent to
3
·xH
2
apolar product after 24 h, however low conversion was achieved.
Nonetheless, when 20 mol% of this Bi(III) salt was used, 19b,28-
epoxy-A-neo-18a-olean-3(5)-ene 12 was selectively obtained after
2
1 h, in refluxing CH
2
2
Cl (Table 3, entry 5). Spectroscopic data
were in agreement with the pointed structure for compound 12.
1
The presence of a well-defined septet at 2.65 ppm on the H NMR
13
spectrum confirmed the presence of the double bond at C3=C5.
Double Wagner-Meerwein rearrangement in lupane compounds
This last result, together with the observation that traces of a
very apolar by-product were seen on the TLC plates of the
Bi(OTf)
rationalized as the result of dehydration of the 18a-oleanan-
8,19b-olide derivative 9, prompted us to study the direct and
3
·xH
2
O-catalyzed reaction of betulinic acid 8, which we
2
selective double Wagner-Meerwein rearrangement on lupane
compounds (Table 4).
Betulin 1 could be selectively converted into the corresponding
rings A and E rearranged 18a-olean-3(5)-ene compound 12, by
using 20 mol% of Bi(OTf)
3
·xH
2
O inrefluxingCH
2
Cl . Thereaction
2
was completed after 40 h and the product was isolated in 98% yield
(Table 4, entry 1). As observed on the TLC plates, betulin 1 was
initially converted into allobetulin 2, which was then converted
into compound 12. The same reaction, performed in the presence
Fig. 3 Dehydration of the 3b-hydroxyl group on triterpenes followed by
Wagner-Meerwein rearrangement on ring A.
Under more vigorous reaction conditions than the ones needed
for the “betulin-allobetulin rearrangement”, further Wagner-
Meerwein rearrangement may take place on ring A of lupane
compounds. Thus, the loss of the 3b-hydroxyl group induces an
additional Wagner-Meerwein rearrangement, with migration of
the C4-C5 bond electrons that generate olefinic ring A contracted
products, with a five-membered A-ring bearing a 3-isopropyl
of a higher amount of Bi(OTf)
3
·xH
2
O (50 mol%), showed a higher
conversion rate, and a highly apolar product was obtained after
8 h of reaction. Analytical data of this compound indicated
that a more complex rearrangement had occurred, with selective
formation of 19b,28-epoxy-A-neo-5b-methyl-25-nor-18a-olean-
13
13
9(10)-ene 15 (Table 4, entry 2).
5
12 | Org. Biomol. Chem., 2009, 7, 508–517
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a
Table 4 Bi(OTf)
3
·xH
2
O promoted dehydration and double Wagner-Meerwein rearrangement of lupane derivatives 1, 8, and 18
b
Entry
Substrate Bi(OTf) O (mol%) Time (h) Product
3
·xH
2
Yield (%)
1
2
3
20
40
98
96
92
50
20
20
20
8
16
9
c
d
4
95 (77:23)
e
5
22
82
a
b
c
Reactions performed in refluxing CH
2
Cl
2
(5 mL/0.10 mmol of substrate); Isolated yield; Yield of the reaction crude based on the major product;
d
1
e
The ratio was determined by integration of the 3a-H and 4-H signals of 9 and 17, respectively, on the H NMR spectrum of the crude mixture; After
flash column chromatography on SiO using toluene/diethyl ether 95:5 (v/v) as eluent.
2
Under the same reaction conditions (50 mol% of Bi(OTf)
3
·
Rearrangement of betulin 1 in the presence of Bi(OTf)
either proceeds to rings A and B or occurs exclusively on ring
E depending on the amount of catalyst. Conversion of the
3
·xH
2
O
xH O, in refluxing CH Cl ), compound 15 can also be selectively
2
2
2
obtained from allobetulin 2 in 97% yield, after 20 h of reaction.
This journal is © The Royal Society of Chemistry 2009
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Scheme 4 Bi(OTf)
3
·xH
2
O-promoted isomerisation of the 18a-olean-3(5)-ene compound 12 into the 5b-methyl-25-nor-18a-olean-9(10)-ene compound
1
5.
1
8a-olean-3(5)-ene compound 12 into the 5b-methyl-25-nor-18a-
by flash column chromatography in 17% yield. Spectroscopy data
13
olean-9(10)-ene compound 15, under strongly acidic conditions,
has been previously reported.
In order to understand whether the Bi(OTf)
of product 17 was in accordance with literature, however its
structure was unequivocally elucidated by single-crystal X-ray
diffractometry analysis (Fig. 4).§
42
3
·xH
2
O-promoted
transformation of betulin 1 to product 15 occurs by the inter-
mediacy of a discrete cationic species only, or directly from the
2
intermediate compound 12, reaction with 12 in the presence of
Bi(OTf)
3
·xH
2
O (50 mol%) in CH
2
Cl , at reflux, was performed.
2
After 15 h, the A-neo-5b-methyl-25-nor-18a-olean-9(10)-ene com-
pound 15 has been isolated in 98% yield (Scheme 4).
The reaction of both betulin-3b-yl acetate 4 and betulonic acid
6
in the presence of 20 mol% of Bi(OTf)
corresponding ring E rearranged products 5 and 7, after 22 and
0 h, in 87 and 92% yield, respectively, as the result of a single
Wagner-Meerwein rearrangement. These results showed that both
b-acetoxy and 3-oxo groups are stable under the reaction
3
·xH
2
O afforded the
2
3
conditions used, and do not undergo further rearrangements.
When the reaction was carried out with betulinic acid 8, in the
Fig. 4 ORTEP diagram of compound 17 (50% probability level, H atoms
of arbitrary sizes).
presence of 20 mol% of Bi(OTf)
3
·xH
2
O, the reaction proceeded
similarly to the one observed with betulin 1 under the same
reaction conditions (Table 4, entry 3). Betulinic acid 8 was initially
converted into its corresponding ring E rearranged product 9 along
with a highly apolar compound, as observed by TLC. After 16 h,
a white solid was isolated and analysis of its spectroscopic data
showed formation of the new triterpenic compound, A-neo-5b-
methyl-25-nor-18a-olean-9(10)-ene-28,19b-olide 16, in 92% yield
In order to establish whether Bi(OTf)
to promote the dehydration with subsequent Wagner-Meerwein
3
·xH
2
O is a suitable reagent
rearrangement of ring A only, we used methyl 3b-hydroxylup-
43
2
0(29)-en-28-oate 18 as the substrate. However, contrary to our
expectations, cleavage of the methyl ester function occurred, and
subsequent double Wagner-Meerwein rearrangement afforded
compound 16 (Table 4, entry 5).
(
Table 4, entry 3). EI-mass spectrometry showed a 438 molecular
ion peak indicative of the loss of a H O molecule. No signal
2
at 2.65 ppm or at the olefinic region was observed on the
1
Conclusions
H NMR spectrum, however the characteristic 19a-H signal at
1
3
3
.96 ppm was present. C NMR spectroscopy confirmed the
In conclusion we have developed a novel procedure for the Wagner-
Meerwein rearrangement of lupane compounds involving the
expansion of ring E with formation of an additional O-containing
ring, using the “eco-friendly” bismuth(III) salts as catalysts. This
new process allowed the preparation of several 18a-oleanane
compounds in high yields. The optimized reaction conditions
were extended to the sesquiterpene (-)-caryophyllene oxide and
oleanonic acid with success. Under more vigorous conditions,
presence of two olefinic carbons at 130.5 and 142.5 ppm and a
carbonyl group at 179.9 ppm. The olefinic carbons were not found
on the DEPT 135 experiment, which confirmed the existence
of olefinic quaternary carbons. This data, combined with the
13,14
available analytical information for related compounds
us to assign the structure of compound 16.† Using 50 mol% of
Bi(OTf) O, under the same reactions conditions, the A-neo-
·xH
b-methyl-25-nor-18a-oleanene product 16 was quantitatively
allowed
3
2
5
using 20–50 mol% of Bi(OTf)
3
·xH
2
O, an additional Wagner-
obtained, after 8 h.
The reaction of betulinic acid 8 in the presence of 20 mol% of
Meerwein rearrangement occurred on ring A of lupane and
Bi(OTf)
3
·xH
2
O was then repeated and stopped after full conver-
1
sion of the substrate 8 (Table 4, entry 4). Analysis of the H NMR
spectrum of the crude mixture allowed the determination of a 77:23
ratio of the 18a-oleanan-28,19b-olide compound 9 and the A-neo-
§ Crystal data for compound 17. C30
H
46
O
2
, M = 438.67, monoclinic, a =
3.2214(4), b = 6.4962(2), c = 29.8420(9) A˚ , V = 2558.00(13) A˚ , T =
3
1
2
93(2) K, space group C2, Z = 4, 22819 reflections measured, 2655 unique
(
R
int = 0.061) which were used in all calculations. Final R indices: R1 =
3
(5)
2
1
8a-D product 17 (Table 4, entry 4). Compound 17 was isolated
0.046 for 1677 reflections with I > 2s(I), wR(F ) was 0.116 (all data).
5
14 | Org. Biomol. Chem., 2009, 7, 508–517
This journal is © The Royal Society of Chemistry 2009

View Online
18a-oleanane derivatives with the selective formation of A-
dissolved in diethyl ether (50 mL). The organic phase was washed
neo-18a-oleanene compounds. Full structural elucidation of the
obtained products was made using IR, MS, NMR spectroscopy
and X-ray crystallography. Some mechanistic considerations were
provided, namely the confirmation that the true catalytic species
involved is a Brønsted acid generated in situ.
with NaHCO
3
(10% aq), water, dried with anhydrous Na
2
SO , and
4
concentrated under reduced pressure to give allobetulin (19b,28-
epoxy-18a-olean-3b-ol) 2 as a white solid (42.0 mg, 95% yield).
◦
13
◦
-1
Mp 264–266 C (from ethanol) (lit., 266–268 C); nmax(film)/cm
3394, 2927, 1450, 1025; d (300 MHz; CDCl ; Me Si) 0.77 (3 H, s),
.80 (3 H, s), 0.85 (3 H, s), 0.91 (3 H, s), 0.93 (3 H, s), 0.97 (6 H, s),
.20 (1 H, dd, J 10.9 and 5.4, 3a-H), 3.44 (1 H, d, J 7.8, 28-H ), 3.53
); d (75 MHz;
Si) 13.5, 15.4, 15.7, 16.5, 18.2, 20.9, 24.5, 26.4, 26.2,
H
3
4
0
3
a
Experimental section
(
1 H, s, 19a-H), 3.78 (1 H, dd, J 7.8 and 0.9, 28-H
b
C
CDCl
3
; Me
4
General methods
26.4, 27.4, 27.9, 28.8, 32.7, 33.9, 34.1, 36.2, 36.7, 37.2, 38.8, 38.9,
+
Betulin [lup-20(29)-en-3b,28-diol] 1, betulinic acid [3b-hydroxy-
lup-20(29)-en-28-oic acid] 8, (-)-caryophyllene oxide 10 and
commercial bismuth salts were purchased from Sigma-Aldrich
Co. Solvents were obtained from VWR Portugal and used without
further purification. Betulin-3b-yl acetate [28-hydroxylup-20(29)-
40.6, 40.7, 41.4, 46.8, 51.0, 55.4, 71.2, 78.9, 87.9; m/z (EI) 442 (M ,
12%), 424 (27), 371 (14), 220 (19), 207 (28), 189 (100), 149, (38),
119 (39).
19b,28-Epoxy-18a-olean-3b-yl acetate 5. Obtained from 28-
30
hydroxylup-20(29)-en-3b-yl acetate 4 in 96% yield, after 1 h under
the above described reaction conditions. Recrystallization from
ethanol/n-hexane at room temperature gave colourless single
en-3b-yl acetate] 4, betulonic acid [3-oxolup-20(29)-en-28-oic
44
45
acid] 6, oleanonic acid (3-oxo-olean-12-en-28-oic acid) 13 and
43
methyl 3b-hydroxylup-20(29)-en-28-oate 18 were synthesized
as previously described. Bismuth triflate, Bi(OTf) O (with
·xH
<x<5) was prepared according to the literature. Kieselgel 60
254/Kieselgel 60G was used for TLC plates. Silica gel 60 (230–
00 mesh ASTM) was used for flash column chromatography.
◦
crystals suitable for X-ray crystallography. Mp 285–287 C (from
3
2
13
◦
-1
46
ethanol/n-hexane) (lit., 285–287 C); nmax(film)/cm 2925, 1727,
250, 1219; d (300 MHz; CDCl ; Me Si) 0.80 (3 H, s), 0.84 (3 H,
s), 0.85 (3 H, s), 0.87 (3 H, s), 0.91 (3 H, s), 0.93 (3 H, s), 0.97 (3
H, s), 2.05 (3 H, s, 3b-COCH ), 3.44 (1 H, d, J 7.8, 28-H ), 3.53
1 H, s, 19a-H), 3.77 (1 H, d, J 7.8, 28-H ), 4.48 (1 H, m, 3a-H);
Si) 13.5, 15.7, 16.5, 16.5, 18.1, 21.0, 21.3,
1
1
H
3
4
F
4
3
a
Melting points were determined on a Buchi Melting point B-540
apparatus and are uncorrected. IR spectroscopy was performed
(
b
1
13
d
2
3
1
C
(75 MHz; CDCl
3.7, 24.5, 26.2, 26.4 (2 C), 27.9, 28.8, 32.7, 33.8, 34.1, 36.2, 36.7,
7.1, 37.8, 38.6, 40.6, 40.7, 41.4, 46.8, 51.0, 55.5, 71.2, 81.0, 87.9,
3
; Me
4
on a Jasco FT/IR 420 spectrophotometer. H and C NMR
were recorded on a Bruker AMX 300 MHz or on a Bruker
Avance III 400 MHz. 2D NMR spectroscopy, which included
+
71.0; m/z (EI) 484 (M , 20%), 424 (100), 409 (34), 381 (63), 355
2
D Homonuclear Correlation (COSY), Nuclear Overhauser En-
(41), 204 (49), 189 (78), 119, (75).
hancement Spectroscopy (NOESY), 2D Heteronuclear Single
Quantum Correlation (HSQC) or 2D Heteronuclear Multiple
Quantum Correlation (HMQC), and 2D Heteronuclear Multiple
Bond Correlation (HMBC), were recorded on a Bruker Avance
3
-Oxo-18a-olean-28,19b-olide 7. Obtained from betulonic
acid 6 in 97% yield, after 3 h under the above described
◦
reaction conditions. Mp 310–312 C (from n-hexane/CH
2
2
Cl )
3
00 MHz or 500 MHz equipped with a BBO-ATMA 5 mm probe
or on a Bruker Avance III 400 MHz. The NMR samples were
prepared in a CDCl or CDCl /THF-d8 solution with Me Si
10
◦
-1
(
lit., 315 C); nmax(film)/cm 2942, 1760, 1710, 1448, 1119, 966,
25; d (500 MHz; CDCl /THF-d8; Me Si) 0.83 (3 H, s), 0.87
3 H, s), 0.88 (3 H, s), 0.89 (3 H, s), 0.94 (3 H, s), 0.94 (3 H, s)
.99 (3 H, s), 2.31–2.45 (2 H, m, 2-H ), 3.86 (1 H, s, 19a-H); d
125 MHz; CDCl /THF-d8; Me Si) 12.6, 14.3, 15.4, 18.6, 19.9,
9
(
0
(
H
3
4
3
3
4
as internal standard. Chemical shifts (d) are given in ppm and
coupling constants are presented in Hz. Mass spectral analysis
was performed by direct injection on a Thermo Finnigan PolarisQ
GC/MS Benchtop Ion Trap equipped with a direct insertion
probe. Single-crystal X-ray diffractometry analysis was made on a
Bruker-Nonius Kappa Apex II CCD diffractometer using graphite
2
C
3
4
2
3
2
0.6, 22.8, 24.7, 25.6, 25.7, 27.0, 27.7, 31.0, 31.5, 32.1, 32.7, 33.0,
5.3, 36.1, 38.9, 39.1, 39.6, 45.1, 45.7, 46.2, 49.7, 54.0, 84.8, 178.4,
16.0; m/z (EI) 454 (M , 39%), 436 (14), 327 (15), 203 (24), 190
+
(100), 134 (32), 119, (38), 91 (37).
˚
monochromated Mo Ka radiation (l= 0.71073 A). The structures
were solved by direct methods and conventional Fourier synthesis
3b-Hydroxy-18a-olean-28,19b-olide 9. Obtained from be-
(
SHELXS-97). The refinement of the structures was made by full
tulinic acid 8, under the above described reaction conditions. TLC
analysis after 30 h of reaction showed spots corresponding to the
starting compound, the product 9 and traces of a highly apolar
by-product. There was a 79% conversion of betulinic acid 8, as
calculated by integration of the 29-Ha and 19a-H signals of 8 and
2
matrix least-squares on F (SHELXL-97). All non-H-atoms were
refined anisotropically. The H atoms positions were initially placed
at idealized calculated positions and refined with isotropic thermal
factors while allowed to ride on the attached parent atoms using
SHELXL-97 defaults.
1
9, respectively, in the H NMR spectrum of the crude mixture. The
main product 9 was isolated by flash column chromatography on
◦
SiO
2
using CHCl
3
/petroleum ether 40–60 C 80:20 (v:v) as eluent,
General experimental procedure for the Bi(OTf)
Wagner-Meerwein rearrangement on terpenes
3
·xH
2
O-catalyzed
◦
and isolated as a white solid in 66% yield. Mp 335–337 C (from
13
◦
-1
n-hexane/CH
1764, 1446, 1387, 1025, 969; d
2
Cl
2
) (lit., 338–340 C); nmax(film)/cm 3424, 2938,
(400 MHz; CDCl ; Me Si) 0.76 (3
H, s), 0.84 (3 H, s), 0.87 (3 H, s), 0.91 (3 H, s), 0.95 (3 H, s), 0.97
To a solution of betulin 1 (44.2 mg, 0.10 mmol) in CH
2
Cl
O (3.6 mg, 0.005 mmol) was added. After
h under magnetic stirring at reflux temperature, the reaction
2
H
3
4
(
3
5 mL), Bi(OTf)
3
·xH
2
(3 H, s), 1.03 (3 H, s), 3.20 (1 H, dd, J 11.2 and 4.9, 3a-H), 3.93 (1
was completed as verified by TLC control. The reaction mixture
was concentrated under reduced pressure and the resulting residue
H, s, 19a-H); d
C
(100 MHz; CDCl
3
; Me Si) 13.7, 15.4, 15.6, 16.5,
4
18.2, 20.9, 24.0, 25.6, 26.6, 27.4, 27.9, 28.0, 28.8, 32.0, 32.4, 33.6,
This journal is © The Royal Society of Chemistry 2009
Org. Biomol. Chem., 2009, 7, 508–517 | 515

View Online
3
8
2
3.8, 36.1, 37.3, 38.9, 39.0, 40.0, 40.6, 46.1, 46.8, 51.3, 55.6, 79.0,
6.0, 179.8; m/z (EI) 457 [(M + 1) , 4%], 438 (10), 423 (4), 395 (7),
04 (13), 189 (25), 119, (56), 91 (100).
A-neo-5b-methyl-25-nor-18a-olean-9(10)-ene-28,19b-olide 16.
Obtained from betulinic acid 8 in 92% yield, after 16 h under
+
◦
the above described reaction conditions. Mp 185–187 C (from
-
1
n-hexane/acetone); nmax(film)/cm 2951, 1763, 1451, 1372, 1156,
115, 1048; d (400 MHz; CDCl ; Me Si) 0.74 (3 H, s), 0.79 (3
H, s), 0.89 and 0.94 (each 3 H, 2d, J 6.6, 23-CH and 24-CH ),
.94 (3 H, s), 1.00 (3 H, s), 1.03 (3 H, s), 3.96 (1 H, s, 19a-H); d
100 MHz; CDCl ; Me Si) 15.3, 17.9, 22.8, 23.0, 23.9, 25.5, 25.6,
Clov-2-en-9a-ol 11. Obtained from (-)-caryophyllene oxide 10
1
H
3
4
after 10 minutes, under the above described reaction conditions.
The product was purified by flash column chromatography on
SiO
3
3
0
C
2
using toluene/diethyl ether 95:5 (v/v) as eluent and isolated
(
3
4
◦
34
as a white solid in 60% yield. Mp 77–80 C (from acetone) (lit.,
25.7, 26.0, 26.5, 27.5, 28.5, 28.7, 29.3, 29.8, 31.8, 32.3, 33.6, 37.1,
◦
-1
7
9–80 C); nmax(film)/cm 3373, 3030, 2947, 1468, 1359, 983; d
300 MHz; CDCl ; Me Si) 0.94 (3 H, s), 0.95 (3 H, s), 1.06 (3 H,
s), 3.35 (1 H, m, 9b-H), 5.26 (1 H, d, J 5.6), 5.34 (1 H, d, J 5.6);
H
3
7.4, 40.0, 40.2, 42.8, 46.4, 46.6, 59.1, 86.0, 130.5, 142.6, 179.8;
(
3
4
+
m/z (EI) 438 (M , 70%), 423 (40), 395 (100), 204 (60), 189 (46),
1
3
59 (51), 119, (41), 105 (36).
Compound 16 could also be obtained directly from methyl
b-hydroxylup-20(29)-en-28-oate 18, after 22 h, under the above
d
3
5
9
C
(75 MHz; CDCl
3
; Me Si) 21.2, 24.9, 27.3, 28.3, 32.8, 33.4, 33.6,
4
+
4.2, 35.4, 47.9, 49.6, 49.9, 74.4, 136.4, 138.9; m/z (EI) 220 (M ,
%), 205 (41), 203 (100), 187 (56), 161 (98), 131 (17), 119, (19),
3 (10).
described reaction conditions. The product was purified by flash
column chromatography on SiO using toluene/diethyl ether 95:5
v/v) as eluent and isolated as a white solid in 82% yield.
2
(
General experimental procedure for the Bi(OTf)
dehydratation and double Wagner-Meerwein rearrangement
on terpenes
3
·xH
2
O promoted
A-neo-18a-olean-3(5)-en-28,19b-olide 17. Obtained from be-
tulinic acid 8, under the above described reaction conditions.
TLC analysis after 9 h of reaction showed complete conversion
of the starting compound, and two spots corresponding to more
To a solution of betulin 1 (44.2 mg, 0.10 mmol) in CH
Bi(OTf) O (14.4 mg, 0.02 mmol) was added. After 40 h
under magnetic stirring at reflux temperature, the reaction was
completed as verified by TLC control. The reaction mixture was
concentrated under reduced pressure and the resulting residue
dissolved in diethyl ether (50 mL). The organic phase was washed
2
2
Cl (5 mL),
1
3
·xH
2
apolar products. H NMR analysis of crude mixture after work-
up showed a 77:23 ratio of compounds 9 and 17. Product 17
was isolated by flash column chromatography on SiO
2
using
◦
CHCl
3
/petroleum ether 40–60 C 80:20 (v:v) as eluent, as a white
solid in 17% yield. Recrystallization from n-hexane/CH
2
Cl
2
at
with NaHCO
3
(10% aq), water, dried with anhydrous Na
2
SO ,
4
room temperature gave colourless single crystals suitable for X-ray
◦
13
and concentrated under reduced pressure to give 19b,28-epoxy-A-
neo-18a-olean-3(5)-ene 12 as a white solid (41.5 mg, 98% yield).
Mp 205–208 C (from acetonitrile/acetone) (lit., 208–211 C);
crystallography. Mp 292–294 C (from n-hexane/CH
2
2
Cl
91–293 C); nmax(film)/cm 2939, 1758, 1451, 1380, 1123, 969; d
400 MHz; CDCl ; Me Si) 0.83 (3 H, s), 0.86 (3 H, d, J 0.6), 0.92
and 0.98 (each 3 H, 2d, J 6.8, 23-CH and 24-CH ), 0.96 (3 H, s),
.97 (3 H, s), 1.03 (3 H, s), 2.64 (1 H, sept, J 6.8, 4-H), 3.96 (1
H, s, 19a-H); d (100 MHz; CDCl ; Me Si) 13.6, 14.1, 19.1, 19.7,
2
) (lit.,
◦
-1
H
◦
13
◦
(
3
4
max(film)/cm- 2928, 1455, 1380, 1363, 1040; d
CDCl ; Me Si) 0.80 (3 H, s), 0.86 (3 H, d, J 0.7), 0.87 (3 H,
s), 0.92 and 0.98 (each 3 H, 2d, J 6.8, 23-CH and 24-CH ), 0.94
3 H, s), 1.04 (3 H, s), 2.65 (1 H, sept, J 6.8, 4-H), 3.45 (1 H, d,
1
(400 MHz;
n
H
3
3
3
4
0
3
3
C
3
4
(
2
3
1
1.3, 21.8, 23.6, 24.0, 25.6, 26.3, 26.6, 27.4, 28.2, 28.8, 32.0, 32.4,
J 7.8, 28-H
a
), 3.56 (1 H, s, 19a-H), 3.80 (1 H, dd, J 7.8 and 1.1,
2.4, 33.6, 36.5, 39.7, 40.8, 42.3, 46.2, 46.7, 49.8, 50.3, 86.0, 136.5,
+
2
2
3
1
1
8-H
b
); d
C
(100 MHz; CDCl ; Me Si) 13.4, 14.3, 19.2, 19.8, 21.3,
3
4
39.7, 179.9; m/z (EI) 439 [(M + 1) , 8%], 423 (12), 395 (97), 349
1.9, 23.7, 24.6, 26.3, 26.4, 26.5, 26.8, 27.4, 28.8, 32.6, 32.8, 34.7,
6.3, 36.8, 40.6, 40.8, 41.5, 42.2, 46.9, 49.9, 50.1, 71.3, 88.0, 136.2,
39.9; m/z (EI) 425 [(M + 1) , 31%], 409 (12), 381 (100), 259 (15),
(5), 285 (8), 259 (21), 135, (38), 121 (100).
+
Procedure for the lactonization of oleanonic acid 13. To a
solution of oleanonic acid 13 (91.4 mg, 0.20 mmol) in CH
2
Cl
2
75 (10), 161 (22), 121, (28), 95 (12).
(
10 mL), Bi(OTf) O (29.1 mg, 0.04 mmol) was added.
3
·xH
2
Compound 12 could also be obtained from allobetulin 2 in 94%
After 24 h under magnetic stirring at reflux temperature, the
reaction was completed as verified by TLC control. The reaction
mixture was concentrated under reduced pressure and the resulting
residue dissolved in diethyl ether (100 mL). The organic phase
yield, after 21 h under the above described reaction conditions.
19b,28-Epoxy-A-neo-5b-methyl-25-nor-18a-olean-9(10)-ene 15.
Obtained from betulin 1 in 96% yield, after 8 h under
the above described reaction conditions, with 50 mol% of
was washed with NaHCO
3
(10% aq), water, dried with anhy-
◦
13
Bi(OTf)
3
·xH
2
O. Mp 147–149 C (from n-hexane/CH
2
Cl
2
) (lit.,
drous Na SO , and concentrated under reduced pressure to give
2
4
◦
-1
148–150 C); nmax(film)/cm 2950, 2867, 1468, 1453, 1381, 1363,
3-oxo-18a-olean-28,13b-olide 14 as a white solid (86.8 mg, 95%
yield). Mp thermal decomposition observed at about 310
◦
1
037; d
H
(300 MHz; CDCl
3
; Me
4
Si) 0.78 (3 H, s), 0.79 (3 H, s), 0.81
and 24-CH ),
.94 (3 H, s), 1.08 (3 H, s), 3.46 (1 H, d, J 7.8, 28-H ), 3.56 (1
H, s, 19a-H), 3.81 (1 H, dd, J 7.8 and 0.8, 28-H ); d (75 MHz;
CDCl ; Me Si) 15.5, 17.9, 22.9, 23.1, 24.5, 25.7, 26.0, 26.1, 26.4,
6.5, 27.1, 27.5, 28.8, 29.3, 29.8, 32.7, 35.6, 36.3, 36.6, 37.3, 40.2,
1.0, 41.7, 42.7, 46.8, 59.1, 71.3, 87.9, 131.2, 141.8; m/z (EI) 424
C
-
1
(
3 H, s), 0.90 and 0.94 (each 3 H, 2d, J 6.6, 23-CH
3
3
(from acetonitrile/acetone); nmax(film)/cm 2958, 1757, 1703,
1447, 1393, 1260; d (400 MHz; CDCl ; Me Si) 0.84 (3 H, s),
0.89 (3 H, s), 1.00 (3 H, s), 1.04 (3 H, s), 1.09 (3 H, s), 1.15 (3 H,
d, J 0.5), 1.22 (3 H, s), 2.41 (1 H, ddd, J 15.8, 7.3 and 4.2, 2-H ),
2.54 (1 H, ddd, J 15.8, 10.3 and 7.5, 2-H ); d (100 MHz; CDCl
Me Si) 16.0, 17.8, 18.7, 19.1, 19.4, 21.1, 23.1, 26.0, 26.5, 26.6, 27.8,
0
a
H
3
4
b
C
3
4
a
2
4
b
C
3
;
4
+
(
(
M , 96%), 409 (24), 381 (97), 363 (26), 204 (54), 190 (100), 147,
39), 121 (31).
29.9, 31.5, 33.0, 34.1, 34.2, 35.2, 36.2, 36.7, 39.8, 41.3, 43.9, 45.0,
47.3, 47.4, 49.4, 54.9, 89.5, 179.1, 217.6; m/z (EI) 455 [(M + 1) ,
+
Compound 15 could also be obtained from allobetulin 2 in 97%
yield, after 20 h under the above described reaction conditions.
18%], 437 (5), 409 (4), 235 (15), 218 (38), 203 (64), 189, (100),
119 (93).
5
16 | Org. Biomol. Chem., 2009, 7, 508–517
This journal is © The Royal Society of Chemistry 2009

View Online
Acknowledgements
22 D. Thibeault, C. Gauthier, J. Legault, J. Bouchard, P. Dufour and A.
Pichette, Bioorg. Med. Chem., 2007, 15, 6144–6157.
23 D. Thibeault, J. Legault, J. Bouchard and A. Pichette, Tetrahedron
Lett., 2007, 48, 8416–8419.
J. A. R. Salvador thanks Universidade de Coimbra for financial
support. R. M. A. Pinto (SFRH/BD/18013/2004) and R. C.
Santos (SFRH/BD/23770/2005) thank Funda c¸ a˜ o para a Ci eˆ ncia
e Tecnologia for the above mentioned grants. We are grateful
to Dr. Yannick Chollet (Service Commun de RMN, Universite´
Paul Sabatier, Toulouse, France) for his help with the acquisition
and data treatment of some of the 2D NMR spectra. We also
acknowledge the Nuclear Magnetic Resonance Laboratory of the
Coimbra Chemistry Centre (www.nmrccc.uc.pt), Universidade de
Coimbra, for obtaining part of the NMR data.
2
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