Expeditious synthesis of the aromatic spiroketal skeleton using hetero-Diels-Alder cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2006.03.092

The hetero-Diels-Alder reactions of enolic ethers generated from methylenation of various esters are described, which allow for the rapid synthesis of various substituted [6,6] aromatic spiroketal skeletons.

Full text of DOI:10.1016/j.tetlet.2006.03.092

Tetrahedron Letters 47 (2006) 3349–3352
Expeditious synthesis of the aromatic spiroketal skeleton
using hetero-Diels–Alder cycloaddition
Guanglian Zhou, Deping Zheng, Shijun Da, Zhixiang Xie* and Ying Li*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
Received 18 January 2006; revised 14 March 2006; accepted 15 March 2006
Abstract—The hetero-Diels–Alder reactions of enolic ethers generated from methylenation of various esters are described, which
allow for the rapid synthesis of various substituted [6,6] aromatic spiroketal skeletons.
Ó 2006 Elsevier Ltd. All rights reserved.
Aliphatic spiroketals have attracted much attention, and
there are many examples for the synthesis of the non-
anomeric structures.1 However, the aromatic spiroketal
skeletons, which are found in a broad range of bioactive
natural products such as heliquinomycin (1) and its ana-
logues (Fig. 1),2 remain a formidable challenge despite
the progress, which has been achieved in this area in
the recent years.3 Our interest in the structures of diverse
aromatic spiroketal skeletons promoted us to consider
methods for expeditious synthesis of these molecules.
The synthesis of aliphatic spiroketals using hetero-
Diels–Alder reactions have been explored by Pzul in
1954.4 o-Quinone methides are known to react with a
range of dienophiles to perform [4+2] cycloaddition.5
To our knowledge, the use of hetero-Diels–Alder reac-
tion for the synthesis of the aromatic spiroketal skele-
tons such as A has not previously been reported
(Fig. 2). We envisioned that the aromatic spiroketal
skeleton A could arise from a cycloaddition between
the o-quinone methides B and the enolic ethers C or
D. In this letter, we wish to report our results on the
rapid synthesis of various substituted [6,6] aromatic
spiroketal skeletons by using hetero-Diels–Alder
reactions.
Because of our experience with o-quinone methide reac-
tivity, we firstly examined their capacity of reacting with
commercially available ethoxyethene (8). Initially, the
o-quinone methides for the reaction were prepared on
the basis of the simple protocol described by Bolon.7a
As shown in Figure 3, to generate the o-quinone methide
from o-cresol (7), oxidation reagent Ag2O was added,
then ethoxyethene was mixed at room temperature,
but no product was found. Using 2-methylbenzene-1,4-
diol (10) as o-quinone methide precursor, 2-methylcyclo-
hexa-2,5-diene-1,4-dione (11) was obtained in 80% yield.
Very recently, a new and efficient method for o-quinone
methides intermediate generation from o-methylene-
acetoxy-phenols has been developed and applied by
Baldwin.5h Based on this methodology, o-quinone
methides precursor were prepared. The syntheses of
o-quinone methides precursor was started from com-
mercially available o-hydroxybenzaldehyde (12 or 13).
The corresponding aldehydes 14 and 15 were readily
prepared by acylation of o-hydroxybenzaldehyde (12
or 13) with Ac2O in the presence of K2CO3 in ethyl
ether. The conversion of the aldehyde (14 or 15) to the
o-quinone methides precursor (16 or 17) was realized
by using borane–DMS complex reduction (Scheme 1).
o-Quinone methides are extremely reactive transient spe-
cies, undergoing dimerization or trimerization in the ab-
sence of a nucleophile or electron-rich alkene.6 There are
many strategies, which have been established in order to
generate o-quinone methides in situ in the past years.7
o-Quinone methides generated in the presence of the eth-
oxyethene lead to cycloaddition, adduct 18 (Table 1),
which thus verifies the Baldwin’s methodology. After
optimization of the reaction time and temperature cyclo-
addition adduct 18 was obtained in 60% yield.
*
Corresponding authors. Tel.: +86 0931 8912526 (Z.X.); tel.: +86
0931 8912788; fax: +86 0931 8913103 (Y.L.); e-mail addresses:
xiezx@lzu.edu.cn; liying@lzu.edu.cn
Enolic ethers D for the reaction can be readily prepared
on the basis of the protocol described in the literature.8
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.092

3350
G. Zhou et al. / Tetrahedron Letters 47 (2006) 3349–3352
O
O
HO
O
HO
O
O
O
OH
O
OH
O
MeO
MeO
CO2Me
CO2Me
O
O
O
O
OH
OH
OMe O
OMe
β-Rubromycin 2
O
HO
Heliquinomycin 1
O
O
HO
O
HO
O
O
O
OH
O
O
OH
MeO
MeO
CO2Me
O
CO2Me
O
O
O
R
OH
OH
R
OH
OH
Griseorhodin C 5: R = OH
Griseorhodin G 6: R = OH
α-Rubromycin 3: R = H
Purpuromycin 4: R = OH
Figure 1. Examples of biologically active aromatic spiroketal.
Table 1. Cycloaddition of 2-acetoxymethyl-5-acetoxyphenol with
ethoxyethene
R
R
R
O
O
C
OAc
O
n
O
2.5 eq,
PhH, 110 ºC, 16 h
R
OEt
R
AcO
O
OEt
AcO
OH
18
O
B
17
A
D
n = 1 or 2
Entry
Time (h)
Temperature (°C)
Yield (%)
1
2
3
4
10
16
24
24
110
110
110
130
52
60
60
60
Figure 2. Proposed construction of the aromatic spiroketal skeletons A
by cycloaddition of the o-quinone methides B and the enolic ethers C
or D.
OH
O
O
OEt
OEt
Ag2O, rt
+
the case where no catalyst was used, the o-quinone met-
hides precursor 17 and the enolic ethers 19 gave spiro-
ketal product 24a as a single regioisomer in 59% yield;
the addition of TiCl4 as catalyst improved the yield to
71%. Variation of enolic ethers D was carried out.
Results (entries 2–5) suggest that the yield of spiroketal
product was not significantly affected by the enolic
ethers.9 Using compound 16 as the o-quinone methides
precursor, the yield of spiroketal products was slightly
decreased (entries 6 and 7).
8
9
7
OH
+
OEt
Ag2O, rt
HO
O
11
10
8
Figure 3. Using Bolon’s protocol to generate the o-quinone methide.
In order to further explore the versatility of this cyclo-
addition, we tried to synthesize various substituted
[5,6] aromatic spiroketal skeletons by hetero-Diels–
Alder reactions. The synthesis of enolic ethers such as
C was carried out using Yan’s methodology.8 Unfortu-
nately, methylenation with benzofuran-2(3H)-one (25)
under the standard conditions gave an olefin isomeriza-
tion product 27, which is believed to be derived from the
normal product 26 (Scheme 2). Now the synthesis of the
enolic ethers such as 26 is under process.
K2CO3
CHO
OAc
CHO
OH
Ac2O, Et2O,
rt 30 min
R
R
14 R = -H
15 R = -OAc
12 R = -H
13 R = -OH
THF, 0 ºC-rt
BH3-DMS
OAc
OH
R
16 (R = -H), 17 (R = -OAc)
In conclusion, the hetero-Diels–Alder reactions of enolic
ethers generated from methylenation of various esters
are described, which allow for the rapid synthesis of
various substituted [6,6] aromatic spiroketal skeletons.
These heterocyclic compounds may be prove to be med-
ically interesting molecules in the future.
Scheme 1. Preparation of o-quinone methides precursor.
Our studies then focused on the hetero-Diels–Alder
cycloaddition between the o-quinone methides B and
the enolic ethers D. As shown in Table 2, entry 1, in

G. Zhou et al. / Tetrahedron Letters 47 (2006) 3349–3352
Table 2. Cycloaddition of the o-quinone methides precursor C with enolic ethers D
3351
Entry
o-Quinone methides precursor
Enolic ethers
Spiroketal product
Yield (%)a
AcO
59b
71c
O O
1
17
O
19
24a
AcO
Br
O O
Br
2
3
4
17
17
17
48
O
20
24b
AcO
O O
58b
70c
O
21
24c
OMe
AcO
60b
73c
O O
MeO
O
O
22
24d
OMe
Br
AcO
Br
O O
5
17
59
MeO
23
24e
O O
6
7
16
16
51
47
O
19
24f
OMe
Br
Br
O O
MeO
O
23
24g
a Yields were calculated after column chromatography.
b Yield obtained without any catalyst.
c Yield obtained by the catalysis of TiCl4.
O
TiCl4, Mg, THF, Toluene
CH2Cl2, 0 ºC-rt
2. (a) Brockmann, H.; Lenk, W.; Schwantje, G.; Zeeck, A.
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O
O
26
25
O
27
Scheme 2. Preparation of the enolic ethers such as C.
Acknowledgements
We are grateful for the financial support of the National
Natural Science Foundation of China (Grant Nos.
20272020 and 20021001).
References and notes
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ketals: In a sealed tube was stirred 6-bromo-3,4-dihydro-2-
methylene-2H-benzopyran (112.0 mg, 0.50 mmol) with
2-acetoxymethyl-5-acetoxyphenol (17) (112.0 mg, 0.50 mmol)
in benzene (1.0 mL) at 110 °C under argon for 28 h. After
evaporation of benzene under reduced pressure, the colour-
less oil obtained was purified by flash silica gel chromato-
graphy (16:1 30–60 P.E.:EtOAc) to give a white solid
(90.1 mg, 48%) of spiroacetal (24b). Mp 123–124 °C; 1H
NMR (300 MHz, CDCl3, d ppm): 7.25 (d, 1H), 7.09–
7.17 (m, 2H), 6.59–6.65 (m, 2H), 6.49 (d, J = 2.1 Hz, 1H),
3.17–3.23 (m, 2H), 2.68–2.76 (m, 2H), 2.24 (s, 3H), 2.17–
2.21 (m, 2H), 1.90–2.00 (m, 2H). 13C NMR (75 MHz,
CDCl3, d ppm): 20.4, 20.7, 21.1, 30.7, 30.9, 96.2, 110.4,
113.0, 114.2, 118.9, 119.7, 124.3, 129.5, 130.0, 131.5, 149.5,
151.1, 152.4, 169.6. MS (ESI) FW = 388.03, m/z = 388.00.
HRMS calcd for C19H17BrO4 (M+NHþ4 Þ 406.0648, found
406.0650.
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