Synthesis of collinin, an antiviral coumarin

Article abstract of DOI:10.1071/CH02177

The synthesis of collinin, an antivirus coumarin was presented. Collinin was synthesized in three steps and 24.6% overall yield from pyrogallol and propiolic acid. The coumarin nucleas 7,8-dihydroxycoumarin was made using a concentrated H₂SO₄ catalyzed Pechmann-type condensation between pyrogallol and propiolic acid under solvent free conditions at 120°C for 30 minutes. The method presented an alternative and valuable route to obtain collinin for biological test purposes.

Full text of DOI:10.1071/CH02177

CSIRO PUBLISHING
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Aust. J. Chem. 2003, 56, 59–60
Synthesis of Collinin, an Antiviral Coumarin
Massimo Curini,A,C Francesco Epifano,A Federica Maltese,A Maria Carla Marcotullio,A
Sylvia Prieto GonzalesB and Juan Carlos RodriguezB
A Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Organica, Università degli Studi,
Via del Liceo, 06123 Perugia, Italy.
B Departamento de Síntesis Química, Centro de Química Farmacéutica, Calle 200 y 21, Atabey, Playa,
P.O. Box 165 042, Ciudad de la Habana, 11600, Cuba.
C Author to whom correspondence should be addressed (fax: (+39) 0755855116; e-mail: curmax@unipg.it).
Collinin (1), a geranyloxycoumarin, has been synthesized in three steps and 24.6% overall yield from pyrogallol
(2) and propiolic acid (3).
Manuscript received: 5 September 2002.
Final version: 4 November 2002.
Collinin (1) (Diagram 1) is a geranyloxycoumarin isolated
for the first time from Flindersia maculata (Rutaceae) by
Ritchie[1] and coworkers in 1954, and from Haplophyllum
alberti-regelli (Rutaceae) by Tikhomirova and coworkers in
1977.[2] About twenty years later, collinin was also isolated
by Chen and coworkers from the root bark of Zanthoxylum
schinifolium (Rutaceae).[3–5] These latter authors showed
1-chloro-3,7-dimethyl-octa-2,6-diene using sodium ethylate
in ethanol has been reported to date.[6]
The coumarin nucleus, 7,8-dihydroxycoumarin (4)
(daphnetin), was made using a concentrated H2SO4 catalyzed
Pechmann-type condensation between pyrogallol (2) and
propiolic acid (3) under solvent-free conditions at 120˚C for
30min. Daphnetin(4)wasobtainedin59%yieldaftercrystal-
lization (Et2O). Subsequent geranylation of (4) with geranyl
bromide and K2CO3 in refluxing acetone for 5 h or NaH in
THF at 0◦C for 3 h was not selective. In both cases an equimo-
lar, inseparable mixture of 7- and 8-geranylated products was
obtained in 70 and 74% overall yield, respectively, along
with a small amount (5% yield) of the 7,8-dialkylated com-
pound. However, the 7-OH was selectively geranylated by
employing sterically-hindered amines. Reaction of (4) with
(iPr)2EtN (Hünig’s base) or 1,8-diazabicyclo[5.4.0]undec-7-
ene (DBU) in acetone at room temperature for 3 h gave the
desired 7-geranyloxy-8-hydroxy-coumarin (5) in 32 and 65%
yield, respectively. This selectivity may be explained by a
preferential hydrogen abscission by bulky amines from the
more accessible 7-OH. Finally, methylation of 8-OH with
that collinin exerted anti-platelet aggregation (50 µg mL−1
,
100%inhibition)andanti-hepatitisBvirus(HBV)replication
activities (IC50 = 17.1µg mL−1) associated with inhibition
of the DNA-synthesis step of virus life-cycles.[4,5]
Unfortunately, only Z. schinifolium is a good source of
collinin and in other plants it is present in traces ranging from
278 to 139 ppm.[3–5] Therefore, huge quantities of plant mate-
rial would be needed to isolate collinin in sufficient quantities
to carry out experiments to better define its biological profile.
Up to now the biological profile of collinin has not been ade-
quately characterized, especially when compared with that of
other naturally occurring coumarins.
In connection with projects devoted to study the in vitro
and in vivo anti-inflammatory activity of natural and semi-
synthetic prenylated coumarins, we wish to report here a
simple and short synthesis of collinin (1) from pyrogallol
(2) and propiolic acid (3) (Scheme 1) that make available
sufficientquantitiesofthiscompoundinpureformforbiolog-
ical testing. To the best of our knowledge, only a partial syn-
thesis of (1) from 7-hydroxy-8-methoxy-chromen-2-one and
OH
OH
8
CO2H
(3)
(a)
(b)
HO
OH
HO
O
O
7
+
(2)
(4)
OH
OCH3
(c)
O
O
O
O
O
O
(1)
(5)
(1)
Scheme 1. (a) conc. H2SO4 (cat.), 120◦C; (b) geranyl bromide, DBU,
Diagram 1.
rt; (c) MeI, NaH 60%, DMF, rt.
© CSIRO 2003
10.1071/CH02177
0004-9425/03/010059

60
M. Curini et al.
methyl iodide and NaH in N,N-dimethylformamide at room
temperature for 2 h gave collinin (1) in 64% yield. Although
we were not able to obtain authentic samples of the natural
material, our analytical data for (1) was in full agreement
with those previously reported.[3–5]
In conclusion, we have developed an easy and short syn-
thesis of collinin (1) in three steps and 24.6% overall yield,
which provides an alternative and valuable route to obtain
collinin for biological testing purposes. Studies to synthesize
suitably functionalized analogues and to further explore the
biological activity of (1) in order to define a structure–activity
relationship profile are now in progress.
CH3CCH3), 1.22–1.08 (3 H, m, CH2CH3CCH). δC (CDCl3) 160.3,
152.8, 147.5, 144.6, 144.2, 131.9, 123.9, 123.5, 118.7, 113.0, 112.5,
111.9, 111.8, 70.2, 39.5, 26.4, 26.2, 17.6, 16.4.
Collinin (1)
To a stirred suspension of NaH (0.011 g of a 60% dispersion in mineral
oil, 0.44 mmol), previously washed with n-hexane to remove mineral oil,
in anhydrous DMF (4 mL) at –10◦C under nitrogen was added a solu-
tion of (5) (0.12 g, 0.38 mmol) dissolved in anhydrous DMF (3 mL).
The resulting solution was stirred at room temperature for 2 h. The solu-
tion was again cooled to –10◦C, iodomethane (0.05 mL, 0.76 mmol)
was added and the stirring was continued at room temperature for 1 h.
The reaction mixture was then poured into saturated brine (5 mL) and
the aqueous layer was extracted with ether (4 × 15 mL). The collected
organic phases were dried over Na2SO4 and evaporated. The residue
was subjected to flash chromatography (silica, 99 : 1 CH2Cl2/MeOH
elution) to afford, after concentration of the appropriate fraction
(RF 0.7), the title compound (1) (0.08 g, 64%) as a white solid, m.p.
67–69◦C (Found: C, 73.2; H, 7.4%; M+•, 328.1677. C20H24O4 requires
C, 73.2%, H, 7.4%; M+•, 328.1674). νmax(neat)/cm−1 1728. δH see ref.
[3]. δC (CDCl3) 160.5, 156.1, 148.5, 143.6, 142.7, 134.7, 131.6, 123.9,
123.3, 120.1, 113.6, 113.3, 108.3, 69.8, 55.9, 39.6, 26.4, 25.6, 16.4, 14.1.
Experimental
7,8-Dihydroxycoumarin (4)
To a mixture of pyrogallol (2) (1.0 g, 7.94 mmol) and propiolic acid
(3) (1.1 g, 15.88 mmol) was added one drop of concentrated H2SO4.
The resulting suspension was stirred at 120◦C for 30 min, cooled and
dissolved in EtOAc (10 mL). This solution was washed twice with 5%
NaHCO3, dried over Na2SO4, and evaporated under vacuum. Recrystal-
lization (Et2O) of this material afforded the title compound (4) (0.83 g,
59%) as a white solid, m.p. 255–256◦C (lit.[7] 256–257◦C) (Found: C,
60.7; H, 3.4%; M+•, 178.0271. C9H6O4 requires C, 60.7%; H, 3.4%;
M+•, 178.0266). νmax (neat)/cm−1 3500, 1730. δH (CD3OD) 7.82 (1 H,
d, H4), 7.15 (1 H, d, H3), 6.85 (1 H, d, H5), 6.21 (1 H, d, H6). δC see
ref. [8].
Acknowledgments
The authors wish to thank Università degli Studi di Perugia,
ItalyforgrantssupportingItaly–Cubascientificcollaboration
projects.
References
7-Geranyloxy-8-hydroxycoumarin (5)
[1] R. F. C. Brown, P. T. Gilham, G. K. Hughes, E. Ritchie, Aust. J.
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[2] L. I. Tikhomirova, G. A. Kuznetsova, M. G. Pimenov, Chem. Nat.
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To a solution of (4) (0.3 g, 1.68 mmol) in acetone (5 mL) were added
DBU (0.255 g, 1.68 mmol) and geranyl bromide (0.365 g, 1.68 mmol),
and the resulting solution was stirred at room temperature for 3 h.
The mixture was diluted with 2% citric acid (10 mL) and extracted
with CH2Cl2 (3 × 10 mL). The collected organic phases were dried
over Na2SO4 and evaporated under vacuum. The residue was subjected
to flash chromatography (silica gel, 99 : 1 CH2Cl2/MeOH elution) to
afford, after concentration of the appropriate fraction (RF 0.5), the title
compound (5) (0.34 g, 65%) as a white solid, m.p. 97–99◦C (Found: C,
72.6; H, 7.0%; M+•, 314.1521. C19H22O4 requires C, 72.6; H, 7.1%;
M+•, 314.1518). νmax (neat)/cm−1 3500, 1726. δH (CDCl3) 7.15 (1 H,
d, H4), 6.92 (1 H, d, H3), 6.28 (1 H, d, H5), 6.19 (1 H, d, H6), 5.68–5.45
(1 H, m, CHCH2O), 5.10–5.00 (1 H, m, CHCH2CH2), 4.88 (2 H, d,
CH2O), 2.25–1.87 (4 H, complex m, CH2CH2), 1.86–1.29 (6 H, m,
[7] R. J. Molineux, L. Jurd, Aust. J. Chem. 1974, 27, 2697.
[8] H. Duddeck, M. Kaiser, Org. Magn. Reson. 1982, 20, 55.