A Short, Atom-Economical Entry to Tetrahydroxanthenones

Article abstract of DOI:10.1002/anie.200352154

A reaction that takes to water: The domino Michael addition/aldol condensation of salicylic aldehydes like 1 as the nucleophile and 2-cyclohexen-1-one (2) as the Michael acceptor provides 2,3,4,4a-tetrahydroxanthen-1-ones such as 3 in good yields. DABCO =

Full text of DOI:10.1002/anie.200352154

Angewandte
Chemie
Privileged Structures
A Short, Atom-Economical Entry to
Tetrahydroxanthenones**
Bernhard Lesch and Stefan Bräse*
Dedicated to Professor Burchard Franck
Heterocycles play an important role in the design and
[
1]
discovery of new physiologically active compounds. In the
field of modern medicine “privileged structures,” groups of
compounds whose members bind on different classes of
[
2]
receptors, have attracted much attention. The best known
[
2]
examples are the benzodiazepines.
The xanthones, which have more than 600 members, over
00 of which display a tetrahydroxanthone moiety, are among
1
[
3]
these privileged structures. Secalonic acids (Scheme 1) and
[
4]
ergochromes are members of this group of natural products.
All secalonic acids are 2,2’-fused xanthone dimers, differing
only with respect to the configuration of several C atoms in
[
5]
the framework. The secalonic acids exhibit toxic, antibacte-
[
6]
[7]
rial, and mutagenic properties, along with fetotoxic and
[
8]
teratogenic actions. Some derivatives of the secalonic acids
were tested as cytostatics. Secalonic acid D inhibits HIV
protease
acid F is phytotoxic.
[
9]
[
10]
[11]
and several protein kinases,
while secalonic
[
12]
Despite the potential of xanthones as privileged structures
in the search for new pharmaceuticals, only one successful
total synthesis of a member of this group is known, that of 10-
[
13]
methyl-10-demethoxycarbonylhemisecalonic acid A.
The
[*] Prof. Dr. S. Bräse
Institut für Organische Chemie
Universität Karlsruhe (TH)
Fritz-Haber-Weg 6, 76131 Karlsruhe (Germany)
Fax: (+49)721-608-8581
E-mail: braese@ioc.uka.de
Dipl.-Chem. B. Lesch
KekulØ-Institut für Organische Chemie und Biochemie
Rheinische Friedrich-Wilhelms-Universität Bonn
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
[**] This work was supported by the Fonds der Chemischen Industrie
and the Deutschen Forschungsgemeinschaft (DFG) (SFB 380).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 115 –118
DOI: 10.1002/anie.200352154
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115

Communications
Scheme 1. Selected natural products with a tetrahydroxanthone moiety.
key step in this synthesis is the oxidative ring closure of a
[
14]
benzophenone derivative. Several other routes to partially
hydrogenated tetrahydroxanthones have also been de-
[
15]
scribed.
From a retrosynthetic point of view, tetra- and hexahy-
droxanthones can be dissected into an arene and a cyclohex-
ane. In order to sidestep CÀO and CÀC coupling reactions on
Scheme 3. Reaction conditions: 0.5 equiv DABCO, water, RT, sonifica-
tion, 48 h, 83%.
the arene unit, the bridging carbon and the oxygen atoms
must be derived from the arene, which sets fewer limitations
on the substitution pattern of the arene unit. Based on these
considerations we chose 2-hydroxybenzaldehyde as the arene
core and 2-cyclohexen-1-none for the cyclohexane building
block.
The attempted Baylis–Hillman reaction of O-benzyl-
ated salicylic aldehyde (2) and 2-cyclohexen-1-one (3) gave
the desired allylic alcohol 4 in poor yields (Scheme 2). In
[
17a]
carbonate
hol,
or potassium tert-butoxide in tert-butyl alco-
[
17b]
which supports the domino oxa-Michael/aldol con-
densation pathway. However, when DABCO was used as a
base, a sequence of the Baylis–Hillman reaction and a
Michael addition was invoked.
that the Baylis–Hillman reaction is accelerated by sonifica-
tion. The reaction described in Scheme 3 can be performed
with potassium carbonate as a base, while attempts with
triphenylphosphane, a known catalyst for the Baylis–Hillman
reaction, failed. The reaction presented should therefore be
regarded as a domino oxa-Michael addition/aldol condensa-
[
17d,e]
Furthermore, it is known
[
16]
[
18]
[
19]
tion reaction. Using sonification instead of stirring ensured
the effective mixture of the biphasic system.
To gain deeper insight into the scope and limitations of
this method, several electron-rich and electron-poor o-
hydroxybenzaldehydes were used as substrates, along with
cyclohexenone and cyclopentenone. The products obtained
are listed in Table 1. Since the starting materials are not
soluble in water, dioxane/water mixtures were used as
solvents without further optimization of the conditions. 2-
Cyclohexen-1-one was superior to the more sensitive 2-
cyclopent-1-one as a substrate, probably because the latter
oligomerizes under basic conditions. Substitution of C3 of
the cyclohexenone is not tolerated under the tested con-
ditions. Donor-substituted or benzoannelated tetrahydroxan-
thones could be isolated in reasonable yields. Only the
acceptor-substituted product 6c was obtained in moderate
yield, probably due to the lower nucleophilicity of the
corresponding phenolate anion.
Scheme 2. a) K CO , BnBr, CH CN, reflux, 18 h, 89%; b) DABCO
2
3
3
(
1.0 equiv), dioxane/water 1:1, RT, 72 h, 13%. RT=room temperature.
contrast, the analogous reaction of unprotected salicylic
aldehyde (1) with 2-cyclohexen-1-one did not result in the
Baylis–Hillman adduct 5, but rather the tetrahydroxanthone
[
20]
6
a (Scheme 3) in good yields. The best results, 83% yield,
were obtained when the reaction was conducted in degassed
water, with 1,4-diazabicyclo[2.2.2]octane (DABCO) as a base,
and with sonification.
Tetrahydroxanthone 6a may be formed by two different
routes (Scheme 3): The first route starts with a Baylis–
Hillman reaction followed by an oxa-Michael addition and
dehydration. In the second approach the sequence is initiated
by the Michael addition of the phenol on the cyclohexenone
and a subsequent aldol condensation provides the tetrahy-
droxanthone.
The chemistry of the a,b-unsaturated system 6a was
examined with respect to the total synthesis of the secalonic
acids. This required careful control of the oxidation states at
C1, C9, and C9a. Since the direct osmium-catalyzed dihy-
droxylation of 6a failed, the ketone was reduced with NaBH4
The synthesis of chromenes starting from 2-hydroxybenz-
aldehydes and acyclic Michael acceptors is a known reac-
to give the allylic alcohol 7 (Scheme 4). This was dihydroxy-
[
17]
[21]
tion. Typically it is performed in dioxane with potassium lated using Upjohn conditions, giving rise to the triol 8,
1
16
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Angewandte
Chemie
Table 1: Range of products from the domino oxa-Michael/aldol con-
densation between salicylic aldehydes and cyclohexenone and cyclo-
pentenone.
1
2
3
4
R
R
R
R
n
Product
Yield [%]
H
OH
H
H
OH
H
H
H
H
H
H
H
H
OCH3
H
H
NO2
H
H
OCH3
H
H
H
H
H
H
H
H
H
H
2
2
2
1
1
2
2
2
6a
6b
6c
6d
6e
6 f
83
48
25
23
19
93
63
67
Scheme 5. a) KOH, H O , MeOH, 08C, 30 min, 61%; b) 0.1 equiv
2
2
KOH, 1.1 equiv PhSH, 1 equiv NEt , THF/MeOH 4:1, RT, 1 h, 90%
3
À1
(
NMR); c) aq phosphate buffer (c=0.1 molL , pH 2.5), RT, 18 h,
quant.
OCH3
H
6g
6h
H
H
2
6i
70
while the acetylated derivative 9 yielded the hydroxyketone
0 when two equivalents of the oxidant were used. If only one
equivalent was used, the diol 11 was isolated along with traces
of the hydroxyketone 10 (Scheme 4).
Scheme 6. a) NBS, H O, DMSO, 08C to RT, 2 h, 80%; b) 3 equiv
2
DABCO, dioxane, RT, 18 h, 73%. DMSO=dimethyl sulfoxide,
NBS=N-bromosuccinimide.
1
under mild reaction conditions. This method provides an
efficient route to this complex class of natural products.
Studies on a possible asymmetric variant of the reaction are in
progress. We are also examining the not-well-studied oxida-
[
22]
tive coupling of the monomeric xanthones
secalonic acids.
to give the
Received: June 11, 2003 [Z52154]
Keywords: domino reactions · Michael addition ·
.
secalonic acids · xanthones
Scheme 4. a) NaBH , MeOH, RT, 4 h, 77%; b) K OsO , K CO ,
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2
4
2
3
1
.1 equiv NMO, acetone/water 5:1, RT, 72 h, 51%; c) 2 equiv Ac O,
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pyridine, 08C to RT, 4 h, 83%; d) K OsO , K CO , 2.2 equiv NMO, ace-
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