Highly enantioselective [3+2] coupling of cyclic enamides with quinone monoimines promoted by a chiral phosphoric acid

Article abstract of DOI:10.1039/c6cc01200k

Enantioselective [3+2] coupling of cyclic enamides with quinone monoimines was realised using a chiral phosphoric acid as a catalyst. This transformation allowed for the synthesis of highly enantioenriched polycyclic 2,3-dihydrobenzofurans (up to 99.9% ee). The absolute configuration of one product was determined by an X-ray crystal structural analysis. We also found a possible mechanism for this reaction.

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Highly Enantioselective [3+2] Coupling of Cyclic Enamides with
Quinone Monoimines Promoted by a Chiral Phosphoric Acid
Minmin Zhang,a,b Shuowen Yu,a,b Fangzhi Hu,a,b Yijun Liao,a,b Lihua Liao,a,b Xiaoying Xu,a Weicheng
Yuana and Xiaomei Zhang*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Enantioselective [3+2] coupling of cyclic enamides with quinone enriched compounds.3d,5
monoimines was realised using a chiral phosphoric acid as a Recently we studied transformations involving quinone
catalyst. This transformation allowed for the synthesis of highly derivatives.5d,5e,6 For example, we used a chiral phosphoric
enantioenriched polycyclic 2,3-dihydrobenzofurans (up to 99.9% acid7 to catalyze [3+2] coupling of 3-substituted indoles with a
ee). The absolute configuration of one product was determined by quinone monoimine for the synthesis of highly enantio-
an X-ray crystal structural analysis. We also found a possible enriched benzofuroindolines.5d To further our understanding
mechanism for this reaction.
of reactions of quinone derivatives, we conducted this study to
show that chiral phosphoric acid promoted highly
enantioselective [3+2] coupling of cyclic enamides with
2,3-Dihydrobenzofurans are important building blocks found in
a
wide array of natural products and pharmaceutical
quinone monoimines that produced
a large variety of
substances.1 Particularly, polycyclic 2,3-dihydrobenzofuran
sub-structures exist in many biologically active compounds,2
such as galanthamine,2a aflatoxin B2 and morphine alkaloids2b-
polycyclic 2,3-dihydrobenzofurans in moderate to good yields
with generally good enantioselectivities.
First, several chiral phosphoric acids were evaluated in
catalyzing [3+2] coupling of N-(3,4-dihydronaphthalen-1-yl)
2d
etc. (Figure 1). Therefore, the construction of polycyclic 2,3-
dihydrobenzofurans is of great interest to the researchers.3
acetamide
dienylidene) benzene-sulfonamide 2a in dichloromethane at
. As shown in Table 1, chiral phosphoric acids (S)-PA4 and
1a
with
4-methyl-N-(4-oxocyclohexa-2,5-
O
RO
OH
0
℃
O
H
(R)-PA5 which have bulky groups in the 3,3’ positions of BINOL,
promoted an efficient reaction and produced good yields of
polycyclic 2,3-dihydrobenzofuran 3a with excellent ee values
(Table 1, entries 4 and 5), but the yield was higher with (R)-
PA5. Therefore PA5 was determined as the optimal catalyst
and was used through out our study. When the catalyst
loading was reduced to 5 mol%, the good yield and ee value
were only maintained by prolonging the reaction time from 7
hours to 12 hours (Table 1, entry 6). As such the catalyst
loading was determined as 5 mol%. Next, we tested several
solvents. The reaction in 1,2-dichloroethane led to slightly
lower yield and enantioselectivity (Table 1, entry 7). No
products were produced in toluene and acetonitrile (Table 1,
O
O
O
H
MeO
MeO
H
NMe
NMe
R'O
O
galanthamine
O
R = R' = H: morphine
R = Me, R' = H: codeine
R = R' = Me: thebaine
H
aflatoxin B2
Figure 1. Representative biologically active polycyclic 2,3-dihydrobenzofurans.
Quinone derivatives are highly active electrophiles which have
been used in reactions with a large variety of nucleophiles to
construct structurally diversed molecules.4,5 Quinone
derivatives are commonly used in asymmetric reactions and
for the efficient preparation of numerous valuable enantio-
entries
8 and 9). The reaction in THF had good
enantioselection but a very poor yield (Table 1, entry 10).
Therefore dichloromethane was determined as the optimal
solvent for the reaction.
a.Key Laboratory for Asymmetric Synthesis and Chiraltechnology of Sichuan
Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu, China, Fax: (+86)28-85257883; Tel: (+86)28-85257883; E-mail:
xmzhang@cioc.ac.cn
b.University of Chinese Academy of Sciences, Beijing,China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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after 12 hours (Table 2, entries 2 and 3). We then tested a
range of benzo six-membered cyclic enamides bearing various
substituents at the benzene ring. In most cases, the products
had moderate to good yields with excellent
enantioselectivities (up to 99.9 %) (Table 2, entries 4-16). Some
substrates resulted in poor yields (Table 2, entries 7, 8 and 15).
By increasing the catalyst loading to 10 mol%, the yields
increased (Table 2, entries 7 and 8). When 4-methyl quinone
monoimine 2b was used in the reaction with enamide 1a, no
product was detected (Table 2, entry 17). Meanwhile, 2-
methyl-enamide 1q was found to be inactive in the reaction
with quinone monoimine 2a (Table 2, entry 18).
Table 1 Enantioselective [3+2] coupling of N-(3,4-dihydronaphthalen-1-yl) acetamide
1a with 4-methyl-N-(4-oxocyclohexa-2,5-dienylidene) benzene-sulfonamide 2a.a
Ts
AcHN
N
NHAc
O
Cat*
+
Solvent
NHTs
0 o
C
3a
2a
1a
O
i-Pr
i-Pr
R
i-Pr
O
O
O
O
O
O
P
P
OH
OH
The reactions using the benzo five-membered cyclic enamides
in general had lower yields but very high ee values (Table 2,
entries 19-22). The benzo seven-membered cyclic enamide 1v
exihibited lower acticity and produced a poor yield even when
the reaction was prolonged for 110 hours. However the ee
value was not affected (Table 2, entry 23). Then a non-benzo-
fused enamide 1w was used in the coupling with quinone
monoimine 2a. The yield was fair but had a very poor
enantioselectivity (Table 2, entry 24), which may be attributed
to a lack of aromatic ring of this enamide. The coupling of
acyclic enamide 1x with quinone monoimine 2a provided a
poor dr value of 34.5:65.5 but good enantioselectivities for the
diastereomers (Table 2, entry 25). N-Benzoyl quinone
monoimine 2c was also used in the coupling with enamide 1a
and good ee value was obtained (Table 2, entry 26). Finally, we
tried to expand the substrate scope to 1,4-benzoquinone and
1,4-naphthoquinone. However, only traces of the products
were detected and most of the enamide 1a decomposed
(Table 2, entries 27 and 28).
i-Pr
R
PA1: R = H
PA2: R = 1-naphthyl
PA3: R = 2-naphthyl
PA4: R = 9-anthracyl
i-Pr
i-Pr
Yield (%)b ee (%)c
PA5
Entry Cat* (mol%)
Solvent
CH2Cl2
t (h)
10
10
10
10
7
1
2
3
4
5
6
7
8
9
PA1 (10)
PA2 (10)
PA3 (10)
PA4 (10)
PA5 (10)
PA5 (5)
PA5 (5)
PA5 (5)
PA5 (5)
PA5 (5)
81
45
92
83
89
88
85
Trace
Trace
28
23.3
90.8
83.0
98.8
-99.1
-99.6
-99.1
-
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
12
12
12
12
12
ClCH2CH2Cl
Toluene
CH3CN
THF
-
10
-97.1
a Unless otherwise specified, the reactions used 0.10 mmol of 1a, 0.15 mmol of
b
2a and the corresponding chiral phosphoric acid in 1 mL of the solvent at 0 ℃.
Isolated yield based on 1a. c The ee values were determined by using chiral HPLC.
Once we determined the optimized conditions, we next
studied its substrate scope. The results are summarized in
Table 2. First, when N-benzoyl enamide 1b or N-Cbz enamide
1c was used, only a trace of the desired product was observed
Table 2 Enantioselective [3+2] coupling of cyclic enamides 1 with quinone monoimines or quinones 2.a
R4
X
NHR2
R2HN
O
PA5 (5 mmol%)
R4
R3
+
R1
R1
CH2Cl2, 0oC
XH
R3
n
n
O
3
1: n = 1, 2, 3
2: X = NR5 or O
Entry
3
t (h)
12
12
Yield (%)b
88
trace
trace
ee (%)c,d
99.6
-
-
3a: R2 = Ac
R2HN
1
2
3
3b: R2 = Bz
3c: R2 = Cbz
O
12
NHTs
4
5
6
7
8
9
10
11
12
13
14
15
16
3d: R1 = 2-OMe
3e: R1 = 2-Me
3f: R1 = 2-F
12
36
36
36
72
40
48
40
48
36
48
48
12
70
83
74
99.9
97.2
97.7
2
3g: R1 = 2-Cl
20 (51e)
38 (72e)
89
96.2 (97.5e)
97.8 (97.9e)
99.3
AcHN
R1
3
3h: R1 = 2-Br
3i: R1 = 3Me
O
1
3j: R1 = 3-F
98
82
98
81
81
63
89
99.5
99.7
98.6
97.0
98.5
93.7
99.2
4
NHTs
3k: R1 = 4-Me
3l: R1 = 4-F
3m: R1 = 4-Cl
3n: R1 = 4-CF3
3o: R1 = 2,3-diMe
3p: R1 = 2,3-diOMe
2 | J. Name., 2012, 00, 1-3
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AcHN
AcHN
17
3q
3r
12
NR
NR
-
O
O
Me
NHTs
18
12
-
NHTs
Me
19
20
21
22
O
3s: R1 = H
3t: R1 = F
3u: R1 = Cl
3v: R1 = Br
24
24
24
24
52
83
64
40
99.5
99.6
99.9
99.0
AcHN
NHTs
R1
23
3w
110
30
94.7
AcHN
O
NHTs
24
25
O
3x
3y
15
8
70
99
11
AcHN
EtO
NHTs
O
97.0
99.8f
O
HN
NHTs
Ph
AcHN
AcHN
26
27
28
3z
4
75
94.3
O
NHBz
OH
3A
3B
12
12
trace
trace
-
-
O
AcHN
O
OH
a Unless otherwise specified, the reactions used 0.10 mmol of 1, 0.15 mmol of 2 and 0.005 mmol of PA5 in 1 mL of CH2Cl2 at 0 ℃. b Isolated yield based on 1. c The ee
values were determined by using chiral HPLC. d The absolute configuration of 3d was determined by an X-ray crystal structural analysis.8 The absolute configurations of
other products were assigned by analogy. e10 mol% of PA5 was used. f The dr value is 34.5:65.5.
Next the absolute configuration of product 3d (6aR,11aS) was
determined by an X-ray crystal structural analysis8 (See the
supporting information). Consequently, the absolute
configurations of other products except 3y can be assigned
by analogy.
Based on the absolute configuration of the product 3d, we
found a possible reaction mechanism (Scheme 1).
MeO
MeO
Trip
NAc
HO
NAc
NHTs
Aromatization
Ts
N
H
O
1,4-addition
O
O
O
O
H
P
NHTs
(S)-B
HO
(S)-A
Ac
N
MeO
Cyclization
AcHN
MeO
Trip
O
NHTs
(6aR,11aS)-3d
Scheme 1 A possible reaction mechanism of enantioselective [3+2] coupling of cyclic enamide 1d with quinone monoimine 2a.
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Ueda, S. Kagehira, H. Komei, N. Tohnai, M. Miyata, T. Naito
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As shown in Scheme 1, first, the Brønsted acid moiety of the
phophoric acid protonated the quinone monoimine and the
Lewis base moiety of the phophoric acid activated the
enamide through H-bond. The enamide attacked the quinone
4
5
For reviews, see: (a) K. C. Nicolaou, S. A. Snyder, T.
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monoimine to produce the intermediate (S)-
experienced immediate aromatization to produce the phenol
intermediate (S)- . The phenol attacked the imine from Si-
face spontaneously to generate polycyclic 2,3-
dihydrobenzofuran (6aR,11aS)-3d
A which
B
.
In conclusion, we developed a highly enantioselective [3+2]
coupling of cyclic enamides with quinone monoimines
promoted by
transformation,
a
chiral phosphoric acid. Through this
wide variety of polycyclic 2,3-
a
dihydrobenzofurans were synthesized in moderate to good
yields with generally good enantioselectivities. The absolute
configuration of one product was determined as (6aR,11aS)
by an X-ray crystal structural analysis. We also found a
possible reaction mechanism for this reaction.
Notes and references
‡ We are grateful for the financial support from National
Natural Science Foundation of China (21372218). We thank
LetPub for its linguistic assistance during the preparation of this
manuscript.
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This journal is © The Royal Society of Chemistry 20xx
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