Cascade Claisen Rearrangement: Rapid Synthesis of Polysubstituted Salicylaldehydes and Total Syntheses of Hemigossypol and Gossypol

Article abstract of DOI:10.1002/anie.201801612

A cascade Claisen rearrangement of a well-organized maltol propargyl ether for the construction of polysubstituted salicylaldehydes is reported. This reaction features high atom economy (100 %), as well as catalyst-free and gram-scale conditions. Based on this novel methodology, the total synthesis of hemigossypol, gossypol, and their analogues has been realized.

Full text of DOI:10.1002/anie.201801612

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Accepted Article
Title: Cascade Claisen Rearrangement: Rapid Synthesis of
Polysubstituted Salicylaldehydes and Total Synthesis of
Hemigossypol and Gossypol
Authors: Shifa Zhu, Tongxiang Cao, Yi Kong, Kui Luo, and Lianfen
Chen
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801612
Angew. Chem. 10.1002/ange.201801612
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10.1002/anie.201801612
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Cascade Claisen Rearrangement
Cascade Claisen Rearrangement: Rapid Synthesis of Polysubstituted
Salicylaldehydes and Total Synthesis of Hemigossypol and Gossypol
Tongxiang Cao, Yi Kong, Kui Luo, Lianfen Chen, and Shifa Zhu*
[
10]
Abstract: A cascade Claisen rearrangement of well-organized
maltol propargyl ether for the construction of polysubstituted
salicylaldehydes was reported. This reaction featured high atom
economy (100%), as well as catalyst-free and gram-scale
conditions. Based on this novel methodology, we have realized the
total synthesis of hemigossypol, gossypol, and their analogues.
difficult.
The complementary methods using a parent arene to
introduce the desired functional groups by means of Friedel-Crafts
reaction, S Ar reaction, cross-coupling reaction or C(sp )-H
2
N
activation can serve as a good solution. However, these reactions
usually need pre-activation, pre-functionalization of the arene,
directing group assistance, or extensive reaction condition
optimization for satisfactory selectivity and reactivity. Therefore,
the development of efficient and practical methods for the rapid
synthesis of polysubstituted salicylaldehyde derivatives would be a
challenging but promising project.
Maltol and kojic acid, pyrone-containing natural products, have
been widely used in oxidopyrylium-based [5+2] cycloaddition
Scheme 2).
[
11]
P
olysubstituted salicylaldehydes and their derivatives are
ubiquitous in pharmaceuticals, natural products and agrochemicals,
such as hemigossypol, gossypol, helicocide H , Taiwaniaguinol B,
1
[
1]
brussonol, and bryopogonic acid (Scheme 1). Among them,
gossypol is found in flowers, seeds, roots and foliage of cotton
plants, where it serves as a defense compound against insect pests
[
12]
(
In addition to the synthetic methodology, Wender
[
2]
and co-workers also applied this method to the landmark total
and pathogens. It has attracted a lot of interest for its multiple
pharmacological activities including spermicidal, antiparasitic,
[
13]
syntheses of phorbol and C6,C7-epi-yuanhuapin. In these [5+2]
cycloaddition reactions, the pyrone moiety served as a five-carbon
synthon to assemble the oxa-bridged bicyclic system. Herein we
disclose an entirely new reaction type for pyrone, a cascade Claisen
rearrangement of well-organized maltol propargyl ether for the
rapid synthesis of polysubstituted salicylaldehyde through a cut-
and-sew strategy, where the aromatic pyrone was torn apart and
then fused into benzene ring. The reaction is a catalyst-free process
and proposed to occur through the 1,6-Michael addition of p-
quinone-methide (p-QM) intermediate. This protocol featured high
atom economy (100%) and gram-scale conditions (Scheme 2).
[
3]
anticancer, and antiviral activities.
Hemigossypol is the
biosynthetic precursor of gossypol and has shown improved anti-
[
4]
fungal activity compared to gossypol. Despite the tremendous
progress achieved in transition metal-catalyzed polyphenol
[
5]
synthesis, construction of these compounds in a concise manner
[
14]
[
6]
still remains a difficult problem due to low selectivity and
oxidant sensitivity (such as oxidative phenolic coupling and
[
1d-e, 7]
dearomatic reactivity),
which may result in protecting-group
or redox manipulation and multistep processes for the introduction
of other substituents.
Scheme 1. Natural products containing polysubstituted phenol.
[
8]
[9]
Traditionally, Diels-Alder and 6π-electrocyclization reaction
can assemble the cyclohexene skeleton, but further oxidation is
commonly required to access the benzene structure. Dehydro-
Diels-Alder and transition metal-catalyzed [2+2+2] reactions can
form the benzene skeleton, but a mixture of isomers is often
obtained, and the introduction of polyphenolic hydroxyl groups is
[
] Mr. T. Cao, Mr. Y. Kong, Mr. K. Luo, Dr. L. Chen, and Prof. S. Zhu
School of Chemistry and Chemical Engineering
Scheme 2. Pyrone-based transformations.
First, maltol propargyl ether 1a, which can easily be prepared
from naturally occurring maltol and propargyl bromide in only one
step with a 94% yield, was chosen as the model substrate for this
investigation. Styrene was used as the nucleophile to trap the
South China University of Technology, Guangzhou 510640 (China)
E-mail: zhusf@scut.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201xxxxxx.
[15]
proposed p-QM intermediate (Scheme 2). As shown in Table 1,
1
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Angewandte Chemie International Edition
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[
a]
that the gram-scale reactions proceeded smoothly as well, giving
the desired products in good yields (2a-b: 1-10 gram scale).
Furthermore, the reactions of maltol propargyl ether 1a with a
variety of alkene substrates as nucleophiles were carried out (2d-v).
In addition to styrene, various styrene derivatives effectively
reacted with 1a, furnishing 2d-n in 39-71% yields. Both electron-
rich and electron-poor styrene derivatives functioned well to afford
the desired fully substituted salicylaldehydes. The results indicated
that electron-rich styrenes were better substrates and gave the
products in higher yields. When gem-substituted styrenes were
used, the products with a quaternary carbon center were formed in
moderate yields (2o-p).The sterically congested spiro-compound
was tolerated as well, albeit with a lower yield (2q). However, the
simple aliphatic alkene did not work (2r). The more electron-rich
conjugated diene and enyne were investigated as well, furnishing
the corresponding products in good yields (2s-u). It’s worth
mentioning that estrone-derived styrene was also a good substrate
for this reaction, delivering the desired product 2v in 48% yield. In
addition, we have tried both allyl trimethylsilane and allyl boronic
acid pinacol for this reaction, but no desired products were
observed. Internal alkyne ethers were also treated with styrene
under the standard conditions, however, it only led to complicated
mixtures (see details in SI). The structure of compounds 2j, 2t, and
Table 1. Optimization of the reaction conditions.
o
Entry
Cat.
Add.
Sol.
DCE
T ( C)
2a (%)
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
-
3
3
3
3
PAuCl
PAuCl
PAuCl
PAuCl
AgBF
AgBF
4
60
ND
ND
ND
53
4
DCE
120
120
150
150
150
150
150
NaBArF
DCE
NaBArF
MeCN
MeCN
DCE
-
-
-
-
59
[
b]
b]
-
67
64
75
[
-
PhMe
PhCl
[
b]
-
[
a] Unless otherwise noted, the reaction was performed with 1a (0.25 mmol)
and styrene (0.88 mmol) for 13 h under the N atmosphere. The yield was
]. [b] Isolated yield.
2
1
3 2 6 3 4
determined by H NMR. NaBArF: Na[B(3,5-(CF ) C H )
gold salts were initially utilized as the catalyst owing to their high
efficiency in promoting the transformation of alkynes through
activating the C≡C bond. However, no product was detected at
0 C, and the reaction didn’t work even at an elevated temperature
of 120 C with Ph PAuCl/AgBF or Ph PAuCl/NaBArF as the
catalyst (Table 1, entries 1-3). Encouragingly, a 1,6-Michael
addition/Friedel-Crafts product 2a was detected in 53% yield when
the temperature was further raised to 150 C with CH CN as the
solvent (entry 4). However, the control reaction without the gold
salt proceeded equally well, which indicated that this reaction is a
non-catalytic thermolysis process (entry 5). In the absence of
catalysts and additives, the yield of 2a was further enhanced to
5% by variation of solvent (entries 6-8, see SI for more details).
With the optimized conditions (Table 1, entry 8) in hand, the
[
16]
o
6
o
3
4
3
2
v was confirmed by X-ray diffraction analysis.
o
3
A plausible mechanism is proposed in Scheme 3. The initial
dearomatic propargylic-Claisen rearrangement establishes a well-
organized 1,5-ene-allene intermediate A, which then undergoes a
second allenylic-Claisen rearrangement to furnish the aldehyde B.
After tautomerization, the key intermediate p-QM C is formed and
trapped by an intermolecular 1,6-Michael addition of an alkene to
give D, followed by an intramolecular Friedel-Crafts reaction and
7
substrate scope was then explored. As shown in Table 2, this
cascade reaction was successfully extended to propargyl ethers 1
derived from different maltols. For example, the propargyl ethers
from ethyl maltol and isopropyl maltol were transferred to the
products 2b and 2c in 74% and 50% yields, respectively. It is noted
1
,5-hydrogen shift to deliver the desired product 2.
[
a]
Table 2. Evaluation of various alkenes and maltol ethers.
Scheme 3. Proposed mechanism.
To investigate the necessity of the substituent at the C2-position,
a progargyl ether of kojic acid 3 was then synthesized (Scheme 4).
[
17]
Consistent with Elmore’s results, the furo[3,2-b]pyrone 4a was
formed in 56% yield when the reaction was conducted in the
absence of trapping reagent. At the same time, an unexpected
product chromone 4b was also obtained in 25% yield. Compounds
4
a and 4b might come from the cyclization of the rearomatized
allene intermediate G. These results demonstrated the importance
of the anchor group at C2-position, which might block the
rearomatization pathway.
[a] Reaction conditions: 1 (0.25 mmol) and alkene (0.88 mmol), under N
2
; [b]
estrone-derived styrene (0.2 mmol) and 1a (0.7 mmol).
Scheme 4. Investigation of the substituent effect at C2-position.
2
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The reaction was easily scaled up to 10-gram quantities without
loss of yield (5a). p-Methoxybenzyl alcohol (PMB-OH) was also a
good nucleophile for this reaction, affording the desired PMB-
protected ether 5d in 65% yield. Naturally occurring alcohols
geraniol and prasterone were also employed to trap the transient
Michael acceptor, leading to the products 5e and 5f in 72% and
In order to trap the cationic intermediate D, benzyl alcohol,
which might act as a nucleophile, was added to the reaction
mixture of 1a and styrene. A mixture of 2 and 5a was ultimately
furnished rather than the desired three-component adducts.
Fortunately, when internal alkyne ether 6a was used, 7a and 8 were
obtained in 46% and 8% yields, respectively. The yield of 8 was
increased to 39% when no alcohol was added. 8 might come from
the trapping of 6a-derived p-QM intermediate by 1,1-
diphenylethylene to form a relatively stable cationic intermediate,
followed by an elimination process. Although we failed to directly
trap D, the generation of 8 demonstrated that a D-like cationic
intermediate was involved in the cascade process (Scheme 5).
5
4% yields, respectively. What’s more, fully substituted
salicylaldehyde products 7a-t were furnished with internal
propargyl maltol ethers 6 as the substrates and Bn-OH or PMB-OH
as the nucleophile. As shown in table 3, the reactions proceeded
smoothly when the propargyl group was capped with different aryl
groups (7a-p). It seems that the reaction was not very sensitive to
the electronic properties of the aryl groups (7a-n), with the product
yields ranging from 45% to 69%. The structure of product 7g was
unambiguously confirmed by X-ray diffraction analysis. The
naphthyl-, thienyl- and alkyl-substituted alkynes were tolerated as
well, giving the desired products (7o-r) in slightly lower yields.
Products 7s and 7t bearing an allylic handle group, aimed at the
total synthesis of gossypol and its analogues, were obtained on a
large scale in an acceptable yield.
In the efforts to demonstrate the synthetic utility of this
procedure, we took advantage of the highly substituted parent
benzene for further transformations. As shown in Scheme 6,
product 5a was transferred to the bromo-salicylaldehyde 9 in 41%
yield with Br /HOAc as the brominating reagent. Furthermore, the
2
deprotection and oxidation of 5d gave rise to aldehyde 10 in 43%
Scheme 5. Attempts to trap the cationic intermediate.
yield.
Based on the above observation, we then moved to trap the
proposed p-QM intermediate with different alcohols, aiming for
penta- and hexa-substituted salicylaldehyde derivatives, which
might be used as a key precursor for the total synthesis of
hemigossypol and gossypol. Considering the benzyl ether could be
easily deprotected, benzyl alcohol (Bn-OH) was initially tested as
the nucleophile. As expected, the desired pentasubstituted
salicylaldehyde products 5a-c were produced in 63-72% yields
from terminal propargyl ethers 1 derived from different maltols.
Scheme 6. Further transformation of products 5.
To further illustrate the practicability of this unique
methodology, we began the journey of the total synthesis of
hemigossypol, gossypol and their analogues (Scheme 7). The
synthesis started with methylation and reduction of fully
substituted salicylaldehyde 7t to furnish 11 in 86% yield over three
steps. After Wacker oxidation and a Wittig reaction of 11, the
alkene 12 was obtained in 88% yield. Deprotection of 12 with
DDQ and subsequent oxidation with IBX gave aldehyde 13 in 76%
yield. An efficient intramolecular Alder-ene reaction occurred for
the aldehyde 13 to assemble the bicyclic tetrahydronaphthol 14 in
[
a]
Table 3. Evaluation of various alcohols and maltol ethers.
8
0% yield, which differed from the previous synthetic strategy by
[
18-19]
using a Friedel-Crafts reaction
to construct the naphthalene
skeleton. Afterward, oxidation and methylation took place to
generate naphthalene 15 in 68% total yield. According to the
[
18c]
reported protocol,
the methyl ether 15 was selectively
deprotected, followed by IBX oxidation to provide 16, which was
then globally demethylated by BBr to deliver hemigossypol 17 in
3
5
2% yield. The endgame to complete the total synthesis of
t
gossypol 18 was achieved by treating 17 with BuO Ac under
nitrogen at 80 C for 2.5 hours in 41% yield. The spectral data of
2
o
synthetic 17 and 18 was in full agreement with those reported for
these natural products. It’s worth mentioning that the methyl
analogues of hemigossypol 17’ and gossypol 18’ were also
obtained from polysubstituted salicylaldehyde 7s following a
similar procedure (see SI for details).
Prevously several groups realized the total synthesis of gossypol.
In 1958, Edwards reported the first synthesis using a late-stage
[
18a, 19a]
formylation strategy (9 steps).
In 1997, Meyers achieved the
first asymmetric total synthesis of (S)-(+)-gossypol (23 steps and
8
.71% yield), highlighted by
a
chiral oxazoline-induced
Recently, Wang develop-
[
a] Reaction conditions: 1 or 6 (0.2 mmol) and alcohol (0.7 mmol), DCE, 150
[
18b]
o
C, 13 h, under N
2
; [b] PhCl as solvent; [c] prasterone (0.2 mmol) and 1a (0.7
diastereoselective Ullmann coupling.
ed a practical route to gossypol from commercially available
o
mmol); [d] 140 C, 24 h; Bn: benzyl group; PMB: p-methoxybenzyl.
3
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Angewandte Chemie International Edition
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Scheme 7. Total synthesis of hemigossypol, gossypol and their analogues.
carvacrol (19 steps and 6.67% yield), which featured an oxidative
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[
18c]
1
964, 57, 283; b) J. E. Mellon, C. A. Zelaya, M. K. Dowd, S. B. Beltz,
phenolic dimerization.
Our synthesis with polysubstituted
M. A. Klich, J. Agric. Food Chem. 2012, 60, 2740.
salicylaldehyde 7t as the starting material successfully preinstalled
[
[
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[
18c,19h]
otherwise difficult to access.
Although the inevitable
protection/deprotection of these groups resulted in a slightly
lengthy procedure (15 steps and 3.73% yield), the intramolecular
carbonyl-ene reaction for the rapid synthesis of the polysubstituted
naphthol skeleton added another highlight to this total synthesis.
In summary, we have disclosed a novel reaction type for pyrone,
the cascade Claisen rearrangement of well-organized maltol
propargyl ether for the rapid synthesis of polysubstituted
salicylaldehyde through a cut-and-sew strategy, where the aromatic
pyrone was torn apart and then fused into benzene ring. This
reaction is a catalyst-free process and proposed to go through the
cascade dearomatic propargylic-Claisen rearrangement/allenylic-
Claisen rearrangement/1,6-Michael addition. It featured high atom
economy (100%) and easy scale-up (up to 18-gram quantities).
Based on this methodology, we also realized the total synthesis of
hemigossypol, gossypol, and their analogues, which were
highlighted by maltol-type cascade Claisen rearrangement and
intramolecular Alder-ene reaction. Benefiting from the obvious
advantages, this method holds great potential for the synthesis of
polyphenolic natural products.
6
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We are grateful to Ministry of Science and Technology of the People’s
Republic of China (2016YFA0602900), National Natural Science Foundation
of China (21672071), the Science and Technology Program of Guangzhou
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[
Keywords: Claisen rearrangement • gram-scale • atom economy •
catalyst-free • gossypol
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Angewandte Chemie International Edition
10.1002/anie.201801612
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Cascade Claisen Rearrangement
Tongxiang Cao, Yi Kong, Kui Luo,
Lianfen Chen, and Shifa Zhu*
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Cascade Claisen Rearrangement: Rapid
Synthesis of Polysubstituted
Salicylaldehydes and Total Synthesis of
Hemigossypol and Gossypol
A cascade Claisen rearrangement of well-organized maltol propargyl ether for the
construction of polysubstituted salicylaldehydes was reported. This reaction
featured high atom economy (100%), as well as catalyst-free and gram-scale
conditions. Based on this novel methodology, we have realized the total synthesis
of hemigossypol, gossypol, and their analogues.
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