Synthesis and anti-inflammatory activity of 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans propenoic acid and its ester derivatives

Article abstract of DOI:10.1016/j.bmcl.2007.07.058

Different esters of 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans propenoic acid (1), an anti-inflammatory principle of Acronychia baueri Schott (Rutaceae), were synthesized. Their topical anti-inflammatory activity was evaluated using the Croton oil ear tes

Full text of DOI:10.1016/j.bmcl.2007.07.058

Bioorganic & Medicinal Chemistry Letters 17 (2007) 5709–5714
Synthesis and anti-inflammatory activity
of 3-(40-geranyloxy-30-methoxyphenyl)-2-trans
propenoic acid and its ester derivatives
Francesco Epifano,a,* Salvatore Genovese,b Silvio Sosa,c
Aurelia Tubaroc and Massimo Curinib
a
`
Dipartimento di Scienze del Farmaco, Via dei Vestini 31, Universita ‘‘G. D’Annunzio’’,
Chieti-Pescara 66013 Chieti Scalo (CH), Italy
bDipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica,
`
Universita degli Studi di Perugia, Via del Liceo, 06123 Perugia, Italy
cDepartment of Materials and Natural Resources, University of Trieste, Via A. Valerio 6, 34127 Trieste, Italy
Received 26 June 2007; revised 11 July 2007; accepted 15 July 2007
Available online 19 August 2007
Abstract—Different esters of 3-(40-geranyloxy-30-methoxyphenyl)-2-trans propenoic acid (1), an anti-inflammatory principle of Acr-
onychia baueri Schott (Rutaceae), were synthesized. Their topical anti-inflammatory activity was evaluated using the Croton oil ear
test in mice as a model of acute inflammation. The activity of the paracetamol, guaiacol and hydroquinone esters of (1) was higher
than that of the parent compound, being similar to that exerted by indomethacin, used as reference drug.
Ó 2007 Elsevier Ltd. All rights reserved.
3-(40-Geranyloxy-30-methoxyphenyl)-2-trans propenoic
Since inflammation is a universal and physiological
acid (1) is a secondary metabolite biosynthetically
related to ferulic acid in which a geranyl chain is at-
tached to the phenolic group. It has been isolated in
1966 from the bark of Acronychia baueri Schott, an Aus-
tralian small plant belonging to the family of Rutaceae.1
Although known for four decades, only in the last 5
years this natural compound showed valuable pharma-
cological properties that have been recently reviewed.2
In particular, the ethyl ester of (1) showed valuable ton-
gue and colon cancer chemopreventive and anti-inflam-
matory effects, the latter consisting in suppressing
inducible nitric oxide synthase and the cyclooxygenase-
2 promoter activity.2
response closely related to the process of carcinogenesis,
the evaluation of topical anti-inflammatory properties of
novel natural and semi-synthetic derivatives of (1) is a
field of current and growing interest, in the search of
alternatives of steroids. Continuing our research aimed
to better define the pharmacological profile of 3-(40-ger-
anyloxy-30-methoxyphenyl)-2-trans propenoic acid (1)
and its derivatives, we evaluated the topical anti-inflam-
matory activity of compound (1) and of a series of its
semisynthetic esters with alcohols or phenols, already
known to possess in vivo anti-inflammatory actions or
related in vitro effects, such as umbelliferone (2),3 2-
hydroxynaphthoquinone (3) (also known as lawsone,4)
paracetamol (4), salicylic acid (5),5 ferulic acid (6),6
vanillic acid (7),7 guaiacol (8),8 caffeic acid (9),9 hydro-
quinone (10),10 anthraflavic acid (11)11 and naringenin
(12).12 These esters were drawn in such a structure in or-
der to obtain a synergism of anti-inflammatory action,
once the two portions of the ester would be cleaved by
exo- or endocellular esterases.
COOH
O
OMe
1
3-(40-Geranyloxy-30-methoxyphenyl)-2-trans propenoic
acid was synthesized in 98% yield as already reported.13
Esters of (1) were synthesized in two steps by conversion
of the acid into the corresponding acyl chloride by
Keywords: Anti-inflammatory activity; 3-(40-Geranyloxy-30-methoxy-
phenyl)-2-trans propenoic acid; Rutaceae; Prenyloxyphenypropanoids.
*
Corresponding author. E-mail: fepifano@unich.it
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.07.058

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F. Epifano et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5709–5714
OH
H
N
O
COOH
O
HO
HO
O
O
HO
5
4
O
2
3
OH
O
R1
OH
HO
O
OH
HO
HO
HO
10
OH
O
R2
O
12
11
6 R1 = -CH=CH-COOH; R2 = -OMe
7 R1 = -COOH; R2 = -OMe
8 R1 = -H; R2 = -OMe
9 R1 = -CH=CH-COOH; R2 = -OH
reaction with oxalyl chloride in dry diethyl ether at rt,
followed by its reaction with the alcohol or phenol
and triethylamine in dry diethyl ether at rt (Scheme 1).14
of natural and semi-synthetic compounds, often avail-
able only in limited amounts during their isolation or
semisynthesis.
Yields of ester derivatives are reported in Table 1.
Male CD-1 mice (28–32 g, Harlan Italy, Udine, Italy)
were anaesthetised with ketamine hydrochloride
(145 mg/kg, intraperitoneally; Virbac, Milan, Italy).
Inflammation was induced on the right ear (surface:
about 1 cm2) by application of 80 lg of Croton oil
(Sigma Chemical Co., St. Louis, USA) dissolved in
acetone. Control mice received only the irritant solu-
tion, whereas the others received both the irritant
and the compounds under test dissolved in acetone.
Six hours later, mice were sacrificed and a plug
(6 mm B) was excised from both the treated and un-
treated ears to quantify oedema as weight difference
between the two plugs. The anti-inflammatory activity
was expressed as percent of oedema reduction in mice
treated with the compounds under test with regard to
control mice. Oedema values, expressed as means
standard error of the mean, were analysed by one-
way analysis of variance by Dunnett’s test for multiple
comparison of unpaired data. A probability level low-
er than 0.05 was considered as significant. Experi-
ments complied with the Italian D.L. n. 116 of
January 1992 and associated guidelines in the Euro-
pean Communities Council Directive of 24 November
1986.
Crucial for the success of this synthetic scheme is the
reaction time to convert acid (1) into the corresponding
chloride that had to be rigorously of 5 min, while, for
longer reaction times, the acyl chloride went rapidly
through decomposition. Moreover, each attempt to syn-
thesize esters by direct condensation of the acid with
alcohols or phenol in the presence of different reagents,
like dicyclohexyl carbodiimide or 1,1-carbonyl diimidaz-
ole, was unsuccessful.
The topical anti-inflammatory activity of compound (1)
and its esters was evaluated as inhibition of the Croton
oil-induced ear oedema in mice.15 The main irritant
principle of Croton oil is 12-O-tetradecanoylphorbol-
13-acetate (TPA), which induces an acute inflammatory
response after single skin application. This in vivo
inflammatory model possesses the advantage of using
very small amounts of pure compounds under test,
being particularly suitable in the biological screening
COOH
COCl
a
The results on the anti-inflammatory activity of
compounds (1)–(23), administered at the dose of
0.3 lmol/cm2, are reported in Table 2, in comparison
to that of the same dose of the nonsteroidal anti-inflam-
matory drug indomethacin, used as a reference. The
natural precursor 3-(40-geranyloxy-30-methoxyphenyl)-
2-transpropenoicacid(1)induced41%oedemainhibition,
being slightly less active than indomethacin, which
reduced the oedematous response by 62% at the same
dose level (0.3 lmol/cm2). It is noteworthy that, at
0.3 lmol/cm2, the activity of (1) is higher than that of
the well-known nonsteroidal anti-inflammatory drug
GerO
GerO
OMe
OMe
b
COOR(Ar)
GerO
OMe
Scheme 1. Reagents and conditions: (a) (COCl)2, dry Et2O, rt 5 min;
(b) ROH (ArOH), Et3N, dry Et2O, rt 40 min.

F. Epifano et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5709–5714
Table 1. Synthesis of ester derivatives of acid 1
5711
Substrate
Product
Yielda (%)
O
O
O
O
2
65
GerO
OMe
13
O
O
O
O
3
95
GerO
OMe
14
H
N
O
O
O
4
90
GerO
GerO
OMe
OMe
15
O
O
Methyl salicylate
81
COOMe
16
COOMe
O
O
Methyl ferulate
63
OMe
GerO
OMe
17
O
COOMe
O
Methyl vanillate
80
OMe
OMe
GerO
GerO
OMe
OMe
18
O
O
8
87
19
(continued on next page)

5712
F. Epifano et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5709–5714
Table 1 (continued)
Substrate
Product
Yielda (%)
COOMe
O
OGer
O
9
36
O
GerO
OMe
OMe
O
20
OGer
OMe
O
O
O
10
69
O
GerO
OMe
21
OGer
OMe
O
O
O
11
44
O
O
O
GerO
22
OMe
OGer
O
OMe
GerO
MeO
O
O
O
12
31
GerO
O
O
O
23
MeO
O
a Yields of pure isolated product fully characterized by IR, GC-MS, 1H NMR and 13C NMR.
paracetamol (4) (41% and no significant oedema reduc-
tion, respectively). Among the alcohol precursors of
esters (2)–(12), only compounds (2)–(7), (11) and (12)
provoked significant inhibition of oedema, which ranged
from 13% to 43%, while compounds (4), (8), (10) and
(12) were almost inactive in our in vivo model. Consid-
ering the semisynthetic esters, all the compounds
induced a significant oedema reduction, which ranged
from 29% to 57%. In particular, esters (15), (19) and
(21), whose alcoholic portion is represented by para-
cetamol (4), guaiacol (8) or hydroquinone (10),
showed an effect (49–57% oedema inhibition) signifi-
cantly higher than that of the parent acid (1) and
comparable to that of indomethacin, even though
their phenol precursors (4), (8) and (10) were inactive,
at the administered dose. The activity of the other
esters was not significantly different from that of the
parent acid (1), except that of ester (18), which was
significantly lower (29% oedema inhibition). Neverthe-
less, the anti-inflammatory effect of the semisynthetic
esters was slightly higher than that of the relevant
alcohol precursors.
From the data reported herein it could be concluded
that esterification of 3-(40-geranyloxy-30-methoxyphe-
nyl)-2-trans propenoic acid (1) with the phenol deriv-
atives paracetamol [ester (15)], guaiacol [ester (19)] or
hydroquinone [ester (21)] slightly increases its topical
anti-inflammatory effect to a level comparable to that
of the nonsteroidal anti-inflammatory drug indometh-
acin (Fig. 1). In contrast, the anti-inflammatory activ-
ity of (1) is not affected by its esterification with the
phenol derivative salicylic acid [ester (16)] or is signif-
icantly reduced by vanillic acid esterification [ester
(18)]. Furthermore, no influence on the topical anti-
inflammatory activity of (1) is determined by its
esterification with the phenyl propanes ferulic and
caffeic acids [esters (17) and (20)] as well as with
the flavonoid naringenin [ester (23)] or the anthraqui-
none derivative anthraflavic acid [ester (22)]. It is
noteworthy that the esterification of a well-established
nonsteroidal anti-inflammatory drug such paraceta-
mol, inactive at the topically administered dose, ex-
erts an antioedematous effect similar to that of
indomethacin.

F. Epifano et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5709–5714
5713
Table 2. Anti-inflammatory activity of compound 1 derivatives and of
their precursors (administered dose: 0.3 lmol/cm2)
2. Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M. C.;
Menghini, L. Anticancer Agents Med. Chem. 2006, 6, 571,
and references cited herein.
3. Chen, Y. F.; Tsai, H. Y.; Wu, T. S. Planta Med. 1995,
61, 2.
4. Ali, B. H.; Bashir, A. K.; Tanira, M. O. Pharmacology
1995, 51, 356.
5. Botting, R. M. J. Physiol. Pharmacol. 2006, 57, 113.
6. Ou, S.; Kwok, K. C. J. Sci. Food Agric. 2004, 84, 1261.
7. Miles, E. A.; Zoubouli, P.; Calder, P. C. Nutrition 2005,
21, 389.
Substance
N
**. an.
Oedema (mg)
mean SE
% Reduction
Controls
30
30
10
10
6.9 0.3
4.1 0.2*
5.3 0.4*
4.3 0.6*
—
41
23
38
Compound 1
Compound 2
Compound 13
Compound 3
Compound 14
10
10
5.3 0.5*
3.9 0.3*
23
43
8. Azuma, Y.; Ozasa, N.; Ueda, Y.; Takagi, N. J. Dent. Res.
1986, 65, 53.
9. Shiratoki, K.; Ohgami, K.; Ilieva, I.; Jin, X. H.; Yoshida,
K.; Kase, S.; Ohno, S. J. Ocul. Pharmacol. Ther. 2005, 21,
298.
Compound 4
Compound 15
10
10
6.0 0.4
3.4 0.4*,**
13
51
Compound 5
Compound 16
10
10
6.0 0.2*
4.0 0.4*
13
42
10. Macedo, S. M.; Lourenco, F. L.; Borelli, P.; Fock, R. A.;
Ferreira, J. M., Jr.; Farsky, S. H. Toxicology 2006, 220,
126.
Compound 6
Compound 17
10
10
5.8 0.2*
3.9 0.3*
16
43
11. Sheu, S. Y.; Chiang, H. C. Anticancer Res. 1997, 17, 3293.
12. Yonathan, M.; Asres, K.; Assefa, A.; Bucar, F.
J. Ethnopharmacol. 2006, 108, 462.
13. Curini, M.; Epifano, F.; Genovese, S. Bioorg. Med. Chem.
Lett. 2005, 15, 5049.
Compound 7
Compound 18
10
10
5.5 0.3*
20
29
4.9 0.3*,**
Compound 8
Compound 19
10
10
6.2 0.4
3.5 0.3*,**
10
49
14. Experimental: Synthesis of esters of 3-(40-geranyloxy-30-
methoxyphenyl)-2-trans propenoic acid. General procedure.
To a solution of 3-(40-geranyloxy-30-methoxyphenyl)-2-
trans propenoic acid (N) (0.55 mmol) in anhydrous Et2O
(2.5 mL) oxalyl chloride (1.11 mmol) was added and the
resulting solution was stirred under N2 for 5 min at room
temperature. The solvent was evaporated under vacuum,
the resulting syrup was dissolved in anhydrous Et2O
(3 mL) and to this solution was added dropwise over a
Compound 9
Compound 20
10
10
6.5 0.5
4.3 0.2*
6
38
Compound 10
Compound 21
10
10
6.6 0.4
3.0 0.3*,**
4
57
Compound 11
Compound 22
10
10
5.4 0.5*
3.9 0.5*
22
43
Compound 12
Compound 23
10
10
3.9 0.3*
3.4 0.3*
43
51
period of 30 min
a solution of phenol derivative
(0.48 mmol) and Et3N (1.2 mmol) in anhydrous Et2O
(3 mL). The resulting mixture was stirred for 10 min and
the white precipitate formed was filtered under vacuum
and washed twice with Et2O (5 mL). The filtrate was then
extracted twice with a 1% solution of citric acid (10 mL),
the organic phase washed twice with a 1% solution of
NaHCO3 (5 mL), dried over anhydrous Na2SO4 and the
solvent evaporated under vacuum to yield the desired
ester.
Indomethacin
10
2.6 0.2*
62
* p < 0.05 at the analysis of variance, as compared with controls.
** p < 0.05 at the analysis of variance, as compared with compound 1.
70
*
*
60
50
40
30
20
10
0
Umbelliferyl (2E)-3-(4-{[(2E)-2,7-dimethylocta-2,6-die-
nyl]oxy}-3-methoxyphenyl)prop-2-enoate (13): White
solid; yield 65%; mp: 186–188 °C; IR (KBr): 1687,
*
*
*
1
1684 cmꢀ1; H NMR (200 MHz, CDCl3 d): 1.62 (s, 3H),
1.69 (s, 3H), 1.75 (s, 3H), 2.09–2.20 (m, 4H), 3.95 (s, 3H),
4.69–4.72 (m, 2H), 4.97–5.13 (m, 2H), 5.47–5.56 (m, 1H),
6.48 (d, 1H, J = 9.9 Hz), 6.74 (d, 1H, J = 12.4 Hz), 6.92 (d,
1H, J = 8.1 Hz) 7.15–7.29 (m, 4H), 7.54 (d, 1H,
J = 8.1 Hz), 7.73 (d, 1H, J = 9.9 Hz), 7.86 (d, 1H,
J = 12.4 Hz); 13C NMR (50 MHz, CDCl3 d) 16.5, 17.6,
25.4, 26.0, 39.4, 55.9, 65.9, 110.1, 111.6, 114.3, 115.3,
115.9, 116.7, 118.0, 119.4, 121.9, 123.6, 128.4, 130.1, 131.8,
141.6, 144.1, 144.4, 146.2, 150.7, 156.1, 158.0, 161.7, 165.3;
Anal. Calcd for C29H30O6: C, 73.40; H, 6.37; O, 20.23.
Found: C, 73.39, H, 6.34; O, 20.24.
1
4
15
8
19
10
21
IND
Compound
Figure 1. Improvement of the topical anti-inflammatory activity of (1)
(0.3 lmol/cm2) by its esterification with paracetamol [(4) and (15)],
guaiacol [(8) and (19)] or hydroquinone [(10) and (21)]; IND,
indomethacin (*p < 0.05 at the analysis of variance, as compared with
controls).
1,4-Dioxo-1,4-dihydronaphthalen-2-yl (2E)-3-(4-{[(2E)-
2,7-dimethylocta-2,6-dienyl]oxy}-3-methoxyphenyl)prop-
2-enoate (14): Yellowish solid; yield 95%; mp: 208–
;
209 °C; IR (KBr): 1705, 1695, 1685 cmꢀ1 1H NMR
(200 MHz, CDCl3 d): 1.62 (s, 3H), 1.69 (s, 3H), 1.73 (s,
3H), 2.08–2.21 (m, 4H), 3.97 (s, 3H), 4.71–4.73 (m, 2H),
4.98–5.11 (m, 2H), 5.51– 5.59 (m, 1H), 6.67 (d, 1H,
J = 12.3 Hz) 6.94–8.17 (m, 4H); 13C NMR (50 MHz,
CDCl3 d) 16.2, 17.4, 25.1, 25.6, 26.2, 39.5, 55.9, 65.9,
107.5, 111.6, 114.4, 119.8, 121.9, 123.9, 127.1, 127.3, 129.6,
131.2, 131.3, 132.8, 133.5, 134.1, 134.9, 141.6, 144.3, 147.4,
References and notes
1. Prager, R. H.; Thregold, H. M. Aust. J. Chem. 1966, 19,
451.

5714
F. Epifano et al. / Bioorg. Med. Chem. Lett. 17 (2007) 5709–5714
146.9, 150.7, 152.2, 161.8, 176.7, 183.8; Anal. Calcd for
C30H30O6: C, 74.06; H, 6.21; O, 19.73. Found: C, 74.03, H,
6.19; O, 19.70.
17.5, 25.4, 26.2, 39.4, 55.8, 55.9, 65.9, 111.6, 114.4, 114.8,
117.7, 119.9, 121.9, 123.8, 123.9, 125.0, 126.6, 128.8, 131.3,
141.7, 142.5, 144.4, 146.2, 150.8, 151.2, 165.0; Anal. Calcd
for C27H32O5: C, 74.29; H, 7.39; O, 18.33. Found: C,
74.28, H, 7.37; O, 18.35.
4-(Acetylamino)phenyl (2E)-3-(4-{[(2E)-2,7-dimethyloc-
ta-2,6-dienyl]oxy}-3-methoxyphenyl)prop-2-enoate (15):
White solid; yield 90%; mp: 223–224 °C; IR (KBr): 1685,
Methyl (2E)-3-(3,4-bis{[(2E)-3-(4-{[(2E)-3,7-dimethyl-
octa-2,6- dienyl]oxy}-3-methoxyphenyl)prop-2-enoyl]ox-
y}phenyl)prop-2-enoate (20): Yellowish solid; yield 36%;
1
1630 cmꢀ1; H NMR (200 MHz, CDCl3 d): 1.59 (s, 3H),
1.66 (s, 3H), 1.74 (s, 3H), 2.09–2.23 (m, 4H), 1.59 (s, 3H),
2.18 (s, 3H), 3.92 (s, 3H), 4.66–4.69 (m, 2H), 4.99–5.12 (m,
2H), 5.48–5.57 (m, 1H), 6.47 (d, 1H, J = 12.8 Hz), 6.88 (d,
1H, J = 6.2 Hz) 7.11–7.27 (m, 4H), 7.54 (d, 1H,
J = 6.2 Hz), 7.80 (d, 2H, J = 12.8 Hz); 13C NMR
(50 MHz, CDCl3 d) 16.1, 17.5, 25.1, 25.6, 26.2, 39.4,
55.9, 65.8, 111.8, 114.1, 116.7, 119.8, 121.9, 122.4, 122.6,
123.8, 128.4, 131.3, 134.7, 141.6, 144.4, 146.3, 146.9, 150.8,
165.7, 167.6; Anal. Calcd for C28H33O5: C, 72.55; H, 7.18;
O, 17.26. Found: C, 72.57, H, 7.17; O, 17.24.
mp: 208–210 °C; IR (KBr): 1699, 1695 cmꢀ1
;
1H NMR
(200 MHz, CDCl3 d): 1.64 (s, 6H), 1.68 (s, 6H), 1.72 (s,
6H), 2.11–2.20 (m, 8H), 3.97 (s, 6H), 3.99 (s, 3H), 4.65–
4.72 (m, 4H), 5.05–5.11 (m, 2H), 5.50–5.56 (m, 2H), 6.40–
7.82 (m, 16H); 13C NMR (50 MHz, CDCl3 d) 16.5, 17.9,
25.4, 26.0, 39.3, 51.4, 55.9, 65.9, 111.6, 114.3, 116.7, 117.8,
119.4, 121.9, 122.0, 123.7, 126.6, 128.5, 129.5, 131.8, 134.8,
136.5, 141.3, 144.4, 144.6, 146.1, 146.4, 150.7, 164.8, 164.9,
168.2; Anal. Calcd for C50H58O10: C, 73.33; H, 7.14; O,
19.54. Found: C, 73.35, H, 7.11; O, 19.56.
Methyl 2-{[(2E)-3-(4-{[(2E)-2,7-dimethylocta-2,6-die-
nyl]oxy}-3-methoxyphenyl)prop-2-enoyl]oxy}benzoate
(16): Yellow solid; yield 81%; mp: 182–183 °C; IR (KBr):
4-{[(2E)-3-(4-{[(2E)-3,7-Dimethylocta-2,6-dienyl]oxy}-
3-methoxyphenyl)prop-2-enoyl]oxy}phenyl (2E)-3-(4-{[(2E)-
3,7-dimethylocta-2,6-dienyl]oxy}-3-ethylphenyl)prop-2-
enoate (21): Bright yellow solid; yield 69%; mp: 232–233
(d) °C; IR (KBr): 1693 cmꢀ1; 1H NMR (200 MHz, CDCl3
d): 1.61 (s, 6H), 1.67 (s, 6H), 1.70 (s, 6H), 2.09–2.17 (m,
8H), 3.93 (s, 6H), 4.67–4.72 (m, 4H), 5.08–5.12 (m, 4H),
5.52–5.56 (m, 2H), 6.53–7.67 (m, 14H); 13C NMR
(50 MHz, CDCl3 d) 16.1, 17.4, 25.7, 26.3, 39.4, 55.8,
65.7, 111.8, 114.3, 116.8, 119.7, 119.8, 121.8, 123.8, 128.5,
131.5, 141.4, 144.2, 145.4, 146.2, 150.9, 165.8; Anal. Calcd
for C46H54O9: C, 77.02; H, 7.70; O, 15.28. Found: C,
77.01, H, 7.68; O,15.30.
6-{[(2E)-3-(4-{[(2E)-2,7-Dimethylocta-2,6-dienyl]oxy}-
3-methoxyphenyl)-1-methyleneprop-2-enyl]oxy}-9,10-dim-
ethylene-9,10- dihydroanthracen-2-yl (2E)-3-(4-{[(2E)-
2,7-dimethylocta-2,6-dienyl]oxy}-3- methoxyphenyl)prop-
2-enoate (22): Yellowish solid; yield 44%; mp: 252–255
(d) °C; IR (KBr): 1695 cmꢀ1; 1H NMR (200 MHz, CDCl3
d): 1.63 (s, 6H), 1.67 (s, 6H), 1.70 (s, 6H), 2.07–2.20 (m,
8H), 3.97 (s, 6H), 4.67–4.71 (m, 4H), 5.08–5.11 (m, 2H),
5.51–5.54 (m, 2H), 6.50–8.43 (m, 16H); 13C NMR
(50 MHz, CDCl3 d) 16.2, 17.6, 25.6, 26.1, 39.4, 55.9,
65.8, 111.6, 114.7, 116.7, 119.8, 120.3, 121.9, 123.8, 127.6,
128.4, 129.2, 131.3, 132.0, 137.6, 141.8, 144.4, 146.9,
150.7, 157.0, 165.7, 182.9; Anal. Calcd for C54H56O10: C,
74.98; H, 6.53; O, 18.50. Found: C, 74.95, H, 6.51; O,
18.46.
1
1698, 1695 cmꢀ1; H NMR (200 MHz, CDCl3 d): 1.67 (s,
3H), 1.69 (s, 3H), 1.75 (s, 3H), 2.10–2.18 (m, 4H), 3.98 (s,
3H), 3.99 (s, 3H), 4.68–4.72 (m, 2H), 5.06–5.09 (m, 1H),
5.50–5.53 (m, 1H), 6.54–8.08 (m, 9H); 13C NMR (50 MHz,
CDCl3 d) 16.4, 17.7, 25.7, 26.6, 27.5, 39.6, 51.4, 56.1, 67.9,
111.7, 114.2, 116.7, 119.4, 121.0, 121.9, 123.3, 123.9, 127.8,
128.6, 131.9, 132.1, 133.2, 135.2, 144.8, 146.2, 150.9, 155.0,
168.2, 168.5; Anal. Calcd for C28H32O6: C, 72.39; H, 6.94;
O, 20.66. Found: C, 72.40, H, 6.93; O, 20.68.
2-Methoxy-4-[(1E)-3-methoxy-3-oxoprop-1-enyl]phenyl
(2E)-3-(4-{[(2E)-2,7-dimethylocta-2,6-dienyl]oxy}-3-
methoxyphenyl)prop-2-enoate (17): Yellowish solid; yield
63%; mp: 159–161 °C; IR (KBr): 1695, 1692 cmꢀ1
;
1H
NMR (200 MHz, CDCl3 d): 1.62 (s, 3H), 1.69 (s, 3H), 1.75
(s, 3H), 2.11–2.20 (m, 4H), 3.92 (s, 3H), 3.94 (s, 3H), 3.97
(s, 3H), 4.68–4.71 (m, 2H), 5.09–5.11 (m, 1H), 5.49–5.53
(m, 1H), 6.51–7.89 (m, 7H); 13C NMR (50 MHz, CDCl3 d)
16.2, 17.6, 25.8, 26.9, 27.2, 39.4, 55.7, 55.9, 67.9, 111.7,
112.9, 114.0, 117.7, 118.4, 121.5, 123.6, 123.8, 123.9, 127.8,
128.5, 131.5, 132.1, 132.6, 139.2, 144.2, 144.7, 146.4, 150.5,
152.9, 164.9, 169.8; Anal. Calcd for C31H36O7: C,
71.52; H, 6.97; O, 21.51. Found: C, 71.50, H, 6.98; O,
21.50.
Methyl 4-{[(2E)-3-(4-{[(2E)-2,7-dimethylocta-2,6-die-
nyl]oxy}-3-methoxyphenyl)prop-2-enoyl]oxy}-3-meth-
oxybenzoate (18): Yellowish solid; yield 80%; mp: 162–
1
163 °C; IR (KBr): 1698, 1695 cmꢀ1; H NMR (200 MHz,
4-(5,7-Bis{[(2E)-3-(4-{[(2E)-3,7-dimethylocta-2,6-die-
nyl]oxy}-3-methoxyphenyl)prop-2-enoyl]oxy}-4-oxo-3,4-
dihydro-2H-chromen-2-yl)phenyl (2E)-3-(4-{[(2E)-3,7-
dimethylocta-2,6-dienyl]oxy}-3-methoxyphenyl)prop-2-
enoate (23): Yellowish solid; yield 31%; mp: 262–264 (d)
CDCl3d): 1.62 (s, 3H), 1.69 (s, 3H), 1.74 (s, 3H), 2.11–2.19
(m, 4H), 3.94 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 4.68–4.71
(m, 2H), 5.06–5.11 (m, 1H), 5.49–5.53 (m, 1H), 6.51–7.89
(m, 8H); 13C NMR (50 MHz, CDCl3 d) 16.5, 17.6, 25.6,
26.9, 27.3, 39.6, 51.2, 55.9, 56.0, 67.9, 111.7, 112.8, 114.0,
117.7, 121.9, 122.3, 123.6, 126.0, 127.7, 128.8, 131.5, 132.1,
144.8, 146.0, 146.2, 149.2, 150.4, 164.8, 166.2; Anal. Calcd
for C29H34O7: C, 70.43; H, 6.93; O, 22.64. Found: C,
70.41, H, 6.92; O, 22.65.
;
°C; IR (KBr): 1695, 1693 cmꢀ1 1H NMR (200 MHz,
CDCl3 d): 1.64 (s, 9H), 1.68 (s, 9H), 1.75 (s, 9H), 2.09–2.26
(m, 14H), 3.95 (s, 9H), 4.69–4.75 (m, 6H), 5.08–5.56 (m,
7H), 6.53–7.82 (m, 20H); 13C NMR (50 MHz, CDCl3 d)
16.3, 17.5, 25.6, 26.4, 39.3, 55.6, 65.9,78.5, 106.1 108.3,
111.7, 113.1, 114.5, 116.6, 116.7, 119.8, 121.6, 121.8, 123.9,
128.7, 130.0, 131.3, 135.9, 142.0, 144.4, 146.2, 150.1, 150.8,
153.5, 158.4, 165.2, 165.7, 169.3, 189.8; Anal. Calcd for
C75H84O14: C, 74.48; H, 7.00; O, 18.52. Found: C, 74.49,
H, 7.02; O, 18.51.
2-Methoxyphenyl (2E)-3-(4-{[(2E)-3,7-dimethylocta-2,6-
dienyl]oxy}-3-methoxyphenyl)prop-2-enoate (19): Orange
solid; yield 87%; mp: 145–147 °C; IR (KBr): 1696 cmꢀ1
;
1H NMR (200 MHz, CDCl3 d): 1.62 (s, 3H), 1.69 (s, 3H),
1.72 (s, 3H), 2.11–2.20 (m, 4H), 3.91 (s, 3H), 3.94 (s, 3H),
4.68–4.71 (m, 2H), 5.07–5.12 (m, 1H), 5.50–5.53 (m, 1H),
6.53–7.86 (m, 9H); 13C NMR (50 MHz, CDCl3 d) 16.2,
15. Tubaro, A.; Dri, P.; Del Bello, G.; Zilli, C.; Della Loggia, R.
Agents Actions. 1985, 17, 347.