Concise total syntheses of (±)isopaucifloral F, (±) quadrangularin A, and (±)pallidol

Article abstract of DOI:10.1016/j.tetlet.2011.03.002

Concise total syntheses of (±)isopaucifloral F, (±) quadrangularin A, and (±)pallidol, starting from commercially available 3,5-dimethoxybenzoic acid, have been achieved by a sequential process. The overall synthetic strategy involves Nazarov cyclization, Ramberg-Backlund olefination, and Friedel-Crafts alkylation. Crown Copyright

Full text of DOI:10.1016/j.tetlet.2011.03.002

Tetrahedron Letters 52 (2011) 2815–2817
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise total syntheses of ( )isopaucifloral F, ( )quadrangularin A,
and ( )pallidol
⇑
Chen Zhong, Jun Zhu, Jun Chang, Xun Sun
School of Pharmacy, Fudan University, 826 Zhangheng Road, Shanghai 201203, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Concise total syntheses of ( )isopaucifloral F, ( )quadrangularin A, and ( )pallidol, starting from commer-
cially available 3,5-dimethoxybenzoic acid, have been achieved by a sequential process. The overall
synthetic strategy involves Nazarov cyclization, Ramberg–Backlund olefination, and Friedel–Crafts
alkylation.
Received 22 December 2010
Revised 22 February 2011
Accepted 22 February 2011
Available online 6 March 2011
Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
Keywords:
Natural products
Pallidol
Quadrangularin A
Isopaucifloral F
Total syntheses
Natural polyphenols, such as resveratrol (1), ( )isopaucifloral F
(2), ( )quadrangularin A (3), and ( )pallidol (4) as members of
the resveratrol family ( Fig. 1), have been isolated in different
plants, and some of which commonly occur even in red wine. These
natural products have been demonstrated to possess a variety of
biological activities, such as anti-cancer, anti-fungal, anti-bacterial,
and anti-oxidant.1–8 Particularly, ( )pallidol (4) has been found to
enable the modulation of the function of the estrogen receptor9
and thus exerts estrogen-like activity. The intriguing structures
coupled with their largely unexplored potential in medicine or
as tools for biological studies, rendered these natural products as
attractive targets for total synthesis.
Recently, Hou and co-workers reported an elegant approach for
the synthesis of ( )quadrangularin A via an indirect radical dimer-
ization of a cis-stilbene derivative.10 Subsequently, Snyder et al.
also described a general method by using a stilbene derivative as
the common building block and applying a variety of highly selec-
tive and reagent-control reaction cascades to accomplish the syn-
theses of up to 25 diverse natural products and analogues in the
resveratrol family.11 And Sarpong and co-workers also reported
an approach to the synthesis of the precursors of these dimeric
resveratrol natural products via a palladium-catalyzed domino
reaction.12 Although the reported synthetic strategies for those
natural products have their individual advantages, we would like
to explore a novel approach to synthesize these types of natural
products and analogues by our early reported Nazarov cyclization
HO
OH
OH
HO
HO
HO
OH
OH
O
( )isopaucifloral F (2)
resveratrol (1)
HO
HO
OH
H
OH
HO
HO
OH
OH
H
HO
HO
HO
OH
( )pallidol (4)
( )quadrangularin A (3)
Figure 1. Some representative examples of polyphenol.
incorporated with Ramberg–Backlund olefination, and Friedel–
Crafts alkylation. Herein we present our efforts to the synthesis
of ( )isopaucifloral F (2), ( )quadrangularin A (3), and ( )pallidol
(4).
Our retrosynthetic route to these natural products is outlined
(Scheme 1). From the biogenetic viewpoint, ( )pallidol may have
evolved from ( )quadrangularin A via a cation-based rearrange-
ment, in other words, by intramolecular electrophilic attack of
carbonium ion on benzyl position to another electron-richer and
⇑
Corresponding author.
E-mail address: sunxunf@shmu.edu.cn (X. Sun).
0040-4039/$ - see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.002

2816
C. Zhong et al. / Tetrahedron Letters 52 (2011) 2815–2817
MeO
results from Marco13, Flynn14 and our previous work on the total
MeO
synthesis of caraphenol C,15 another resveratrol-type natural prod-
uct. 2-Arylchalcone 6 could be conveniently prepared from the
commercially available 3,5-dimethoxybenzoic acid (5).
OMe
OMe
H
H
MeO
Friedel-Crafts
MeO
As shown in Scheme 2, our synthesis commenced with the acid 5.
The acid 5 was rapidly dimerized to give diaryl ketone 10 in 55%
yield by the treatment with Li-naphthalene reagent, as the modified
method.16 Then the ketone 10 was subjected to the Wittig–Horner
OMe
OMe
MeO
MeO
MeO
9
8
OMe
reaction condition to provide a,b-unsaturated ketone intermediate
COOH
6 in 78% yield as a mixture of E- and Z-isomer. It is noteworthy that
such obtained mixture could be used directly and have no influence
on the next Nazarov cyclization step.
Olefination
MeO
MeO
OMe
OMe
5
Based on our experience on the Nazarov cyclization reaction,14
trans-2,3-aryl indanone 7 (trans stereochemistry was supported by
vicinal coupling constant 2.6 Hz), as a more thermodynamic stabi-
lized conformation than its cis isomer, which could be offered in
MeO
MeO
Nazarov
Cyclization
OMe
MeO
OMe
85% yield after treating
a
,b-unsaturated ketone 6 with BF3ÁEt2O
OMe
O
MeO
O
at room temperature in dichloromethane for 40 h. With 7 in hand,
( )isopaucifloral F (2) was conveniently obtained in 54% after
removal of the protective methyl of 7 with BBr3 at 0 °C in dichloro-
methane for 8 h.
OMe
6
7
Scheme 1. Retrosynthetic route to the target natural products.
Meanwhile, we aimed at the second natural product, ( )qua-
drangularin A (3), and envisaged to achieve its precursor 8 from
7 in one step through straightforward olefination. However, in
our hands, tremendous efforts to this transformation were unsuc-
cessful by the routine methods such as Wittig, Tebbe, or Peterson
olefination reaction. Fortunately, Ramberg–Backlund olefination
for the aim was disclosed during this period.11 Thus, 7 was first re-
duced to 11 in an almost quantitative yield (>99%) by using sodium
borohydride in the mixed solvents of THF and MeOH for 30 min,
though 11 was obtained as a mixture of two isomers due to the
lack of the selectivity of the reductive reagent. However, this will
space-favorable aryl ring. Thus, 4 or its precursor 9 could be pro-
duced by intramolecular Friedel–Crafts alkylation if the desired
carbonium ion successfully generated from 8, and this strategy
for synthesis of 4 is unprecedented. Intermediate 8, a precursor
of ( )quadrangularin A (3), could be hypothesized to be available
via a simple olefination of 7, the precursor of ( )isopaucifloral F
(2). Although the outcome is uncertain for the steric configuration
of the olefin produced, intermediate 7 could be obtained from the
suitable 2-arylchalcone 6 through Nazarov cyclization based on the
MeO
OMe
OMe
COOH
O
p
-CH3O-PhCH2P(O)Ph2 (15)
BF3·Et2O
Li-naphthalene, THF
(CH3)3COK, Toluene, 25 oC
25 oC, 40 h
0 o
C
MeO
MeO
OMe
OMe
O
MeO
OMe
O
(74%)
(85%)
(44%)
OMe
OMe
6
5
10
MeO
MeO
MeO
OMe
OMe
MeO
MeO
p
-CH3O-PhCH2SH, In(OTf)3, CH2Cl2
NaBH4, THF, CH3OH
25 oC, 30 min (99%)
OMe
OMe
MeO
MeO
25 oC, 1 h
MeO
MeO
*
*
(75%)
OMe
(99%)
S
OMe
HO
O
OMe
12
BBr3, CH2Cl2
7
11
0 oC to 25 oC, 8 h
(54%)
( )isopaucifloral F (2)
MeO
MeO
HO
MeO
1) BH3·THF, THF
25 oC, 18 h
OMe
OMe
MeO
AlCl3, CH2Cl2
25 oC, 2 h
H
OMe
2) NaOH, 30% H2O2
MeO
MeO
MeO
1)
m
CPBA, NaHCO3, CH2Cl2
Na2SO3, 0 o
C
0 to 25 oC, 25 min
*
OMe
OMe
H
MeO
*
2) KOH, CCl4/t-BuOH/H2O = 5/5/1
(68%)
OMe
(81%)
OMe
80 oC, 12 h
(61%)
MeO
OMe
( )pallidol (4)
OMe
13
( )pallidol (4)
BBr3, CH2Cl2
BBr3, CH2Cl2
9
BBr3, CH2Cl2
8
0 oC to 25 oC, 8 h
0 oC to 25 oC, 8 h
(39%)
0 oC to 25 oC, 8 h
(55%)
( )quadrangularin A
(46%)
(3)
Scheme 2. Total syntheses of ( )isopaucifloral F (2), ( )quadrangularin A (3), and ( )pallidol (4).

C. Zhong et al. / Tetrahedron Letters 52 (2011) 2815–2817
2817
HO
MeO
HO
OH
HO
OMe
MeO
MeO
OH
BBr3, CH2Cl2
0 to 25 oC, 8 h
HO
HO
OH
OMe
(43%)
HO
OH
OH
( )parthenocissin A (14b)
OMe
OH
14a
Z-8
Scheme 3. An unexpected reaction of Z-isomer of 8 aiming at ( )parthenocissin A.
not be problematic since the new-formed chiral center will be
abolished at the later stage. Subsequently introduction of the
fourth suitable aryl ring into compound 11 through the In(OTf)3-
catalyzed nucleophilic substitution under dark in CH2Cl2 at room
temperature for 1 h, the sulfide 12 was obtained in 75% yield.
The sulfide 12 was further oxidized by mCPBA for 0.5 h in basic
aqueous solution and dichloromethane, the crude product ob-
tained without purification was used directly for Ramberg–Backl-
und reaction as the described protocol,11 to furnish 8, which was
identified as E-isomer, in 61% yield. Meanwhile, we can also get
the Z-isomer of 8 in 7% yield (Z-8), which is a potential precursor
for the synthesis of another natural product ( )parthenocissin A
(14b) (Scheme 3). After demethylation of 8 by the above-men-
tioned method for 2, we could smoothly get ( )quadrangularin A
(3) in 39% yield. Unexpectedly, when the corresponding Z-isomer
(Z-8) was performed under the same de-protective condition, it
was converted to 14a rather than the desired ( )parthenocissin A
(14b). Possibly, the resulting exo double bond preferrly shifts to
form a more stable endo form due to bulky hindrance of its neigh-
boring aryl rings.
Having completed the preparation of ( )quadrangularin A, our
attention was turned to the more complicated compound, ( )pall-
idol (4). According to the retrosynthetic approach, the desired ben-
zyl carbonium ion generated from 8 is required to undergo
intramolecular Friedel–Crafts alkylation in order to produce 9.
Although it would in principle be accomplished by straightforward
protonation of the olefin under appropriate Lewis or Bransted
acidic medium, we failed to complete this concise transformtion
after several attempts. Thus, an indirect transformation had to be
executed. Intermediate 8 was regio-selectively converted into the
alcohol 13 in 75% yield according to the standard hydroboration/
oxidation procedure, but it was very difficult to characterize the
alcohol 13 by NMR spectra data due to the existence of its three
other inseparable isomers. Then the mixed 13 was investigated
for the next step under various acidic conditions. It was found that
13 was successfully converted to the precursor of ( )pallidol (9) in
68% yield by being subjected to AlCl3 in CH2Cl2 at room tempera-
ture for 2 h, which was further being transformed into ( )pallidol
(4) in 46% yield by treating with BBr3. Interestingly, ( )pallidol
(4) could be efficiently obtained in one step from 13 in 55% yield
when BBr3 was used in our later detailed study, probably BBr3 is
strong enough to enable the alkylation and de-protection to occur
simultaneously.
The 1H and 13C NMR spectra of compounds 3 and 4 are in great
agreement with the respective reported data.11,17 Combined with
our previous work on the synthesis of caraphenol C, four members
of reservatrol family have been synthesized through the intermedi-
ate 2-arylchalone (6), which demonstrated that 2-arylchalone
could also serve as a common building block for the synthesis of
other resveratrol-type natural products.
Acknowledgments
The work was financially supported by the National Drug Inno-
vative Program (2009ZX09301-011), the National Natural Science
Foundation of China(30973612), and the Shanghai Municipal Com-
mittee of Science and Technology (08JC1401600). We are grateful
to Dr. Xinsheng Lei of School of Pharmacy, Fudan University for
invaluable discussions.
Supplementary data
Supplementary data (The material of experimental procedure
(Compound 2, 3, 4, 6, 7, 8, Z-8, 9, 10, 11, 12, 13, 14a, 15) and full
spectroscopic data for all the compounds is availble free of charge
via the Internet at http://www.sciencedirect.com/science/journal/
00404039) associated with this Letter can be found, in the online
version, at doi:10.1016/j.tetlet.2011.03.002.
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(four steps, 15% overall yield), ( )quadrangularin A (3) (seven
steps, 5% overall yield), and ( )pallidol (4) (eight steps, 5% overall
yield) have been achieved in a straightforward fashion, starting
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