Enantioselective synthesis and vanilloid activity evaluation of 1-β-(p-methoxycinnamoyl)polygodial, an antinociceptive compound from Drymis winteri barks

Article abstract of DOI:10.1016/j.bmcl.2007.10.001

A simple strategy is outlined for preparation of the antinociceptive 1-β-(p-methoxycinnamoyl)polygodial, isolated from Drymis winteri barks. The synthesized compound showed vanilloid activity.

Full text of DOI:10.1016/j.bmcl.2007.10.001

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 17 (2007) 6444–6447
Enantioselective synthesis and vanilloid activity evaluation
of 1-b-(p-methoxycinnamoyl)polygodial, an antinociceptive
compound from Drymis winteri barks
Carmela Della Monica,a Luciano De Petrocellis,b Vincenzo Di Marzo,c
Raffaella Landi,a Irene Izzoa and Aldo Spinellaa,*
a
`
Dipartimento di Chimica, Universita di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy
bEndocannabinoid Research Group, Istituto di Cibernetica, CNR, Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy
cEndocannabinoid Research Group, Istituto di Chimica Biomolecolare del CNR, Via Campi Flegrei 34, 80078 Pozzuoli, NA, Italy
Received 31 August 2007; revised 28 September 2007; accepted 1 October 2007
Available online 5 October 2007
This work is dedicated to the memory of Prof. G. Sodano.
Abstract—A simple strategy is outlined for preparation of the antinociceptive 1-b-(p-methoxycinnamoyl)polygodial, isolated from
Drymis winteri barks. The synthesized compound showed vanilloid activity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Drymis winteri is a plant (Winteraceae) used in folk
medicine, in many countries of South America, for treat-
ment of inflammatory and dolorous processes.1 Re-
cently it has been shown that some drimane
compounds, isolated from D. winteri barks, such as
polygodial (1), drimanial (2) and 1-b-(p-methoxycinna-
moyl)polygodial (3), exhibit significant antinociceptive
activity.2 Moreover, antifungal properties, well known
for polygodial 1, were also recorded for its cinnamoyl
derivative 3.3
O
CHO
O
CHO
CHO
CHO
MeO
1
OH
2
O
I
1
O
CHO
CHO
9
1
I
4
Recent studies have been focused only on compounds 1
and 2, showing evidences for the involvement of gluta-
matergic4 and vanilloid5,6 receptors in their antinocicep-
tive activity. These activities have stimulated our interest
to afford a synthetic strategy for 3 in order to assay its
vanilloid activity. In the course of our studies on the
vanilloid activity of terpenoidic dialdehydes, we have re-
cently prepared 1(R)-hydroxypolygodial (4) using a syn-
thetic strategy (Scheme 1) involving a stereoselective
Diels–Alder reaction of a chiral diene 5 prepared using
MeO
3
The synthesis of 3 was first investigated starting from
1(R)-hydroxypolygodial (4). However, our initial efforts
did not allow the installation of the cinnamoyl moiety at
1-position in effective and convenient way. In fact, a
preliminary study on direct acylation showed that
1-hydroxypolygodial (4), under typical acylation condi-
tions, gave rise to a complex mixture of reaction prod-
ucts (Scheme 2). The main obtained products were the
enolacyl derivatives 88 (90%) and 10 (80%), respectively,
using commercially available compounds 7 and 9. Very
low yields of the desired acylated product at C-1 were
achieved. In both cases, enolization at C-9 and subse-
a
Corey–Bakshi–Shibata oxazaborolidine-mediated
reduction.7
Keywords: Polygodial; Drymis winteri; Antinociception; Vanilloid
activity.
*
Corresponding author. Fax: +39 089969603; e-mail: spinella@unisa.it
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.10.001

C. Della Monica et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6444–6447
6445
HO
conditions, which caused acetonide migration to afford
primary alcohol 13.
OTBS
OH
TBSO
CHO
OH
CHO
O
O
5
6
4
OH
Scheme 1. Synthetic strategy for the preparation of 1(R)-hydroxypo-
lygodial (4).
13
OMe
The transformation of 12 into the desired ester 14 was
quantitatively carried out by treatment of 12 with
p-methoxycinnamic acid (7) in the presence of DCC
and DMAP (Scheme 4). Deprotection of the acetonide
moiety was initially performed using catalytic amount
of p-toluenesulfonic acid (p-TsOH) in THF/MeOH.
However, this reaction was not very clean, affording a
mixture containing the expected ester 159 (33%) together
with isomeric products, derived by migration of the acyl
moiety, respectively, to the alcohol groups at C-11 and
at C-12. To circumvent this problem, the acetonide 14
was finally deprotected using pyridinium p-toluenesulfo-
nate (PPTS) in THF/MeOH to afford 15 along with
unreacted starting acetonide. The recovered 14 was ex-
posed again to the deprotection conditions affording
15 in 79% overall yield. Oxidation of primary alcohols
in 15 to the corresponding dialdehyde using Swern con-
ditions completed the synthesis of 1-b-(p-methoxycinna-
moyl)polygodial (3). The spectroscopic data of our
synthetic sample10 were identical with those of the natu-
ral compound.11
O
O
OH
O
OH
MeO
CHO
7
DCC, DMAP, CH2Cl2, 0 ˚C
r.t.
8
4
O
O
O
Cl
OH
CHO
9
NEt3, DMAP, CH2Cl2, 0 ˚C
r.t.
10
Scheme 2. Direct acylation of 1-hydroxypolygodial (4).
Finally, the synthesized compound was tested for its
vanilloid activity. Furthermore, in order to evaluate
the influence of some structural requirements, the vanil-
loid activity of 3 was compared with those of 1(R)-
hydroxypolygodial (4) and diol 15 (Table 1).
quent acylation of the resulting enol was faster than
acylation at C-1, even controlling reaction times and
conditions.
Therefore, the synthetic scheme, previously developed to
obtain 4, was modified starting from diol 6, as shown in
Scheme 3.
O
Before transformation of the hydroxy group at C-1 of 6,
it was required to install appropriate protecting groups
at diol moiety. Thus, both primary hydroxy groups were
protected by preparation of acetonide 11 (93% yield).
Removal of TBS protecting group (TBAF, 88% yield)
furnished alcohol 12. Careful manipulation of com-
pound 12 was needed because of its lability in acidic
O
O
O
a
b
12
MeO
14
O
HO
O
OH
O
O
OTBS
OH
O
O
c
3
b
a
6
MeO
15
11
12
Scheme 4. Reagents and conditions: (a) 7, DCC, DMAP, CH2Cl2,
0 ꢁC ! rt, 12 h, quant; (b) PPTS (6%), THF/MeOH (1:1), 2· 30 h,
79%; (c) DMSO, (COCl)2, NEt3, ꢀ78 ꢁC ! rt, 86%.
Scheme 3. Reagents and conditions: (a) (CH3O)2C(CH3)2, p-TsOH, rt,
2 h, 93%; (b) TBAF, THF, 0 ꢁC ! rt, 16 h, 88%.

6446
C. Della Monica et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6444–6447
Table 1. Vanilloid activity assays for compounds 3, 4, and 15 (1 lM)
5. Andre, E.; Ferreira, J.; Malheiros, A.; Yunes, R. A.;
Calixto, J. B. Neuropharmacology 2004, 46, 590.
OR1 R2
´
6. Andre, E.; Campi, B.; Trevisani, M.; Ferreira, J.; Malhei-
R3
ros, A.; Yunes, R. A.; Calixto, J. B.; Geppetti, P. Biochem.
Pharm. 2006, 71, 1248.
7. Della Monica, C.; Della Sala, G.; Izzo, I.; De Petrocellis,
L.; Di Marzo, V.; Spinella, A. Tetrahedron 2007, 63, 6866.
8. Compound 8: Rf = 0.20 (30% ethyl acetate in hexane). H
1
Compound R1
R2, R3
p-Methoxycinnamoyl CHO
CHO
p-Methoxycinnamoyl CH2OH
% VAa (RA)b
NMR (CDCl3, 400 MHz): d 0.91 (3H, s, CH3), 0.96 (3H, s,
CH3), 1.00 (3H, s, CH3), 1.37 (1H, m, H-3a), 1.53 (1H,
ddd, J = 3.1, 3.1, 13.4 Hz, H-3b), 1.66 (1H, dd, J = 5.6,
11.5 Hz, H-5), 1.78–1.84 (2H, m, H2-2 overlapped), 2.44
(1H, ddd, J = 3.4, 11.4, 21.2 Hz, H-6a), 2.63 (1H, ddd,
J = 4.8, 5.6, 21.2 Hz, H-6b), 3.86 (3H, s, CH3O), 4.22 (1H,
t-like, J = 9.0 Hz, H-1), 6.34 (1H, d, J = 15.9 Hz, H-20),
6.79 (1H, dd, J = 3.4, 4.8 Hz, H-7), 6.93 (2H, d,
J = 8.8 Hz, H-60 and H-80), 7.54 (2H, d, J = 8.8 Hz, H-50
and H-90), 7.84 (1H, d, J = 15.9 Hz, H-30), 7.89 (1H, s, H-
11), 9.50 (1H, s, OHCC-8). 13C NMR (CDCl3, 62.9 MHz):
d 13.5 (CH3), 21.5 (CH3), 26.2 (CH2), 26.7 (CH2), 32.1
(CH3), 33.5 (C), 39.7 (CH2), 44.9 (C), 47.6 (CH), 55.4
(CH3), 73.4 (CH), 112.6 (CH), 114.4 (2·) (CH), 122.3 (C),
126.5 (C), 130.4 (2·) (CH), 130.9 (CH), 137.3 (C), 147.9
3
4
40.4 (22)
H
0
0
15
a Results are reported as a percent of the maximum possible absolute
effect obtained with 4 lM ionomycin.
b Residual Ca2+ influx activity after treatment with IRTX.
Vanilloid activity was evaluated by measuring the entry
of Ca2+ (the concentration of internal calcium [Ca2+
]
i
before and after the addition of test compounds) into
human embryonic kidney HEK-293 cells transfected
with the human TRPV1, a typical TRPV1-mediated
effect.12 Compound 3 caused Ca2+ influx activity in these
assays. However, this activity was only partially due to
the interaction with vanilloid receptor because calcium
mobility was not completely inhibited with the selective
TRPV1 antagonist 5-iodo-resiniferatoxin (IRTX). Com-
pounds 4 and 15 resulted not active, showing that the
presence in the molecule of dialdehyde moiety may be
important but not sufficient for the vanilloid activity.
21
(CH), 152.9 (CH), 162.1 (C), 162.9 (C), 192.3 (CH). ½aꢁD
ꢀ9.2 (c = 0.33, CHCl3). ESIMS: m/z 411 [M+H]+. Anal.
Calcd for C25H30O5: C, 73.15; H, 7.37; O, 19.49. Found:
C, 73.55; H, 7.67; O, 19.89.
9. Compound 15: Rf = 0.60 (60% ethyl acetate in petroleum
1
ether). H NMR (CDCl3, 400 MHz): d 0.90 (3H, s, CH3),
0.94 (3H, s, CH3), 1.05 (3H, s, CH3), 1.34 (1H, dd, J = 4.8,
11.4 Hz, H-5), 1.45–1.49 (2H, m, H2-3 overlapped), 1.67–
1.79 (2H, m, H2-2 overlapped), 1.95–2.13 (2H, m, H2-6
overlapped), 2.39 (1H, m, H-9), 3.71 (1H, dd, J = 6.8,
11.0 Hz, H-11a), 3.85 (3H, s, CH3O), 3.97 (1H, br d,
J = 12.3 Hz, H-12a), 4.15 (1H, br d, J = 11.0 Hz, H-11b),
4.30 (1H, br d, J = 12.3 Hz, H-12b), 4.92 (1H, dd, J = 4.9,
10.9 Hz, H-1), 5.85 (1H, m, H-7), 6.35 (1H, d, J = 15.9 Hz,
H-20), 6.91 (2H, d, J = 8.7 Hz, H-60 and H-80), 7.50 (2H, d,
J = 8.7 Hz, H-50 and H-90), 7.67 (1H, d, J = 15.9 Hz, H-
30). 13C NMR (acetone-d6, 100 MHz): d 10.7 (CH3), 22.4
(CH3), 23.8 (CH2), 26.0 (CH2), 33.3 (CH3), 33.6 (C), 40.3
(CH2), 41.2 (C), 50.5 (CH), 55.1 (CH), 55.8 (CH3), 62.2
(CH2), 66.8 (CH2), 83.5 (CH), 115.3 (2·) (CH), 117.2
(CH), 125.8 (CH), 128.1 (C), 130.9 (2·) (CH), 139.5 (C),
In conclusion, the synthesis of 1-b-(p-methoxycinna-
moyl)polygodial (3) has been accomplished starting
from chiral diene 5.7 The vanilloid activity showed by
the synthesized compound may furnish an insight into
its antinociceptivity. Further application of this strategy
to the synthesis of other biologically active compounds
for the studies of structure–activity relationship is cur-
rently underway in our laboratory.
25
145.0 (CH), 162.6 (C), 166.8 (C). ½aꢁD ꢀ42.0 (c = 1.0,
acetone). ESIMS: m/z 415 [M+H]+. Anal. Calcd for
C25H34O5: C, 72.43; H, 8.27; O, 19.30. Found: C, 72.03;
H, 8.57; O, 19.70.
Acknowledgments
10. Compound 3: Rf = 0.5 (40% ethyl acetate in petroleum
`
Financial support from Universita di Salerno and from
1
ether). H NMR (CDCl3, 400 MHz): d 0.96 (3H, s, CH3),
MIUR-COFIN 2004 ‘‘La chemorecezione gustativa:
progettazione razionale di nuove molecole, modellazi-
`
one dell’attivita biologica e applicazioni nell’industria
farmaceutica ed alimentare’’ is gratefully acknowledged.
1.01 (3H, s, CH3), 1.06 (3H, s, CH3), 1.42 (1H, dd,
J = 5.2, 11.2 Hz, H-5), 1.47–1.60 (2H, m, H2-3 over-
lapped), 1.68 (1H, dddd, J = 4.0, 11.5, 12.8, 12.8 Hz, H-
2a), 1.88 (1H, dddd, J = 3.8, 4.0, 4.0, 12.8 Hz, H-2b),
2.35–2.51 (2H, m, H2-6 overlapped), 3.34 (1H, m, H-9),
3.84 (3H, s, CH3O), 4.87 (1H, dd, J = 4.0, 11.5 Hz, H-1),
6.26 (1H, d, J = 15.9 Hz, H-20), 6.90 (2H, d, J = 8.8 Hz,
H-60 and H-80), 7.06 (1H, m, H-7), 7.48 (2H, d,
J = 8.8 Hz, H-50 and H-90), 7.62 (1H, d, J = 15.9 Hz,
H-30), 9.33 (1H, s, OHCC-8), 9.81 (1H, d, J = 2.7 Hz,
OHCC-9). 13C NMR (CDCl3, 100 MHz): d 10.6 (CH3),
22.2 (CH3), 24.1 (CH2), 24.5 (CH2), 32.6 (CH3), 32.8 (C),
39.3 (CH2), 42.3 (C), 48.9 (CH), 55.4 (CH3), 59.2 (CH),
81.5 (CH), 114.3 (2·) (CH), 115.2 (CH), 126.9 (C), 130.0
(2·) (CH), 140.4 (C), 145.4 (CH), 151.9 (CH), 161.5 (C),
References and notes
1. Houghton, P. J.; Manby, J. Ethnopharmacology 1985, 13,
89.
2. Malheiros, A.; Filho, V. C.; Schmitt, C. B.; Santos, A. R.
S.; Scheidt, C.; Calixto, J. B.; Delle Monache, F.; Yunes,
R. A. Phytochemistry 2001, 57, 103.
3. Malheiros, A.; Filho, V. C.; Schmitt, C. B.; Yunes, R. A.;
Escalante, A.; Svetaz, L.; Zacchino, S.; Delle Monache, F.
J. Pharm. Pharmaceut. Sci. 2005, 8, 335.
4. Scheidt, C.; Santos, A. R. S.; Ferreira, J.; Malheiros, A.;
Cechinel-Filho, V.; Yunes, R. A.; Calixto, J. B.
Neuropharmacology 2002, 43, 340.
25
166.4 (C), 192.3 (CH), 200.4 (CH). ½aꢁD +21.6 (c = 1.0,
acetone). ESIMS: m/z 433 [M+Na]+. Anal. Calcd for
C25H30O5: C, 73.15; H, 7.37; O, 19.49. Found: C, 72.85;
H, 7.67; O, 19.79.

C. Della Monica et al. / Bioorg. Med. Chem. Lett. 17 (2007) 6444–6447
6447
11. We thank Prof. Yunes, R. A. (Federal University of Santa
´
12. The effect of the substances on the influx of Ca2+ into cells
Catarina, Florianopolis, SC, Brazil) for providing spectral
data of natural 1-b-(p-methoxycinnamoyl)polygodial (3).
was determined by using Fluo-4 (4 lM Molecular Probes),
a selective intracellular fluorescent probe for Ca2+
.