The double oxa-Michael-aldol condensation: Straightforward access to dimeric tetrahydroxanthenones

Article abstract of DOI:10.1055/s-2007-992365

Symmetrical dimeric tetrahydroxanthenones can be obtained in a single step starting from dimeric salicylic aldehydes and cyclohexenones employing a double oxa-Michael-aldol condensation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-992365

LETTER
2987
The Double Oxa-Michael–Aldol Condensation: Straightforward Access to
Dimeric Tetrahydroxanthenones
A
C
ccess to
D
imeri
a
c
Tetrahyd
r
l
none
s
Friedrich Nising, Anne Friedrich, Stefan Bräse*
Institute of Organic Chemistry, University of Karlsruhe (TH), Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany
Fax +49(721)608858; E-mail: braese@ioc.uka.de
Received 12 September 2007
Dedicated to Prof. L. F. Tietze, a pioneer of domino reactions
tions of such obtained tetrahydroxanthenones directed
towards the substitution pattern of the secalonic acids. In
this context, the overall synthetic strategy of our envis-
aged total synthesis involved late-stage biaryl coupling of
fully functionalized tetrahydroxanthone monomers.
Abstract: Symmetrical dimeric tetrahydroxanthenones can be ob-
tained in a single step starting from dimeric salicylic aldehydes and
cyclohexenones employing a double oxa-Michael–aldol condensa-
tion.
4
Key words: tetrahydroxanthenones, domino reactions, oxa-Micha-
el–aldol condensation, mycotoxins, secalonic acids
However, a complementary and possibly more straight-
forward approach would consist of a double oxa-Micha-
el–aldol condensation between a dimeric salicylic
Tetrahydroxanthenones represent the core of various nat- aldehyde 3 and a functionalized cyclohexenone 4 as out-
ural products, many of which display interesting biologi- lined in Scheme 1.
cal activity. Especially toxic metabolites produced by
fungi (mycotoxins) often posses a tetrahydroxanthenone
structure. Prominent examples are the secalonic acids 1
and the dicerandrols 2, symmetrical dimeric tetrahydrox-
HO
O
OPG O
+
1
anthenones (Figure 1).
O
OPG
OH
PGO
OPG
HO
CO2Me
3
4
Me
O
OH
O
OH
OH
2
2′
OH
O
OH
O
Me
MeO2C
HO
CO2Me
O
OH
O
O
OH
OH
secalonic acids (1)
OH
O
OH
OR1
AcO
MeO2C
Me
O
OH
O
O
OH
1
2
2′
Scheme 1 Envisaged double oxa-Michael–aldol condensation
OH
O
OH
Me
Herein, we wish to report on the implementation of this
strategy leading to the first double domino oxa-Michael–
aldol condensation, a reaction that comprises four individ-
ual reaction steps.
OAc
2
R O
1
2
dicerandrol A (2a, R , R = H)
1
2
dicerandrol B (2b, R = Ac, R = H)
dicerandrol C (2c, R , R = Ac)
1
2
At first, we focused on the synthesis of a suitable dimeric
salicylic aldehyde as a model substrate. Starting from
commercially available 5-bromo-2-methoxysalicylalde-
Figure 1 The secalonic acids and the dicerandrols
We recently developed the domino oxa-Michael–aldol hyde (5), its dimeric product 6 could be obtained in excel-
condensation as an efficient access to tetrahydroxan- lent yield by using a one-pot Suzuki coupling with
2
,3
5
thenones. Furthermore, we also reported transforma- bis(pinacolato)diboron (Scheme 2). Alternatively, more
traditional versions of the Suzuki coupling involving pro-
tected versions of aldehyde 5 were also successful, but
less effective due to additional deprotection steps. In or-
der to address tetrahydroxanthenone natural products pos-
SYNLETT 2007, No. 19, pp 2987–2990
Advanced online publication: 08.11.2007
DOI: 10.1055/s-2007-992365; Art ID: G29207ST
x
x
.x
x
.2
0
0
7
6
©
Georg Thieme Verlag Stuttgart · New York

2
988
C. F. Nising et al.
LETTER
sessing a 4,4¢-biaryl unit we also synthesized dimeric ters are simultaneously formed in the reaction. The
aldehyde 8 by applying the same method. With com- reasons for this diastereoselectivity are not fully under-
pounds 6 and 8 in hand, we focused on the deprotection to stood yet and we are currently investigating this issue fur-
the corresponding salicylic aldehydes. After considerable ther, by both theoretical and chemical methods.
optimization, deprotection of aldehyde 6 proceeded with
With regard to 4,4¢-linked dimeric tetrahydroxan-
good yields, whereas salicylic aldehyde 10 could only be
thenones, we then tried to react salicylic aldehyde 10 un-
obtained in low yields, due to the formation of complex
der similar reaction conditions (Scheme 5). However, all
reaction mixtures (Scheme 3). Interestingly, only alumi-
attempts only resulted in the formation of complex reac-
num chloride with or without additional sodium iodide
tion mixtures along with large amounts of recovered start-
turned out to be effective for methyl ether cleavage,
ing material. This observation is most likely attributable
whereas other standard reagents (boron tribromide, thio-
to the considerable steric hindrance present in aldehyde
lates) only resulted in complex reaction mixtures. The
structure of compound 10 was unequivocally established
by NOE experiments.
1
0. Since it is well established that the first step of the
domino reaction, the oxa-Michael addition is reversible,
this reaction is often highly sensitive towards steric hin-
drance of the Michael acceptor. The present case under-
7
PdCl2(dppf)
O
lines that the steric properties of the salicylic aldehyde
also exert considerable influence on the outcome of the re-
action.
K2CO3, DMSO, 80 °C
Br
88%
OMe
O
O
O
O
5
MeO
B
B
O
AlCl3, NaI
CH2Cl2, MeCN
O
MeO
O
OMe
r.t.
O
6
46%
HO
O
OMe
O
6
OH
OMe O
9
PdCl2(dppf)
K2CO3, DMSO, 80 °C
OMe O
62%
OMe O
OMe O
OMe
OMe
OMe
O
O
O
O
B
B
Br
AlCl3, benzene
OH
OH
OMe
OMe
7
OMe O
80 °C
4%
8
Scheme 2 Synthesis of protected dimeric salicylic aldehydes
OMe O
10
OMe O
8
We then investigated the double oxa-Michael–aldol con-
densation of compounds 9 and 10 using 2-cyclohexenone
as Michael acceptor. We initially employed reaction pro-
tocols developed for simple domino oxa-Michael–aldol
Scheme 3 Deprotection of salicylic aldehydes
HO
O
DABCO
dioxan–H O
O
2
2
condensations , but had to realize that considerable opti-
r.t., 48 h
+
mization was necessary to achieve a double domino oxa-
Michael–aldol condensation. Thus, by varying reaction
parameters as solvent mixtures, concentration and reac-
tion time, we were able to obtain dimeric tetrahydroxan-
thenone 12 in excellent yield (Scheme 4). To the best of
our knowledge, the reaction presented here is the first ex-
ample of a double domino oxa-Michael–aldol condensa-
tion as well as the first synthetic access to homodimeric
tetrahydroxanthenones. Compound 12 was received as a
O
90%
OH
9
11
O
O
2
8a
2
'
7
6
O
O 10a 5
1
2
1
yellow solid and as a single diastereomer, according to H
NMR spectroscopy and TLC analysis. This is a remark-
able observation due to the fact that two stereogenic cen-
Scheme 4 Double domino oxa-Michael–aldol condensation
Synlett 2007, No. 19, 2987–2990 © Thieme Stuttgart · New York

LETTER
Access to Dimeric Tetrahydroxanthenones
2989
OMe O
EtOAc, 5:1). The product was obtained as a pale yellow solid (88
mg, 46% yield).
DABCO
dioxane–H2O
O
R = 0.19 (cyclohexane–EtOAc, 5:1). IR: 2963, 1663, 1414, 1282,
f
5–72 h
–
1 1
OH
OH
1098 cm . H NMR (400 MHz, CDCl ): d = 7.10 (d, J = 9.6 Hz, 2
3
+
H, 5,5¢-H), 7.70–7.75 (m, 4 H, 2,2¢-H, 6,6¢-H), 9.99 (s, 2 H, alde-
various conditions
OMe
1
3
hyde-H), 11.02 (s, 2 H, OH). C NMR (100 MHz, CDCl ):
3
1
1
d = 118.5 (C-5,5¢), 121.1 (C-3,3¢), 131.7 (C-2,2¢), 131.9 (C-1,1¢),
O
135.5 (C-6,6¢), 161.4 (C-4,4¢), 196.8 (C-aldehyde). MS (EI, 70 eV):
OMe O
+
+
m/z = 242 [M ], 43 [C H O]. HRMS: m/z calcd [M ]: 242.0579;
2
3
10
found: 242.0581.
O
O
2
,2¢-Dihydroxy-3,3¢-diformyl-4,4¢-dimethoxybiphenyl (10)
In a 50 mL Schlenk flask equipped with reflux condenser 2,2¢,4,4¢-
tetramethoxy-3,3¢-diformylbiphenyl (8, 0.560 g 1.70 mmol) was
dissolved in benzene (15 mL) and AlCl (0.460 g, 3.45 mmol) were
3
OMe
O
added with stirring. The mixture was stirred at reflux temperature
for 15 h. After quenching the reaction by adding deionized H O, the
1
3
2
biphasic mixture was extracted with CH Cl (5 × 50 mL). The com-
2
2
Scheme 5 Attempted synthesis of 4,4¢-linked dimeric tetrahydro-
bined organic phase was then dried over Na SO . After evaporation
2 4
xanthenones
of the solvent, the residue was purified by column chromatography
cyclohexane–EtOAc, 2:1). The product was obtained as a pale yel-
(
low solid (20 mg, 4% yield).
In summary, we have developed an efficient access to
dimeric tetrahydroxanthenones employing a double dom-
ino oxa-Michael–aldol condensation protocol. To the best
of our knowledge the reaction described here is the first of
its kind and represents the first synthetic access to dimeric
R = 0.49 (cyclohexane–EtOAc, 2:1). IR: 3025, 1629, 1268, 1093,
f
–
1 1
9
64 cm . H NMR (250 MHz, CDCl ): d = 3.93 (s, 6 H, CH ), 6.47
3
3
(d, J = 8.5 Hz, 2 H, 6,6¢-H), 7.53 (d, J = 8.5 Hz, 2 H, 5,5¢-H), 10.38
(s, 2 H, aldehyde-H), 12.41 (s, 2 H, OH). C NMR (62.5 MHz,
13
CDCl ): d = 56.2 (CH ), 101.0 (C-6,6¢), 111.1 (C-3,3¢ 117.4 (C-
3
3
tetrahydroxanthenones. The dimeric aldehyde substrates 1,1¢), 140.8 (C-5,5¢), 161.4 (C-2,2¢), 162.4 (C-4,4¢), 194.8 (C-alde-
+
+
are readily available by a one-pot Suzuki coupling and hyde). MS (EI, 70 eV): m/z = 302 [M ]. HRMS: m/z calcd [M ]:
3
02.0786; found: 302.0790.
dimeric tetrahydroxanthenones can be obtained in excel-
lent yields. However, the reaction is also sensitive towards
steric hindrance and hindered salicylic aldehydes are not
suitable substrates for this reaction.
5
,6,7,10a,5¢,6¢,7¢,10¢a-Octahydro[2,2¢]bixanthenyl-8,8¢-dione
(
12)
In a 5 mL single neck flask a mixture of dioxane–H O (1:1; 0.8 mL)
2
was degassed for 15 min (Ar stream). After adding 4,4¢-dihydroxy-
3
,3¢-diformylbiphenyl (9, 47 mg, 0.190 mmol), 2-cyclohexene-1-
Solvents and chemicals used for reactions were purchased from
commercial suppliers. Solvents were dried under standard condi-
tions, chemicals were used without further purification. All reac-
tions were carried out under Ar in flame-dried glassware.
Evaporation of solvents and concentration of reaction mixtures
were performed in vacuo at 40 °C on a Büchi rotary evaporator.
Thin-layer chromatography (TLC) was carried out on silica gel
plates (Kieselgel 60, F254, Merck) with detection by UV and visu-
alization by spraying with the Seebach solution. Normal-phase sili-
ca gel (Silica gel 60, 230-400 mesh, Merck) was used for
preparative chromatography. IR spectra were recorded on a Bruker
one (11, 0.05 mL, 0.047 g, 0.480 mmol), and DABCO (21.8 mg,
.19 mmol), the mixture was sonicated for 48 h. After the addition
of deionized H O, the mixture was extracted with CH Cl (3 × 5 ml)
0
2
2
2
and the combined organic phase dried over Na SO . After evapora-
2
4
tion of the solvent, the crude product was recrystallized from
dichlorobenzene. The product was obtained as a yellow solid (70
mg, 90% yield).
–
1 1
R = 0.16 (cyclohexane–EtOAc, 5:1). IR: 3442, 1675 cm . H NMR
(500 MHz, CDCl ): d = 1.68–1.79 (m, 2 H, CH ), 1.99–2.14 (m, 4
H, CH ), 2.31–2.63 (m, 6 H, CH ), 5.03 (ddd, J = 10.7 Hz, 5.9 Hz,
f
3
2
2
2
–
1
1
13
IFS88. Absorption is reported as n values in cm . H NMR and
NMR spectra were recorded on Bruker AC-250, AM-400 or DRX
00 spectrometers. Chemical shifts are reported as d values (ppm)
C
1.9 Hz, 2 H, 10a,10¢a-H), 6.94 (d, J = 8.5 Hz, 2 H, 4,4¢-H), 7.36 (d,
J = 2.2 Hz, 2 H, 1,1¢-H), 7.41 (dd, J = 8.5 Hz, 2.20 Hz, 2 H, 3,3¢-H),
1
3
5
7.47 (d, J = 1.9 Hz, 2 H, 9,9¢-H). C NMR (100 MHz, CDCl3):
downfield from internal TMS in the indicated solvent. High-resolu-
tion mass spectra (HRMS) were determined on a Finnigan MAT90.
d = 18.0, 29.7, 38.9 (CH ), 74.9 (C-10a,10¢a), 116.4 (C-4,4¢), 122.4
2
(C-9a,9¢a), 127.7 (C-1,1¢), 130.3 (C-3,3¢), 130.9 (C-2,2¢), 131.3 (C-
9
,9¢), 134.3 (C-8a,8¢a), 155.2 (C-4a,4¢a), 197.4 (C-ketone). MS (EI,
+ + +
4
,4¢-Dihydroxy-3,3¢-diformylbiphenyl (9)
In a 50 mL Schlenk flask 4,4¢-dimethoxy-3,3¢-diformylbiphenyl (6,
.217 g, 0.800 mmol) was dissolved in MeCN (10 mL) and CH Cl
70 eV): m/z = 398 [M ], 342 [(M – C H O) ], 286 [(M – C H O ) ].
HRMS: m/z calcd for [M ]: 398.1518; found: 398.1516.
3 4 6 8 2
+
0
2
2
(
10 mL) and then cooled to 0 °C. Then, AlCl (0.535 g, 4.01 mmol)
3
and NaI (0.602 g, 4.01 mmol) were added with stirring. After stir- Acknowledgment
ring for 48 h at r.t., the mixture was quenched by adding deionized
H O and then extracted with CH Cl (5 × 100 mL). The combined
organic phase was washed with sat. aq Na S O solution and deion-
Financial support from the Schering-Stiftung (fellowship for
C.F.N.) and the Landesgraduiertenförderung Baden-Württemberg
2
2
2
2
2
3
(fellowship for A.F.) is gratefully acknowledged.
ized H O, then dried over Na SO . After evaporation of the solvent,
2
2
4
the residue was purified by column chromatography (cyclohexane–
Synlett 2007, No. 19, 2987–2990 © Thieme Stuttgart · New York

2
990
C. F. Nising et al.
LETTER
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Synlett 2007, No. 19, 2987–2990 © Thieme Stuttgart · New York

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