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E. C. Row et al. / Bioorg. Med. Chem. 14 (2006) 3865–3871
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of a number of the other furanocoumarins. The synthesis
of 60,70-epoxy-8-geranyloxypsoralen (8-EGP, 5) was ini-
tially carried out by treatment of 8-geranyloxypsoralen
(1) with m-chloroperoxybenzoic acid.12 However, this
resulted in the formation of the desired epoxide (8-
EGP, 5) in low yields, and of by-products, a bis-epoxide
(10) (Fig. 4) and the hydrolysed phenol xanthotoxol (3).
It was thought that the high acidity of m-chloroperoxy-
benzoic acid was causing hydrolysis of the labile ether
linkage, and that a procedure that could selectively
epoxidise the terminal double bond under basic
conditions would be more successful. Thus, conditions
previously used in the selective epoxidation of 3,20-bis-
ethylenedioxy-17a-hydroxy-19-norpregna-5(10),9(11)-
diene13 were employed. Hexafluoroacetone trihydrate,
hydrogen peroxide, and disodium hydrogenphosphate
were stirred vigorously in dichloromethane at ꢀ10 ꢁC
for 30 min to generate the active dioxirane species. After
addition of 8-geranyloxypsoralen (1), the reaction mix-
ture was allowed to warm to room temperature and left
stirring overnight (Scheme 1). Selective epoxidation of
the geranyl terminal double bond was observed with no
formation of the hydrolysis by-product xanthotoxol
(3). Purification afforded 60,70-epoxy-8-geranyloxypsora-
len (5) in good yields.
OH
OH
Pd/C 10%, TEA
HCO2H
O
O
O
O
O
O
77%
8
3
Geranyl bromide,
DMF, K2CO3
73%
O
O
O
O
9
Scheme 2. Synthesis of the 2,3-dihydroderivaties 8 and 9.
(TCNE) was used for this purpose.15,16 Treatment of
8-EGP (5) with a catalytic amount of TCNE in metha-
nol gave 60-hydroxy-70-methoxy-8-geranyloxypsoralen
(7) (Scheme 1) with the highly regioselective introduc-
tion of the methoxy group at the more substituted oxi-
1
rane carbon affording the secondary alcohol. H NMR
analysis with D2O shake saw the disappearance of the
peak at 2.48 and the simplification of the multiplet at
3.39–3.33 to a doublet of doublets at 3.26 (J 2.5, 9.9),
and confirmed the presence of dicyanoketene dimethyl
acetal ((CN)2C@C(OCH3)2), as a singlet around d 4.1.
Removal of this by-product, formed during the methan-
olysis of TCNE, proved difficult by column chromatog-
raphy due to the close running nature of the analytes.
When the reaction was scaled up, the product could be
purified by recrystallisation rather than chromatogra-
phy, affording a 16% increase in yield. The activation
of the C–O oxirane bond by alcohols is thought to be
initiated by single electron transfer to the p-system of
TCNE from the oxygen of the epoxide.16
Like the epoxide (5), preparation of 60,70-dihydroxy-8-
geranyloxypsoralen (8-DOHGP, 6) was initially carried
out under acidic conditions,12 which again resulted in
a low yield of the desired product and a high yield of
the hydrolysed phenolic by-product (3). A number of di-
lute acids (1M) were then tested, and sulfuric acid was
found to mediate the formation of the diol (6), produc-
ing only a small quantity of the phenolic by-product (3).
Treatment of the epoxide (5) with a catalytic amount of
dilute sulfuric acid was scaled up, affording 8-DOHGP
(6) in good yields (Scheme 1). After purification by col-
umn chromatography, 8-DOHGP (6) was obtained as a
colourless oil. In a previous study14, this compound had
been produced as a solid with a melting point of
92–94 ꢁC. However, a number of unsuccessful attempts
were made to crystallise the compound, which was iden-
tified as the desired product from other analytical data.
We prepared the corresponding hydroxy-ether (7) by
ring opening of 8-EGP (5) using camphor sulfonic acid
in methanol, thus introducing the ether linkage at the
more substituted position. When employing these condi-
tions, problems of acid hydrolysis of the ether substitu-
ent at the 8-position were again encountered, leading to
the formation of xanthotoxol (3). A mild catalyst for the
methanolysis of epoxides that would leave acid-labile
functions intact was required, and tetracyanoethylene
The reduction of the unsaturated furan derivative xan-
thotoxol (3) using both transfer hydrogenation and cat-
alytic hydrogenation17,18 methods at low and high
pressure was investigated. Initially the unreactive nat-
ure of these furans towards catalytic hydrogenation
was thought to be due to the limited solubility of the
starting material in a number of solvents. However,
high yields of marmesins have been obtained by
transfer hydrogenation with Pd/C, formic acid and tri-
ethylamine.19 Using this procedure, dihydro-8-hydrox-
ypsoralen (8-DHOH, 8) was obtained in good yields
(77%) (Scheme 2). The reaction time was kept as
short as possible to prevent hydrogenation of the
unsaturated lactone, which was detected after 15 min.
Subsequent alkylation afforded the dihydro-8-geranyl-
oxypsoralen derivative (9) (Scheme 2).
O
O
2.2. Inhibition of CYP3A4
O
O
O
O
O
O
O
O
O
With the exception of xanthotoxol (3) the furanocoum-
arin monomers showed a dose-dependent inhibition of
the formation of 6b-hydroxytestosterone from testoster-
one (Table 1). Thus, the absence of the alkyl chain from
the 8-geranyloxy structure resulted in a loss of activity
with IC50 values >100 lM. The 8-geranyloxy series
10
5
Figure 4. The desired mono epoxide (8-EGP, 5) and the bis-epoxide
by-product (10) obtained from the epoxidation of 8-geranyloxypsor-
alen (1) using m-chloroperoxybenzoic acid.