An easy and stereoselective rearrangement of an abietane diterpenoid into a bioactive microstegiol derivative

Article abstract of DOI:10.1016/j.phytol.2010.09.001

Parvifloron D was isolated from Plectranthus ecklonii together with sugiol and mixtures of β-sitosterol and stigmasterol and ursolic and oleanolic acids. Treatment of parvifloron D [2α-(4-hydroxy)benzoyloxy-11-hydroxy-5, 7,9(11),13-abietatetraen-12-one] w

Full text of DOI:10.1016/j.phytol.2010.09.001

Phytochemistry Letters 3 (2010) 234–237
Contents lists available at ScienceDirect
Phytochemistry Letters
journal homepage: www.elsevier.com/locate/phytol
An easy and stereoselective rearrangement of an abietane diterpenoid into
a bioactive microstegiol derivative
a
a
a
a
b,
*
´
´
˜
´
´
Marıa Fatima Simoes , Patricia Rijo , Aida Duarte , Diogo Matias , Benjamın Rodrıguez
a
´
Faculdade de Farmacia da Universidade de Lisboa, iMed. UL, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal
b
´
Instituto de Quı´mica Organica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain
A R T I C L E I N F O
A B S T R A C T
Article history:
Parvifloron D was isolated from Plectranthus ecklonii together with sugiol and mixtures of
and stigmasterol and ursolic and oleanolic acids. Treatment of parvifloron D [2 -(4-hydroxy)benzoy-
loxy-11-hydroxy-5,7,9(11),13-abietatetraen-12-one] with acid-washed molecular sieves gave the
microstegiol derivative -(4-hydroxy)benzoyloxy-11
-hydroxy-4(5 ! 11),20(10 ! 5)diabeo-
5(10),6,8,13-abietatetraen-12-one in moderate yield (26%). The new microstegiol derivative
inhibited the growth of some Staphylococcus and Enterococcus species with significant MIC values
ranging from 3.91 to 7.81 g/ml.
b-sitosterol
Received 9 June 2010
a
Received in revised form 1 September 2010
Accepted 1 September 2010
Available online 17 September 2010
2
b
b
a
Keywords:
m
Plectranthus ecklonii
Labiatae
ß 2010 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
Abietanes
Rearranged abietanes
Microstegiol derivative
Acid-washed molecular sieves as catalyst
1. Introduction
and Eugster, 1978; Van Zyl et al., 2008). Compounds 2, 3 and sugiol
(4) were tested against a panel of Gram-negative and Gram-
Abietanes and rearranged abietanes are a family of naturally
occurring diterpenoids which have been isolated from a variety of
terrestrial plant sources. These compounds exhibit an array of
interesting biological activities which has generated significant
interest from the synthetic community. Microstegiol (1, Fig. 1)
(Ulubelen et al., 1992) is a rearranged abietane isolated from
several Labiatae plants belonging to the Salvia (Li et al., 2000;
Topcu and Ulubelen, 1996; Ulubelen et al., 1992, 1997) and Ajuga
(Ko¨kdil et al., 2002) genera and it has shown pharmacological
properties as an antileukemic, cytotoxic (Topcu et al., 2003) and
antibacterial agent (Kabouche et al., 2005; Ulubelen et al., 2000).
Surprisingly, only one total synthesis of the hydrocarbon
framework of microstegiol (1) and its naturally occurring 3-oxo
derivative (Chyu et al., 2005) has been reported until now (Taj et
al., 2009). In this communication, we wish to report a simple
method for transforming parvifloron D (2) (Ru¨edi and Eugster,
positive bacteria and Candida albicans, and their MIC (minimum
inhibitory concentration) values determined.
2. Results and discussion
Repeated chromatographic processes on an acetone extract of
Plectranthus ecklonii Benth. whole plant, allowed the isolation of
parvifloron D (2) together with sugiol (4) and other constituents
(Section 3.3).
Treatment of a dichloromethane solution of parvifloron D (2)
with acid-washed molecular sieves for 24 h at room temperature
gave a complex mixture of compounds. Column chromatography
allowed the isolation of 3, the main and most polar reaction
product (Section 3.4). Compound 3 had a molecular formula
C
27H30O5, as that of the starting material (2). The 1H and 13C NMR
spectra of (Table 1) were almost identical to those of
3
1978; Van Zyl et al., 2008) into the 2b-(4-hydroxy) benzoyloxy
microstegiol (1) (Ulubelen et al., 1992) and the observed
differences were consistent with the presence in the former of
a 4-hydoxybenzoyloxy group attached to the C-2 position instead
of the C-2 methylene group of the latter. The HMBC correlations
observed between the Me-20 protons and the C-5, C-6 and C-10
carbons, and between the Me-18 and Me-19 protons and the C-3,
C-4 and C-11 carbons, as well as those between the 11-OH and the
C-9, C-11 and C-12 carbons (Table 1), supported that 3 arises from
the abietane skeleton of 2 by a 4(5 ! 11),20(10 ! 5)diabeo-
rearrangement.
derivative of microstegiol (3). This method could be an easy and
stereoselective entry to other microstegiol derivatives starting
from the parviflorons, that are natural diterpenoids widely
distributed in several Plectranthus species (Abdel-Mogib et al.,
2002; Gaspar-Marques et al., 2008; Narukawa et al., 2001; Ru¨edi
* Corresponding author. Tel.: +34 915622900; fax: +34 915644853.
E-mail address: iqor107@iqog.csic.es (B. Rodrı´guez).
1874-3900/$ – see front matter ß 2010 Phytochemical Society of Europe. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.phytol.2010.09.001

[
M.F. Simo˜es et al. / Phytochemistry Letters 3 (2010) 234–237
235
18 19
4
16
group at C-11 because irradiation at
caused NOE enhancement in the signals of the H-1
and Me-18 protons ( 4.04, 1.65, 4.63 and 0.85, respectively),
whereas the signals of the H-1 , H-3 and Me-19 ( 3.11, 1.65 and
0.88, respectively) were enhanced when the H-2 proton ( 4.85)
was irradiated. Furthermore, irradiation of the C-11 hydroxyl
proton ( 4.63) produced NOE enhancement only in the signals of
the H-1 and H-3 protons.
The formation of compound such as
d
2.73 (H-3
b
b
axial proton)
, H-3a, 11-OH
O
O
15
3
12
HO 11
d
17
20
13
14
11
9
HO
10
R
1
a
a
d
R
14
9
a
d
10
8
1
8
4
5
d
b
5
20
b
19
18
a
3 starting from
1
3
2
R = H
parvifloron D (2) under acid catalysis should be rationalized as
it is outlined in Fig. 2. Compound 2 rearranges, via a C-10
carbonium ion intermediate (A) (Karanatsios et al., 1966;
Matsumoto et al., 1995), to the 4,5-seco-20(10 ! 5)abeo-abietane
B, a class of rearranged abietanes that have been found in several
Labiatae plants (Sexmero-Cuadrado et al., 1992; Li et al., 2000;
Ulubelen et al., 1997). 12-O-deprotonation of B followed by a
stereoselective attack of the 9,11-aromatic bond from the Si-face
on the 3,4-olefin produces compound 3. The total stereoselectivity
for the conversion of 2 into 3 could be attributed to the presence in
the former of a chiral centre at C-2 (Acun˜a et al., 2009).
The formation of the C-4–C-11 bond in 3 promoted by a 12-O-
deprotonation of the intermediate B may be in competition with an
alternative reaction in which a nucleophilic attack of the 11-OH on
the 3,4-olefin may produce an 8-membered cyclic ether, like in the
acid-catalyzed rearrangement of the quinone methide diterpene
fuerstion (Karanatsios et al., 1966). In the case of the reaction of
parvifloron D (2) with acid-washed molecular sieves the formation
of cyclic ether derivatives could not be excluded because the
characterization of all the reaction products was unsuccessful
(Section 3.4).
R = 4-HO-C6H4COO
R = 4-HO-C6H4COO
OH
O
H
4
Fig. 1. The structures of the diterpenoids.
The absolute configuration of 3 and the stereochemistry of its
seven-membered ring substituents were established as follows.
Obviously, the C-2 asymmetric centre must have the same absolute
stereochemistry in 2 (Ru¨edi and Eugster, 1978) and 3, and the H-2
proton of 3 is axially oriented because it showed two trans diaxial
a
(J2
(J2
= 11.8 Hz and J2
= 2.1 Hz and J2
= 12.3 Hz) and two cis axial-equatorial
= 3.7 Hz) vicinal couplings (Table 1).
,1
,1
,3
a
a
b
a
b
It is of interest to indicate that, to the best of our knowledge, this
is the first report on the transformation of an abietane diterpene
into a microstegiol derivative and this rearrangement constitutes
,3
a
a
a
Moreover, NOE experiments were in agreement with a cis spatial
relationship between the 2b-4-hydroxybenzoate and the hydroxyl
Table 1
1H and 13C NMR spectroscopic data for compound 3.a
Position
1
dC
dH
HMBC (H ! C)
33.60 t
3.11 dt (12.9,2.1), eqb H-1ac
4.04 dd (12.9, 11.8), axb H-1
C-2, C-3, C-5, C-9, C-10
C-2, C-3, C-5, C-9, C-10
C-70
b
2
3
70.22 d
47.61 t
4.85 dddd (12.3, 11.8, 3.7, 2.1), ax H-2
1.65 ddd (12.8, 3.7, 2.1), eq H-3ac
2.73 dd (12.8, 12.3), ax H-3
a
C-1, C-2, C-4, C-11, C-18, C-19
C-1, C-2, C-4, C-11, C-18, C-19
b
4
5
41.12 s
136.12 s
130.67 d
127.81 d
128.90 s
139.54 s
139.43 s
83.51 s
–
–
6
7.13 br d (7.9)
C-5, C-7, C-8, C-10
7
6.97 d (7.9)
C-5, C-6, C-8, C-9, C-14
8
–
–
9
10
11
12
13
14
15
16f
17f
18
19
20
10
–
d
205.74 s
141.25 s
141.05 d
27.14 d
20.93 q
22.08 q
–
–
7.00 t (1.2)e
C-7, C-8, C-9, C-12, C-13, C-15
C-12, C-13, C-14, C-16, C-17
C-13, C-15, C-17
3.03 septuplet of d (6.8, 1.2)
1.22 d (6.8)
1.16 d (6.8)
C-13, C-15, C-16
28.96 q
21.87 q
21.38 q
123.20 s
131.92 d
115.15 d
159.85 s
165.75 s
0.85 s, eq Me-18
0.88 s, ax Me-19
2.42 s
C-3, C-4, C-11, C-19
C-3, C-4, C-11, C-18
C-5, C-6, C-10
–
20,60
30,50
40
7.98 d (8.8)
C-10, C-30, C-40, C-70
C-10, C-20, C-40
6.86 d (8.8)
g
70
–
a
In CDCl3 solution, at 500 MHz (1H) and 125MHz (13C); chemical shifts are expressed in ppm and J values (Hz) are given in parentheses.
b
c
d
e
f
ax and eq designate axial and equatorial hydrogen, respectively, and for positions 18 and 19 axial or equatorial methyl substituent.
The H-1
a
and H-3
a
d
equatorial protons showed a W-type coupling (J = 2.1 Hz).
4.63 s, that showed HMBC correlations with the C-9, C-11 and C-12 carbons.
Hydroxyl proton at
The H-14 proton is long-range coupled with both H-6 and H-15 protons (J = 1.2 Hz).
For these positions, the numbering system is interchangeable.
g
Hydroxyl proton at
d 5.74 br.

[
M.F. Simo˜es et al. / Phytochemistry Letters 3 (2010) 234–237
Fig. 2. Formation of compound 3 from parvifloron D (2).
the experimental evidence of the biogenesis of the microstegiol
skeleton.
(Perkin-Elmer Spectrum One spectrophotometer). UV: in MeOH
solution (Perkin-Elmer Lambda 2 UV/vis spectrophotometer). 1H
and 13C NMR spectra (at 500 and 125 MHz, respectively): in CDCl3
solution at room temperature (Varian SYSTEM 500 MHz spec-
trometer). 1H and 13C NMR chemical shifts are reported with
The use of acid-washed molecular sieves for obtaining
4(5 ! 11),20(10 ! 5) diabeo-rearranged derivatives from suitable
abietane diterpenoids looks particularly attractive due to the
noteworthy simplification of the experimental procedure, the
avoidance of more acidic promoters (Karanatsios et al., 1966;
Matsumoto et al., 1995; Sexmero-Cuadrado et al., 1992; Simo˜es et
al., 1986) and the mildness of the reaction conditions.
Compounds 2–4 were tested for their antibacterial activity
against Staphylococcus and Enterococcus species, including methi-
cillin- and vancomycin-resistant strains. Most of the strains tested
in this work were not used in the antibacterial activity studies on
some abietanes reported previously (Kabouche et al., 2005;
Ulubelen et al., 2000).
respect to the residual CHCl3 signal (
d 7.26) and to the solvent
signals ( 77.00), respectively. EIMS: positive mode (Hewlett–
d
Packard Model 5973 instrument, 70 eV). HRESIMS: Agilent 6520
Accurate-Mass QTOF LC/MS apparatus. Merck silica gel (70–230
mesh and 230–400 mesh, for gravity flow and flash chromatogra-
phy, respectively) was used for column chromatography. Merck
5554 Kieselgel 60 F254 sheets were used for thin-layer chro-
matographic (TLC) analysis.
3.2. Plant material
Parvifloron D (2), previously reported as an antibacterial
metabolite from P. ecklonii (Nyila et al., 2009), inhibited E. faecalis
ATCC 51299 (low-VRE: vancomycin resistant Enterococcus) and E.
P. ecklonii Benth. was grown in the Hortum of the Faculty
of
Pharmacy (Lisbon University, Portugal) from seeds
provided by the Herbarium of the National Botanic Garden of
Kirstenbosch, South Africa. Whole plants were collected in
July 1998 and voucher specimens, identified by Enrico S.
Martins, are deposited in the Herbarium of the Instituto de
Investigac¸a˜o Cientifica Tropical, Lisbon (ref. C. Marques S/No.
LISC).
faecalis FFHB with MIC values of 7.81 and 3.90
m
g/ml, respectively,
and showed lower MIC values (15.62
ATCC 43866 and CIP 106760.
mg/ml) against both S. aureus
Compound 3 was tested against Gram-negative and Gram-
positive bacteria, andCandidaalbicans. Theresultsobtained revealed
very interesting MIC values againstS. aureus ATCC6538and S. aureus
ATCC 43866 (3.90
methicillin resistant S. aureus), S. epidermis ATCC 12228, E. faecalis
ATCC 51299 (low-MRSA) and E. hirae ATCC 10541 (7.81 g/ml).
Compound 3 also showed MIC values of 31.25 g/ml against S.
aureus ATCC 700699 and S. aureus FFHB 29593 (MRSA) and showed
higher MIC values (62.50 g/ml) towards S. aureus ATCC 25923, M.
smegmatisandC. albicans. Thoughmicrostegiol(1)hasbeenreported
(Kabouche et al., 2005; Ulubelen et al., 2000) as a weak microbial
growth inhibitory compound, its derivative 3 revealed a higher
activity against six of the Gram-positive strains tested, those that
mg/ml), and against S. aureus CIP 106760 (MRSA:
3.3. Extraction and isolation
m
Dried and powdered P. ecklonii (whole plant, 7.0 kg) was
extracted with Me2CO (6 ꢀ 7 l, room temperature, 15 days).
Filtration and evaporation of the solvent under vacuum at low
temperature (40 8C) yielded a residue (284.4 g, 4.06% of dry
plant material), which was subjected to column chromatogra-
phy over silica gel (Merck, no. 7734, 3 kg), using n-hexane–
EtOAc mixtures of increasing polarity (1:0–0:1) and EtOAc–
MeOH (1:0–0:1) as eluents. Eight crude fractions were obtained,
accordingly to differences in composition, as monitored by TLC.
Successive chromatographic processes (over silica gel and using
n-hexane–EtOAc mixtures as eluents) on the initial fractions
eluted with n-hexane–EtOAc (7:3) to EtOAc (100%) yielded, in
order of chromatographic polarity, the following compounds:
m
m
gave MIC values ranges from 3.91 to 7.81
mg/ml.
The lower MIC value (62.5 g/ml) exhibited by sugiol (4) was
m
against E. faecalis FFHB 427483, which is in agreement with a very
low antibacterial activity reported previously for this compound
(Politi et al., 2003; Ulubelen et al., 2000).
´
sugiol (Kupchan et al., 1969; Rodrıguez, 2003) (4, 18.9 mg,
0.00027%, on dry plant material), a mixture of -sitosterol
and stigmasterol (1.61 g, 0.023%), a mixture of ursolic and
oleanolic acids (105 mg, 0.0015%) and parvifloron
3. Experimental
b
3.1. General experimental procedures
D
(2, 19.2 g, 0.27%) (Ru¨ edi and Eugster, 1978; Gaspar-Marques
et al., 2008).
Melting-points, uncorrected: Kofler block. Optical rotations: in
CHCl3 solution (Perkin-Elmer 241 MC polarimeter). IR: in KBr

M.F. Simo˜es et al. / Phytochemistry Letters 3 (2010) 234–237
237
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All the isolated compounds were identified by their physical
(mp, [
]D) and spectroscopic (IR, 1H and 13C NMR and mass
a
spectra) data.
Chyu, C.-F., Lin, H.-C., Kuo, Y.-H., 2005. New abietane and seco-abietane diter-
penes from the roots of Taiwania cryptomerioides. Chem. Pharm. Bull. 53,
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3.4. Preparation of compound 3 from parvifloron D (2)
To a solution of 2 (351 mg) in CH2Cl2 (30 ml) was added acid-
´
Gaspar-Marques, C., Rijo, P., Simo˜es, M.F., Duarte, M.A., Rodrıguez, B., 2006.
Abietanes from Plectranthus grandidentatus and P. hereroensis against
methicillin- and vancomycin-resistant bacteria. Phytomedicine 13,
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˚
washed 4 A molecular sieves AW-300 (12.5 g, purchased from
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and phenolics from Plectranthus strigosus, bioactivity screening. Nat. Prod. Res.
22, 167–177.
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2005. Components and antibacterial activity of the roots of Salvia jaminiana.
Fitoterapia 76, 450–452.
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Acta 49, 1151–1172.
Ko¨kdil, G., Topcu, G., Go¨ren, A., Voelter, W., 2002. Steroids and terpenoids from Ajuga
relicta. Z. Naturforsch. 57b, 957–960.
Aldrich, 1.6 mm pellets) and the mixture was left at room
temperature until disappearance of the initial red colour of the
solution (24 h). Then, after filtration and washing of the molecular
sieves with CH2Cl2 (3 ꢀ 15 ml), the organic solution was evaporated
to dryness yielding 180 mg of a mixture of several compounds (TLC).
Flash column chromatography [silica gel, n-hexane–EtOAc (2:1) as
eluent] gave 91.2 mg of pure 3 (26% yield, most polar compound).
Kupchan, S.M., Karim, A., Marcks, C., 1969. Tumor inhibitors. XLVIII. Taxodione and
taxodone, two novel diterpenoid quinone methide tumor inhibitors from
Taxodium distichum. J. Org. Chem. 34, 3912–3918.
3.5. Compound characterization
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prionitis. J. Nat. Prod. 63, 139–141.
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ecklonii constituents. Nat. Prod. Commun. 4, 1177–1180.
Politi, M., Braca, A., Tommasi, N., Morelli, I., Manunta, A., Battinelli, L., Mazzanti, G.,
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drupacea. Planta Med. 69, 468–470.
Rodrı´guez, B., 2003. 1H and 13C NMR spectral assignments of some natural abietane
diterpenoids. Magn. Reson. Chem. 41, 741–746.
2
b
-(4-Hydroxy)benzoyloxy-11
diabeo-5(10),6,8,13-abietatetraen-12-one (3): Fine yellowish nee-
dles from EtOAc–n-hexane, mp 192–195 8C; [
20 +271.2 (c 0.229,
CHCl3); UV (MeOH), max nm (log ): 336 (3.89); IR (KBr), nmax
b
-hydroxy-4(5!11),20(10!5)
a
]
D
l
e
3402, 2965, 2929, 2868, 1706, 1679, 1655, 1609, 1592, 1513, 1466,
1372, 1312, 1275, 1165, 1097, 1027, 950, 852, 773, 698 cmꢁ1; EIMS
70 eV, m/z (rel. int.) 434 [M]+ (1), 296 (76), 240 (11), 227 (100), 121
(27), 93 (5); HRESIMS: m/z 435.2170 [M + H]+ (calc. for C27H31O5:
435.2166). For 1H and 13C NMR spectra (see Table 1).
3.6. Biological evaluation
Ru¨ edi, P., Eugster, C.H., 1978. Leaf-gland pigments: 6 novel p-quinomethanes of
the abietane series from Plectranthus parviflorus Willd. Helv. Chim. Acta 61,
709–715.
Sexmero-Cuadrado, M.J., de la Torre, M.C., Lin, L.-Z., Cordell, G.A., Rodrı´guez, B.,
Perales, A., 1992. Cyclization reactions of the o-naphthoquinone diterpene
The strains tested in this work were selected from strain
collections of the Microbiology Laboratory, Faculty of Pharmacy
(University of Lisbon). The analyses were performed as described
previously (Gaspar-Marques et al., 2006). The antimicrobial activity
of the solvent (DMSO) was evaluated and ampicillin, methicillin and
vancomycin were used as control antibiotics. Vancomycin showed
aethiopinone.
4722–4728.
A
revision of the structure of prionitin. J. Org. Chem. 57,
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Simo˜es, F., Michavila, A., Rodrı´guez, B., Garcı´a-Alvarez, M.C., Hasan, M., 1986. A
quinone methide diterpenoid from the root of Salvia moorcraftiana. Phytochem-
istry 25, 755–756.
MIC values in the range 1.95–7.81
mg/ml against Staphylococcus
Taj, R.A., Abhayawardhana, A., Green, J.R., 2009. Cyclohepta[de]naphthalenes and
the rearranged abietane framework of microstegiol via Nicholas reaction
chemistry. Synlett 292–296.
strains and 0.97–62.50
mg/ml for Enterococcus strains.
Topcu, G., Ulubelen, A., 1996. Abietane and rearranged abietane diterpenes from
Salvia montbretii. J. Nat. Prod. 59, 734–737.
Acknowledgements
Topcu, G., Altiner, E.N., Gozcu, S., Halfon, B., Aydogmus, Z., Pezzuto, J.M., Zhou, B.-N.,
Kingston, D.G.I., 2003. Studies on di- and triterpenoids from Salvia staminea
with cytotoxic activity. Planta Med. 69, 464–467.
Ulubelen, A., Topcu, G., Tan, N., Lin, L.-J., Cordell, G.A., 1992. Microstegiol, a rear-
ranged diterpene from Salvia microstegia. Phytochemistry 31, 2419–2421.
Ulubelen, A., So¨nmez, U., Topcu, G., 1997. Diterpenoids from the root of Salvia
sclarea. Phytochemistry 44, 1297–1299.
This work was supported by funds from the Spanish Ministerio
´
de Ciencia e Innovacion, grant no. CTQ2009-10343, from the
´
´
Consejerıa de Educacion de la Comunidad de Madrid (Project
CAPOTE-S2009/PPQ-1752) and from the Portuguese Fundac¸a˜o para
ˆ
a Ciencia e a Tecnologia (FCT-MCTES to iMed.UL and as a PhD grant
¨
Ulubelen, A., Oksu¨z, S., Kolak, U., Bozok-Johansson, C., C¸elik, C., Voelter, W., 2000.
no. SFRH/BD/19250/2004).
Antibacterial diterpenes from the roots of Salvia viridis. Planta Med. 66, 458–
462.
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