Catalytic asymmetric addition of alkyl enol ethers to 1,2-dicarbonyl compounds: Highly enantioselective synthesis of substituted 3-alkyl-3- hydroxyoxindoles

Article abstract of DOI:10.1002/anie.201007145

A familiar ring: An efficient catalytic asymmetric hetero-ene reaction of 1,2-dicarbonyl compounds (including isatins, α-ketoesters, and glyoxal derivatives) is described. The catalyst system derived from 1 can be used for a broad substrate scope and the

Full text of DOI:10.1002/anie.201007145

DOI: 10.1002/anie.201007145
Asymmetric Catalysis
Catalytic Asymmetric Addition of Alkyl Enol Ethers to 1,2-Dicarbonyl
Compounds: Highly Enantioselective Synthesis of Substituted 3-Alkyl-
3-Hydroxyoxindoles**
Ke Zheng, Chengkai Yin, Xiaohua Liu, Lili Lin, and Xiaoming Feng*
The catalytic asymmetric ene reaction of carbonyl compounds
has attracted much attention because it provides an efficient
way to construct versatile and useful building blocks.[1] In
contrast to the extensive and fruitful studies on asymmetric
ene reactions using a-methyl styrene[2] as a nucleophile, fewer
cases have been reported in which enol ethers serve as the
nucleophile.[3,4] The problems associated with the reaction are
the instability of enol ethers in the presence of a Lewis acid
and the competitive Mukaiyama aldol reaction (Scheme 1,
Cu(OTf)2 to afford b-hydroxyenol ether products with
excellent outcomes (up to 98% yield, > 99% ee) under mild
reaction conditions.
3-Substituted 3-hydroxyoxindoles constitute a common
structural motif in various natural products and biologically
active compounds, and they have a stereogenic quaternary
carbon atom (Scheme 2).[5,6] Molecules that include this
structural unit constitute major targets in the development
of drug candidates. Therefore, we initially aimed to develop a
catalytic asymmetric hetero-ene reaction of isatins.
Scheme 1. Competing formation of ene product A and the Mukaiyama
aldol product B in the Lewis acid catalyzed addition of enol ethers to
electrophiles.
product B). In addition, the nucleophilicity of an alkyl enol
ether is lower than that of a silyl enol ether, which has been
used in asymmetric carbonyl-ene reactions.[3] To date, only
one successful transformation of aryl aldehydes reacting with
an alkyl enol ether as the ene component was disclosed by
Jacobsen and co-workers, and the ene products are isolated in
high yields enantioselectivity by using a chiral CrIII catalyst.[4b]
The nucleophilic addition of alkyl enol ethers to construct
chiral quaternary carbon centers seems more interesting and
challenging (Scheme 1, product A). Herein, we report the
first catalytic enantioselective hetero-ene reaction of alkyl
enol ethers with three kinds of 1,2-dicarbonyl compounds
(including isatins, a-ketoesters, and glyoxal derivatives) using
the chiral N,N’-dioxide complex of either Mg(OTf)2 or
Scheme 2. Examples of biologically active 3-substituted 3-hydroxy-
oxindoles.
The isatin 1l was chosen to react with 2-methoxypropene
(2a) in the presence of our established N,N’-dioxide/metal
complex as a catalyst.[7] Accordingly, several chiral Lewis acid
catalysts that were generated in situ from metal salts and the
N,N’-dioxide L4 were screened to evaluate their performance
in the hetero-ene reaction. As shown in Table 1, the reaction
proceeded sluggishly in the presence of metal salts such as
Ca(ClO4)2, Zn(OTf)2, and Sc(OTf)3; however, both the L4/
Cu(OTf)2 and L4/Mg(OTf)2 complexes promoted the reac-
tion to afford the 3-substituted 3-hydroxyoxindole 3l
(Table 1, entries 1–5 versus entries 6 and 7). The L4/Mg-
(OTf)2 complex furnished the products with moderate yield
and excellent enantioselectivity (Table 1, entry 7). Gratify-
ingly, none of the corresponding Mukaiyama aldol products 4
were detected under these reaction conditions. To improve
the reactivity and enantioselectivity of the reaction, various
N,N’-dioxides were investigated. Notably, only the ligands
having iPr substituents at the ortho position of aniline were
found to be appropriate for this transformation (Table 1,
[*] K. Zheng, C. K. Yin, Dr. X. H. Liu, Dr. L. L. Lin, Prof. Dr. X. M. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry, Sichuan University
Chengdu 610064 (China)
Fax: (+86)28-8541-8249
E-mail: xmfeng@scu.edu.cn
[**] We appreciate the financial support from the National Natural
Science Foundation of China (Nos. 20732003 and 21021001 and
20872096) and the National Basic Research Program of China (973
Program: No. 2010CB833300). We thank the Sichuan University
Analytical & Testing Centre for NMR and X-ray diffraction analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007145.
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Table 1: Optimization of the reaction conditions.[a]
as the temperature, solvent, and additives were also exam-
ined, but no superior results were obtained (see the Support-
ing Information).
With the optimal reaction conditions established, the
substrate scope was extended. As summarized in Table 2,
both N-protected isatins and N-unprotected isatins gave the
desired 3-substituted 3-hydroxyoxindoles with good enantio-
selectivity. Up to greater than 99% ee values were obtained
for all N-protected isatins (Table 2, entries 1–11 and
entries 22–24), and the reactions of the N-unprotected isatins
proceeded with slightly decreased yields and enantioselectiv-
ity as a result of the poor solubility in CH2Cl2 (Table 2,
entries 12–21). The electronic nature and the position of the
substituents on the isatins had no influence on the selectivity,
but they did have a significant effect on the activity, especially
for N-unprotected istatins. For example, the isatins having
electron-withdrawing substitutents showed higher reactivity
and enantioselectivity even with a catalyst loading of 1–
5 mol% (Table 2, entries 2–7 and entries 13–18). In contrast,
Entry
Metal
Ligand
1
Yield of 3 [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
Ca(ClO4)2
Ba(ClO4)2
[Cu(acac)2]
Zn(OTf)2
Sc(OTf)3
Cu(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Mg(OTf)2
Cu(OTf)2
L4
L4
L4
L4
L4
L4
L4
L1
L2
L3
L5
L6
L4
L4
L4
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1l
1a
1a
45 (3l)
43 (3l)
trace (3l)
40 (3l)
trace (3l)
53 (3l)
3
À17
–
20
–
94
98
–
55 (3l)
Table 2: Substrate scope for the catalytic asymmetric hetero-ene reaction
of isatins.[a]
trace (3l)
trace (3l)
trace (3l)
50 (3l)
48 (3l)
75 (3l)
9
–
–
10
11
12
13[d]
14[d]
15[d]
47
95
98
>99
>99
92 (3a)
85 (3a)
Entry 1: R1, R2
2
x
Product Yield [%][b] ee [%][c]
[a] Unless otherwise noted, the reaction conditions were: isatins 1
(0.1 mmol), 2a (2.0 equiv), 3 ꢀ molecular sieves (25 mg), CH2Cl2
(0.5 mL), 308C, 48 h. [b] Yield of isolated product. [c] Determined by
HPLC analysis using a chiral stationary phase. [d] 5.0 equiv 2a was used.
acac=acetylacetonate, M.S.=molecular sieves, Tf=trifluoromethane-
sulfonyl.
1[d]
2
3
1a: H, Me
2a 10 3a
93
94
96
85
98
92
97
93
88
91
94
75
78
78
90
92
72
68
58
64
62
82
95
80
52
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
98
94
97
96
>99
95
98
98
96
98
>99
>99
>99
97
1b: 5-F, Me
1c: 7-F, Me
1d: 5-Cl, Me
1e: 4-Br, Me
1 f: 5-Br, Me
1g: 6-Br, Me
1h: 5-Me, Me
1i: 5,7-Me2, Me
1j: 5-OMe, Me
1k: 5-NO2, Me
1l: H, H
1m: 5-F, H
1n, 7-F, H
1o: 5-Cl, H
1p: 4-Br, H
1q: 5-Br, H
1r: 6-Br, H
1s: 5-Me, H
1t: 5,7-Me2, H
1u: 5-OMe, H
1v: H, Bn
1w: H, 2-methylallyl 2a 10 3w
1a: H, Me
1l: H, H
2a
2a
2a
2a
2a
2a
2
5
2
1
2
5
3b
3c
3d
3e
3 f
4
5[e]
6
7
8
9
3g
2a 10 3h
2a 10 3i
2a 10 3j
2a 10 3k
2a 10 3l
2a 10 3m
2a 10 3n
2a 10 3o
entry 7), and ligands having other substituents on aniline
showed poor activity under the standard reaction conditions
(Table 1, entries 8–10). These facts indicated that the nature
of the substituents on aniline had an impact on reactivity and
suggested that a bulkier electron-donating group at the ortho
position of aniline would greatly adjust the electronic and
stereoinductive environment of the catalyst. A change in the
chiral backbone of the ligand affected neither the yield nor
the enantioselectivity. For example, neither the l-pipecolic
acid derived L6 nor l-proline derived L5 exhibited superior
results (Table 1, entries 11 and 12). In the above cases, the
lack of reactivity might be attributed to the weak nucleophi-
licity and lower boiling point of 2a (b.p. 34–368C). Therefore,
the amount of 2a was increased to 5.0 equivalents, and as
expected the yield was improved to 75% with a 98% ee
(Table 1, entry 13).[8] To our delight, when the N-methyl-
protected isatin 1a, which has better solubility in CH2Cl2, was
used instead of isatin 1l, both the yield and enantioselectivity
were improved (Table 1, entry 14). Similar results were
obtained when the reaction was carried out using the L4/
Cu(OTf)2 complex as catalyst (Table 1, entry 15). The process
is insensitive to both atmospheric oxygen and humidity, thus
making the catalytic system practical. Other conditions such
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
2a
5
3p
2a 10 3q
2a 10 3r
2a 10 3s
2a 10 3t
2a 10 3u
2a 10 3v
2b 10 3x
2b 10 3y
[a] Unless otherwise noted, the reaction conditions were: isatins 1
(0.1 mmol), 2a (5.0 equiv), 3 ꢀ molecular sieves (25 mg), CH2Cl2
(0.5 mL), 308C, 48 h. [b] Yield of isolated product. [c] Determined by
HPLC analysis using a chiral stationary phase. [d] The reaction was
carried out with 5.0 mmol isatin 1a, 5.0 equiv enol ether 2a, and 3 ꢀ
molecular sieves (500 mg) in CH2Cl2 (25 mL) at 308C for 48 h. [e] The
absolute configuration of the adduct (R)-3e was determined by X-ray
diffraction analysis.[9]
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Table 3: Substrate scope for the catalytic asymmetric hetero-ene reaction
istatins having electron-donating substituents reacted to give
moderate product yields (Table 2, entries 19–21). Notably, the
isatin 1e having the an electron-withdrawing group at C4
showed extremely high reactivity, thus giving the desired
product in 98% yield and greater than 99% ee by using only
1.0 mol% of the catalyst (Table 2, entry 5). The protecting
group on the isatin had little effect on the product yields; both
the N-benzyl-protected isatin 1v and N-(2-methylallyl)-pro-
tected isatin 1w gave satisfying results (Table 2, entries 22 and
23). Moreover, another nucleophile, 2b, was also tested with
both the N-methyl-protected isatin 1a and the N-unprotected
isatin 1l, giving the products in 80% yield with a greater than
99% ee and 52% yield with 97% ee, respectively (Table 2,
entries 24 and 25). The absolute configuration of 3e was
determined by X-ray crystallography to be R.[9]
of glyoxal derivatives.[a]
Entry 7: R1
2
x
Product Yield [%][b] ee [%][c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
7a: C6H5
7a: C6H5
7a: C6H5
2a
2a
1
1
8a/9a
8a/9a
78/18
87/10
97
89
92
96
80
94
90
94
96
90
80
95
92
98
90
95/92
98/95
98
98
98
98
97
97
97
95
96
97
97
97
97
96
98
2a 0.2 8a
2a 0.2 8b
2a 0.2 8c
2a 0.5 8d
2a 0.2 8e
2a 0.5 8 f
2a 0.2 8g
2a 0.5 8h
2a 0.2 8i
2a 0.2 8j
2a 0.2 8k
7b: 2-MeC6H4
7c: 3-MeC6H4
7d: 4-MeC6H4
7e: 4-FC6H4
7 f: 3-ClC6H4
7g: 4-ClC6H4
7h: 3,4-Cl2C6H3
7i: 4-BrC6H4
7j: 3-MeOC6H4
7k: 4-MeOC6H4
Encouraged by the above results, a-ketoesters were also
examined under the optimal reaction conditions. As shown in
Scheme 3, the results revealed that the a-ketoesters were
suitable substrates for this hetero-ene reaction. The electronic
nature of the aryl ring of the a-ketoesters had little effect on
the reaction efficiency and stereoselectivity.
7l: 3,4-(MeO)2C6H3 2a 0.5 8l
7m: 2-naphthyl
7n: 2-furyl
7o: Cy
7p: OEt
7a: C6H5
2a 0.5 8m
2a 0.5 8n
2a 0.2 8o
2a 0.2 8p
2b 0.2 8q
89
97
87
98
[a] Unless otherwise noted, the reaction conditions were: glyoxal
derivatives 7 (0.1 mmol), enol ether 2 (1.2 equiv), 3 ꢀ molecular sieves
(50 mg), CH2Cl2. [b] Yield of isolated product. [c] Determined by HPLC
analysis using a chiral stationary phase. [d] The reaction was carried out
with L4/Mg(OTf)2. Cy=cyclohexyl.
Scheme 3. Catalytic asymmetric hetero-ene reaction of a-ketoesters.
Next glyoxal derivatives were tested in the reaction with
alkyl enol ethers. To our delight, the addition of the 2a to
phenylglyoxal (7a) in the presence of 1 mol% of the L4/
Mg(OTf)2 complex resulted in an efficient reaction, thus
achieving up to greater than 98% conversion after
30 minutes. The reaction can be monitored easily by the
color change of the catalyst system, which changes from
yellow to colorless, and the ene product 8a was afforded in
78% yield with 95% ee. However, the Mukaiyama aldol
product 9a was also obtained in 18% yield with 92% ee
(Table 3, entry 1). The Mukaiyama aldol product might be
generated from the high reactivity of the glyoxal derivatives
and the easily hydrolysis of 8a under the acidic conditions.[10]
We envisioned that decreasing the activity of the catalyst
might achieve two objectives: 1) slow the competitive reac-
tion and 2) avoid the subsequent hydrolysis of the hetero-ene
products. Pleasingly, when we used the less active L4/Cu-
(OTf)2 complex instead of L4/Mg(OTf)2 as the catalyst, the
yield of the ene products improved and excellent enantiose-
lectivity was obtained (Table 3, entry 2). An additional
decrease in the catalyst loading to 0.2 mol% did hinder the
Mukaiyama aldol reaction, and only the ene product 8a was
obtained with up to 97% yield and 98% ee (Table 3, entry 3).
Next, the scope of the glyoxal derivatives was explored as
shown in Table 3. Neither electron-donating nor electron-
withdrawing substituents on the aromatic ring at the ortho,
meta, or para positions had an impact on the enantioselectiv-
ity, and all of them underwent the hetero-ene reaction in less
than 2 hours (Table 3, entries 3–14). Notably, the condensed-
ring glyoxal 7m and the heteroaromatic glyoxal 7n performed
well, giving the corresponding products in high yields with
excellent ee values (Table 3, entries 15 and 16). The aliphatic
glyoxal 7o also reacted with 2a in excellent enantioselectivity
(Table 3, entry 17). In addition, the hetero-ene product 8p
resulting from glyoxylate 7p was obtained with 89% yield and
87% ee (Table 3, entry 18). The nucleophile 2b was also
tolerated, giving the desired product 8q in 97% yield with
98% ee (Table 3, entry 19).
To show the utility of the current method, a demonstration
of the synthetic value of the reaction was described
(Scheme 4). Asymmetric synthesis of (R)-convolutamy-
dine A, which exhibits a potent inhibitory activity towards
the differentiation of HL-60 human promyelocytic leukaemia
cell discovered by Kamano et al. in 1995,[5a] could be
efficiently achieved. As shown in Scheme 4, 4,6-dibromo-
isatin (1z) was used as the substrate under optimized reaction
conditions to synthesize the hetero-ene product 3z in 87%
yield and 97% ee. Product 3z then underwent hydrolysis
upon treatment with 2n HCl to generate (R)-convolutamy-
dine A in 98% yield with 97% ee (Scheme 4A). The b-
hydroxyenol ether products formed in these reactions are also
valuable chiral building blocks. For example, the cyclopen-
ta[b]indole derivative 11, which contains the key structural
unit of many natural products and biologically active com-
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Communications
85% yield). Moreover, the extremely high enantioselectivity,
broad substrate scope, facile procedure, and mild reaction
conditions demonstrate the potential of the catalytic system
for practical syntheses. Additional studies of the application
of this catalyst to other reactions are underway.
Received: November 14, 2010
Published online: February 14, 2011
Keywords: asymmetric catalysis · copper · ene reaction ·
.
heterocycles · magnesium
Scheme 4. Asymmetric synthesis of A) (R)-convolutamydine A and
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pounds,[11] was readily obtained in excellent yield and
enantioselectivity by treatment of product 3a with LiAlH4
in THF (Scheme 4B).
Preliminary studies of the mechanism were carried out,
and HRMS analysis on the dynamic intermediates showed
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complex indicated that both oxygen atoms of the amide and
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complex.[9] On the basis of the absolute configuration of the
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Figure 1. Proposed transition state and the X-ray crystallographic
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30% probability.
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The isatin could coordinate to the MgII in a bidentate fashion
with its dicarbonyl groups. The Re face of the isatin is therfore
shielded by the neighboring 2,6-diisopropylphenyl group of
the ligand, and the nucleophile 2a attacks from the Si face
predominantly to give the R-configured product.
In conclusion, we have described the first highly enantio-
selective hetero-ene reaction of 1,2-dicarbonyl compounds
(including isatins, a-ketoesters, and glyoxal derivatives)
catalyzed by chiral N,N’-dioxide complexes of either Mg-
(OTf)2 or Cu(OTf)2 using alkyl enol ethers as nucleophiles.
The method enables efficient access to enantioenriched 3-
substituted 3-hydroxyoxindole derivatives, which are impor-
tant building blocks for the synthesis of natural products and
pharmaceuticals. (R)-Convolutamydine A was synthesized
with an excellent ee value and in high yield (97% ee and
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[8] The excess 2-methoxypropene (2a) could be readily removed in
vacuo after the completion of the reaction.
[9] CCDC 796553 (3e) and 804337 (L4/Mg(OTf)2) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For more data see the Supporting Information.
[10] The ene product 8a was easily hydrolyzed in CHCl3.
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[12] The peak at m/z 884.5173 was detected when the mixtures
of isatin 1a, Mg(OTf)2, and N,N’-dioxide L4 were injected;
this corresponded to the complex [Mg2+ + L4 + (1a)-H+]+
(m/z 884.5177).
[7] For selected examples of N,N’-dioxide-metal complexes, see:
a) Z. P. Yu, X. H. Liu, Z. H. Dong, M. S. Xie, X. M. Feng,
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Angew. Chem. Int. Ed. 2011, 50, 2573 –2577
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www.angewandte.org
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