Synthesis of thio- and oxo-analogues of isopsoralen

Article abstract of DOI:10.1016/S0040-4020(02)00161-8

A range of novel 5′-substituted 7-oxo and 7-thioisopsoralens were synthesized via a Claisen rearranged allyl aryl ether followed by reductive ozonolysis in the presence of a suitable solvent. In some cases dimethylthiocarbamoyl chloride was used as a protecting group and to introduce the thiol moiety.

Full text of DOI:10.1016/S0040-4020(02)00161-8

TETRAHEDRON
Pergamon
Tetrahedron 58 .2002) 2831±2837
Synthesis of thio- and oxo-analogues of isopsoralen
Dino J. Clarke and Ross S. Robinsonp
The Warren Research Laboratory, School of Chemical and Physical Sciences, University of Natal, Private Bag XO1, Scottsville,
Pietermaritzburg 3209, South Africa
Received 11 October 2001; accepted 14 February 2002
0
AbstractÐArange of novel 5 -substituted 7-oxo and 7-thioisopsoralens were synthesized via a Claisen rearranged allyl aryl ether followed
by reductive ozonolysis in the presence of a suitable solvent. In some cases dimethylthiocarbamoyl chloride was used as a protecting group
and to introduce the thiol moiety. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Coumarin derivatives such as psoralens and isopsoralens
.angelicin) are a class of natural and synthetic compounds,
which exhibit photo-biological and photo-therapeutic
properties.1 This has resulted in the widespread use of
these compounds as a treatment for topical skin diseases
such as psoriasis and vitiligo,2,3 as well as probes for nucleic
acid structure and function,4 and have proved to be useful
model compounds for mutagenesis and repair studies.5 They
have recently also been shown to be effective against
cutaneous T-cell lymphoma and other autoimmune
diseases.6 The biological activity of psoralens is due to
their activity towards DNA, to which they are able to bind
covalently via photo-addition reactions with the base pairs
of the DNAhelix, after exposure to UVAradiation
.320±400 nm) thus hindering cellular replication.
Our interest in these compounds lies in developing a new
route to the synthesis of 50-substituted derivatives of 7-oxo-
and 7-thioisopsoralen derivatives. The general approach to
the 7-oxo-50-substituted psoralens is outlined in Scheme 1.
The allyl aryl coumarins .3a,b) were isolated in high yields
from 7-hydroxycoumarin .1), and these molecules were
subsequently rearranged under thermal conditions to afford
regioselective rearrangement to the 8-position in good yield.
8-Allyl-7-hydroxycoumarin .4a) was subsequently treated
with ozone, followed by reductive workup with dimethyl
sul®de to afford the aldehyde .5).
This aldehyde .5a) was isolated, as the hemiacetal .6a). This
underwent nucleophilic substitution in the presence of the
solvent methanol, to afford the novel compound 8-methoxy-
8,9-dihydro-2H-furo[2,3-h]chromen-2-one .7a) in 66%
yield, which was characterised by NMR spectroscopy and
X-ray diffraction analysis .Fig. 1). From the crystal structure
it can be observed that the isopsoralen derivative lies in the
monoclinic crystal system with the space group being P21=a:
The two enantiomers are related by a centre of inversion in
the space group. The crystal structure also shows the
expected planarity of the molecule, and in the solid state
the molecules are shown to be packed tightly together in the
unit cell, indicating the potential for p-stacking of these
compounds and hence the potential for intercalation into
the DNAdouble helix.
There has therefore been great interest in the synthesis of
these compounds in recent years,7±9 with emphasis on the
synthesis of new analogues with enhanced activity than
those which have seen general clinical use, such as
8-methoxypsoralen
.8-MOP),
5-methoxypsoralen
.5-MOP), and 4,50,8-trimethylpsoralen. These compounds
are photoinduced to form interstrand crosslinks, which
have been found to be responsible for the undesired side
effects of PUVA.psoralen plus UVA) treatment, namely
the risk of skin cancer and skin phototoxicity.2,10 As a result
of these undesired effects, isopsoralen analogues have been
studied due to their angular structure, which prevents inter-
strand crosslinks between the base pairs of the DNAhelix.
This allows only monoadducts to form, which has been
shown to result in the reduction of the unwanted side effects,
whilst still maintaining the desired biological activity.11,12
The hemiacetal .6a) was isolated from reactions carried out
in THF, and was shown to be surprisingly stable. Dehydra-
tion of the hemiacetal in the presence of p-toluene sulfonic
acid afforded the known isopsoralen13 8a in high yield. A
range of other o-substituted nucleophiles was incorporated
into the system by making use of various other alcoholic
solvents viz. ethanol, isopropanol, and tert-butanol. These
afforded the isopsoralen derivatives 7b±d.
Keywords: benzopyrans; rearrangements; ozonolysis.
Corresponding author. Tel.: 127-33-260-6272; fax: 127-33-260-5009;
e-mail: robinsonr@nu.ac.za
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020.02)00161-8

2832
D. J. Clarke, R. S. Robinson / Tetrahedron 58 32002) 2831±2837
Scheme 1. .i) K2CO3, acetone, re¯ux, 92% 3a and 86% 3b; .ii) N,N-Diethylaniline, re¯ux, 3 h, 84% 4a and 77% 4b; .iii) O3, THF, 2788C, then dimethyl
sul®de, 2108C to rt; .iv) R0OH, 66±75%; .v) p-toluene sulfonic acid, toluene, re¯ux, 100% 8a and b.
carbocation intermediate .9) formed by the protonation of
the carbonyl by the p-toluene sulfonic acid .Fig. 2). This
carbocation would then undergo rapid cyclisation and
dehydration to afford the expected product.
The cyclisation reaction was then repeated in the presence
of methanol .Scheme 2) in order to bring about the nucleo-
philic substitution of the methoxy group, which should
occur more readily than the dehydration reaction. This
procedure afforded the expected isopsoralen derivative
.10) in quantitative yield.
Figure 1.
Extension of this work to include other moieties at the
50-position was also carried out, by making use of
3-bromo-2-methylpropene .2b) instead of allyl bromide
.2a). In the case where RvCH3, cyclisation of the ketone
.5b) to the hemiacetal .6b) initially failed to take place .!).
This may be attributed to the electron releasing methyl
group resulting in a less electrophilic carbonyl. However,
cyclisation of the ketone intermediate .5b) was induced in
Ê
re¯uxing toluene containing p-toluene sulfonic acid as a
catalyst, this then afforded the dehydrated product and
known isopsoralen14 8b in quantitative yield. The success
of this reaction may be attributed to the formation of the
Scheme 2. .i) Methanol, p-TSA, 4 A molecular sieve, re¯ux, 100%.
Attention has subsequently been directed towards extending
this approach to include a sulfur heteroatom into the
isopsoralen ring system. This was successfully achieved
by the method outlined in Scheme 3. Methods exist in the
literature by which the alcohol moiety may be converted
into a thiol;15 however, if one converts the hydroxyl moiety
directly into the thiol, it has been shown that during the
Claisen rearrangement the thiol reacts with the alkene to
afford a variety of undesired products.16 As a result of this
problem, dimethylthiocarbamoyl chloride was utilised, thus
allowing for the conversion of the alcohol moiety into a
Figure 2.

D. J. Clarke, R. S. Robinson / Tetrahedron 58 32002) 2831±2837
2833
Scheme 3. .i) DMF, NaH, then Me2NCSCl, 96%; .ii) 2408C, 86%; .iii) THF, O3, 2788C, then dimethyl sul®de, 2108C to rt; .iv) MeOH, p-TSA, re¯ux, 84%;
.v) CH3OH, KOH, re¯ux, then H1, H2O, 29%.
protected thiol. Subsequent deprotection could then be
performed only after the terminal alkene had been cleaved
via ozonolysis. In this approach the alcohol moiety of the
Claisen rearranged allyl aryl ether was converted into the
dimethylcarbamothioate .11), which was subsequently
thermally rearranged to afford S-.8-allyl-2-oxo-2H-
chromen-7-yl) N,N-dimethylcarbamothioate .12).
4.1.1. 7-)Allyloxy)-2H-chromen-2-one )3a). 3-Bromo-1-
propene .2a) .5.71 ml, 66 mmol) was added dropwise
under dry nitrogen to a stirred mixture of 7-hydroxy-
coumarin .5.0 g, 30 mmol) and anhydrous K2CO3 .5.8 g,
41 mmol) in dry acetone .150 ml). The resulting mixture
was then boiled under re¯ux for 5 h, after which it was
allowed to cool, and the K2CO3 ®ltered off and washed
with fresh acetone. The solvent was removed in vacuo and
the resulting crystals recrystallised from methanol to
afford, as pale, cream-yellow crystals, 7-.allyloxy)-2H-
chromen-2-one .3a) .5.62 g, 92%), mp 78±798C .from
methanol) .lit.,14 93±93.58C) Found: M1 202.06349,
C12H10O3 requires M, 202.06299; nmax.KBr) cm21 1723
Ozonolysis in THF followed by reductive workup with
dimethyl sul®de, afforded the aldehyde .13), which was
subsequently protected as the acetal .14). Deprotection
and cleavage of the dimethylcarbamothioate group in
methanol afforded the crystalline thio-isopsoralen,
8-methoxy-8,9-dihydro-2H-thieno[2,3-h]chromen-2-one
.15) in 29% yield.
0
0
and 1614; dH .500 MHz, CDCl3) 4.60 .2H, d, J1 ,2
ˆ
5.3 Hz, 10-CH2), 5.34 .1H, dd, Jcisˆ10.4 and Jgemˆ1.2 Hz,
CvCH) and 5.44 .1H, dd, Jtransˆ17.2 and Jgemˆ1.2 Hz,
0
0
CvCH), 6.05 .1H, ddt, Jtransˆ17.2, Jcisˆ10.4 and J2 ,1
ˆ
5.3 Hz, 20-H), 6.26 .1H, d, J3,4ˆ9.4 Hz, 3-H), 6.83 .1H, d,
J8,6ˆ2.3 Hz, 8-H), 6.87 .1H, dd, J6,8ˆ2.3 and J6,5ˆ8.5 Hz,
6-H), 7.38.1H, d, J5,6ˆ8.6 Hz, 5-H) and 7.64 .1H, d, J4,3ˆ
9.4 Hz, 4-H); dC .125 MHz, CDCl3) 69.9 .C-10), 102.4 .C-
8), 113.2 .C-4a), 113.80 .C-3), 113.86 .C-6), 119.2 .C-30),
129.4 .C-5), 132.8 .C-20), 114.0 .C-4), 156.5 .C-8a), 161.8
.C-7) and 162.4 .C-2); m/z 202 .M1, 100%) and 187 .71).
3. Conclusion
In conclusion, a range of novel oxo-analogues and one thio-
analogue of isopsoralen have been synthesized in moderate
to good yields. Various investigations into the observed
regioselectivity and extention of this approach to include
selenium heteroatoms are currently under investigation.
4.1.2. 8-Allyl-7-hydroxy-2H-chromen-2-one )4a). 7-
.Allyloxy)-2H-chromen-2-one .3a) .5.0 g, 24.7 mmol) was
dissolved in N,N-diethylaniline .50 ml) in a two-necked
¯ask attached to a nitrogen line and boiled under re¯ux at
ca. 2208C for 3 h. The reaction mixture was then cooled,
during which precipitation of some of the product occurred;
hexane .40 ml) was added in order to precipitate out the
remaining product. The precipitate was ®ltered, washed
with hexane, dried by vacuum ®ltration, and recrystallised
from ethyl acetate to yield, as cream crystals, 8-allyl-7-
hydroxy-2H-chromen-2-one .4a) .4.2 g, 84%), mp
151±1538C .from ethyl acetate) .lit.,14 165±1668C)
Found: M1 202.06313, C12H10O3 requires M, 202.06299;
4. Experimental
4.1. General
NMR spectra were obtained from CDCl3 or CD3OD solu-
tions on a Varian Unity-Inova 500 MHz spectrometer and
are referenced using the solvent signals .dH 7.26 and dC
77.0 ppm for CDCl3). Low-resolution mass spectra were
recorded by a Hewlett Packard 5890 mass spectrometer
and high-resolution data on a Kratos MS80RF double-
focusing magnetic sector instrument .Cape Technikon
Mass Spectrometry Unit). Melting points were recorded
using a Ko¯er hot stage apparatus and are uncorrected. IR
spectra were recorded on a Perkin±Elmer spectrum one. All
solvents were dried prior to use. Flash chromatography was
performed using Merck silica gel 60 .230±400 mesh;
particle size 0.040±0.063 nm).
n
max.KBr) cm21 3332, 1699 and 1600; dH .500 MHz,
CDCl3) 2.81 .1H, s, OH), 2.81 .1H, s, OH), 3.61 .2H, d,
J1 ,2 ˆ6.2 Hz, 10-CH2), 5.0 .1H, dd, Jcisˆ10.1 and
Jgemˆ1.8 Hz, CvCH) and 5.12 .1H, dd, Jtransˆ17.2 and
Jgemˆ1.8 Hz, CvCH), 6.01 .1H, ddt, Jtransˆ17.2,
0
0

2834
D. J. Clarke, R. S. Robinson / Tetrahedron 58 32002) 2831±2837
0
0
0
Jcisˆ10.1 and J2 ,1 ˆ6.2 Hz, 2 -H), 6.20 .1H, d, J3,4ˆ9.6 Hz,
3-H), 6.80 .1H, d, J6,5ˆ8.5 Hz, 6-H), 7.21 .1H, d,
J5,6ˆ8.5 Hz, 5-H) and 7.64 .1H, d, J4,3ˆ9.6 Hz, 4-H); dC
.125 MHz, CDCl3) 27.3 .C-10), 112.2 .C-3), 112.7 .C-4a),
113.2 .C-6), 114.7 .C-8), 115.9 .C-30), 127.2 .C-5), 135.7
.C-20), 145.1 .C-4), 154.2 .C-8a), 159.5 .C-7) and 162.9
.C-2); m/z 202 .M1, 100%) and 187 .75).
4.1.5. 8-Isopropoxy-8,9-dihydro-2H-furo[2,3-h]chromen-
2-one )7c). 8-Allyl-7-hydroxy-2H-chromen-2-one .4a)
.0.80 g, 3.96 mmol) was dissolved in THF .40 ml) and
ozone was passed through the system for ca. 80 min at
2788C. Dimethyl sul®de .0.4 ml, 5.5 mmol) was added,
and following the procedure outlined for the synthesis of
8-methoxy-8,9-dihydro-2H-furo[2,3-h]chromen-2-one .7a)
yielded, as an orange oil from which yellow crystals
crystallised out, 8-isopropoxy-8,9-dihydro-2H-furo[2,3-
h]chromen-2-one .7c) .0.73 g, 75%) mp 117±1198C .from
isopropanol) Found: M1 246.08952, C14H14O4 requires M,
246.08921; nmax.KBr) cm21 3419, 1625 and 1715; dH
.500 MHz, CDCl3) 1.20±1.25 [6H, 2£d, Jˆ6.1 Hz,
CH.CH3)2], 3.23 .1H, dd, Jgemˆ16.9 and J9a,8ˆ2.4 Hz,
9-CHa) and 3.45 .1H, dd, Jgemˆ16.9 and J9b,8ˆ6.9 Hz,
9-CHb), 4.08 .1H, heptet, Jˆ6.2 Hz, 10-H), 6.01 .1H, dd,
J8,9aˆ2.4 and J8,9bˆ6.9 Hz, 8-H), 6.23 .1H, d, J3,4ˆ9.4 Hz,
3-H), 6.79 .1H, d, J6,5ˆ8.2 Hz, 6-H), 7.29 .1H, d,
J5,6ˆ8.2 Hz, 5-H) and 7.64 .1H, d, J4,3ˆ9.4 Hz, 4-H); dC
.125 MHz, CDCl3) 22.0 and 23.6 [CH.CH3)2], 34.2
.9-CH2), 71.8 .C-10), 106.2 .C-8), 107.4 .C-6), 107.6
.C-4a), 112.5 .C-3), 112.8 .C-9a), 128.9 .C-5), 144.3
.C-4), 151.6 .C-9b), 160.8 .C-6a) and 162.4 .C-2); m/z
246 .M1, 53%), 204 .44) and 175 .100).
4.1.3. 8-Methoxy-8,9-dihydro-2H-furo[2,3-h]chromen-2-
one )7a). 8-Allyl-7-hydroxy-2H-chromen-2-one .4a) .2.0 g,
9.9 mmol) was dissolved in THF .60 ml) and placed in a
three-necked ¯ask ®tted with a re¯ux condenser and
attached to an ozone generator and two traps containing
acidi®ed 1.1 M KI solution to mop up any unreacted
ozone. The ¯ask was cooled to 2788C in a solid CO2/
acetone bath. Ozone was passed through the mixture for
100 min at a rate of ca. 1 ml/min, after which analysis by
TLC showed no starting material to be present. Dimethyl
sul®de .0.9 ml, 12.4 mmol) was added, the reaction mixture
warmed to 2108C .salt/ice bath), and stirred for 3 h, allow-
ing the mixture to slowly warm to room temperature.
Methanol .30 ml) was then added, and the mixture was
boiled under re¯ux for 3 h and left stirring overnight. The
solvent was removed in vacuo to leave a dark orange oil
from which the product crystallized out as orange crystals.
This was then recrystallised from methanol to afford
8-methoxy-8,9-dihydro-2H-furo[2,3-h]chromen-2-one .7a)
.1.43 g, 66%), mp 144±1458C .from methanol) Found:
M1 218.05846, C12H10O4 requires M, 218.05791; nmax.KBr)
cm21 1724 and 1615; dH .500 MHz, CDCl3) 3.24 .1H, dd,
Jgemˆ17.1 and J9a,8ˆ2.3 Hz, 9-CHa) and 3.45 .1H, dd,
Jgemˆ17.1 and J9b,8ˆ6.6 Hz, 9-CHb), 3.56 .3H, s, CH3),
5.80 .1H, dd, J8,9aˆ2.3 and J8,9bˆ6.6 Hz, 8-H), 6.22 .1H,
d, J3,4ˆ9.6 Hz, 3-H), 6.81 .1H, d, J6,5ˆ8.2 Hz, 6-H), 7.30
.1H, d, J5,6ˆ8.2 Hz, 5-H) and 7.64 .1H, d, J4,3ˆ9.6 Hz, 4-H);
dC .125 MHz, CDCl3) 34.28 .9-CH2), 56.93 .10-CH3), 107.9
.C-6), 109.8 .C-8), 113.1 .C-9a), 113.2 .C-3), 114.1 .C-4a),
129.4 .C-5), 144.9 .C-4), 151.9 .C-9b), 161.7 .C-2) and
162.8 .C-6a); m/z 218 .M1, 100%) and 187 .60).
4.1.6. 8-)tert-Butoxy)-8,9-dihydro-2H-furo[2,3-h]chro-
men-2-one )7d). 8-Allyl-7-hydroxy-2H-chromen-2-one
.4a) .0.80 g, 3.96 mmol) was dissolved in THF .40 ml)
and ozone was passed through the system for 80 min at
2788C. Dimethyl sul®de .0.4 ml, 5.5 mmol) was added,
and following the procedure outlined for the synthesis of
8-methoxy-8,9-dihydro-2H-furo[2,3-h]chromen-2-one .7a)
yielded, as an orange oil from which the product crystallised
out as yellowish crystals, 8-.tert-butoxy)-8,9-dihydro-2H-
furo[2,3-h]chromen-2-one .7d) .0.74 g, 71%) mp 119±
1228C .from tert-butanol) Found: M1 ±C.CH3)3,
204.04375, C11H7O4 requires M, 203.03443; nmax.KBr)
cm21 3385, 1729 and 1621; dH .500 MHz, CDCl3) 1.25
.9H, s, C.CH3)3), 3.24 .1H, dd, Jgemˆ17.0 and
J9a,8ˆ2.3 Hz, 9-CHa) and 3.43 .1H, dd, Jgemˆ17.0 and
J9b,8ˆ6.6 Hz, 9-CHb), 5.79 .1H, dd, J8,9aˆ2.3 and
J8,9bˆ6.6 Hz, 8-H), 6.21 .1H, d, J3,4ˆ9.6 Hz, 3-H), 6.80
.1H, d, J6,5ˆ8.2 Hz, 6-H), 7.29 .1H, d, J5,6ˆ8.2 Hz, 5-H)
and 7.64 .1H, d, J4,3ˆ9.6 Hz, 4-H); dC .125 MHz, CDCl3)
29.9 [C.CH3)3], 33.8 .9-CH2), 102.7 .C-10), 107.5 .C-6),
109.3 .C-8), 112.7 .C-3), 113.6 .C-4a), 125.1 .C-9a),
129.0 .C-5), 144.3 .C-5), 151.5 .C-9b), 161.3 .C-6a) and
162.3 .C-2); m/z 260 .M1, 16%), 204 .67) and 176 .100).
4.1.4. 8-Ethoxy-8,9-dihydro-2H-furo[2,3-h]chromen-2-
one )7b). 8-Allyl-7-hydroxy-2H-chromen-2-one .4a)
.0.80 g, 3.96 mmol) was dissolved in THF .40 ml) and
ozone was passed through the system for ca. 80 min at
2788C. Dimethyl sul®de .0.4 ml, 5.5 mmol) was added,
and following the procedure outlined for the synthesis of
8-methoxy-8,9-dihydro-2H-furo[2,3-h]chromen-2-one .7a)
yielded, as yellow crystals, 8-ethoxy-8,9-dihydro-2H-
furo[2,3-h]chromen-2-one .7b) .0.62 g, 67%) mp 107±
1098C .from ethanol) Found: M1 232.07441, C13H12O4
4.1.7. 8-Hydroxy-8,9-dihydro-2H-furo[2,3-h]chromen-2-
one )6a). 8-Allyl-7-hydroxy-2H-chromen-2-one .4a) .1.0 g,
4.95 mmol) was dissolved in THF .40 ml) and ozone was
passed through the system for 80 min at 2788C. Dimethyl
sul®de .0.45 ml, 6.2 mmol) was added, the reaction mixture
taken to 2108C .salt/ice bath), and stirred overnight, allow-
ing the mixture to slowly warm to room temperature. The
solvent was then removed in vacuo and the resulting residue
was passed through a column .50:50 ethyl acetate/hexane as
a running solvent) to yield, as white crystals, 8-hydroxy-8,9-
dihydro-2H-furo[2,3-h]chromen-2-one .6a) .0.52 g, 51%),
mp 137±1398C .from ethyl acetate) Found: M1 204.0426,
C11H8O4 requires M, 204.04226; nmax.KBr) cm21 3302,
1689 and 1614; dH .500 MHz, CD3OD) 3.19 .2H, d,
requires M, 232.07356; nmax.KBr) cm21 1726 and 1613;
0
0
0
dH .500 MHz, CDCl3) 1.26 .3H, t, J2 ,1 ˆ7.1 Hz, 2 -CH3),
3.23 .1H, dd, Jgemˆ16.9 and J9a,8ˆ2.5 Hz, 9-CHa) and 3.45
.1H, dd, Jgemˆ16.9 and J9b,8ˆ6.7 Hz, 9-CHb), 3.69 and 3.95
0
0
0
.2H, 2£dq, Jgemˆ9.4 and J1 ,2 ˆ7.1 Hz, 1 -CH2), 5.91 .1H,
dd, J8,9aˆ2.5 and J8,9bˆ6.7 Hz, 8-H), 6.21 .1H, d,
J3,4ˆ9.4 Hz, 3-H), 6.79 .1H, d, J6,5ˆ8.2 Hz, 6-H), 7.29
.1H, d, J5,6ˆ8.2 Hz, 5-H) and 7.64 .1H, d, J4,3ˆ9.4 Hz,
4-H); dC .125 MHz, CDCl3) 15.68 .20-CH3), 34.38
.9-CH2), 65.45 .10-CH2), 107.91 .C-6), 108.67 .C-8),
113.08 .C-3), 113.14 .C-9a), 113.96 .C-4a), 129.37 .C-5),
144.72 .C-4),151.99 .C-9b), 61.72 .C-2) and 162.84 .C-6a);
m/z 232 .M1, 79%) and 175 .100).

D. J. Clarke, R. S. Robinson / Tetrahedron 58 32002) 2831±2837
2835
J9,8ˆ5.3 Hz, 9-CH2), 4.89 .1H, t, J8,9ˆ5.3 Hz, 8-H), 6.21
.1H, d, J3,4ˆ9.4 Hz, 3-H), 6.88 .1H, d, J6,5ˆ8.5 Hz, 6-H),
7.31 .1H, d, J5,6ˆ8.5 Hz, 5-H) and 7.78 .1H, d, J4,3ˆ9.4 Hz,
4-H); dC .125 MHz, CD3OD) 30.9 .9-CH2), 98.2 .C-8),
111.5 .C-3), 111.9 .C-4a), 112.7 .C-9a), 113.8 .C-6),
127.7 .C-5), 145.9 .C-4), 154.4 .C-9b), 160.5 .C-6a) and
163.5 .C-2); m/z 204 .M1, 34%), 174 .100) and 146 .75).
3.64 .2H, s, 10-CH2), 4.81 and 4.90 .2H, 2£s, 30-CH2), 6.25
.1H, d, J3,4ˆ9.4 Hz, 3-H), 6.56 .1H, br. s, OH), 8.86 .1H, d,
J6,5ˆ8.5 Hz, 6-H), 7.27 .1H, d, J5,6ˆ8.5 Hz, 5-H) and 7.66
.1H, d, J4,3ˆ9.4 Hz, 4-H); dC .125 MHz, CDCl3) 22.5
.CH3), 31.4 .10-CH2), 112.5 .30-CH2), 112.6 .C-3), 112.8
.C-4a), 113.2 .C-8), 113.5 .C-6), 127.4 .C-5), 143.6
.C-20), 144.6 .C-4), 153.7 .C-8a), 159.1 .C-7) and 162.1
.C-2); m/z 216 .M1, 87%) and 201 .100).
4.1.8. 2H-Furo[2,3-h]chromen-2-one )8a). 8-Hydroxy-
8,9-dihydro-2H-furo[2,3-h]chromen-2-one .6a) .0.03 g,
0.15 mmol) was placed in a two-necked round bottomed
¯ask containing THF .20 ml) and connected to a re¯ux
condenser and a nitrogen line. p-Toluene sulfonic acid
4.1.11. 7-Hydroxy-8-)2-oxopropyl)-2H-chromen-2-one
)5b). 7-Hydroxy-8-.2-methyl-2-propenyl)-2H-chromen-2-
one .4b) .0.8 g, 3.7 mmol) was dissolved in dry methanol
.40 ml) in a three necked round bottomed ¯ask, cooled to
2788C .dry ice/acetone) and ozone was passed through the
system for ca. 80 min. Dimethyl sul®de .0.33 ml,
4.57 mmol) was then added and the reaction mixture stirred
overnight under nitrogen while allowing to warm to room
temperature. The solvent was then removed in vacuo to
leave an orange oil from which the ®nal product crystallised
out. This was then recrystallised from methanol to yield, as
orange crystals, 7-hydroxy-8-.2-oxopropyl)-2-Hchromen-2-
one .5b) .0.56 g, 68%), mp 188±1908C .from methanol);
Found: M1 218.05768, C12H10O4 requires M, 218.05791;
Ê
.0.01 g) and some 3 A molecular sieve were added to the
¯ask and the reaction mixture was boiled under re¯ux for
2 h. The mixture was then passed through a plug of silica gel
to remove the catalyst, and the solvent removed under
vacuum to afford 2H-furo[2,3-h]chromen-2-one .8a)
.0.028 g, 100%), mp 131±1328C .from methanol) .lit.,10
137±137.58C); nmax.KBr) cm21 3385, 1709 and 1620; dH
.500 MHz, CD3OD) 6.35 .1H, d, J3,4ˆ9.4 Hz, 3-H), 6.59
.1H, d, J9,8ˆ2.2 Hz, 9-H), 6.98 .1H, d, J8,9ˆ2.2 Hz, 8-H),
7.21 .1H, d, J5,6ˆ8.3 Hz, 5-H), 7.39 .1H, d, J6,5ˆ8.3 Hz,
6-H) and 8.06 .1H, d, J4,3ˆ9.4 Hz, 4-H); dC .125 MHz,
CDCl3) 98.4 .C-9), 106.8 .C-6), 113.2 .C-3), 114.1
.C-4a), 117.6 .C-9a), 125.2 .C-5), 146.1 .C-4), 146.2
.C-8), 147.9 .C-9b), 156.8 .C-6a) and 161.2 .C-2); m/z
186 .M1, 100%), 158 .94) and 102 .28).
n
max.KBr) cm21 3317, 1729 and 1614; dH .500 MHz,
CD3OD) 2.29 .3H, s, 30-CH3), 3.99 .2H, s, 10-CH2), 6.19
.1H, d, J3,4ˆ9.4 Hz, 3-H), 6.85 .1H, d, J6,5ˆ8.5 Hz, 6-H),
7.33 .1H, d, J5,6ˆ8.5 Hz, 5-H) and 7.75 .1H, d, J4,3ˆ9.4 Hz,
4-H); dC .125 MHz, CD3OD) 29.4 .30-CH3), 37.8 .20-CH2),
109.5 .C-8), 111.3 .C-3), 112 .C-4a), 112.6 .C-6), 127.9
.C-5), 145.2 .C-4), 153.8 .C-8a), 159.9 .C-2), 162.7 .C-7)
and 207.5 .C-20); m/z 218 .M1, 100%) and 187 .52).
4.1.9. 7-[)2-Methyl-2-propenyl)oxy]-2H-chromen-2-one
)3b). 3-Bromo-2-methyl-1-propene .2a) .5 ml, 49.6 mmol)
was added dropwise under nitrogen to a stirred mixture of
7-hydroxy coumarin .1) .4.02 g, 24.3 mmol) and K2CO3
.4.66 g) in dry acetone .130 ml). The mixture was then
boiled under re¯ux for 5 h, allowed to cool, and the
K2CO3 ®ltered and washed with fresh acetone. The solvent
was then removed in vacuo and the residue recrystallised
from methanol to afford 7-[.2-methyl-2-propenyl)oxy]-2H-
chromen-2-one .3b) .4.55 g, 86%), mp 59±608C .from
methanol) Found: M1 216.07878, C13H12O3 requires M,
216.07864; nmax.KBr) cm21 1734, 1609 and 3454; dH
.500 MHz, CDCl3) 1.82 .3H, s, CH3), 4.49 .2H, s, 10-
CH2), 5.02 and 5.09 .2H, 2£s, 30-CH2), 6.24 .1H, d,
J3,4ˆ9.6 Hz, 3-H), 6.81 .1H, d, J8,6ˆ2.4 Hz, 8-H), 6.86
.1H, d, J6,5ˆ8.7 and J6,8ˆ2.4 Hz, 6-H), 7.36 .1H, d,
J5,6ˆ8.7 Hz, 5-H) and 7.63 .1H, d, J4,3ˆ9.6 Hz, 4-H); dC
.125 MHz, CDCl3) 19.9 .CH3), 72.9 .10-CH2), 102.4 .C-
8), 113.3 .C-4a), 113.7 .C-6), 113.8 .C-3), 114.2 .30-CH2),
129.4 .C-5), 140.4 .C-20), 144.1 .C-4), 156.5 .C-8a), 161.9
.C-7) and 162.6 .C-2); m/z 216 .M1, 100%) and 201 .61).
4.1.12. 8-Methyl-2H-furo[2,3-h]chromen-2-one )8b). 7-
Hydroxy-8-.2-oxopropyl)-2H-chromen-2-one .5b) .0.25 g,
1.25 mmol), and p-toluene sulfonic acid .0.05 g) were
dissolved in toluene .20 ml) in a two necked round
bottomed ¯ask ®tted with a Dean and Stark apparatus
Ê
containing 4 A molecular sieve, and a nitrogen line. The
mixture was re¯uxed for 4 h to afford, on removal of solvent
and after passing through a silica gel plug, a quantitative
yield of 8-methyl-2H-furo[2,3-h]chromen-2-one .8b) as
white crystals, mp 124±1268C .from toluene) .lit.,14 153±
1548C) Found: M1 200.04702, C12H8O3 requires M,
200.04734; nmax.KBr) cm21 3317, 1705 and 1614; dH
.500 MHz, CD3OD) 2.38 .3H, s, 10-CH3), 6.39 .1H, d,
J3,4ˆ9.1 Hz, 3-H), 6.78 .1H, s, 9-H), 7.40 .1H, d,
J6,5ˆ8.5 Hz, 6-H), 7.43 .1H, d, J5,6ˆ8.5 Hz, 5-H) and 8.04
.1H, d, J4,3ˆ9.1 Hz, 4-H); dC .125 MHz, CD3OD) 20.1
.10-CH3), 99.2 .C-9), 108.2 .C-6), 113.1 .C-3), 113.8
.C-4a), 118.1 .C-9a), 123.2 .C-5), 145.8 .C-4), 147.4
.C-9b), 157.4 .C-8), 157.5 .C-6a) and 161.9 .C-2); m/z
200 .M1, 100%) and 171 .73).
4.1.10. 7-Hydroxy-8-)2-methyl-2-propenyl)-2H-chromen-
2-one )4b). 7-[.2-Methyl-2-propenyl)oxy]-2H-chromen-2-
one .3b) .3.80 g, 17.6 mmol) was dissolved in N,N-diethyl-
aniline .40 ml) in a ¯ask ®tted with a re¯ux condenser and
nitrogen line and boiled under re¯ux for 3 h. The reaction
mixture was then left to cool and hexane .40 ml) was added
to precipitate out the product, which was then recrystallised
from ethyl acetate to afford 7-hydroxy-8-.2-methyl-2-
propenyl)-2H-chromen-2-one .4b) .2.95 g, 77%), mp
123±1258C .from ethyl acetate) Found: M1 216.07875,
C13H12O3 requires M, 216.07864; nmax.KBr) cm21 3442,
1684 and 1603; dH .500 MHz, CDCl3) 1.77 .3H, s, CH3),
4.1.13. 8-Methoxy-8-methyl-8,9-dihydro-2H-furo[2,3-
h]chromen-2-one )10). 7-Hydroxy-8-.2-oxopropyl)-2H-
chromen-2-one .5b) .0.25 g, 1.25 mmol), and p-toluene sul-
fonic acid .0.02 g) were dissolved in dry methanol in a two
necked round bottomed ¯ask ®tted with a condenser and
Ê
containing 4 A molecular sieve. The mixture was then
re¯uxed for 5 h under nitrogen, and was then passed through
a plug of silica gel to remove the catalyst. Removal of the
solvent then afforded, as white crystals, 8-methoxy-8-
methyl-8,9-dihydro-2H-furo[2,3-h]chromen-2-one
.10)

2836
D. J. Clarke, R. S. Robinson / Tetrahedron 58 32002) 2831±2837
.0.29 g, 100%), mp 121±1228C .from methanol) Found: M1
232.07352, C13H12O4 requires M, 232.073562; nmax.KBr)
cm21 2941, 1728 and 1615; dH .500 MHz, CDCl3) 1.73
.3H, s, CH3), 3.20 and 3.42 .2H, 2£d, Jgemˆ17.1 Hz,
9-CH2), 3.32 .3H, s, OCH3), 6.20 .1H, d, J3,4ˆ9.6 Hz,
3-H), 6.75 .1H, d, J6,5ˆ8.2 Hz, 6-H), 7.28 .1H, d,
J5,6ˆ8.2 Hz, 5-H) and 7.63 .1H, d, J4,3ˆ9.6 Hz, 4-H); dC
.125 MHz, CDCl3) 24.2 .CH3), 37.1 .9-CH2), 50.2 .OCH3),
106.8 .C-6), 112.3 .C-3), 112.9 .C-8), 113.0 .C-4a), 114.2
.C-9a), 128.8 .C-5), 144.1 .C-4), 151.1 .C-9b), 160.9 .C-6a)
and 162.1 .C-2); m/z 232 .M1, 100%), 201 .68) and 171 .52).
2H-chromen-7-yl)
N,N-dimethylcarbamothioate
.12)
.1.0 g, 3.46 mmol), was dissolved in dry THF, cooled to
2788C, and ozone was passed through for 80 min until
analysis by TLC showed the disappearance of starting
material. Dimethyl sul®de .0.3 ml, 4.15 mmol) was then
added and the mixture stirred at 2108C for 3 h while
allowing to warm to room temperature. Methanol .20 ml),
Ê
p-toluene sulfonic acid .20 mg) and some 4 A molecular
sieve were then added and the reaction mixture boiled
under re¯ux for 4 h until TLC showed there was no starting
material left. The volatile components were removed in
vacuo and the ®nal product puri®ed via radial chromato-
graphy .50:50 ethyl acetate/hexane as a running solvent)
to afford S-[8-.2,2-dimethoxyethyl)-2-oxo-2H-chromen-7-
yl]-N,N-dimethylcarbamothioate .14) .0.99 g, 84%) mp
96±998C .from methanol) Found: M1 337.09877,
C16H19O5SN requires M, 337.09839; nmax.KBr) cm21
2948, 1727 and 1654; dH .500 MHz, CDCl3) 3.00 and
3.12 [6H, 2£s, N.CH3)2], 3.34 .6H, s, 2£OCH3), 3.40 .2H,
4.1.14.
O-)8-Allyl-2-oxo-2H-chromen-7-yl)
N,N-di-
methylcarbamothioate )11). 8-Allyl-7-hydroxy-2H-chro-
men-2-one .4a) .2.0 g, 9.9 mmol) was dissolved in dry
DMF .20 ml) in a two-necked ¯ask ®tted with a thermo-
meter, re¯ux condenser, and nitrogen line, and NaH .0.53 g
of a 50% oil dispersion, 11 mmol) was added. Once the
evolution of hydrogen gas had ceased, dimethylthiocarba-
moyl chloride .1.29 g, 10.5 mmol) was added and the reac-
tion mixture was heated at 608C for 30 min. The reaction
mixture was then poured onto 50 ml cold water and the
precipitate obtained was ®ltered, dried, and recrystallised
from ethanol to afford, as cream crystals, O-.8-allyl-2-
oxo-2H-chromen-7-yl) N,N-dimethylcarbamothioate .11)
.2.71 g, 96%), mp 103±1048C .from ethanol) Found: M1
289.07775, C15H15O3SN requires M, 289.07727; nmax.KBr)
0
0
0
0
0
0
d, J1 ,2 ˆ5.7 Hz, 1 -CH2), 4.69 .1H, t, J2 ,1 ˆ5.7 Hz, 2 -H),
6.43 .1H, d, J3,4ˆ9.4 Hz, 3-H), 7.35 .1H, d, J6,5ˆ8.2 Hz,
6-H), 7.45 .1H, d, J5,6ˆ8.2 Hz, 5-H) and 7.68 .1H, d,
J4,3ˆ9.4 Hz, 4-H); dC .125 MHz, CDCl3) 31.9 .10-CH2),
36.9 [N.CH3)2], 53.9 .2eOCH3), 104 .C-20), 117 .C-3),
119.2 .C-4a), 125.6 .C-6), 129.8 .C-8), 133.2 .C-5), 134.5
.C-7), 143.3 .C-4), 152.3 .C-8a), 160.1 .C-2) and 165.5
[NC.O)S]; m/z 337 .M1, 28%), 234 .28) and 203 .100).
cm21 1723 and 1671; dH .500 MHz, CDCl3) 3.38 and 3.47
0
4.1.17.
8-Methoxy-8,9-dihydro-2H-thieno[2,3-h]chro-
0
0
.6H, 2£s, N.CH3)2), 3.54 .2H, d, J1 ,2 ˆ6.3 Hz, 1 -CH2),
men-2-one )15). S-[8-.2,2-Dimethoxyethyl)-2-oxo-2H-
chromen-7-yl]-N,N-dimethylcarbamothioate .14) .0.8 g,
2.3 mmol) was added to a mixture of dry methanol contain-
ing KOH .0.168 g, 3 mmol) and heated under re¯ux for ca.
4 h, monitoring with TLC. The reaction mixture was then
acidi®ed with HCl and boiled under re¯ux for another two
hours. Water .5 ml) was then added and the product was
then extracted with ether .3£30 ml). The organic layer was
dried with magnesium sulfate and removed under vacuum to
yield, as an orange oil from which the product crystallised
out, 8-methoxy-8,9-dihydro-2H-thieno[2,3-h]chromen-2-
one .15) .0.156 g, 29%) mp 141±1438C .from methanol);
Found: M1 234.03381, C12H10O3S requires M, 234.03507;
5.03 .1H, dd, Jcisˆ10 and Jgemˆ1.5 Hz, CvCH) and 5.08
.1H, dd, Jtransˆ17.1 and Jgemˆ1.6 Hz, CvCH), 5.95 .1H,
0
0
0
ddt, Jtransˆ17.1, Jcisˆ10.0 and J2 ,1 ˆ6.3 Hz, 2 -H), 6.40
.1H, d, J3,4ˆ9.6 Hz, 3-H), 7.03 .1H, d, J6,5ˆ8.4 Hz, 6-H),
7.38 .1H, d, J5,6ˆ8.4 Hz 5-H) and 7.69 .1H, d, J4,3ˆ9.6 Hz,
4-H); dC .125 MHz, CDCl3) 28.7 .C-10), 39.5 and 44.1
[N.CH3)2], 116.5 .C-3), 116.8 .C-30), 117.5 .C-4a), 121.1
.C-6), 122.4 .C-8), 126.5 .C-5), 135.1 .C-20), 144.1 .C-4),
153.5 .C-8a), 155.4 .C-7), 161.2 .C-2) and 187.1 .CvS);
m/z 289 .M1, 24%) and 217 .100).
4.1.15.
S-)8-Allyl-2-oxo-2H-chromen-7-yl)
N,N-di-
methylcarbamothioate )12). O-.8-Allyl-2-oxo-2H-chro-
men-7-yl)N,N-dimethylcarbamothioate .11) .2.7 g, 9.34
mmol) was heated neat in a two-necked ¯ask containing a
thermometer and nitrogen line to ca. 2308C for 40 min,
cooled, and the residue recrystallised from ethanol to afford
the rearranged product, S-.8-allyl-2-oxo-2H-chromen-7-yl)
N,N-dimethylcarbamothioate .12) .2.32 g, 86%) mp 101±
1058C .from EtOH) Found: M1 289.07765, C15H15O3SN
requires M, 289.07727); nmax.KBr) cm21 1723 and 1603;
dH .500 MHz, CDCl3) 3.02 and 3.14 .6H, 2£s, N.CH3)2),
n
max.KBr) cm21 1718 and 1603; dH .500 MHz, CDCl3) 3.38
.3H, s, CH3), 3.51 .1H, dd, Jgemˆ17.3 and J9a,8ˆ5.5 Hz,
9-CHa) and 3.78 .1H, d, Jgemˆ17.3 Hz, 9-CHb), 5.54 .1H,
d, J8,9aˆ5.5 Hz, 8-H), 6.30 .1H, d, J3,4ˆ9.6 Hz, 3-H), 7.18
.1H, d, J6,5ˆ8.0 Hz, 6-H), 7.29 .1H, d, J5,6ˆ8.0 Hz, 5-H)
and 7.66 .1H, d, J4,3ˆ9.6 Hz, 4-H); dC .125 MHz, CDCl3)
40.1 .9-CH2), 56.3 .10-CH3), 92.7 .C-8), 114.5 .C-3), 115.9
.C-9a), 118.8 .C-6), 125.3 .C-4a), 127.6 .C-5), 143.6 .C-4),
145.7 .C-6a), 150.6 .C-9b) and 160.6 .C-2); m/z 234 .M1,
92%) and 203 .100).
0
0
0
0
3.81 .2H, d, J1 ,2 ˆ6.2 Hz, 1 -CH2), 5.01±5.04 .2H, m, 3 -
0
0
CH2), 5.97 .1H, ddt, Jtransˆ17.6, Jcisˆ9.8 and J2 ,1 ˆ6.2 Hz,
20-H), 6.44 .1H, d, J3,4ˆ9.6 Hz, 3-H), 7.36 .1H, d,
J6,5ˆ8.2 Hz, 6-H), 7.46 .1H, d, J5,6ˆ8.2 Hz, 5-H) and 7.69
.1H, d, J4,3ˆ9.6 Hz, 4-H); dC .125 MHz, CDCl3) 32.1 .10-
CH2), 37.3 [N.CH3)2], 116.5 .30-CH2), 117.5 .C-3), 119.8
.C-4a), 125.8 .C-6), 132.8 .C-8), 133.4 .C-5), 133.5 .C-7),
135.1 .C-20), 143.6 .C-4), 152.3 .C-8a), 160.6 .C-1) and
165.7 [NC.O)S]; m/z 289 .M1, 30%) and 217 .100).
4.2. X-Ray crystallography
The crystallographic measurements on 8-methoxy-8,9-di-
hydro-2H-furo[2,3-h]chromen-2-one .7a) were made using
a Philips X-ray Generator with a 3 KW X-ray Tube and an
Enraf Nonius CAD 4 diffractometer. The structure was
solved using the direct methods program SHELXS-97,17
as implemented by the crystallographic program OSCAIL.18
The ®nal model was plotted using ORTEP.19 Detailed
crystallographic data for compound 7a have been deposited
4.1.16. S-[8-)2,2-Dimethoxyethyl)-2-oxo-2H-chromen-7-
yl] N,N-dimethylcarbamothioate )14). S-.8-Allyl-2-oxo-

D. J. Clarke, R. S. Robinson / Tetrahedron 58 32002) 2831±2837
2837
5. Zolan, M. E.; Smith, C. A.; Hanawalt, P. C. Biochemistry
1984, 23, 63±69.
at the Cambridge Crystallographic Data Centre .No. CCDC
169113) and are available on request.
6. Gasparro, F. P. Extracorporeal Photochemotherapy, Clinical
Aspects and the Molecular Basis for Ef®cacy; R.G. Landes:
Austin, TX, 1994.
Crystal data of compound 7a. C12H10O4, Mˆ218.20,
Ê
Tˆ293.2) K, lˆ0.71073 A, monoclinic aˆ7.902.3), bˆ
Ê
7. Rodighiero, P.; Chilin, A.; Guitto, A. Gaz. Chim. Ital. 1984,
114, 509±515.
7.2686.14), cˆ17.500.5) A, aˆ90.031.19)8, bˆ99.44.3)8,
Ê 3
gˆ90.00.3)8, Vˆ991.6.5) A , space group P21/a, Zˆ4,
Dxˆ1.462 mg m23, mˆ0.111 mm21, F.000)ˆ456. Crystal
size 1.40£0.80£0.25 mm3; u range for data collection 2.36±
27.968; index range 210,h,10, 23,k,9, 24,l,23;
re¯ections collected 3555; independent re¯ections 2339
[R.int)ˆ0.0221]; re®nement method full-matrix least-squares
on F2; data/restraints/parameters 2339:0:152; goodness-of-
®t on F2 1.209; R.F) [I.2.I)]ˆ0.0812; wR2ˆ0.3114; largest
8. Guitto, A.; Chilin, A.; Manzini, P.; Dall'Acqua, F.; Bordin, F.;
Rodighiero, P. IL Farmaco 1995, 50, 479±488.
9. Jakobs, E. A.; Christiaens, L. E.; Rnesen, M. Tetrahedron
1994, 31, 9315±9324.
10. Stern, R. S.; Lange, R. J. Invest. Dermatol. 1988, 91, 120.
11. Guiotto, A.; Rodighiero, P.; Manzini, P.; Pastorini, G.; Bordin,
F.; Baccichetti, F.; Carlassare, F.; Vedaldi, D.; Dall'Acqua, F.;
Tamaro, M.; Recchia, G.; Cristofolini, M. J. Med. Chem.
1984, 27, 959±967.
Ê 23
diff. peak and hole 0.594 and 20.419 e A
12. Mosti, L.; Presti, E.; Menozzi, G.; Marzano, C.; Baccichetti,
F.; Falcone, G.; Filippelli, W.; Piucci, B. IL Farmaco 1998,
53, 602±610.
Acknowledgements
The authors wish to thank Dr O. Q. Munro for the X-ray data
collection, the National Research Foundation .NRF) and the
University of Natal for generous ®nancial support.
13. Wulff, W. D.; McCallum, J. S.; Kunng, F.-A. J. Am. Chem.
Soc. 1988, 110, 7419±7434.
14. Kaufman, K. D. J. Org. Chem. 1961, 26, 117±119.
15. Newman, M. S.; Hetzel, F. W. Org. Synth. 1971, 51, 139±141.
16. Rhoads, S. J.; Raulins, N. R. Org. React. 1975, 22, 46±49.
17. Sheldrick, G. M. SHELXL-97; University of Gottingen:
Gottingen. .a) Sheldrick, G. M. Acta Crystallogr. 1990, A46,
467±473. .b) Sheldrick, G. M. Acta Crystallogr. 1993, D49,
18±23. .c) Sheldrick, G. M.; Schneider, T. R. In Methods in
Enzymology; Carter, C. W., Sweet, R. M., Eds.; Macro-
molecular Crystallography Part B; 1997; Vol. 277, pp 319±
343.
References
1. Boyer, V.; Moustacchi, E.; Sage, E. Biochemistry 1988, 27,
3011.
2. Parrish, J. A.; Stern, R. S.; Pathak, M. A.; Fitzpatrick, T. B.
Photochemotherapy of Skin Diseases. In The Science of
Photomedicine; Regan, J. D., Parrish, J. A., Eds.; Plenum:
New York, 1982; pp 595±624.
18. McArdle, P. Oscail Version 8, Crystallography Centre,
Chemistry Department: NUI Galway, Ireland.
3. Danno, K. Psoralen Photochemotherapy and its Action
Mechanisms. In Frontiers of Photobiology; Shima, A., Ed.;
Elsevier: New York, 1993; pp 97±99.
19. Farrugia, L. J. ORTEP 3 for Windows V1.01 beta, Department
of Chemistry, University of Glasgow: Scotland, 1998.
4. Cimino, G. D.; Gamper, H. B.; Isaacs, S. T.; Hearst, J. E. Ann.
Rev. Biochem. 1985, 54, 1151±1193.