Total synthesis of pulverolide: Revision of its structure

Article abstract of DOI:10.1016/j.tetlet.2010.07.044

A flexible and practical strategy toward the synthesis of rare 2H-furo[3,2-b]benzopyran-2-one skeleton has been developed. With a microwave-assisted cyclization-dehydration as the key transformation, the first total synthesis of pulverolide has been compl

Full text of DOI:10.1016/j.tetlet.2010.07.044

Tetrahedron Letters 51 (2010) 4874–4876
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Tetrahedron Letters
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Total synthesis of pulverolide: revision of its structure
c,
Wanqiu Yang a,b, Jikai Liu a,b, , Hongbin Zhang
*
*
a State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan 650204, PR China
b Graduate School of Chinese Academy of Sciences, Beijing 100049, PR China
c Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming, Yunnan 650091, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A flexible and practical strategy toward the synthesis of rare 2H-furo[3,2-b]benzopyran-2-one skeleton
has been developed. With a microwave-assisted cyclization–dehydration as the key transformation,
the first total synthesis of pulverolide has been completed in 10 steps with 9% overall yield, leading to
the revision of its proposed structure.
Received 26 May 2010
Revised 7 July 2010
Accepted 9 July 2010
Available online 15 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Pulverolide
Butenolide
Total synthesis
Revision of structure
Pulveroboletus ravenelii is a genus in the Boletaceae. The fruiting
bodies are known as edibles and are used in traditional Chinese
medicine to cure lumbago and painful legs, numbed limbs, and
to stop bleeding.1 The chemical study of P. ravenelii resulted in a
new butenolide-type fungal pigment pulverolide (1, Fig. 1).2 The
structure of pulverolide, with a rare 2H-furo[3,2-b]benzopyran-2-
one skeleton, was assigned on the basis of spectroscopic analysis.
To date, there are only two analogs (aurantricholides A and B)
found in nature.3 These compounds are scarce components and
could be isolated in only small amounts from higher fungi. Our pre-
vious biological assay indicated that pulverolide potentiated the
one ring of pulverolide (1) could be assembled directly from inter-
mediate 4 by a Lewis acid-mediated cyclization–dehydration. The
key compound 4 could be accessed by a vinylogous aldol reaction.
Starting from commercially available isovanillin, we expected that
the highly rigid pulverolide-type skeleton could be obtained in an
efficient fashion.
We began our research by the reaction of isovanillin with allyl
bromide in the presence of potassium carbonate. The resulting allyl
ether (7) was then subjected to a solvent-free Claisen rearrange-
ment assisted by microwave irradiation5 to afford phenol 8 in
90% yield. By treatment of phenol 8 with chloromethoxymethane
in the presence of sodium hydride in THF, aldehyde 9 was obtained
in 68% yield. Baeyer–Villiger oxidation of aldehyde 9 followed by
hydrolysis of the resulting phenol ester gave phenol 10 (83% yield).
After protection of the phenol group with benzyl bromide, isomer-
ization of the double bond in the presence of t-BuOK6 gave com-
glutamatergic transmission which is mediated by
a-amino-3-hy-
droxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor.4
Therefore pulverolide could possibly serve as a starting point to-
ward the discovery of drug candidates for treating Alzheimer’s dis-
ease. Because of its unique structure and interesting bioactivity, we
were prompted to undertake the synthesis of pulverolide (1). Here-
in we report the first total synthesis of pulverolide and the revision
of its structure.
4'
R
5'
3'
2'
D
Although a synthetic route leading to aurantricholides A and B
has been reported, which also served as a means for the confirma-
tion of its structures,3a the key irradiation-mediated cyclization
step in this synthesis gave only 1% yield of the desired cyclization
products. In seeking a more efficient and flexible synthesis of 1 and
its analogs, we designed a new synthetic plan as outlined in
Scheme 1. We envisioned that the 2H-furo[3,2-b]benzopyran-2-
O
1'
3"
2"
1"
O
B
O
3
2
4"
HO
HO
O
O
C
A
O
O
O
O
1
O
4
6"
OH
O
5
OH
1: Pulverolide
2: Pulverolide
3a: R = H, Aurantricholide A
3b: R = OH, Aurantricholide B
(proposed structure) (revised structure)
* Corresponding authors. Fax: +86 871 5150227 (J.L.), +86 871 5035538 (H.Z.).
E-mail addresses: jkliu@mail.kib.ac.cn (J. Liu), zhanghb@ynu.edu.cn (H. Zhang).
Figure 1. Natural products with 2H-furo[3,2-b]benzopyran-2-one.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.044

W. Yang et al. / Tetrahedron Letters 51 (2010) 4874–4876
4875
Br
OMe
O
HO
1, K2CO3, Acetone
2, t-BuOK, THF
OH
OMe
OH
HO
OH
O
+
O
O
O
O
O
95%
O
Et
O
O
O
6
OH
R
1
4
OMe
OMe
OH
OH
OH
OH
HO
38%
OH
+
O
H
HO
O
LDA, HMPA
THF, -55 C
MeO
HO
O
O
O
OBn
OBn O
O
º
O
MeO
O
R
14
4a
O
Isovanillin
6
5
OMe
15
MW, NH4OAc
245 ºC
Scheme 1. Retrosynthetic analysis of pulverolide.
OH
O
O
60%
BnO
OH
pound 12 (see Scheme 2, 78% over two steps). An oxidative cleav-
age of the double-bond in olefin 12 followed by hydrolysis in the
presence of aqueous hydrochloric acid (3 N) in acetone resulted
in aldehyde 14 (63%, two steps).
HO
4'
5'
OMe
OMe
2"
Having obtained intermediate 14, we then synthesized 3-phen-
yltetronic acid 6 via a Dieckmann condensation between phenyla-
cetic acid and ethyl bromoacetate in the presence of bases (see
Scheme 3, two steps, 95%).7 Next, we came to the key stage of
our research, a vinylogous aldol reaction and a ring-closing ether-
ification. Aldol reaction between a sterically hindered aldehyde
such as compound 14 and tetronic acid 6 has not been reported;
therefore we decided to attempt the reaction by following a similar
procedure documented in the literature.7 The dianion form of
tetronic acid 6 was generated by treatment of compound 6 with
lithium diisopropylamide (LDA) in THF at -78 °C. To the dianion
solution, salicylaldehyde 14 in THF was added. To our disappoint-
ment, low yield of alcohol 4a (2%) was obtained. No desired prod-
2'
1'
HBr/HOAc
91%
O
3
4"
5"
2
O
O
1
O
4
BnO
1"
5
O
O
OH
16
1
Scheme 3. Studies on the synthesis of pulverolide (originally proposed structure).
uct was detected when the reaction was conducted with LDA
(3.0 equiv) in the presence of zinc chloride (1.0 equiv) or copper io-
dide (1.0 equiv). Finally we found that the yield could be increased
by using lithium diisopropylamide (3.0 equiv) in the presence of
hexamethylphosphoramide (HMPA). Under the optimal reaction
condition, we were able to obtain alcohol 4a as a mixture of two
diastereoisomers (38% yield, see Scheme 3).
OMe
OMe
OMe
OH
O
OH
º
MW, 200 C
allyl bromide
With compound 4a in hand, we came to the final stage toward the
synthesis of pulverolide. Direct dehydration under high tempera-
ture (150 °C in DMF) in the presence of a Lewis acid (e.g., BF3-Et2O,
TsOH) proved to be fruitless, giving a complex mixture. We then
decided to attempt the ring-closing etherification under microwave
heating in the presence of a Lewis acid. After a few screenings, we fi-
nally found that compound 16 could be obtained in 60% yield under
the irradiation of microwave at 245 °C in o-xylene (see Scheme 3).
Although amino acids such as glycine and proline could mediate this
transformation, ammonium acetate, might serve as acid–base cata-
lyst as well as dehydration agent, proved to be the best additive in
this microwave-assisted reaction. This dehydration–cyclization
might go through an intermediate (15) as highlighted in Scheme 3.
The target molecule was finally obtained after the removal of ben-
zyl-protecting group by hydrolysis in the presence of a strong acid
(33 wt % HBr in acetic acid, 91% yield).8
The NMR spectral data of compound 1 unfortunately did not
match that of natural pulverolide (see Supplementary data). The
chemicalshifts (1H NMR) of protons attaching to the polysubstituted
phenolic C-ring of natural pulverolide are found at 7.12 and
7.17 ppm, and are significantly downfield in comparison with the
corresponding proton signals of synthetic compound 1, which
appear at 6.85 and 7.09 ppm. Differences of chemical shifts in the
13C NMR were also noticed (see Supplementary data). The NMR data
indicated that synthetic compound 1 and natural pulverolide are not
the same. The methoxyl group in natural pulverolide, previously as-
signed at C-2 position, should be relocated to C-5 position as showed
in Figure 1.
K2CO3, DMF
95%
90%
O
H
O
H
O
H
7
8
Isovanillin
MOMCl
NaH, THF
68%
a, m-CPBA
NaHCO3, DCM
O
H
HO
OMe
OMe
b, K2CO3, MeOH
83%
OMOM
OMOM
10
9
BnBr, K2CO3
Acetone, reflux
90%
BnO
t-BuOK
THF, N2, rt.
BnO
OMe
OMe
OMOM
OMOM
87%
12
11
OsO4, NMNO
THF/t-BuOH/H2O
NaIO4, Acetone/H2O
69%
3 N HCl, Acetone
91%
BnO
OMe
BnO
O
OMe
O
OH
OMOM
13
14
Scheme 2. Synthesis of aldehyde 14.

4876
W. Yang et al. / Tetrahedron Letters 51 (2010) 4874–4876
Deprotection of benzyl group with HBr (33% wt.) in acetic acid finally
OMe
H
O
H
provided pulverolide 2 (95%, Scheme 4). 1H and 13C NMR spectra as
well as IR spectroscopic data of synthetic compound 2 were identical
to those reported for natural pulverolide. Therefore the revised
structure for pulverolide 2 was confirmed.
BnBr, K
2CO3
OH
OMe
OBn
Acetone, reflux, 94%
8
17
82%
O
In conclusion, we have developed the first practical and flexible
method for the synthesis of 2H-furo[3,2-b]benzopyran-2-one skele-
tons. Based on a vinylogous aldol reaction and a microwave-assisted
cyclization–dehydration, we successfully synthesized pulverolide.
This synthetic work leads to the revision of its originally proposed
structure. Further pulverolide analogs are now being prepared for
bioassay, and the results will be reported in due course.
a, m-CPBA, NaHCO3CH2Cl2
b, K2CO3, MeOH
OH
t-BuOK, THF, N2, rt.
HO
OMe
OBn
BnO
84%
OMe
19
18
OsO4, NMNO
Acknowledgments
62%
THF/t-BuOH/H2O
NaIO4, Acetone/H2O
This work was supported by National Basic Research Program of
China (973 Program 2009CB522300), Natural Science Foundation
of China (20832005), and Natural Science Foundation of Yunnan
Provincial Science & Technology Department (2007B0006Z).
O
OMe
OH
LDA, HMPA
THF, -55ºC
O
O
HO
O
OBn
O
OH
OH
BnO
+
40%
MeO
OH
20
O
Supplementary data
21
MW, NH4OAc,
245 C, 70%
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.044.
º
HBr, HOAc
95%
O
O
O
References and notes
O
O
MeO
MeO
OBn
1. Duncan, C. J. G.; Cuendet, M.; Fronczek, F. R.; Pezzuto, J. M.; Mehta, R. G.;
Hammann, M. T.; Ross, S. A. J. Nat. Prod. 2003, 66, 103.
OH
2
22
2. Zhang, L.; Wang, F.; Dong, Z. J.; Steglich, W.; Liu, J. K. Heterocycles 2006, 68, 1455.
3. (a) Klostermeyer, D.; Knops, L.; Sindlinger, T.; Polborn, K.; Steglich, W. Eur. J. Org.
Chem. 2000, 603; (b) Knops, L.; Nieger, M.; Steffan, B.; Steglich, W. Liebigs Ann.
1995, 77.
Scheme 4. Synthesis of pulverolide (revised structure).
4. Yang, W. Ph.D. Thesis. Graduate School of Chinese Academy of Sciences, 2010, p
3.
5. Kumar, H. M. S.; Anjaneyulu, S.; Reddy, B. V. S.; Yadav, J. S. Synlett 2000, 1129.
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Pelter, A.; Al-Bayati, R. I. H.; Ayoub, M. T.; Lewis, W.; Pardasani, P.; Hansel, R. J.
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8. Cherney, R. J.; Brogan, J. B.; Mo, R.; Lo, Y. C.; Yang, G.; Miller, P. B.; Scherle, P. A.;
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To confirm the structure, compound 8 was then converted to
benzyl ether 17 by treating with benzyl bromide in the presence of
potassium carbonate. Baeyer–Villiger oxidation followed by hydro-
lysis of the resulting ester provided 18 (82%). After isomerization of
the double bond, oxidative cleavage of the double-bond in
compound 19 gave salicylaldehyde 20 (52% over two steps). A vinyl-
ogous Aldol reaction with tetronic acid 6 followed by dehydration
under microwave condition afforded the tricyclic compound 22.