Synthesis of 2-hydroxy-3-methylbut-3-enyl substituted coumarins and xanthones as natural products. Application of the Schenck ene reaction of singlet oxygen with ortho-prenylphenol precursors

Article abstract of DOI:10.1016/j.tet.2004.01.033

Application of our original photooxidation-reduction methodology to prenylated dihydroxycoumarin and trihydroxyxanthone compounds led to the corresponding ortho-(2-hydroxy-3-methylbut-3-enyl)phenol derivatives with yields ranging from 8 to 65%. In most of the reported experiments, the oxidation products distribution, after the photooxygenation step, was controlled by the competition between the large group effect and the stabilising phenolic assistance effect. We also showed that ortho-(3-hydroxy-3- methylbut-1-enyl)phenol derivatives could be considered as biogenetic precursors of 2,2-dimethylbenzopyranic structures.

Full text of DOI:10.1016/j.tet.2004.01.033

Tetrahedron 60 (2004) 2293–2300
Synthesis of 2-hydroxy-3-methylbut-3-enyl substituted coumarins
and xanthones as natural products. Application of the Schenck ene
reaction of singlet oxygen with ortho-prenylphenol precursors
*
Jean-Jacques Helesbeux, Olivier Duval, Caroline Dartiguelongue, Denis Seraphin,
´
Jean-Michel Oger and Pascal Richomme
´ ´
SONAS, UFR des Sciences Pharmaceutiques et Ingenierie de la Sante, 16 Bd Daviers, 49100 Angers, France
Received 16 September 2003; revised 21 November 2003; accepted 9 January 2004
Abstract—Application of our original photooxidation–reduction methodology to prenylated dihydroxycoumarin and trihydroxyxanthone
compounds led to the corresponding ortho-(2-hydroxy-3-methylbut-3-enyl)phenol derivatives with yields ranging from 8 to 65%. In most of
the reported experiments, the oxidation products distribution, after the photooxygenation step, was controlled by the competition between the
large group effect and the stabilising phenolic assistance effect. We also showed that ortho-(3-hydroxy-3-methylbut-1-enyl)phenol
derivatives could be considered as biogenetic precursors of 2,2-dimethylbenzopyranic structures.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
3-methylbut-3-enyl)phenol appendage. A second method,
based on the Schenck ene reaction,8 was also reported to
oxidize prenyl side chain into 2-hydroxy-3-methylbut-3-
enyl chain but only in the case of protected phenolic
derivatives.9,10 This methodology, based on the reactivity of
singlet oxygen with olefin bearing allylic hydrogens,
yielded intermediate hydroperoxides which were quanti-
tatively reduced into the corresponding allylic alcohols.
We recently developed a new and selective access to ortho-
(2-hydroxy-3-methylbut-3-enyl)phenols derivatives by
direct photooxygenation of ortho-prenylphenol pre-
cursors.11 In the present paper, we reported the application
of this original strategy to the synthesis of natural
heterocyclic compounds in the coumarin and xanthone
series.
Phytochemical studies of tropical plants, Calophyllum
dispar, Calophyllum caledonicum and Mesua racemosa,
led us to the isolation and the characterization of various
original coumarin and xanthone compounds. Among them,
ortho-(2-hydroxy-3-methylbut-3-enyl)phenol derivatives
retained our attention because of their biological
activity.1–3 First attempts to synthesize this sort of products
relied on the previously described rearrangement of epoxide
starting from ortho-prenylphenol precursors.4,5 This method
required preliminary phenolic group protection to avoid
further intramolecular cyclisation.6,7 As the final deprotec-
tion step limited the overall yield in a 2–5% range,3c we
aimed to develop an alternative access to ortho-(2-hydroxy-
Figure 1. The mammea A/AA, A/BA, B/AA according to the nomenclature proposed by Crombie.18
Keywords: Schenck ene reaction; Photooxygenation; Regioselectivity; ortho-(2-Hydroxy-3-methylbut-3-enyl)phenols; Coumarin; Xanthone.
*
Corresponding author. Tel.: þ33-241-226-674; fax: þ33-241-486-733; e-mail address: olivier.duval@univ-angers.fr
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.033

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Scheme 1. (i) AlCl3, CH2Cl2, rt, overnight; (ii) Me4NHþOH2, pyridine, H2O, reflux, 4 h; (iii) HI, phenol, reflux, 24 h; (iv) 3-methylbut-2-enyl bromide, aq.
KOH 10%, rt, overnight.
2. Results and discussion
leading to 1,3,5-trihydroxyxanthone 8 with 95% yield
(Scheme 1). Thus, the three-steps synthesis of 8 was
performed with a 76% overall yield.
Preparation of the three prenylated 5,7-dihydroxycoumarins
(1–3, Fig. 1) was achieved starting from 1,3,5-trihydroxy-
benzene (phloroglucinol) in accordance with Crombie’s
method.12 The 1,3,5-trihydroxyxanthone was previously
synthesized in one step from phloroglucinol and 2,3-di-
hydroxybenzoic acid with 16% yield13 according to the
Grover, Shah and Shah reaction.14 The same methodology
was also applied to the synthesis of 1,3-dihydroxy-5-
methoxyxanthone using 2,3-dimethoxybenzoic acid as
starting material with yields ranging from 32 to 91%.15,16
In our work, we decided to synthesize the 1,3,5-trihydroxy-
xanthone backbone via a polymethoxybenzophenone inter-
mediate, easily obtained by Friedel–Crafts acylation. Thus,
2,3-dimethoxybenzoyl chloride 4, prepared in situ from the
corresponding acid in the presence of oxalyl chloride,
reacted with 1,3,5-trimethoxybenzene 5 to give 2-hydroxy-
20,3,40,60-tetramethoxybenzophenone 6 with 86% yield
(Scheme 1). As already described by Quillinan,17 a mono-
demethylation occurred on the ring provided by the acid
moiety in the position ortho to the carbonyl function. Then
subsequent base-catalyzed cyclisation17 of 6 led to 1,3,5-
trimethoxyxanthone 7 with 93% yield along with methanol
elimination (Scheme 1).
The last step required the introduction of a prenyl side chain
on the xanthone skeleton at the C-2 and C-4 positions, ortho
to the C-1 and C-3 phenolic groups. Such nuclear
prenylations have previously been achieved in an acidic
medium (e.g., in the presence of boron trifluoride ethe-
rate).21 In these conditions, the expected C-prenylated
xanthones were obtained with particularly low yields. The
prenylation step was also carried out in basic medium, such
as methanolic sodium methoxide.22,23 Starting from the
1,3-dihydroxy-5-methoxyxanthone, Jain et al. reported the
formation of both the C-2 and C-4 monoprenylated
xanthones and the 2,4-diprenylated xanthone.22 The same
basic conditions, applied to the 1,3,5-trihydroxyxanthone 8,
led to a complex mixture, allowing the isolation of the
following pure compounds: the 1,3-dihydroxy-2,4-di-
(3-methylbut-2-enyl)-5-(3-methylbut-2-enyloxy)xanthone,
the 1,3,5-trihydroxy-2,4-di(3-methylbut-2-enyl)xanthone
and the 1,3-dihydroxy-2-(3-methylbut-2-enyl)-5-(3-methyl-
but-2-enyloxy)xanthone.23 Thus, this method never allowed
to isolate the C-2 or C-4 monoprenylated xanthones. Based
on these previous results, we decided to perform the
prenylation of the 1,3,5-trihydroxyxanthone 8 in basic
conditions similar to those already applied to the dihydroxy-
coumarin derivatives. In the presence of an aqueous
Finally, demethylation of 1,3,5-trimethoxyxanthone 7 was
completed in the presence of iodhydric acid and phenol19,20
Figure 2.

J.-J. Helesbeux et al. / Tetrahedron 60 (2004) 2293–2300
2295
potassium hydroxide solution, 8 reacted with 4-bromo-2-
methyl-2-butene to lead to the prenylated derivatives 9, 10
and 11, already known as natural products,24–26 with 11, 13
and 10% yield, respectively (Scheme 1).
that the secondary allylic alcohol is the sole oxidation
product isolated after the two-steps sequence performed at
15 8C.
As an extent to our study on the synthesis of novel natural
secondary allylic alcohol derivatives, the photooxygena-
tion–reduction sequence was applied in the xanthone series.
Thus, Caledol 15 was the sole oxidation product obtained
from the 1,3,5-trihydroxy-2-(3-methylbut-2-enyl)xanthone
9 (Scheme 2).3b Therefore, regarding this result, we
concluded that the oxidation of the prenyl chain located in
the C-2 position on the xanthone skeleton followed the same
regioselectivity rules as previously observed in both the
acetophenone and coumarin series. In this experiment, the
absence of the tertiary allylic alcohol was also observed. As
a matter of fact, the 1H NMR analysis of the crude mixture,
formed via a photooxidation reaction, performed at 230 8C
in CDCl3, showed the presence of signals corresponding to
the secondary and the tertiary allylic hydroperoxides in a 2:1
ratio. After leaving that sample at room temperature for a
few hours, the disappearance of the signals, corresponding
to the tertiary hydroperoxide protons in the 1H NMR
spectrum, confirmed the thermal instability of this
intermediate.
Then, we studied the reactivity of these different prenylated
heterocyclic compounds (e.g., 1, 2, 3, 9, 10, 11) towards the
photooxidation–reduction sequence.
The Mammea A/AA, A/BA and B/AA (1, 2, 3, Fig. 1),
treated in these conditions, led exclusively to the corre-
sponding secondary allylic alcohols 12, 13 and 14 with 60,
63 and 65% yield, respectively, (Fig. 2). These three
coumarins have been characterized from the stem bark and
the fruits of Calophyllum dispar.1,27
The yields, mentioned above in the coumarin series,
underlined that the photooxygenation step followed the
same regioselectivity rules than those observed in the
acetophenone series.11 Actually, in the first part of our
study, we showed that the distribution of the prenyl side
chain oxidation products resulted from a competition
between the well known large group effect28 and a new
stabilising phenolic assistance effect.29,30 Hence, this
competition during the Schenck ene reaction led to the
formation of the 2-hydroperoxy-3-methylbut-3-enyl deriva-
tive as the major oxidation product rather than the 3-hydro-
peroxy-3-methylbut-1-enyl derivative. Moreover, as already
observed in the acetophenone series, the thermal instability
of this tertiary hydroperoxide intermediate could explained
Prior to embark on the oxidation of the 2,4-bisprenylated
xanthone 11, we decided to apply the photooxygenation–
reduction sequence conditions to the C-4 monoprenylated
xanthone 10. Surprisingly, after the reduction step, two
products were isolated from the crude mixture: the
secondary allylic alcohol 16 in 8% yield and as the major
product with 17% yield the pyranoxanthone 17 (Scheme 3),
already known as a natural compound named 6-deoxyiso-
jacareubine.25,31
In order to analyse this unexpected result, starting from 10,
we performed a new photooxidation reaction in CDCl3 at
230 8C. The 1H NMR analysis of the crude mixture allowed
us to observe proton signals corresponding to both the
secondary and the tertiary allylic hydroperoxides 18 and 19
in a 1:2 ratio (Scheme 4).
Scheme 2. (i) hn, O2, tetraphenylporphine, CH2Cl2, 15 8C; (i) PPh3,
CH2Cl2, rt.
Scheme 3. (i) hn, O2, tetraphenylporphine, CH2Cl2, 15 8C; (ii) PPh3, CH2Cl2, rt; (iii) SiO2 (CH2Cl2/MeOH 99:1).
Scheme 4. (i) hn, O2, tetraphenylporphine, CDCl3, 230 8C.

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Scheme 5. (i) hn, O2, tetraphenylporphine, CH2Cl2, 15 8C; (ii) PPh3, CH2Cl2, rt; (ii) SiO2 (CH2Cl2/MeOH 95:5).
This ratio revealed a reverse regioselectivity pattern in the
ene-reaction of the C-4 prenyl appendage with singlet
oxygen. Hence, in that experiment, only the large group
effect, which favoured the formation of the tertiary
hydroperoxide, controlled the oxidation products distri-
bution. Following that low-temperature experiment, we also
showed that the tertiary allylic hydroperoxide was stable
under higher temperature. The same 1:2 mixture of
secondary and tertiary hydroperoxides 18 and 19 was
allowed to reach room temperature, and after a few hours its
1H NMR analysis provided the same spectrum profile than
at low temperature, showing the thermal stability for these
two products. Therefore, the tertiary hydroperoxide was
sufficiently stable to be reduced in the presence of
triphenylphosphine, leading to the corresponding alcohol.
This latter compound, when exposed either to acidic
medium (e.g., silica gel or CDCl3) or to a slight
increase of temperature (e.g., during the evaporation
stage under reduced pressure) quantitatively led to the
pyranoxanthone 17.
distribution depended exclusively on the large group effect.
This result could be due to a weaker acidic phenolic
function, which would not participate to the stabilization of
the intermediate state in the Shenk ene reaction. Moreover,
during these same experiments, we also showed that,
contrary to our previous results, the intermediate tertiary
hydroperoxide was sufficiently stable at room temperature
to be reduced into the tertiary allylic alcohol. So far, tertiary
allylic hydroperoxides were stable at 15 8C when the ortho-
phenolic group was protected. Once again, this unusual
stability pointed out a different acidic character of the C-3
phenolic function.
Hence, the tertiary allylic alcohol could lead under smooth
conditions to the corresponding pyranoxanthone. That result
confirmed a biogenetic hypothesis already evoked in
previous paper for the transformation of ortho-prenylphenol
moiety into a 2,2-dimethylbenzopyranic structure.32 Fur-
thermore, the instability of both ortho-(3-hydroperoxy-3-
methylbut-1-enyl)phenol and ortho-(3-hydroxy-3-methyl-
but-1-enyl)phenol derivatives could explain that such
appendages were rarely isolated and characterized in natural
products.
In similar experimental conditions, 11 led to the xanthone
20 with 21% yield and to the Dicaledol 21 with 14% yield
(Scheme 5). For this particular compound, we should notice
that, despite the presence of two asymmetric carbons, we
were unable to observe different chemical shifts in NMR
analysis (1H, 13C) and to separate them using silica gel
chromatography. The result obtained for the photooxygena-
tion–reduction sequence starting from 11 confirmed that
only the large group effect was implied in the products
distribution during the oxidation of the C-4 prenyl side
chain.
4. Experimental
4.1. General
Dichloromethane was distilled from calcium hydride. Si gel
60 (Macherey–Nagel, 230–400 mesh) was used for column
chromatography and precoated Si gel plates (Macherey–
Nagel, SIL G/UV254, 0.25 mm) were used for preparative
TLC. NMR spectra were recorded in CDCl3 or CD3OD
solutions on a Bruker Avance DRX 500 or a Jeol GSX 270
WB instruments. IR spectra were recorded on a Bruker
Vector22 spectrometer. HREIMS (70 eV) were recorded
on Varian MAT 311 spectrometer and HRFABMS were
recorded on a Jeol JMS-700 spectrometer. Melting points
were determined on an Electrothermal 8100 melting point
apparatus and are uncorrected.
3. Conclusion
As a conclusion, the photooxygenation–reduction sequence
permitted us to synthesize several natural secondary allylic
alcohol derivatives (three in the coumarin series and two
novel compounds in the xanthone series). Thus, according
to this new two-steps synthetic route, the yield for the
oxidation of the Mammea A/AA into the Disparinol A was
increased from 2 to 60%. The regioselectivity rules,
previously established in the acetophenone series,11,31
were applicable to the coumarin series and also for the
oxidation of 1,3,5-trihydroxy-2-(3-methylbut-2-enyl)-
xanthone. Therefore, the phenolic assistance effect seemed
to be still involved in the Schenck ene reaction of singlet
oxygen with these different ortho-prenylphenol compounds.
4.1.1. 2-Hydroxy-20,3,40,60-tetramethoxybenzophenone 6.
Under N2, 2,3-dimethoxybenzoic acid (6 g, 33 mmol) in dry
CH2Cl2 (45 mL) was treated with oxalyl chloride (12 mL,
132 mmol) and thoroughly stirred at room temperature.
After 3 h, the solvent and the excess of oxalyl chloride were
removed under reduced pressure. The residue was dissolved
in dry CH2Cl2 (75 mL) and added to a CH2Cl2 solution
(50 mL) of 1,3,5-trimethoxybenzene (5 g, 29.8 mmol).
Then the reaction mixture was treated with aluminium III
chloride (13.77 g, 103 mmol). After being stirred for 15 h at
During the photooxygenation step of the C-4 prenylated
xanthone derivatives, we showed that the oxidation products

J.-J. Helesbeux et al. / Tetrahedron 60 (2004) 2293–2300
2297
room temperature, the mixture was poured into ice water
containing concentrated HCl and extracted with CH2Cl2
(5£100 mL). The combined organic layers were dried over
Na2SO4. After removal of the solvent under reduced
pressure, purification of the crude product by column
chromatography (1% MeOH/CH2Cl2) yielded 6 as a yellow
solid (8.15 g, 86%), mp 156–157 8C; IR (cm21): 1629,
reaction mixture was stirred for 16 h at room temperature,
acidified with diluted HCl (10%) and extracted with AcOEt
(4£20 mL). Then the combined organic layers were dried
over Na2SO4. After removal of the solvent under reduced
pressure, purification of the crude product by column
chromatography (5% MeOH/CH2Cl2) yielded successively
9, 11, and 10.
1
1607, 1255; H NMR (CDCl3, 270 MHz): d 12.52 (s, 1H,
OH), 7.04 (d, 1H arom., J¼8 Hz), 6.95 (dd, 1H arom., J¼8,
1.5 Hz), 6.73 (t, 1H arom., J¼8 Hz), 6.17 (s, 2H arom.), 3.93
(s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.72 (s, 6H, 2£OCH3);
13C NMR (CDCl3, 67.5 MHz): d 201.4 (CO), 162.7, 158.3,
152.8, 148.4 (5£quat. arom. C), 124.3 (arom. CH), 121.4
(quat. arom. C), 117.9, 117.0 (2£arom. CH), 109.8 (quat.
arom. C), 90.5 (2£arom. CH), 56.2, 55.8, 55.4 (4£OCH3);
EI-HRMS Calcd for C17H18O6 (Mþ) 311.1103, Found
311.1118.
4.2.1. 1,3,5-Trihydroxy-2-(3-methylbut-2-enyl)-9H-
xanthen-9-one 9. The typical conditions described in
Section 4.2 yielded 12 as a yellow solid (44 mg, 11%),
1
mp 157–158 8C; IR (cm21): 3442, 1617, 1457, 1253; H
NMR (CDCl3, 270 MHz): d 13.27 (s, 1H, OH), 9.45 (s, 1H,
OH), 7.68 (dd, 1H arom., J¼7.5, 2 Hz), 7.33 (dd, 1H arom.,
J¼7.5, 2 Hz), 7.27 (dd, 1H arom., J¼7.5, 7.5 Hz), 6.58 (s,
1H arom.), 5.29 (t, 1H, CH2CH, J¼7.5 Hz), 3.37 (d, 2H,
CH2CH, J¼7.5 Hz), 1.78 (s, 3H, CH3), 1.65 (s, 3H, CH3);
13C NMR (CDCl3, 67.5 MHz): d 181.0 (CO), 163.4,
161.5, 154.1, 147.0, 146.3 (5£quat. arom. C), 130.9
(CHvC(CH3)2), 123.7, 122.6 (2£arom. CH), 121.8 (quat.
arom. C), 120.5 (CH2CH), 115.4 (arom. CH), 106.9, 103.6
(2£quat. arom. C), 97.8 (arom. CH), 25.1 (CH3), 21.3
(CH2CH), 17.2 (CH3); EI-HRMS Calcd for C18H16O5 (Mþ)
312.0998, Found 312.0975.
4.1.2.0 1,3,5-Trimethoxy-9H-xanthen-9-one 7. 2-Hydroxy-
20,3,4 ,60-tetramethoxybenzophenone 6 (3.9 g, 12.2 mmol)
was treated with pyridine (72 mL), water (36 mL) and
aqueous 10% tetramethylammonium hydroxide (24 mL).
The mixture was refluxed for 4 h, poured into ice, acidified
with HCl and extracted with AcOEt (5£150 mL). The
combined organic layers were dried over Na2SO4 and
removal of the solvent under reduced pressure yielded 7 as a
white solid (3.29 g, 93%), mp 220–221 8C; IR (cm21):
1649, 1625, 1299; 1H NMR (CDCl3, 270 MHz): d 7.88 (dd,
1H arom., J¼8, 1.5 Hz), 7.26 (dd, 1H arom., J¼8, 1.5 Hz),
7.18 (t, 1H arom., J¼8 Hz), 6.64 (d, 1H arom., J¼2 Hz),
6.36 (d, 1H arom., J¼2 Hz), 4.03 (s, 3H, OCH3), 3.98 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3); 13C NMR (CDCl3, 67.5 MHz):
d 175.2 (CO), 164.8, 161.8, 159.5, 147.8, 145.1, 124.0
(6£quat. arom. C), 123.2, 117.6, 114.3 (3£arom. CH), 107.1
(quat. arom. C), 95.4, 92.8 (2£arom. CH), 56.3, 56.3, 55.7
(3£OCH3); EI-HRMS Calcd for C16H14O5 (Mþ) 286.0841,
Found 286.0845.
4.2.2. 1,3,5-Trihydroxy-4-(3-methylbut-2-enyl)-9H-
xanthen-9-one 10. The typical conditions described in
Section 4.2 yielded 13 as a yellow solid (50 mg, 13%), mp
188–190 8C; IR (cm21): 3446, 1651, 1566, 1293; 1H NMR
(CDCl3, 270 MHz): d 12.97 (s, 1H, OH), 9.52 (s, 1H, OH),
7.65 (dd, 1H arom., J¼8, 1.5 Hz), 7.36 (dd, 1H arom., J¼8,
1.5 Hz), 7.23 (t, 1H arom., J¼8 Hz), 6.35 (s, 1H arom.), 5.36
(t, 1H, CH2CH, J¼7.5 Hz), 3.58 (d, 2H, CH2CH, J¼7.5 Hz),
1.84 (s, 3H, CH3), 1.64 (s, 3H, CH3); 13C NMR (CDCl3,
67.5 MHz): d 181.8 (CO), 164.0, 162.3, 155.4, 147.1, 146.4
(5£quat. arom. C), 131.7 (CHvC(CH3)2), 124.5, 123.4
(2£arom. CH), 122.1 (quat. arom. C), 121.2 (CH2CH), 116.2
(arom. CH), 107.6, 103.7 (2£quat. arom. C), 98.5 (arom.
CH), 25.9 (CH3), 22.1 (CH2CH), 18.0 (CH3); EI-HRMS
Calcd for C18H16O5 (Mþ) 312.0998, Found 312.0988.
4.1.3. 1,3,5-Trihydroxy-9H-xanthen-9-one 8. A mixture
of 7 (1 g, 35 mmol), phenol (19.4 g, 0.2 mol) and an
aqueous solution of HI (47%, 21 mL) was refluxed for 24 h.
Then the reaction mixture was poured into aqueous 37%
NaHSO3 (70 mL). The resulting yellow precipitate was
collected, washed several times with CH2Cl2 and dissolved
in acetone. The solution was filtered and the solvent was
removed under reduced pressure to yield 8 as a yellow solid
(0.81 g, 95%), mp 274—276 8C; IR (cm21): 3567, 1653,
4.2.3. 1,3,5-Trihydroxy-2,4-bis(3-methylbut-2-enyl)-9H-
xanthen-9-one 11. The typical conditions described in
Section 4.2 yielded 14 as a yellow solid (40 mg, 10%), mp
161–162 8C; IR (cm21): 3364, 1642, 1580, 1223; 1H NMR
(CDCl3, 270 MHz): d 13.19 (s, 1H, OH), 7.76 (dd, 1H
arom., J¼7.5, 1.5 Hz), 7.30 (dd, 1H arom., J¼7.5, 1.5 Hz),
7.22 (dd, 1H arom., J¼7.5, 7.5 Hz), 6.56 (s, 1H, OH), 5.87
(s, 1H, OH), 5.30–5.26 (m, 2H, CH2CH), 3.55 (d, 2H,
CH2CH, J¼7 Hz), 3.48 (d, 2H, CH2CH, J¼7 Hz), 1.87
(s, 6H, 2£CH3), 1.80 (s, 3H, CH3), 1.76 (s, 3H, CH3);
13C NMR (CDCl3, 67.5 MHz): d 181.8 (CO), 160.9, 158.6,
152.3, 144.4, 144.3 (5£quat. arom. C), 136.1, 133.3
(2£CHvC(CH3)2), 123.8 (arom. CH), 122.2, 121.2
(2£CH2CH), 120.8 (quat. arom. C), 119.8, 116.8 (arom.
CH), 109.1, 105.4, 103.3 (3£quat. arom. C), 25.9, 25.6
(2£CH3), 22.0, 21.6 (2£CH2CH), 17.9 (2£CH3); EI-HRMS
Calcd for C23H24O5 (Mþ) 380.1624, Found 380.1614.
1
1577, 1169; H NMR (CD3OD, 270 MHz): d 7.59 (dd, 1H
arom., J¼7.5, 2 Hz), 7.21 (dd, 1H arom., J¼7.5, 2 Hz),
7.17 (dd, 1H arom., J¼7.5, 7.5 Hz), 6.42 (d, 1H arom.,
J¼2 Hz), 6.17 (d, 1H arom., J¼2 Hz); 13C NMR (CD3OD,
67.5 MHz): d 182.1 (CO), 167.3, 164.7, 159.1, 147.3, 146.6
(5£quat. arom. C), 124.9 (arom. CH), 122.5 (quat. arom. C),
121.4, 116.3 (2£arom. CH), 103.8 (quat. arom. C), 99.2,
95.2 (2£arom. CH); EI-HRMS Calcd for C13H8O5 (Mþ)
244.0312, Found 244.0373.
4.2. General procedure for the prenylation of 1,3,5-tri-
hydroxyxanthone
4.3. General procedure for the photooxygenation–
reduction sequence at 15 8C
To the 1,3,5-trihydroxyxanthone 8 (0.3 g, 1.23 mmol) in
10% aqueous potassium hydroxide (15 mL) was added
4-bromo-2-methyl-2-butene (0.21 mL, 1.85 mmol). The
Dried air was bubbled through a CH2Cl2 solution (30 mL) of

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prenylated heterocyclic derivative (30 mg) and tetraphenyl-
porphine (3 mg, 0.005 mmol) as the photosensitizer. The
reaction mixture was water-cooled at 15 8C and irradiated
with a halogen lamp (500 W) for 1.5 h. Then 1.1 equiv. of
triphenylphosphine was added and the solution was stirred
overnight at room temperature.
(dd, 1H, CH2CHOH, J¼15, 8 Hz), 2.32 (m, 1H,
CH2CH(CH3)2), 1.81 (s, 3H, CH3), 1.06 (d, 6H, J¼7 Hz,
CH2CH(CH3)2); 13C NMR (CDCl3, 67.5 MHz): d 210.6
(COCH2CH), 167.0, 160.2 (2£quat. arom. C), 159.2
(OCOCH), 156.4, 156.3 (2£quat. arom. C), 146.5
(CH2vC(CH3)), 139.8 (quat. arom. C), 128.2, 127.8,
127.1, 112.3 (6£arom. CH), 110.7 (CH2vC(CH3)), 109.9,
103.8, 102.3 (3£quat. arom. C), 76.8 (CH2CHOH), 46.8
(COCH2CH), 28.7 (CH2CHOH), 27.2 (CH2CH(CH3)2),
18.4 (CH3), 16.6 (CH2CH(CH3)2), 11.9 (CH2CH(CH3)2);
EI-HRMS Calcd for C25H26O6 (Mþ) 422.1729, Found
422.1726.
Purification
Procedure A. The reaction mixture was washed four times
with 30 mL of an aqueous solution of potassium hydroxide
(5%). The combined aqueous layers were acidified down to
pH¼3 by addition of water-diluted chlorhydric acid (10%).
Then this solution was extracted four times with 30 mL
of dichloromethane. The combined organic layers were
concentrated under reduced pressure and were subjected to a
second cycle of basic extraction. The final organic layers
were evaporated under reduced pressure and yielded the
purified secondary allylic alcohol derivative.
4.3.3. Disprorinol A55,7-dihydroxy-8-(2-hydroxy-3-
methylbut-3-enyl)-6-(3-methyl-1-oxobutyl)-2H-4-phenyl-
benzopyran-2-one 14. The typical conditions described
in Section 4.3 were applied to 3 (30 mg, 0.08 mmol). The
purification of the crude product according to procedure B
followed by a recrystallization in AcOEt/hexane afforded 14
as a yellow solid (20 mg, 65%), mp 111–112 8C; acetate IR
1
Procedure B. The work-up, the same than that in procedure
A, was achieved at low temperature (between 0 and 5 8C) by
using cooled aqueous and organic solutions to avoid lactone
ring opening in basic medium.
(cm21): 3306, 1703, 1617, 1579, 1186; H NMR (CDCl3,
270 MHz): d 15.32 (s, 1H, OH), 10.18 (s, 1H, OH), 5.91 (s,
1H arom.), 4.99 (br s, 1H, C(CH3)vCH2), 4.88 (br s, 1H,
C(CH3)vCH2), 4.44 (dd, 1H, CH2CHOH, J¼7.5, 1.5 Hz),
3.24 (dd, 1H, CH2CHOH, J¼15, 1.5 Hz), 2.95 (m, 1H,
CH2CHOH), 2.95 (m, 2H, CH2CH2CH3), 3.07 (dd, 2H,
COCH2CH, J¼6.5, 1.5 Hz), 2.27 (m, 1H, CH2CH(CH3)2),
1.65 (m, 2H, CH2CH2CH3), 1.91 (s, 3H, CH3), 1.01 (t,
3H, J¼7.5 Hz, CH2CH2CH3), 0.94 (d, 6H, J¼6.5 Hz,
CH2CH(CH3)2); 13C NMR (CDCl3, 67.5 MHz): d 212.3
(COCH2CH), 164.3, 161.9 (2£quat. arom. C), 160.6p
(OCOCH), 160.2p, 157.9 (2£quat. arom. C), 145.9
(CH2vC(CH3)), 111.2 (CH2vC(CH3)), 109.5 (arom.
CH), 107.8, 104.6, 103.1 (3£quat. arom. C), 77.6
(CH2CHOH), 53.6 (COCH2CH), 38.6 (CH2CH2CH3), 28.8
(CH2CHOH), 25.2 (CH2CH(CH3)2), 22.8 (CH2CH(CH3)2),
22.6 (CH2CH2CH3), 18.7 (CH3), 14.0 (CH2CH2CH3);
EI-HRMS Calcd for C22H28O6 (Mþ) 388.1886, Found
388.1881.
4.3.1. Disparinol A55,7-dihydroxy-8-(2-hydroxy-3-
methylbut-3-enyl)-6-(3-methyl-1-oxobutyl)-2H-4-
phenyl-benzopyran-2-one 12. The typical conditions
described in Section 4.3 were applied to 1 (30 mg,
0.07 mmol). The purification of the crude product according
to procedure B followed by a recrystallization in AcOEt/
hexane, yielded 12 as a yellow solid (19 mg, 60%), mp
1
115–116 8C; IR (cm21): 1700, 1622, 1580, 756, 697; H
NMR (CDCl3, 270 MHz): d 14.33 (s, 1H, OH), 10.18 (s, 1H,
OH), 7.42 (m, 3H arom.), 7.33 (m, 2H arom.), 5.96 (s, 1H
arom.), 5.03 (br s, 1H, C(CH3)vCH2), 4.94 (br s, 1H,
C(CH3)vCH2), 4.50 (dd, 1H, CH2CHOH, J¼8, 2 Hz),
3.30 (dd, 1H, CH2CHOH, J¼15, 2 Hz), 3.04 (dd, 1H,
CH2CHOH, J¼15, 8 Hz), 3.02 (d, 2H, COCH2CH, J¼
6.5 Hz), 2.23 (m, 1H, CH2CH(CH3)2), 1.93 (s, 3H, CH3),
0.94 (d, 6H, J¼6.5 Hz, CH2CH(CH3)2); 13C NMR (CDCl3,
67.5 MHz): d 212.3 (COCH2CH), 163.4, 162.1 (2£quat.
arom. C), 159.9 (OCOCH), 157.7, 156.7 (2£quat. arom. C),
146.0 (CH2vC(CH3)), 139.4 (quat. arom. C), 128.3, 127.7,
127.2, 112.2 (6£arom. CH), 111.2 (CH2vC(CH3)), 107.4,
104.7, 102.2 (3£quat. arom. C), 77.7 (CH2CHOH), 46.6
(COCH2CH), 28.8 (CH2CHOH), 26.8 (CH2CH(CH3)2),
18.8 (CH3), 16.4 (CH2CH(CH3)2), 11.9 (CH2CH(CH3)2);
EI-HRMS Calcd for C25H26O6 (Mþ) 422.1729, Found
422.1726.
4.3.4. Caledol51,3,5-trihydroxy-2-(2-hydroxy-3-methyl-
but-3-enyl)-9H-xanthen-9-one 15. The typical conditions
described in Section 4.3 were applied to 9 (15 mg,
0.05 mmol). The purification of the crude product according
to procedure A yielded 15 as an orange oil (10 mg, 63%), IR
1
(cm21): 3233, 1645, 1619, 1455, 1223; H NMR (CDCl3,
270 MHz): d 13.46 (s, 1H, OH), 7.67 (dd, 1H arom., J¼7.5,
1.5 Hz), 7.34 (dd, 1H arom., J¼8, 1.5 Hz), 7.27 (dd, 1H
arom., J¼8, 7.5 Hz), 6.50 (s, 1H arom.), 4.93 (br s, 1H,
C(CH3)vCH2), 4.76 (br s, 1H, C(CH3)vCH2), 4.44 (dd,
1H, CH2CHOH, J¼7.5, 4 Hz), 3.09 (dd, 1H, CH2CHOH,
J¼14, 4 Hz), 2.93 (dd, 1H, CH2CHOH, J¼14, 7.5 Hz), 1.84
(s, 3H, CH3); 13C NMR (CDCl3, 67.5 MHz): d 181.2
(CO), 166.0, 161.8, 156.6 (3£quat. arom. C), 148.1
(CH2vC(CH3)), 146.8, 145.8 (2£quat. arom. C), 124.5
(arom. CH), 122.0 (quat. arom. C), 121.0, 116.0 (2£arom.
CH), 110.2 (CH2vC(CH3)), 109.3, 103.3 (2£quat. arom.
C), 95.1 (arom. CH), 76.2 (CH2CHOH), 29.3 (CH2CHOH),
18.1 (CH3); EI-HRMS Calcd for C18H16O6 (Mþ) 328.0947,
Found 328.0940.
4.3.2. Isodisparinol A55,7-dihydroxy-6-(2-hydroxy-3-
methylbut-3-enyl)-8-(3-methyl-1-oxobutyl)-2H-4-phenyl-
benzopyran-2-one 13. The typical conditions described in
Section 4.3 were applied to 2 (30 mg, 0.07 mmol). The
purification of the crude product according to procedure B
yielded 13 as a colorless oil (20 mg, 63%), IR (cm21): 3407,
1717, 1620, 1597, 758, 702; 1H NMR (CDCl3, 270 MHz): d
14.80 (s, 1H, OH), 9.29 (s, 1H, OH), 7.41 (m, 3H arom.),
7.32 (m, 2H arom.), 6.03 (s, 1H arom.), 4.93 (br s, 1H,
C(CH3)vCH2), 4.86 (br s, 1H, C(CH3)vCH2), 4.49 (dd,
1H, CH2CHOH, J¼8.5, 2 Hz), 3.20 (dd, 2H, COCH2CH,
J¼6.5, 1.5 Hz), 3.13 (dd, 1H, CH2CHOH, J¼15, 2 Hz), 2.77
4.3.5. 1,3,5-Trihydroxy-4-(2-hydroxy-3-methylbut-3-
enyl)-9H-xanthen-9-one 16. The typical conditions

J.-J. Helesbeux et al. / Tetrahedron 60 (2004) 2293–2300
2299
described in Section 4.3 were applied to 13 (30 mg,
0.1 mmol). The purification of the crude product by
preparative TLC (1% MeOH/CH2Cl2) yielded 19 as an
orange oil (3 mg, 8%), IR (cm21): 3274, 1648, 1562, 1274;
1H NMR ((CD3)2CO, 270 MHz): d 12.96 (s, 1H, OH), 7.67
(d, 1H arom., J¼8 Hz), 7.37 (d, 1H arom., J¼8 Hz), 7.26
(t, 1H arom., J¼8 Hz), 6.30 (s, 1H arom.), 4.92 (br s, 1H,
C(CH3)vCH2), 4.73 (br s, 1H, C(CH3)vCH2), 4.51 (dd,
1H, CH2CHOH, J¼7.5, 4 Hz), 3.33 (dd, 1H, CH2CHOH,
J¼14.5, 4 Hz), 3.13 (dd, 1H, CH2CHOH, J¼14.5, 7.5 Hz),
1.88 (s, 3H, CH3); 13C NMR ((CD3)2CO, 270 MHz): d
181.9 (CO), 165.5, 162.8, 156.0 (3£quat. arom. C), 148.3
(CH2vC(CH3)), 147.1, 146.2 (2£quat. arom. C), 124.7
(arom. CH), 122.1 (quat. arom. C), 121.2, 116.2 (2£arom.
CH), 110.3 (CH2vC(CH3)), 105.5, 103.7 (2£quat. arom.
C), 99.4 (arom. CH), 76.4 (CH2CHOH), 29.9 (CH2CHOH),
18.6 (CH3); EI-HRMS Calcd for C18H16O6 (Mþ) 328.0947,
Found 328.0936.
4.3.8. 6,11-Dihydroxy-5-(2-hydroxy-3-methylbut-3-
enyl)-3,3-dimethyl-3H,7H-pyrano[2,3-c]-xanthen-7-one
20. The typical conditions described in Section 4.3 were
applied to 11 (20 mg, 0.05 mmol). The purification of the
crude product by preparative TLC (5% MeOH/CH2Cl2)
yielded 20 as a green solid (5 mg, 21%), mp 180–182 8C;
1
IR (cm21): 3397, 1647, 1616, 1118; H NMR ((CD3)2CO,
270 MHz): d 13.49 (s, 1H, OH), 9.18 (s, 1H, OH), 7.69
(dd, 1H arom., J¼8, 1.5 Hz), 7.39 (dd, 1H arom., J¼8,
1.5 Hz), 7.29 (t, 1H arom., J¼8 Hz), 7.07 (d, 1H arom.,
J¼10 Hz), 5.77 (d, 1H arom., J¼10 Hz), 4.75 (br s, 1H,
C(CH3)vCH2), 4.67 (br s, 1H, C(CH3)vCH2), 4.42 (m,
1H, CH2CHOH), 2.96 (dd, 1H, CH2CHOH, J¼13.5,
6.5 Hz), 2.83–2.90 (m, 1H, CH2CHOH), 1.85 (s, 3H,
CH3), 1.52 (s, 6H, 2£CH3); 13C NMR ((CD3)2CO,
270 MHz): d 181.9 (CO), 162.0, 159.8, 150.9 (3£quat.
arom. C), 149.1 (CH2vC(CH3)), 146.9, 146.0 (2£quat.
arom. C), 127.7, 125.0 (2£arom. CH), 122.2 (quat. arom. C),
121.8, 116.5, 116.0 (3£arom. CH), 110.3 (CH2vC(CH3)),
109.9, 103.6, 101.6 (3£quat. arom. C), 79.2 (CHC(CH3)2),
75.2 (CH2CHOH), 29.7 (CH2CHOH), 28.5, 28.4, 17.1
(3£CH3); EI-HRMS Calcd for C23H22O6 (Mþ) 394.1416,
Found 394.1412.
4.3.6. 6-Deoxyisojacareubin56,11-dihydroxy-3,3-di-
methyl-3H,7H-pyrano[2,3-c]-xanthen-7-one 17. The
typical conditions described in Section 4.3 were applied to
10 (30 mg, 0.1 mmol). The purification of the crude product
by preparative TLC (1% MeOH/CH2Cl2) yielded 17 as a
yellow solid (5 mg, 17%), mp 235–236 8C; IR (cm21):
3223, 1646, 1579, 1289; 1H NMR ((CD3)2CO, 270 MHz): d
13.10 (s, 1H, OH), 9.22 (s, 1H, OH), 7.68 (dd, 1H arom.,
J¼8, 1.5 Hz), 7.39 (dd, 1H arom., J¼8, 1.5 Hz), 7.30 (dd,
1H arom., J¼8, 7.5 Hz), 7.05 (d, 1H arom., J¼10 Hz), 6.20
(s, 1H arom.), 5.77 (d, 1H arom., J¼10 Hz), 1.48 (s, 6H,
2£CH3); 13C NMR ((CD3)2CO, 270 MHz): d 181.8 (CO),
164.1, 161.7, 156.1, 146.9, 146.0 (5£quat. arom. C),
128.1, 125.1 (2£arom. CH), 122.2 (quat. arom. C), 122.0,
116.5, 115.7 (3£arom. CH), 104.1, 102.1 (2£quat. arom. C),
99.6 (arom. CH), 79.1 (CHC(CH3)2), 28.4 (2£CH3);
EI-HRMS Calcd for C18H14O5 (Mþ) 310.0841, Found
310.0836.
Acknowledgements
We are grateful to David Rondeau, from the SCAS, UFR
Sciences, 2 Bd Lavoisier, F-49045 Angers Cedex, France,
for the mass spectrometry analysis. We thank the
´
Departement du Maine et Loire for its financial support.
References and notes
4.3.7. Dicaledol51,3,5-trihydroxy-2,4-bis(2-hydroxy-3-
methylbut-3-enyl)-9H-xanthen-9-one 21. The typical
conditions described in Section 4.3 were applied to 11
(20 mg, 0.05 mmol). The purification of the crude product
by preparative TLC (5% MeOH/CH2Cl2) yielded 21 as a
yellow solid (3 mg, 14%), mp 159–161 8C; IR (cm21):
3219, 1641, 1580, 1222; 1H NMR ((CD3)2CO, 270 MHz): d
13.47 (s, 1H, OH), 7.67 (dd, 1H arom., J¼8, 1.5 Hz),
7.36 (dd, 1H arom., J¼8, 1.5 Hz), 7.26 (t, 1H arom.,
J¼8 Hz), 4.92 (br s, 1H, C(CH3)vCH2), 4.86 (br s, 1H,
C(CH3)vCH2), 4.75 (br s, 1H, C(CH3)vCH2), 4.68 (br s,
1H, C(CH3)vCH2), 4.50 (dd, 1H, CH2CHOH, J¼7.5,
4 Hz), 4.42 (dd, 1H, CH2CHOH, J¼8, 4 Hz), 3.29 (dd, 1H,
CH2CHOH, J¼14.5, 4 Hz), 3.14 (dd, 1H, CH2CHOH,
J¼14.5, 7.5 Hz), 3.10 (dd, 1H, CH2CHOH, J¼14, 4 Hz),
2.93 (dd, 1H, CH2CHOH, J¼14, 8 Hz), 1.89 (s, 3H, CH3),
1.85 (s, 3H, CH3); 13C NMR ((CD3)2CO, 270 MHz): d
182.0 (CO), 164.3, 160.3, 154.5 (3£quat. arom. C),
148.6, 148.4 (2£CH2vC(CH3)), 147.0, 146.2 (2£quat.
arom. C), 124.5 (arom. CH), 122.0 (quat. arom. C), 121.1,
116.3 (2£arom. CH), 110.4, 110.1 (2£CH2vC(CH3)),
109.5, 105.8, 103.4 (3£quat. arom. C), 76.5, 76.3
(2£CH2CHOH), 30.3, 29.9 (2£CH2CHOH), 18.4, 18.2
(2£CH3); CI-HRMS Calcd for C23H25O7 ([MþH]þ)
413.1600, Found 413.1585.
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