Bifunctional squaramide-catalyzed synthesis of chiral dihydrocoumarins via ortho-quinone methides generated from 2-(1-tosylalkyl)phenols

Article abstract of DOI:10.1039/c7cc01072a

A bifunctional squaramide-catalyzed reaction of azlactones with o-quinone methides in situ generated from 2-(1-tosylalkyl)-phenols has been successfully developed under basic conditions, providing an efficient and mild access to chiral dihydrocoumarins bearing adjacent tertiary and quaternary stereogenic centers in high yields with excellent diastereo- and enantioselectivities.

Full text of DOI:10.1039/c7cc01072a

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Bifunctional squaramide-catalyzed synthesis of chiral dihydro-
coumarins via the ortho-quinone methides generated from 2-(1-
tosylalkyl)phenols
Received 00th January 20xx,
Accepted 00th January 20xx
Ji Zhou,a,b Mao-Lin Wang,a Xiang Gao,b Guo-Fang Jianga* and Yong-Gui Zhoub*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A bifunctional squaramide-catalyzed reaction of azlactones and o- Xiao’s group reported the construction of the same scaffold by
quinone methides in situ generated from 2-(1-tosylalkyl)-phenols the triple Brønsted acid catalyzed formal [4+2] cycloaddition of
has been succesfully developed under basic condition, providing the azlactones and in situ generated o-QMs from o-hydroxy
an efficient and mild access to chiral dihydrocoumarins bearing benzhydryl alcohols.6n Although the above protocols have
adjacent tertiary and quaternary stereogenic centers in high yields achieved the satisfying results, the limited substrate scope and
with excellent diastereo- and enantioselectivities.
relatively low yields suppress their further application. Hence,
to develop unified catalytic asymmetric strategies remains
highly desirable.
As an important and central structural motif, chiral dihydro-
coumarin skeleton is not only found in a broad range of natural
and pharmaceutical molecules which exhibit diverse biological
activities such as anti-cancer,1 anti-oxidation,2 anti-inflamma-
tory actions3 and anti-microbial properties4 (Scheme 1), but
also applied in numerous synthetic processes.5 Not surprisingly,
considerable attention has been devoted to the development
of asymmetric synthesis of dihydrocoumarin derivatives and
many methods have been reported in recent years.6 However,
only few examples have been concerned the access to chiral
dihydrocoumarins bearing a quaternary amino acid moiety,6k-6n
HO
O
OH Ph
NHCOBn
Br
HO2C
O
O
O
O
HO
O
O
O
O
PMP
TEM β-lactamase inhibitor
Soulamarin
Calomelanol A
Scheme 1. Bioactive chiral dihydrocoumarin derivatives
a
unique skeleton possessing pharmacological activities.7
Among these methods, the reaction of readily ortho-quinone
methides (o-QMs) with enolates was considered to be an
efficient way. As to the o-QMs, it is fairly well known that they
are a crucial class of key intermediates in various biological
processes8 and have been regarded as highly reactive chemical
motifs.9,10 In view of enolates, the azlactones,11 being
endowed with both nucleophilic12 and electrophilic13 proper-
ties due to their interconvertible keto and enol forms, would
naturally be the best option as enolate to react with o-QMs
and acquire chiral dihydrocoumarin derivatives bearing the
quaternary amino acid moiety. In 2015, Feng’s group
developed the first asymmetric synthesis of dihydrocoumarins
from ready-prepared o-QMs and azlactones catalyzed by a
chiral N,N’-dioxide-Sc(III) complex (Scheme 2).6k Subsequently,
As part of our ongoing interest towards the utilization of o-
QMs,14 we focused on bifunctional organocatalytic reactions of
in situ generated o-QMs. Based on this consideration, we
envisioned the combination of 2-(1-tosylalkyl)phenols and
azlactones would enable the synthesis of chiral dihydro-
coumarin derivatives in the presence of inorganic bases and
bifunctional organocatalysts15 (Scheme 2). The bifunctional
organocatalyst could be used for deprotonation of azlactones
to form the nucleophilic species in the chiral environment.
Moreover, the inorganic base should not promote the
following Michael addition to guarantee effective control of
enantioselectivity by the chiral organocatalyst. Thus, the key
point of this tandem reaction is to find a suitable match of
bifunctional organocatalyst and inorganic base. Herein, we
present a facile bifunctional squaramide-catalyzed enantiose-
lective synthesis of dihydrocoumarin derivatives via the in situ
generated o-QMs and azlactones under basic condition in
excellent diastereo- and enantioselectivities with broad
substrate scope.
a State Key Lab of Chemo/Biosensing and Chemometrics, College of Chemistry and
Chemical Engineering, Hunan University, Changsha 410082, P. R. China. E-mail:
gfjiang@hnu.edu.cn.
b State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese
Academy of Sciences, Dalian 116023, P. R. China. E-mail: ygzhou@dicp.ac.cn.
Electronic Supplementary Information (ESI) available: [details of any supplemen-
tary information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
Entry
1
Base
Solvent
CH2Cl2
THF
Cat.
4a
4a
4a
4a
4a
4b
4c
Yield (%)b
83
Ee (%)c
32
4
Scheme 2. Strategies for synthesis of chiral dihydrocoumarins
based on ortho-quinone methides (o-QMs)
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
2
81
3
DMF
95
0
At the outset, 2-(1-tosylalkyl)naphthol 1a and azlactone 2a were
chosen as model substrates. The experiment was conducted in
CH2Cl2 by using quinine 4a as catalyst and sodium carbonate as base,
respectively. The reaction proceeded smoothly to give the desired
product 3a with 83% yield and 32% ee (entry 1, Table 1). Then, the
solvent effect was tested (entries 2-5, Table 1). Among the
different kinds of solvents, chloroform was proved to be the most
favorable solvent in terms of enantioselectivity and yield.
4
DCE
93
33
36
96
66
66
61
96
93
96
91
5
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
91
6
89
7
83
8
4d
4e
4f
74
9
83
Subsequently,
a series of bifunctional organocatalysts were
10
11d
12e
13f
66
investigated (entries 6-10, Table 1). In contrast to quinine 4a,
bifunctional thiourea or squaramide catalysts gave higher
enantioselectivities. Obviously, quinine-based squaramide catalyst
4b was the best catalyst with 96% ee. In order to improve the
activity of the reaction, the temperature was also evaluated (entry
11, Table 1). Increasing the reaction temperature, the rate of the
reaction was accelerated slightly but the enantioselectivity declined.
So we prolonged reaction time to 72 h and got the satisfying result
with 95% yield and 96% ee (entry 12, Table 1). Notably, the
diastereoselectivity of the reaction was over 20:1 in all cases. Finally,
we also tried the water-oil diphasic system developed by us and
Liu’s group14g for comparison, which delivered relatively worse
result with 93% yield and 91% ee (entry 13, Table 1). Thus, the
optimized conditions were established as: quinine-based
squaramide catalyst 4b (10 mol %), sodium carbonate (1.2 equiv.),
CHCl3, 30 oC, 72 h.
4b
4b
4b
91
95
Na2CO3 CH2Cl2/H2O
93
a
Reaction conditions: 1a (0.10 mmol), 2a (0.10 mmol), cat. 4 (0.01
mmol), base (0.12 mmol), solvent (1.5 mL), 30 oC, 48 h. The dr were all
over 20:1 detected by 1H NMR spectra Isolated yields. Determined
b
c
by chiral HPLC. d 50 oC. e 72 h. f CH2Cl2/H2O (100 μL/2.0 mL).
sponding products in high yields, good enantioselectivities as
well as excellent diastereoselectivities (up to 95% yield, 97%
ee, >20:1 dr) (3aa-
3ai). Next, the substituent R2 for both benzyl
and alkyl groups were also examined. Chlorine on the benzyl
group apparently increased the yield to 98% (3ai). For the
simple alkyl substituted azlactones 2k and 2l, low activities and
enantioselectivties were obtained under the above standard
condition (no activity for 2k, 82% yield and 69% ee for 2l).
Then we shifted our focus to the water-oil diphasic condition,
which was previously reported by us and Liu’s group14g
Having established the optimal reaction conditions, we then
investigated a wide range of azlactones, and the results are
shown in Table 2. Gratifyingly, azlactones with either electron-
withdrawing or electron-donating substituents on the phenyl
ring in the R1 group could be smoothly converted to the corre-
,
excellent yields and enantioselectivities could be also obtained
(entries 11-12).
Table 2. Substrate Scope of azlactonesa
Table 1. Optimization of Reaction Parametersa
2 | J. Name., 2012, 00, 1-3
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obtained as a colorless crystal after single recrystallization
from dichloromethane/n-hexane/toluene, the absolute confi-
guration was determined to be (3S,4S) based on single crystal
X-ray diffraction analysis.16 (For the detailed, please see the
Supporting Information)
Entry
1
R1
R2
Yield (%)b
91 (3aa)
85 (3ab)
90 (3ac)
91 (3ad)
91 (3ae)
Ee (%)c
96
Ph
Bn
2
3
4-ClC6H4
4-FC6H4
4-BrC6H4
4-F3CC6H4
3,5-Me2C6H3
4-MeC6H4
3-MeC6H4
4-MeOC6H4
Ph
Bn
94
Bn
95
4
Bn
92
5
6d
Bn
92
Bn
95 (3af) (89) 97 (96)
7
Bn
95 (3ag)
95 (3ah)
94 (3ai)
98 (3aj)
89 (3ak)
95 (3al)
88
82
95
93
90
90
8e
9
Bn
Bn
10
11f
12f
4-ClC6H4CH2
Ph
Cy
Ph
Et
a Reaction conditions, 1a (0.20 mmol), 2 (0.20 mmol), Na2CO3 (0.24 mmol),
cat. 4 (0.02 mmol), CHCl3 (3.0 mL), 72-96 h. The dr were all over 20:1 in all
cases. b Isolated yields. c Determined by chiral HPLC. d The reaction at gram
scale was presented in parentheses. e 50 oC. f CH2Cl2/H2O (100 μL/2.0 mL).
Encouraged by above-mentioned results, we continued to
investigate into the variation of the 2-(1-tosylalkyl)phenols. As
shown in Scheme 3, in most cases, the transformations
proceeded successfully, delivering the corresponding chiral
dihydrocoumarins in excellent enantioselectivities and high
yields. For 2-(1-tosylalkyl)naphthols 1a–1h, electronic and
steric property had a slight influence on the enantioselec-
tivities and yields. In addition, the alkyl substituted substrate 1i
was also suitable reaction partner and the reaction performed
well with 91% yield and 85% ee. Furthermore, the reaction
proceeded smoothly with methoxyl substituent substrate 1k
and the sesamol-based substrate 1l. It is worth mentioning
that the water-oil diphasic system worked well for the
substrate 1j and simple 2-(1-tosylalkyl) phenol 1m, which had
low activity under the standard conditions, delivering the
corresponding product 3ja and 3ma with the satisfying results.
In addition, the reaction of alkyl substituted azlactones 2k and
2l with 2-(1-tosylalkyl)phenol 1d and 1l behaved illustriously
under the water-oil diphasic system, which indicated that the
water-oil diphasic system and the chloroform monophasic
system are complementary to some extent.
a Reaction conditions,
mmol), cat. 4 (0.02 mmol), CHCl3 (3.0 mL), 36-120 h. The dr were all
1 (0.20 mmol), 2a (0.20 mmol), Na2CO3 (0.24
over 20:1 in all cases. b CH2Cl2/H2O (100 μL/2.0 mL). c 50 oC.
Scheme 3. Substrate Scope of 2-(1-tosylalkyl)phenolsa
Conclusions
Considering the potential biological activities of the chiral
dihydrocoumarins and in order to show the synthetic utility of
this methodology, the scale-up synthesis of 3af was performed.
2.0 mmol 1a and 2.0 mmol azlactone 2f reacted well under the
standard reaction conditions, affording the desired product 3af
in 89% yield (0.907 g) with 96% ee and >20:1 dr without any
loss of reactivity and enantioselectivty.
In summary, we have successfully realized the bifunctional
squaramide-catalyzed Michael addition/cyclization of o-QMs
generated from 2-(1-tosylalkyl)phenols with azlactones, giving
a facile access to chiral dihydrocoumarin derivatives bearing a
quaternary amino acid moiety with high yields, excellent
diastereo- and enantioselectivities. Highlights of this method
involve the mild reaction condition and wide substrate scope.
Further explorations on the extension of this strategy to
synthesize other compounds are ongoing in our laboratory.
To determine the absolute configuration of products,
optically pure (+)-N-(3-benzyl-2-oxo-4-phenyl-3,4-dihydro-2H-
benzo[h]chromen-3-yl)-3,5-dimethyl-benzamide (+)-3af was
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Financial support from National Natural Science Foundation of
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Table of Contents:
A bifunctional squaramide-catalyzed reaction of azlactones and o-quinone methides in situ generated
from 2-(1-tosylalkyl)-phenols has been succesfully developed under basic condition, providing an
efficient and mild access to chiral dihydrocoumarins bearing adjacent tertiary and quaternary stereogenic
centers in high yields with excellent diastereo- and enantioselectivity.