Remote Construction of Chiral Vicinal Tertiary and Quaternary Centers by Catalytic Asymmetric 1,6-Conjugate Addition of Prochiral Carbon Nucleophiles to Cyclic Dienones

Article abstract of DOI:10.1002/chem.201503530

An unprecedented remote construction of chiral vicinal tertiary and quaternary centers by a catalytic asymmetric 1,6-conjugate addition of prochiral carbon nucleophiles to cyclic dienones has been developed. Both 5H-oxazol-4-ones and 2-oxindoles were found to be very efficient carbon nucleophiles in this reaction at a remote position, giving products with excellent enantio- and diastereoselectivities (up to 99 % ee and >19:1 d.r. for 5H-oxazol-4-ones and up to 97 % ee and >19:1 d.r. for 2-oxindoles).

Full text of DOI:10.1002/chem.201503530

DOI: 10.1002/chem.201503530
Communication
&
Organocatalysis |Hot Paper|
Remote Construction of Chiral Vicinal Tertiary and Quaternary
Centers by Catalytic Asymmetric 1,6-Conjugate Addition of
Prochiral Carbon Nucleophiles to Cyclic Dienones
Yuan Wei, Zunwu Liu, Xinxin Wu, Jie Fei, Xiaodong Gu, Xiaoqian Yuan, and Jinxing Ye*[a]
of 5H-oxazol-4-ones with a,b-unsaturated Michael acceptors
have already been reported.[10] We speculated that a stereose-
Abstract: An unprecedented remote construction of chiral
vicinal tertiary and quaternary centers by a catalytic asym-
metric 1,6-conjugate addition of prochiral carbon nucleo-
philes to cyclic dienones has been developed. Both 5H-
oxazol-4-ones and 2-oxindoles were found to be very effi-
cient carbon nucleophiles in this reaction at a remote po-
sition, giving products with excellent enantio- and diaste-
reoselectivities (up to 99% ee and >19:1 d.r. for 5H-
oxazol-4-ones and up to 97% ee and >19:1 d.r. for 2-oxin-
doles).
lective remote functionalization could be achieved by the em-
ployment of cyclic dienones and 5H-oxazol-4-ones, which
could be activated by a primary–secondary diamine catalyst,
resulting in functionalization of the remote d-positions. At first,
our attention was focused on the 1,6-conjugate addition of
5H-oxazol-4-ones to cyclic dienones catalyzed by primary
amine catalysts.
To test the feasibility of our strategy, we investigated
a series of chiral amine catalysts to achieve the 1,6-conjugate
addition between cyclic dieneone 2a and 5H-oxazol-4-one 3a
in toluene at 258C in the presence of benzoic acid (Table 1).
Catalysts 1a and 1d, which contained a tertiary amine moiety
derived from piperidine, afforded the products with low con-
versions and moderate stereoselectivities (entries 1 and 4). A
lower steric hindrance with the dimethylamine substitution on
catalysts 1b and 1e resulted in slightly better conversions and
stereoselectivities (entries 2 and 5). We envisaged that catalysts
derived from a less steric amine could improve the conversions
and stereoselectivities, and found that cyclohexylamine-de-
rived catalyst 1c revealed excellent results with diastereoselec-
tivity of >19:1 and enantioselectivity of 98% ee (entry 3).[11]
Much to our delight, another catalyst (1 f) derived from cyclo-
hexylamine, which contains a benzhydryl moiety, gave excel-
lent results both in reactivity and stereoselectivity (>19:1 d.r.
and 99% ee; entry 6). The reaction catalyzed by cinchona alka-
loid derived catalyst 1g failed to realize the desired high enan-
tioselectivity (entry 7). Encouraged by the success of the asym-
metric 1,6-conjugate addition of cyclic dienones to 5H-oxazol-
4-ones, we extended these chiral primary amine catalysts to
a 1,6-conjugate addition of 2-oxindoles, which are widely in-
volved in highly enantioselective 1,4-additions to a,b-unsatu-
rated aldehydes, enones, nitroolefins, azodicarboxylate, and al-
dimines.[12] By fine tuning of the catalytic conditions, the 1,6-
conjugate addition of unsubstituted 2-oxindoles to cyclic dien-
ones was successfully achieved with high stereoselectivity
(19:1 d.r. and 97% ee; entries 8–15).
Carbon–carbon bonds constructed by the 1,4-conjugate addi-
tion have already been efficiently explored. However, as the re-
action sites and the stereoselectivity are normally hard to con-
trol, research on the 1,6-conjugate addition through metal cat-
alysis or organocatalysis has been much less developed com-
pared with that on the 1,4-conjugate addition.[1] Therefore,
control of regio-, diastereo- and enantioselectivity in an ex-
tended conjugated system, which possess multiple electrophil-
ic sites, is still a daunting challenge in organic synthesis.[2,3]
The LUMO-lowering effect of vinylogous iminium-ion activa-
tion, which can be transmitted through the conjugated p
system of 2,4-dienones, was originally introduced by Mel-
chiorre.[4] It has already been applied to the enantioselective
remote functionalization reactions but not fully exploited. Only
a few pioneers, such as Melchiorre,[4,5] Hayashi,[6] and Jørgen-
sen,[7] have engaged in this area. This strategy has promoted
our interest in the enantioselective 1,6-conjugate addition of
prochiral carbon nucleophiles to dienones by employing bi-
functional primary–secondary diamine catalysts.
In previous studies, 5H-oxazol-4-ones are characterized by
a strong nucleophilic behavior[8] and easily converted into
chiral hydroxyl carboxylic acids and their derivatives, which are
very important building blocks in natural products and drugs.[9]
The direct catalytic asymmetric 1,4-Michael addition reactions
Having identified the optimized reaction conditions, the
scope of this asymmetric 1,6-conjugate addition reaction was
explored (Table 2). A variety of combinations of cyclic dienones
2 and 5H-oxazol-4-one 3 were applied to the reaction. A signif-
icant tolerance of electronic and structural variations of sub-
strates with exquisite site selectivities was displayed, and excel-
lent diastereo- and enantioselectivities were obtained. Aromat-
ic functionalities in the dienone d-site were compatible with
[a] Y. Wei, Z. Liu, X. Wu, J. Fei, X. Gu, X. Yuan, Prof. Dr. J. Ye
Engineering Research Centre of Pharmaceutical Process Chemistry
Ministry of Education, School of Pharmacy
East China University of Science and Technology
130 Meilong Road, Shanghai 200237 (P. R. China)
E-mail: yejx@ecust.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503530.
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Communication
Table 1. Optimization of reaction conditions in the 1,6-conjugate addi-
tion of 5H-oxazol-4-one and 2-oxindole.[a]
Table 2. Scope of direct 1,6-conjugate addition of various 5H-oxazol-4-
ones to cyclic dienones.[a]
Entry
R
R1
R2
R3
Yield [%][b] d.r.[c]
ee [%][d]
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
89 (4a)
88 (4b)
65 (4c)
71 (4d)
70 (4e)
72 (4 f)
76 (4g)
75 (4h)
85 (4i)
75 (4j)
72 (4k)
76 (4l)
68 (4m)
>19:1 99
2[e]
3[f]
CO2C2H5
2-MeC6H4
4-MeC6H4
4-tBuC6H4
3,4-MeOC6H3
2-naphthyl
3-thienyl
4-ClC6H4
4-FC6H4
4-BrC6H4
4-NO2C6H4
4-CNC6H4
Ph
>19:1
19:1
99
98
98
98
98
98
98
98
99
99
98
98
98
99
99
99
99
99
98
98
98
98
98
98
98
98
98
99
98
98
4[f]
5[f]
6[g]
7[g]
8[g]
9
10
11
12
13
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
9:1
Entry
Cat.
Reagent
Solvent
Conv. [%][b]
d.r.[b]
ee [%][c]
81
14[g]
15
Me 53 (4n)
1
2
3[d,e]
4
1a
1b
1c
1d
1e
1 f
1g
1a
1b
1c
1d
1e
1 f
1g
1 f
3a
3a
3a
3a
3a
3a
3a
5a
5a
5a
5a
5a
5a
5a
5a
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
20 (4a)
50 (4a)
78 (4a)
53 (4a)
73 (4a)
94 (4a)
72 (4a)
66 (6a)
60 (6a)
73 (6a)
84 (6a)
64 (6a)
88 (6a)
75 (6a)
89 (6a)
4:1
6:1
Me Br
Me Br
Me Br
Me Me Ph
Me Me 4-NO2C6H4
Me Me Ph
Et
Et
Et
Et
Ph
4-MeC6H4
Me
H
H
H
H
H
81 (4o)
70 (4p)
61 (4q)
84 (4r)
83 (4s)
85
98
87
92
99
À45
72
66
91
72
16
>19:1
9:1
13:1
>19:1
13:1
2:1
17[g]
18
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
>19:1
5
6[d,e]
7
19
20[g]
21
Me 79 (4t)
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
88 (4u)
78 (4v)
81 (4w)
63 (4x)
50 (4y)
84 (4z)
73 (4aa)
65 (4ab)
75 (4ac)
65 (4ad)
88 (4ae)
8
9
22
CO2C2H5
4-ClC6H4
2-MeC6H4
2-naphthyl
Ph
CO2C2H5
4-MeC6H4
4-ClC6H4
4-BrC6H4
Ph
2:1
18:1
2:1
2:1
14:1
2:1
23[f]
24[e]
25[e]
26
10
11
12
13
14
15[f]
Et
78
93
nPr
nPr
nPr
nPr
nPr
iPr
27
28
À77
19:1
97
29[e]
30
[a] Reaction conditions: a mixture of 2a (0.20 mmol), 3a (0.10 mmol), cat-
alyst (0.01 mmol), and PhCO2H (0.02 mmol) in solvent (0.2 mL) was stirred
at room temperature for 24 h; or a mixture of 2a (0.10 mmol), 5a
(0.15 mmol), catalyst (0.02 mmol), and PhCO2H (0.02 mmol) in solvent
(0.2 mL) was stirred at room temperature for 72 h. [b] Determined by
1H NMR of the crude reaction mixture. [c] Determined by HPLC analysis
on chiral stationary phase. [d] Catalyst (5 mol%). [e] For 48 h. [f] PhCO2H
(10 mol%).
31[f,g]
[a] Reaction conditions: a mixture of 2 (0.40 mmol), 3 (0.20 mmol), catalyst
1 f (0.01 mmol), and PhCO2H (0.02 mmol) in toluene (0.4 mL) was stirred
at room temperature for 72 h. [b] Yields of the isolated products. [c] De-
termined by 1H NMR of the crude reaction mixture. [d] Determined by
HPLC analysis on chiral stationary phase. [e] For 24 h. [f] For 96 h. [g] Cata-
lyst 1 f (10 mol%).
the catalytic system, regardless of their electronic properties
and the substituent position on the aromatic ring. In the case
of the heteroatom-substituted dienone, the reaction also pro-
ceeded well with excellent stereoselectivity and only single
diastereoisomer was obtained (98% ee and >19:1 d.r., respec-
tively; entry 8). Notably, when switching to an aliphatic d-sub-
stituted dienone, the products displayed a slightly lower dia-
stereoselectivity (entry 17). Various substituted 5H-oxazol-4-
ones were also employed in the reaction. The substituents,
such as methyl and bromine, at the aryl group of oxazolone
had no effect on the stereoselectivity (entries 15–20). The alkyl
substituent of 5-alkyloxazole-4(5H)-ones was also varied with
moderate to good yields and excellent enantioselectivities. The
reaction of 5-isopropyloxazole-4(5H)-one exhibited a slightly
lower reactivity, but still maintained an excellent stereoselectiv-
ity (entry 31).
Subsequently, the scope of the 1,6-conjugate addition of the
substituted 2-oxindole to cyclic dienones was investigated
(Table 3). Various d-substituted cyclic dienones, which pos-
sessed diverse electronic properties, were applied to the asym-
metric 1,6-conjugate addition of 3-methyl-substituted 2-oxin-
dole. The valuable building blocks 3,3-disubstituted oxin-
doles[13] were obtained in good yields and excellent stereose-
lectivities (entries 1–12). We also explored the possible varia-
tion in the substituted 2-oxindoles under this catalytic system.
Different substituted 2-oxindoles could be used successfully in
the addition of cyclic dienones, providing 1,6-adducts in gener-
ally good yields and stereoselectivities (entries 13–17). The ab-
solute stereochemistry in the above 1,6-conjugate addition re-
actions was confirmed by single-crystal X-ray crystallography
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Communication
methyl amino or piperidino group). When using catalyst 1 f,
both the diastereo- and enantioselectivity were excellent be-
cause of the reduced steric interaction between carbon nucle-
ophiles and the cyclohexyl amino group. The stereoselective
mechanism can also be exemplified by our observing evidence
in the tuning of the diastereoseletivity of 1,4-Michael addition
reactions by using the disubstituted amino and/or cyclohexyl
amino group.[15] The discovery of the stereocontrol in this 1,6-
conjugate reaction enables the future application of other nu-
cleophilic partners in the remote position. The only drawback
of this 1,6-addition is that it is not applicable to simple linear
dienones, for which 1,4-addition products are obtained. More
thorough studies on this issue are ongoing in our laboratories.
In conclusion, we have developed an unprecedented remote
construction of chiral vicinal tertiary and quaternary centers
through catalytic asymmetric 1,6-conjugate addition of prochi-
ral carbon nucleophiles to cyclic dienones with a new chiral
primary amine catalyst. The reaction proceeded with a broad
substrate scope of different valuable nucleophiles of 5H-
oxazol-4-ones and 2-oxindoles with excellent enantio- and dia-
stereoselectivities (up to 99% ee and >19:1 d.r. for 5H-oxazol-
4-ones and up to 97% ee and >19:1 d.r. for 2-oxindoles).
Table 3. Scope of direct 1,6-conjugate addition of various 2-oxindoles to
cyclic dienones.[a]
Entry
R
R1 R2
R3 Yield [%][b] d.r.[c]
ee [%][d]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
89 (6a)
67 (6b)
78 (6c)
83 (6d)
84 (6e)
19:1
8:1
10:1
11:1
10:1
6:1
>19:1
13:1
9:1
7:1
>19:1
10:1
>19:1
>19:1
>19:1
>19:1
>19:1
97
81
92
94
92
91
81
96
96
91
96
95
82
85
96
89
96
4-NO2C6H4
4-MeC6H4
4-FC6H4
3-thienyl
Ph
CH3 84 (6 f)
2-MeC6H4
CH3
H
H
H
H
H
H
H
H
H
H
H
41 (6g)
65 (6h)
67 (6i)
9
CH3CH2CH2
2-naphthyl
CO2C2H5
4-SO2(CH3)C6H4
C6H5
10
11
12
80 (6j)
67 (6k)
75 (6l)
82 (6m)
77 (6n)
82 (6o)
77 (6p)
82 (6q)
13[e] Bn
14[e] 3-CH3C6H4CH2
C6H5
C6H5
15
16
17
nBu
Bn
4-CNC6H4CH2
Cl C6H5
H CO2C2H5
[a] Reaction conditions: a mixture of 2 (0.20 mmol), 5 (0.30 mmol), cata-
lyst 1 f (0.04 mmol), and PhCO2H (0.04 mmol) in DCM (0.4 mL) was stirred
at room temperature for 5 days. [b] Yields of the isolated products. [c] De-
termined by 1H NMR of the crude reaction mixture. [d] Determined by
HPLC analysis on chiral stationary phase. [e] For 3 days.
Experimental Section
For the synthesis of 4: Catalyst (0.01 mmol), acid (0.02 mmol), and
cyclic dienone (0.4 mmol) were stirred in toluene (0.4 mL) at room
temperature. Then 5H-oxazol-4-one (0.2 mmol) was added. After
the completion of the reaction (monitored by TLC), the solvent
was evaporated and the crude product was purified by silica gel
chromatography to yield the desired addition product. The enan-
tiomeric excess of the product was determined by HPLC analysis
on chiral column.
of compounds 4o and 6e (Scheme 1; see the Supporting Infor-
mation for details).[14]
The mechanism supported by the outcomes of the 1,6-con-
jugate addition is proposed in Scheme 1. When catalyst 1e
was used in the reaction, the diastereo- and enantioselectivity
were low to good because of the steric hindrance between
carbon nucleophiles and the disubstituted amino group (di-
For the synthesis of 6: Catalyst (0.04 mmol), acid (0.04 mmol), and
2-oxindole (0.3 mmol) were stirred in DCM (0.4 mL) at room tem-
perature. Then cyclic dienone (0.2 mmol) was added. After the
completion of the reaction (monitored by TLC), the solvent was
evaporated and the crude product was purified by silica gel chro-
Scheme 1. Postulated stereoselective model for the 1,6-conjugate addition reaction.
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Acknowledgements
This work was partially supported by National Natural Science
Foundation of China (21272068, 21572056), Program for New
Century Excellent Talents in University (NCET-13-0800), and the
Fundamental Research Funds for the Central Universities.
Keywords: amines
synthesis 1,6-conjugate addition
nucleophilic addition
·
asymmetric catalysis
·
asymmetric
·
·
cyclic dienones ·
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Received: October 27, 2015
Published online on November 12, 2015
Chem. Eur. J. 2015, 21, 18921 – 18924
www.chemeurj.org
18924
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