Asymmetric dearomatization of β-naphthols through a bifunctional-thiourea-catalyzed michael reaction

Article abstract of DOI:10.1002/anie.201507998

An intermolecular asymmetric dearomatization reaction of β-naphthols with nitroethylene through a chiral-thiourea-catalyzed Michael reaction is described. Enantioenriched functionalized β-naphthalenones with an all-carbon quaternary stereogenic center could thus be easily constructed from simple naphthol derivatives in good yields and excellent enantioselectivity (up to 79 % yield, 98 % ee). An intermolecular asymmetric dearomatization reaction of β-naphthols with nitroethylene through a chiral-thiourea-catalyzed Michael reaction is described. Enantioenriched functionalized β-naphthalenones with an all-carbon quaternary stereogenic center were easily constructed in good yields and excellent enantioselectivity (up to 79 % yield, 98 % ee).

Full text of DOI:10.1002/anie.201507998

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507998
German Edition: DOI: 10.1002/ange.201507998
Organocatalysis
Asymmetric Dearomatization of b-Naphthols through a Bifunctional-
Thiourea-Catalyzed Michael Reaction
Shou-Guo Wang, Xi-Jia Liu, Qun-Chao Zhao, Chao Zheng, Shao-Bo Wang, and Shu-Li You*
Abstract: An intermolecular asymmetric dearomatization
reaction of b-naphthols with nitroethylene through a chiral-
thiourea-catalyzed Michael reaction is described. Enantioen-
riched functionalized b-naphthalenones with an all-carbon
quaternary stereogenic center could thus be easily constructed
from simple naphthol derivatives in good yields and excellent
enantioselectivity (up to 79% yield, 98% ee).
T
he catalytic asymmetric dearomatization (CADA) reaction
of phenols and their derivatives has emerged as a powerful
method for the construction of enantioenriched multifunc-
[
1]
tionalized cyclic enones, which are frequently encountered
in bioactive natural products and pharmaceuticals. Compared
with the well documented enantioselective oxidative dearo-
matization reactions of phenols, the direct asymmetric
dearomatization of phenol derivatives under non-oxidative
[
2]
[
3]
conditions is limited to alkylation, arylation, and halogen-
Scheme 1. Proposed dearomatization of naphthols and selected natu-
ral products and biologically active compounds containing a tricyclic
hexahydrobenz[e]indole core.
[
4]
ation processes. Recently, we and the Luan group inde-
pendently reported the asymmetric dearomatization of naph-
thols by CÀN bond-forming addition reactions with different
[5]
catalytic systems. Notably, Wang and co-workers realized an
ward processes for the synthesis of this enantioenriched
tricyclic skeleton would be highly desirable. Herein, we report
an intermolecular asymmetric dearomatization reaction of
b-naphthols with nitroethylene in a chiral-thiourea-catalyzed
Michael addition reaction.
enantioselective dearomatization of b-naphthols through
[3f]
a ring-opening reaction with meso-aziridines.
Despite
these elegant contributions, novel catalytic asymmetric dear-
omatization reactions of phenols and their derivatives are still
in great demand. The dearomatization of b-naphthols with
The Michael reaction between 1,3-dimethyl-2-naphthol
(2a) and nitroethylene was chosen as a model reaction to
[6,7]
nitroethylene
is particularly attractive as it affords nitro-
[10]
ethane-substituted b-naphthalenones, which could be readily
converted into the chiral tricyclic hexahydrobenz[e]indoles,
a class of privileged structural motifs widely distributed in
biologically active natural products and therapeutic agents,
such as pyrrolidine-fused tetralins, the hasubanan alkaloids,
optimize the reaction conditions (Table 1). In the presence
of 10 mol% of quinine-derived thiourea catalyst 1a in toluene
at room temperature, the Michael addition reaction pro-
ceeded smoothly to afford the desired product 3a in moderate
yield but with excellent enantioselectivity without the obser-
vation of the oxa-Michael addition side product (42% yield,
94% ee; entry 1). We then screened several bifunctional
thioureas and thiocarbamate 1e, aiming at improving the
reaction efficiency and enantioselectivity. Among the cata-
lysts examined, cinchonine-derived thioureas (1b–1d)
afforded comparable results in terms of yield and enantiose-
lectivity (29–36% yield, 86–90% ee; entries 2–4), indicating
that the electronic properties of the aryl group of the catalyst
did not influence the reaction outcomes significantly.
[
8]
and daphenylline (Scheme 1). In light of the appealing
molecular architecture and promising bioactivities of these
compounds, significant efforts have been devoted to the
development of methods for the construction of this intrigu-
[9]
ing scaffold. Undoubtedly, novel, efficient, and straightfor-
[
*] S.-G. Wang, X.-J. Liu, Q.-C. Zhao, Dr. C. Zheng, S.-B. Wang,
Prof. Dr. S.-L. You
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
[10a,g]
Remarkably, when the Takemoto catalyst 1 f
was
employed, the desired product 3a was generated smoothly
with improved enantioselectivity (94% ee; entry 6). The
analogous urea 1g gave a slightly decreased yield and
enantioselectivity (36% yield, 89% ee; entry 7). Thiocarba-
mate 1e, which bears only one hydrogen-bond donor, proved
to be completely ineffective (entry 5), whereas thiourea alone
could not promote the dearomatization reaction (see the
Supporting Information for details). In the presence of
3
45 Lingling Lu, Shanghai 200032 (China)
E-mail: slyou@sioc.ac.cn
Homepage: http://shuliyou.sioc.ac.cn/
Prof. Dr. S.-L. You
Collaborative Innovation Center of Chemical Science and
Engineering (Tianjin)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507998.
Angew. Chem. Int. Ed. 2015, 54, 14929 –14932
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14929

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Angewandte
Communications
Table 1: Screening of chiral (thio)urea catalysts and optimization of the
reaction conditions.
Table 2: Additive screening.
[
a]
[a]
[b]
[c]
Entry
x
Additive
t [h]
Yield [%]
ee [%]
[
b]
[c]
[d]
Entry
Catalyst
Solvent
x
t [h]
Yield [%]
ee [%]
[d]
1
2
2
2
2
2
2.5
1.5
3 Š M.S.
4 Š M.S.
5 Š M.S.
–
3 Š M.S.
3 Š M.S.
3 Š M.S.
5.5
5.5
5.5
1.5
1.5
3
69
62
65
68
75
79
76
97
97
97
97
98
97
95
[
[
[
[
[
[
d]
2
3
4
5
6
7
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
quinine
1a
1a
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH Cl
6
6
6
6
4
6
6
4
3
4
3
4
27
34
34
22
18
27
29
22
22
22
22
22
42
36
29
29
nd
40
36
20
48
38
49
36
94 (À)
90 (+)
90 (+)
86 (+)
–
94 (+)
89 (+)
24 (+)
90 (À)
90 (À)
94 (+)
89 (+)
d]
e]
e,g]
e,g]
f,g]
2.3
[
(
a] Reaction conditions: 1 f (10 mol%), 2a (0.2 mmol), nitroethylene
x equiv), and additive (100 mg) in CH Cl (2.0 mL) at room temper-
2
2
2
2
ature. [b] Yield of isolated product. [c] Determined by HPLC analysis on
a chiral stationary phase. [d] 1 equiv of 2a was added every 4 h.
[e] 1 equiv of nitroethylene was added hourly. [f] 1.5 equiv of nitro-
ethylene were added by syringe pump over 3 h. [g] 3 Š M.S. (50 mg).
1
1
1
0
1
2
CCl4
1e
1e
CH Cl
2
2
CCl4
[
a] Reaction conditions: catalyst 1 (10 mol%), 2a (0.2 mmol), and
nitroethylene (x equiv) in the indicated solvent (2.0 mL) at room
temperature; nitroethylene (2 equiv) was added every 11 h. [b] 2m
solution in toluene. [c] Yield of isolated product. [d] The ee values were
determined by HPLC analysis on a chiral stationary phase. The sign of
the optical rotation is given in parentheses.
uration of the product was assigned as R by vibrational circular
dichroism (VCD) spectroscopy (see the Supporting Informa-
[11]
tion for details). When substituted nitroolefins, such as (E)-
(2-nitrovinyl)benzene and (E)-benzyl 3-nitroacrylate, were
employed as the Michael acceptors with substrate 2a, the
desired dearomatization reactions did not occur.
Under the optimized reaction conditions, we next
explored the substrate scope of the dearomatization reaction
(Table 3). First, various 1,3-disubstituted 2-naphthol deriva-
tives were investigated. When the substituent at the 1-position
of 2-naphthol was changed to other groups such as ethyl (2b)
or allyl (2c), the reactions occurred smoothly, delivering the
corresponding products in reasonable yields and excellent
enantioselectivity (3b: 54% yield, 98% ee; 3c: 68% yield,
9
4% ee). 1-Methyl-2-naphthol derivatives bearing 3-ethyl
(2d) or 3-benzyl (2e) groups were smoothly converted into
their corresponding dearomatized products with no erosion of
yield or enantioselective control (3d: 60% yield, 96% ee; 3e:
5
7% yield, 98% ee). Furthermore, different groups on the
aromatic ring of 1,3-dimethyl-2-naphthol, such as 7-methyl,
-methoxy, and 7-phenyl substituents, were all well tolerated,
7
quinine, the desired product was obtained in low yield and
enantioselectivity (20% yield, 24% ee; entry 8). These results
emphasize the importance of the bifunctionality of the
thiourea catalysts. Investigations of the solvent effect dis-
closed that CH Cl is the optimal solvent when the Takemoto
affording the dearomatized products in good yields and
excellent enantioselectivity (3 f–3h: 64–67% yield, 93–97%
ee). We further evaluated a series of 2-naphthols without
a substituent at the 3-position, which are challenging sub-
[2h,3e]
strates in asymmetric dearomatization reactions.
2-Naph-
2
2
catalyst 1 f is employed (entry 11).
thols bearing different aliphatic groups, such as ethyl, allyl, or
benzyl moieties, at the 1-position afforded the corresponding
products in good yields and enantioselectivity (3i–3k: 59–
79% yield, 84-92% ee). 1-Methyl-2-naphthols with
6-methoxy, 7-methoxy, or 6-methyl substituents were also
suitable substrates, affording the desired products in moder-
ate yields with slightly decreased enantioselectivity (3l–3n:
62–68% yield, 83–91% ee). To our delight, the 6- or 7-
methoxy-substituted 1-allyl-2-naphthol derivatives could be
smoothly converted into the corresponding dearomatized
products in 78% yield/91% ee (3o) and 61% yield/92% ee
(3p). 1-Methyl-3-bromo-2-naphthol (2q) could not be con-
verted under the current reaction conditions, likely owing to
Further evaluating several additives revealed that molec-
ular sieves could significantly accelerate the reaction rate and
afford improved reaction outcomes in terms of yield and
enantioselectivity (62–69% yield, 97% ee; Table 2, entries 1–
3
). Gratifyingly, when one equivalent of nitroethylene was
added every hour and the reaction was run with 3 Š molecular
sieves as an additive, a dramatic increase in yield without
erosion of the enantioselectivity was observed (79% yield,
9
7% ee; entry 6). Further efforts were made to slowly add the
nitroethylene by using a syringe pump; the dearomatized
product 3a was thus generated smoothly with no improvement
in yield (76% yield, 97% ee; entry 7). The absolute config-
1
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Chemie
Table 3: Substrate scope.
lyst 1 f was believed to contribute significantly to the high
level of asymmetric induction. The two NÀH bonds of the
thiourea moiety and the tertiary amine interact with the
nitroethylene and the hydroxy group of 2-naphthol, respec-
tively, through hydrogen bonding. Therefore, the two sub-
strates are oriented in a highly ordered conformation,
facilitating the Re face attack of 2-naphthol to the b-carbon
atom of nitroethylene. As a consequence, the dearomatized
product is preferentially formed with R configuration, which
is consistent with the experimental observations.
In conclusion, we have developed an intermolecular
asymmetric dearomatization reaction of b-naphthols and
nitroethylene through a chiral-thiourea-catalyzed Michael
addition reaction. b-Naphthalenones bearing an all-carbon
quaternary stereogenic center could be rapidly constructed
from naphthol derivatives with excellent enantioselectivity (up
to 98% ee). The utility of these products was illustrated by the
synthesis of aminotetralin and the formal synthesis of the
common propellane core structure of the hasubanan alkaloids.
[
a]
1
2
[b]
[c]
Entry
R
R
R
x
t [h]
3
Yield [%] ee [%]
1
2
3
4
5
6
7
8
9
Me Me
Et Me
allyl Me
Me Et
Me Bn
Me Me 7-Me
Me Me 7-OMe
Me Me 7-Ph
Et
allyl
Bn
Me
Me
Me
allyl
allyl
H
H
H
H
H
2.5 2.5
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
79
54
68
60
57
67
64
67
79
64
59
68
62
67
78
61
–
97
98
94
96
98
93
97
96
92
92
84
86
83
91
91
92
–
4
3
2
4
3
3
4
3
4
4
3
4
3
4
4
4
23
5
2.5
4
3
3
8
4
7
6
10
5
4
6
5
H
H
H
H
H
H
H
H
H
H
H
7-Me
6-OMe
7-OMe
6-OMe
7-OMe
H
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
Acknowledgements
Me Br
5
[
a] Reaction conditions: 2, nitroethylene (x equiv), 1 f (10 mol%), 3 Š
We thank the National Basic Research Program of China (973
M.S., CH Cl , room temperature; nitroethylene (1 equiv) was added
hourly. [b] Yield of isolated product. [c] Determined by HPLC analysis on
a chiral stationary phase.
2
2
Program,
2015CB856600),
the
NSFC
(21332009,
21361140373, and 21421091), and the Chinese Academy of
Sciences for generous financial support.
its low reactivity, which is due to the electron-
withdrawing effect of the bromide substituent.
Furthermore, substituted phenols, such as 3,5-
dimethyl-(1,1’-biphenyl)-4-ol, displayed no
reactivity under the optimized reaction con-
ditions.
To demonstrate the synthetic utility of the
current method, the dearomatized products
were subjected to further transformations
(
Scheme 2). The reduction of 3n with iron
powder in acetic acid at reflux led to tricyclic
product 4 in 86% yield with complete retention
of enantiomeric purity. The imine moiety of 4
could be reduced with NaBH CN, furnishing
3
the pyrrolidine-fused tetralin 5 in 95% yield
with high diastereoselectivity. The N-tosyl pro-
tecting group could be readily introduced into 5
in the presence of TsCl and Et N without
3
erosion of the ee value (6: 92% ee). Treatment
of
product
3j
(92%
ee)
with Scheme 2. Further transformations. Boc=tert-butoxycarbonyl, Ts =para-toluenesulfonyl.
l-selectride followed by reduction with
LiAlH and chemoselective protection of the
4
resulting amino alcohol with Boc O afforded carbamate 7 in
2
an overall yield of 22% over three steps with good diastereo-
selectivity (86% ee, 4:1 d.r.). Carbamate 7 is a key inter-
mediate in the synthesis of the propellane core structure of the
[
12]
hasubanan alkaloids.
This procedure thus also presents
a novel approach towards the hasubanan alkaloid family.
A working model of the enantioselectivity-determining
transition state was proposed for the current dearomatization
Figure 1. Proposed working model of the enantioselectivity-determin-
ing transition state.
[13]
reaction (Figure 1). The bifunctionality of Takemoto cata-
Angew. Chem. Int. Ed. 2015, 54, 14929 –14932
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Communications
Keywords: asymmetric dearomatization · Michael reaction ·
naphthols · nitroethylene · organocatalysis
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[
Received: August 26, 2015
Published online: October 14, 2015
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