Efficient total synthesis of 5-methoxypsoralen

Article abstract of DOI:10.1055/s-2006-958420

A rapid and efficient synthesis of 5-methoxypsoralen, furocoumarin commonly used in dermatology for the treatment by PUVA therapy of skin diseases, is described using cheap and easily available starting materials. An alternative method to synthesize 7-(2-oxoethoxy)coumarin, the key step to generate the furan ring, is suggested. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958420

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LETTER
129
Efficient Total Synthesis of 5-Methoxypsoralen
Efficient
T
ota
l
Syn
e
thesis of 5-
l
Metho
p
xypsoralen hine Roux,*a Safwat Makki,b,c Françoise Bévalot,a Philippe Humbertb
a
Laboratoire de Pharmacognosie, Faculté de Médecine et de Pharmacie, Place Saint Jacques, 25030 Besançon, France
Fax +33(3)81665568; E-mail: delphine.roux@edu.univ-fcomte.fr
b
c
Laboratoire d’Ingénierie et de Biologie Cutanées, Faculté de Médecine et de Pharmacie, Place Saint Jacques, 25030 Besançon, France
Laboratoire de Pharmacie Galénique, Faculté de Médecine et de Pharmacie, Place Saint Jacques, 25030 Besançon, France
Received 16 October 2006
OCH3
OCH3
OH
Abstract: A rapid and efficient synthesis of 5-methoxypsoralen,
furocoumarin commonly used in dermatology for the treatment by
PUVA therapy of skin diseases, is described using cheap and easily
available starting materials. An alternative method to synthesize 7-
(2-oxoethoxy)coumarin, the key step to generate the furan ring, is
suggested.
H
O
O
O
O
O
O
HO
OH
2
3
1
O
Scheme 1 Retrosynthetic analysis
Key words: furocoumarin, psoralen, medicinal chemistry, total
synthesis, furan ring
of the key step of the formation of the furan ring
(Scheme 1).
Bergapten or 5-methoxypsoralen (5-MOP, 1) is a natural-
ly occurring furocoumarin isolated from citrus bergamia
oil by Kalbrunner in 1834 (Figure 1).1
To begin with, 2,4,6-trihydroxybenzaldehyde (4) was ob-
tained by a Wilsmeier formylation of phloroglucinol (3)
with POCl3 in DMF in a 84% yield (Scheme 2). In
Perkin’s classical reaction, compound 4 was heated with
acetic anhydride and sodium acetate to generate 5,7-
diacetoxycoumarin (5) in a quantitative yield.9 According
to the similar reactivity of the 5- and 7-hydroxy groups,
the partial alkylation of 5,7-dihydroxycoumarin was diffi-
cult. Accordingly, methylation of the per-O-acetylated
compound 5, followed by hydrolysis, was effected to ob-
tain 7-hydroxy-5-methoxycoumarin (6) as the major
product (61%).
OCH3
O
O
O
1
Figure 1
Psoralen and its derivatives are commonly used in derma-
tology for the treatment by PUVA therapy (psoralen +
ultraviolet light A) of skin diseases such as vitiligo and
psoriasis.2 Among furocoumarins utilized at present in
therapy, 5-MOP was reported to have several advantages
compared with 8-MOP, especially for reducing the photo-
toxic response.3 Moreover, 5-MOP has a chemopreven-
tive role in the human hepatocellular carcinoma cell line4
and show inhibitory activity of monoamine oxidase.5
OH
OH
OAc
CHO
OH
b
a
HO
HO
OH
AcO
O
O
3
4
5
c
OCH3
OCH3
d
Several research groups have reported synthetic pathways
for psoralens but most of these methods result in low yield
or numerous steps and no really satisfactory synthesis of
5-methoxypsoralen has yet been reported.6 MacLeod7 and
recently Chimichi8 described a convenient methodology
to obtain linear furanocoumarins by alkaline treatment of
7-(2-oxoethoxy)coumarin. On this basis, the development
of a simple and efficient synthesis of 5-methoxypsoralen
was undertaken. In addition to this result, we are reporting
here a method easily accessible to synthesize 5-methoxy-
7-(2-oxoethoxy)coumarin (2) which was the intermediate
H3CO
HO
O
O
O
O
O
9
6
OCH3
e
OCH3
OCH3
f
H
O
O
O
O
O
O
2
1
O
Scheme 2 Reagents and conditions: (a) POCl3 (1.4 equiv), DMF,
0 °C to r.t., 1 h, 84%; (b) NaOAc, Ac2O, 190 °C, 14 h, 100%; (c) CH3I
(4 equiv), K2CO3, acetone, reflux, 15 h, then 10% aq NaOH, MeOH,
reflux, 5 min, 61%; (d) C4H9BrO2 (2 equiv), NaH (1.5 equiv), DMF,
reflux, 10 h, 71%; (e) TFA, H2O–CH2Cl2, 0 °C to 10 °C, 48 h, 90%;
(f) NaOH, reflux, 4 h, 40%.
SYNLETT 2007, No. 1, pp 0129–0130
0
4.
0
1.
2
0
0
7
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-958420; Art ID: G33006ST
© Georg Thieme Verlag Stuttgart · New York

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130
D. Roux et al.
LETTER
Under normal methylation conditions (CH3I, K2CO3, ace- In conclusion, this work provides an interesting synthetic
tone, reflux), we think that traces of water in the reaction route to bergapten with few and easily workable steps and
medium may hydrolyze chemoselectively the 5-acetyl an overall yield comparable with the one of the total
group leading to the intermediate 7 stabilized by conjugat- synthesis of bergapten via a photochemical aromatic an-
ing effect of the pyrone ring (Scheme 3), whose methyla- nulation strategy described by Danheiser and Trova.6d
tion gave the product 8. Without further purification, This study allows us to suggest the possibility of a
product 8 was deacetylated (10% aq NaOH, MeOH, re- chemoselective O-alkylation of numerous diphenolic cou-
flux) to provide the desired product 6.
marins based on conjugating effect of the pyrone ring.
This result allows us to continue with the synthesis of
other derivatives and biological evaluation of all the re-
sulting linear furocoumarins with the intention of reduc-
ing undesirable symptoms for patients after PUVA
therapy.
OAc
O
CH3I, K2CO3
acetone
trace of H2O
AcO
AcO
O
O–
AcO
O
O
5
7
References
OCH3
OCH3
(1) Fowlks, H. G. J. Invest. Dermatol. 1959, 32, 249.
(2) Hönigsmann, H.; Jaschke, E.; Gschnait, F.; Brenner, W.;
Fritsch, P.; Wolff, K. Br. J. Dermatol. 1979, 101, 369.
(3) (a) Langner, A.; Wolska, H.; Kowalski, J.; Duralska, H.;
Murawska, E. Int. J. Dermatol. 1976, 15, 688. (b) Tanew,
A.; Ortel, B.; Rappersberger, K.; Honigsmann, M. J. Am.
Acad. Dermatol. 1988, 18, 333.
10% aq NaOH
MeOH
HO
O
O
O
O
6
8
Scheme 3
In order to generate the furan ring of 5-MOP, 5-methoxy-
7-(2-oxoethoxy)coumarin (2) was synthesized by a two-
step synthesis (Scheme 2). Coumpound 2 resulted from
O-alkylation of the 7-hydroxy group of compound 6 with
bromoacetaldehyde dimethyl acetal using sodium hydride
as a base10 followed by hydrolysis of the acetal function-
ality of 9 to the corresponding aldehyde with trifluoro-
acetic acid in a biphasic system.11
(4) Lee, Y. M.; Wu, T. H.; Chen, S. F.; Chung, J. G. Toxicol.
In Vitro 2003, 17, 279.
(5) Huong, D. T.; Choi, H. C.; Rho, T. C.; Lee, H. S.; Lee, M.
K.; Kim, Y. H. Arch. Pharm. Res. 1999, 22, 324.
(6) (a) Späth, E.; Wessely, F.; Kubiczek, G. Ber. Dtsch. Chem.
Ges. B 1937, 70, 478. (b) Howell, W. N.; Robertson, A. J.
Chem. Soc. 1937, 293. (c) Caporale, G. Ann. Chim. (Roma)
1958, 48, 650. (d) Danheiser, R. L.; Trova, M. P. Synlett
1995, 573.
(7) MacLeod, J. K.; Worth, B. R.; Wells, R. J. Aust. J. Chem.
1978, 31, 1533.
Finally, 5-MOP (1) was obtained by the cyclization of the
aldehydic compound 2 to form the furan ring according to
the procedure described by Chimichi.8 Repeated modifi-
cations of this general procedure for synthesis of the pso-
ralens did not allow us to obtain a yield better than 40% of
the linear furocoumarin 1 due to the increase in angular
furocoumarin’s proportion which was a result of a
thermodynamically controlled process faced with the 5-
methoxy group.
(8) Chimichi, S.; Boccalini, M.; Cosimelli, B.; Viola, G.;
Vedaldi, D.; Dall’Acqua, F. Tetrahedron 2002, 58, 4859.
(9) Heyes, R. G.; Roberston, A. J. Chem. Soc. 1936, 1831.
(10) Saniger, E.; Campos, J. M.; Entrena, A.; Marchal, J. A.;
Suárez, I.; Aránega, A.; Choquesillo, D.; Niclós, J.; Gallo,
M.; Espinosa, A. Tetrahedron 2003, 59, 5457.
(11) Jacoby, C.; Braekman, J. C.; Daloze, D. Tetrahedron 1996,
52, 10473.
Synlett 2007, No. 1, 129–130 © Thieme Stuttgart · New York