Asymmetric diels-alder and inverse-electron-demand hetero-Diels-Alder reactions of β,γ-unsaturated α-ketoesters with cyclopentadiene catalyzed by N,N′-dioxide copper(II) complex

Article abstract of DOI:10.1002/chem.201001365

Highly enantioselective Diels-Alder (DA) and inverse-electron-demand hetero-Diels-Alder (HDA) reactions of β,γ-unsaturated α-ketoesters with cyclopentadiene catalyzed by chiral N,N′-dioxide- Cu(OTf)₂ (Tf=triflate) complexes have been developed. Quantitative conversion of β,γ-unsaturated α-ketoesters and excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to >99% ee) were observed for a broad range of substrates. Both aromatic and aliphatic β,γ-unsaturated α-ketoesters were found to be suitable substrates for the reactions. Moreover, the chemoselectivity of the DA and HDA adducts were improved by regulating the reaction temperature. Good to high chemoselectivity (up to 94%) of the DA adducts were obtained at room temperature, and moderate chemoselectivity (up to 65%) of the HDA adducts were achieved at low temperature. The reaction also featured mild reaction conditions, a simple procedure, and remarkably low catalyst loading (0.1-1.5 mol%). A strong positive nonlinear effect was observed. Temperature control: Asymmetric (hetero-)Diels-Alder reactions of β,γ-unsaturated α-ketoesters with cyclopentadiene promoted by an N,N′-dioxide- Cu(OTf)₂ complex afforded the products with excellent endo/exo ratios and enantioselectivities (see scheme; Tf=triflate). The chemoselectivity could be controlled by regulating the reaction temperature.

Full text of DOI:10.1002/chem.201001365

FULL PAPER
DOI: 10.1002/chem.201001365
Asymmetric Diels–Alder and Inverse-Electron-Demand Hetero-Diels–Alder
Reactions of b,g-Unsaturated a-KetoACTHNUTRGENUGNesters with Cyclopentadiene Catalyzed
by N,N’-Dioxide Copper(II) Complex
Yin Zhu, Xiaohong Chen, Mingsheng Xie, Shunxi Dong, Zhen Qiao, Lili Lin,
Xiaohua Liu, and Xiaoming Feng*[a]
Abstract:
Diels–Alder (DA) and inverse-elec-
tron-demand hetero-Diels–Alder
(HDA) reactions of b,g-unsaturated a-
ketoesters with cyclopentadiene cata-
Highly
enantioselective
range of substrates. Both aromatic and
aliphatic b,g-unsaturated a-ketoesters
were found to be suitable substrates
for the reactions. Moreover, the che-
moselectivity of the DA and HDA ad-
ducts were improved by regulating the
reaction temperature. Good to high
chemoselectivity (up to 94%) of the
DA adducts were obtained at room
temperature, and moderate chemose-
lectivity (up to 65%) of the HDA ad-
ducts were achieved at low tempera-
ture. The reaction also featured mild
reaction conditions, a simple proce-
dure, and remarkably low catalyst load-
ing (0.1–1.5 mol%). A strong positive
nonlinear effect was observed.
lyzed by chiral N,N’-dioxide–CuACTHNURGTNEUNG(OTf)2
(Tf=triflate) complexes have been de-
veloped. Quantitative conversion of
b,g-unsaturated a-ketoesters and excel-
lent diastereoselectivities (up to 99:1)
Keywords: asymmetric catalysis
·
chemoselectivity · copper · cycload-
dition · N,N’-dioxide
and
enantioselectivities
(up
to
>99% ee) were observed for a broad
Introduction
Bridged bicyclic compounds are key structural subunits of
numerous natural and unnatural products with a wide range
of biological activities.[1] The catalytic asymmetric reactions
of a,b-unsaturated carbonyl derivatives and cyclopentadiene
have enabled a facile synthesis of these core structures.[2–5] It
is important to note that cyclopentadiene not only acts as a
4p component, to give the bridged bicyclic compounds,[6]
but can also behave as a dienophile to furnish the inverse-
electron-demand hetero-Diels–Alder (HDA)[7–9] cycload-
ducts when it reacts with b,g-unsaturated a-ketoesters
(Scheme 1).[11–13] The asymmetric HDA process affords ring-
fused pyran derivatives with three contiguous stereocenters,
Scheme 1. Competing Diels–Alder and hetero-Diels–Alder reactions.
which are of particular value in medicinal chemistry.[14] The
two products are potentially related to each other by a 3,3-
sigmatropic rearrangement.[11b,12a,d,e,13]
Evans and co-workers presented the first enantioselective
example of cyclopentadiene behaving as a dienophile with
a,b-unsaturated acyl phosphonates by using chiral oxazo-
line-copper(II) complexes.[10,11] Subsequently, chiral oxazo-
[a] Y. Zhu, X. Chen, M. Xie, S. Dong, Z. Qiao, Dr. L. Lin, Dr. X. Liu,
Prof. Dr. X. Feng
Key Laboratory of Green Chemistry & Technology
Ministry of Education, College of Chemistry
Sichuan University, Chengdu 610064 (P.R. of China)
Fax : (+86)28-8541-8249
line–scandiumACTHUNTGRNEUNG(III) complexes were applied to the cycloaddi-
tion of b,g-unsaturated a-ketoesters and cyclopentadiene to
give HDA adducts as major products with excellent enantio-
selectivities at extremely low temperature.[13] However, the
question of how to improve the chemoselectivity for the DA
E-mail: xmfeng@scu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001365.
Chem. Eur. J. 2010, 16, 11963 – 11968
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
11963

and HDA products has rarely been addressed. Thus, the
search for easily accessible and efficient asymmetric catalyt-
ic systems that can be applied under mild reaction condi-
tions to obtain the two products with satisfactory stereose-
lectivity is interesting and challenging. According to initial
studies,[6,11–13] it was observed that temperature may play an
important role in the chemoselectivity of the reaction, which
may provide a degree of chemoselective control. Herein, we
present a method that achieves good to high chemoselectivi-
ty for the DA adducts and moderate chemoselectivity for
the HDA adducts by regulating temperature. Excellent
endo/exo ratios of the DA adducts (up to 99:1) and enantio-
selectivities (up to >99% ee) of the two adducts were ob-
served under mild reaction conditions for a broad range of
substrates.
of isomers derived from the two competitive processes
could be easily separated by column chromatography. The
effect of the structure of the N,N’-dioxide ligands, including
both the chiral backbone and the steric hindrance of aniline,
was then examined (Table 1, entries 8–11). To our delight, a
bulkier group at the ortho position of aniline, such as
methyl, could enhance the enantioselectivity (Table 1,
entry 8). More excitingly, N,N’-dioxide L3, which contains
bulky 2,6-diisopropyl aniline groups, gave excellent results
of more than 99% total yield with 96% ee (3a) and 99% ee
(5a) (Table 1, entry 9). Furthermore, as in the case of the
amino acid backbone, the N,N’-dioxide L3, which was based
on l-pipecolic acid, was superior to both l-proline-derived
N,N’-dioxide L4 and l-ramipril acid derived N,N’-dioxide
L5, and afforded the best results (Table 1, entry 9 vs. en-
tries 10 and 11).
Encouraged by the initial results, various solvents were
Results and Discussion
tested in the presence of L3–CuACTHUNGTERNNU(G OTf)2 (10 mol%); the re-
sults are listed in Table 2. The important impact of solvent
on the enantioselectivity and reactivity of the reaction were
thus made apparent. Although the use of acetonitrile gave
comparable enantioselectivities for the DA adduct 3a
(90% ee) and the HDA adduct 5a (97% ee), it led to a dra-
matic loss of chemoselectivity for the HDA adduct 5a
(Table 2, entry 2). 1,2-Dichloroethane (DCE) provided good
yield (>99%), but the enantioselectivities of both adducts
were notably diminished (Table 2, entries 3 vs. 1). Chloro-
form, tetrahydrofuran, and toluene reduced the catalytic ac-
As versatile catalysts, chiral N,N’-dioxide–metal complexes
have been superior in many asymmetric reactions.[15] Initial-
ly, we examined the cycloaddition reaction of (E)-methyl 2-
oxo-4-phenylbut-3-enoate (1a) with cyclopentadiene (2),
promoted by N,N’-dioxide L1 with various metals, and the
significant effect of the central metals on both reactivity and
enantioselectivity were noted (Table 1, entries 1–7). As
shown in Table 1, only the L1–CuACHTUNRGTNEUNG(OTf)2 complex promoted
the reaction, with the desired major DA product 3a being
formed in 16% ee; the HDA product 5a was obtained with
40% ee, in >99% total yield (Table 1, entry 7). The two sets
tivity of the L3–CuACHTNUTRGNE(NUG OTf)2 complex, presumably because of
coordination to the central metal (Table 2, entries 4–6). Fur-
ther studies focusing on the use
of ethers as solvent revealed
Table 1. Central metal and ligand effects on catalytic asymmetric cycloaddition of b,g-unsaturated a-ketoester
1a and cyclopentadiene.[a]
that diethyl ether provided the
HDA adduct 5a with favorable
chemoselectivity, but led to low
enantioselectivities of the prod-
ucts (Table 2, entry 7). There-
fore, dichloromethane was es-
tablished as the best solvent for
the DA and HDA reactions of
b,g-unsaturated
a-ketoester
with cyclopentadiene (Table 2,
entry 1).
Entry
Ligand
Metal
Yield [%][b]
G
E
ee [%][d]
The reaction temperature
and catalyst loading were then
investigated (Table 3). Lower-
ing the temperature led to a
clear drop in reactivity and the
chemoselectivity for the DA ad-
ducts, whereas the enantioselec-
tivity was maintained (Table 3,
entries 1–3). When the temper-
ature was increased to 258C,
the reactivity was greatly in-
creased. Moreover, the chemo-
selectivity for the DA adducts
rose to 85% without loss of
3a
5a
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
Yb
(OTf)3
Ni(acac)2
Sc(OTf)3
La(OTf)3
[Cu(OTf)]2·Tol
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
A
>99
>99
trace
>99
trace
>99
>99
>99
>99
trace
trace
0
0
10
8
0
YACHTUNGTRENNUNG
N
n.d.[e]
0
N
0
R
11
0
16
31
15
26
40
60
99
77
92
N
G
R
9
10
11
G
96
U
n.d.[e]
n.d.[e]
AHCTUNGTRENNUNG
[a] Reagents and conditions: 10 mol% L/CuACHTNURTGNEUNG(OTf)2 (1:1), 1a (0.2 mmol), 2 (200 mL), CH2Cl2 (2.0 mL), N2, 08C,
2 h. [b] Total yield of 3a, 4a, and 5a. [c] Determined by chiral HPLC analysis, the isomeric configuration of 3
was confirmed by H NMR spectroscopic analysis. [d] Determined by HPLC analysis. [e] Not determined.
1
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Chem. Eur. J. 2010, 16, 11963 – 11968

Asymmetric (Hetero-)Diels–Alder Reactions
FULL PAPER
Table 2. Screening of the solvents in the catalytic asymmetric cycloaddi-
mation), gave the optimal conditions for formation of the
DA products: 0.5 mol% L3–CuACHTNUGRTENUNG(OTf)2 complex as the cata-
tion of b,g-unsaturated a-ketoester 1a with cyclopentadiene.[a]
lyst, 258C in dichloromethane (Table 3, entry 7).
Under the optimal conditions, a series of b,g-unsaturated
a-ketoesters proved to be excellent 2p components for this
copper(II)-catalyzed cycloaddition reaction, and provided
the DA adducts 3 as the major products in high chemoselec-
tivity (up to 94:6) and excellent endo/exo ratios (up to 99:1)
with excellent enantioselectivities (up to 97% ee, Table 4).
Entry Solvent
Yield
[%][b]
G
E
[3a]/
U
ee 5a
1
2
3
4
5
6
7
CH2Cl2
CH3CN
DCE
CHCl3
THF
>99
>99
>99
trace
trace
trace
>99
96
90
90
59
30
35
trace
99
97
87
50
40
46
29
Table 4. Substrate scope of the asymmetric DA reactions.[a]
toluene
Et2O
[a] Reagents and conditions: 10 mol% L3/CuACTHNURGTNEUNG(OTf)2 (1:1), 1a
(0.2 mmol), 2 (200 mL), solvent (2.0 mL), N2, 08C, 2 h. [b] Total yield of
3a, 4a, and 5a. [c] Determined by chiral HPLC analysis, the isomeric
configuration of 3a was confirmed by 1H NMR spectroscopic analysis.
[d] Determined by HPLC analysis. [e] Not determined.
Entry
R1
R2
G
[3]/[4][b]
ee 3 [%][c]
1
2
3
4
5
Ph
Ph
Me
Et
Me
Me
Me
95:5
94:6
96:4
96:4
97:3
96
95
96
96
95
4-MeC6H4
4-MeOC6H4
4-PhC6H4
Table 3. Effect of temperature and catalyst loading on the catalytic asym-
metric cycloaddition of 1a and 2.[a]
6
7
Me
Me
96:4
97:3
96:4
97
96
86:14
8
9
2-naphthy
2-thienyl
2-thienyl
Me
Me
Me
Me
Et
81:19
90:10
89:11
92:8
96:4
99:1
98:2
94:6
92
96
92
96
Entry
T
[8C]
t
x
ee 3a
[3a]/
[4a][c]
ACHUTGTNREN[NUG 3a+4a]/ACHTUNGTERN[NUGN 5a]
10[d]
11
[mol%] [%][b]
ACHTUNGTRENNUNG
1
2
3
4
5
6
0
2 h
10
10
10
96
96
96
96
82
96
96
96
96:4
96:4
96:4
96:4
90:10
96:4
95:5
95:5
50:50
40:60
35:65
85:15
89:11
85:15
85:15
85:15
[a] Reagents and conditions: 0.5 mol% L3/CuACTHNUTRGENUG(N OTf)2 (1:1), 1 (0.4 mmol),
À20 5 h
2 (400 mL), CH2Cl2 (4 mL), N2, 258C, 15 min; total yields were all up to
>99%. [b] Determined by chiral HPLC analysis, the isomeric configura-
tion of 3 was confirmed by 1H NMR spectroscopic analysis. [c] Deter-
mined by chiral HPLC analysis. [d] Reagents and conditions: 0.1 mol%
À45 24 h
25
35
25
25
25
15 min 10
15 min 10
15 min
15 min
15 min
1
0.5
0.5
L3/CuACTHUNGTRNEUNG(OTf)2 (1:1), 1a (2.0 mmol), 2 (2 mL), CH2Cl2 (20 mL), N2.
7[d]
8[e]
[a] Reagents and conditions: L3/CuACHTUNGTERN(UNNG OTf)2 (1:1), 1a (0.2 mmol), 2
(200 mL), CH2Cl2 (2.0 mL), N2; total yields were all up to >99%. [b] De-
termined by chiral HPLC analysis. [c] Determined by chiral HPLC analy-
sis, the isomeric configuration of 3a was confirmed by 1H NMR spectro-
Both methyl and ethyl esters gave excellent results (Table 4,
entries 1 and 2). It was noteworthy that the steric hindrance
of the substituent at the aromatic ring had no effect on the
enantioselectivities (95–97% ee), and up to 94% chemose-
lectivity for the DA adducts could be obtained (Table 4, en-
tries 3–6). The reactions proceeded well and generated the
normal DA product 3 with cinnamyl-substituted substrate in
high chemoselectivity with 96% ee (Table 4, entry 7). Fused
ring and heteroaromatic substrates were also applicable,
giving the corresponding products with excellent results
(Table 4, entries 8–10). Inspiringly, high DA chemoselectivi-
ty (89%) with good enantioselectivity (92% ee) was deliv-
ered by using as little as 0.1 mol% catalyst (Table 4,
entry 10). Moreover, the asymmetric cycloaddition of ali-
phatic b,g-unsaturated a-ketoester and cyclopentadiene took
place, for the first time, with good chemoselectivity for the
DA adducts with 96% ee (Table 4, entry 11).
scopic analysis. [d] Reagents and conditions: L3/Cu
ACHTUNGRTEN(NUNG OTf)2 (1:1), 1a
(0.4 mmol), 2 (400 mL), CH2Cl2 (4.0 mL), N2. [e] Reagents and condi-
tions: L3/CuACHTUNGTRENNUNG(OTf)2 (1:1), 1a (0.4 mmol), 2 (400 mL), CH2Cl2 (4.0 mL),
without N2.
enantioselectivity (96% ee) without reducing the endo/exo
ratio (96:4, Table 3, entry 4). A higher chemoselectivity for
the DA adducts was achieved at 358C, but the enantioselec-
tivity of 3a decreased significantly (Table 3, entry 5). Reduc-
ing the catalyst loading from 10 to 0.5 mol% had no evident
influence on the chemoselective formation of the DA ad-
ducts, the endo/exo ratio or the enantioselectivity, and good
outcomes (96% ee, 95:5 endo/exo ratio) could be obtained
within 15min (Table 3, entries 6 and 7). It is also notable
that the process is tolerant of air and moisture (Table 3,
entry 8). Subsequent studies on the reaction parameters,
such as substrate concentration (see the Supporting Infor-
We then aimed to improve the chemoselectivity of the
HDA product. As shown in Table 3, we found that lower
temperature was favorable for the generation of the HDA
Chem. Eur. J. 2010, 16, 11963 – 11968
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www.chemeurj.org
11965

X. Feng et al.
Table 6. Substrate scope of the asymmetric HDA reaction.[a]
adducts. When the temperature was decreased from À20 to
À458C, although the reactivity sharply decreased (Table 5),
the chemoselectivity for the HDA adduct slightly improved
Table 5. Effect of temperature and catalyst loading on the catalytic asym-
metric HDA reaction of 1a and 2.[a]
Entry
R1
R2
[5]/
G
ee [%][b]
3
5
1
2
3
4
5
6
7
8
Ph
Ph
Me
Et
60:40
55:45
56:44
56:44
58:42
65:35
53:47
45:55
50:50
55:45
53:47
55:45
60:40
96
95
96
96
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
3-NO2C6H4
4-ClC6H4
2,4-Cl2C6H3
3-BrC6H4
4-BrC6H4
4-FC6H4
4-CNC6H4
4-PhC6H4
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
n.d.[c]
n.d.[c]
n.d.[c]
n.d.[c]
n.d.[c]
n.d.[c]
n.d.[c]
n.d.[c]
95
Entry
T [8C]
t [h]
x [mol%]
ee 5a [%][b]
ACHUTGTNREN[NUG 5a]/HCATUNGTRENN[UGN 3a+4a]
1
2
3
4
À20
À45
À78
À20
À20
À20
5
24
36
10
12
24
10
10
10
5
1.5
0.5
99
99
60:40
65:35
n.d.[c]
60:40
60:40
60:40
n.d.[c]
99
9
10
11
12
13
5
99
99
6[d]
[a] Reagents and conditions: L3/CuACHTUNGTERN(UNNG OTf)2 (1:1), 1a (0.2 mmol), 2
(200 mL), CH2Cl2 (2.0 mL), N2; the total yields were all up to >99%.
14
15
Me
Me
60:40
22:78
97
96
>99
>99
[b] Determined by HPLC analysis. [c] Not determined. [d] Reagents and
conditions: L3/CuACHTUNGTRENNUNG(OTf)2 (1:1), 1a (0.4 mmol), 2 (400 mL), CH2Cl2
(4.0 mL), N2.
16
17
18
2-naphthyl
2-thienyl
Me
Me
Me
Et
52:48
50:50
46:54
92
96
96
>99
>99
>99
and excellent enantioselectivity (>99% ee, Table 5, entry 2)
was maintained. Unfortunately, a further decrease in tem-
perature led to no product formation (Table 5, entry 3).
When the catalyst loading was reduced from 10 to 1.5 mol%
at À208C, the enantioselectivity (>99% ee) and the chemo-
selectivity for the HDA adduct (60%) were maintained
(Table 5, entries 4 and 5). Moreover, when the catalyst load-
ing was further reduced to 0.5 mol%, similar results could
still be obtained, although longer reaction times were re-
quired (Table 5, entry 6).[16] Other parameters were also
tested, such as substrate concentration, but the results were
not further improved (see the Supporting Information).
Therefore, optimal reaction conditions for obtaining the
[a] Reagents and conditions: 1.5 mol% L3/CuACTHNUTRGENUG(N OTf)2 (1:1), 1 (0.2 mmol),
2 (200 mL), CH2Cl2 (2 mL), N2, À208C, 12 h; total yields >99%. [b] De-
termined by chiral HPLC analysis. [c] Not determined because no suita-
ble HPLC analytical conditions were found.
aliphatic substrate, affording the desired HDA adduct in
moderate chemoselectivity with more than 99% ee (Table 6,
entry 18). In addition, we found that the DA adducts 3 were
obtained in moderate chemoselectivity and with good to ex-
cellent enantioselectivities at À208C (Table 6, entries 1–4
and 13–18).
To further evaluate the synthetic potential of the catalyst
system, gram-scale syntheses of the DA adduct 3a and the
HDA product 5a were performed in the presence of L3–
HDA products were selected as 1.5 mol% L3–Cu
complex as the catalyst, À208C in dichloromethane.
ACHTUNGERTN(NUNG OTf)2
Under the optimized conditions, the substrate scope of
the HDA reaction was evaluated and the results are sum-
marized in Table 6. As seen for the standard substrate, the
reaction of b,g-unsaturated a-ketoester with an ethyl group
worked well, with moderate chemoselectivity and excellent
enantioselectivity (Table 6, entries 1 and 2). Regardless of
the electronic properties or steric hindrance of the substitu-
ent at the aromatic ring of the b,g-unsaturated a-ketoester,
excellent enantioselectivities (>99% ee) and moderate che-
moselectivity of the HDA adducts 5 were obtained (Table 6,
entries 3–14). (3E,5E)-Methyl 2-oxo-6-phenylhexa-3,5-dien-
oate gave the corresponding HDA adduct 5 with up to
>99% ee, however, the chemoselectivity was less satisfacto-
ry (Table 6, entry 15). Furthermore, moderate chemoselec-
tivity for 5 and excellent enantioselectivities were observed
by using condensed-ring and heteroaromatic b,g-unsaturated
a-ketoesters (Table 6, entries 16 and 17). Notably, the cata-
lytic system was also very efficient for the most challenging
CuACTHNUTRGEN(UGN OTf)2 complex as catalyst (0.5 mol%). As shown in
Scheme 2, by treatment of 5 mmol starting material under
the optimized conditions, the corresponding adducts 3a and
5a were obtained without any loss of reactivity, chemoselec-
tivity, or enantioselectivity.
Scheme 2. Gram-scale asymmetric synthesis of 3a and 5a.
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Chem. Eur. J. 2010, 16, 11963 – 11968

Asymmetric (Hetero-)Diels–Alder Reactions
FULL PAPER
Under the optimized condition at 258C, Cu
(OTf)2 did not
quired remarkably low catalyst loading (0.1–1.5 mol%). Fur-
ther investigations into the mechanism of this catalytic
system are underway.
catalyze the conversion of 5a into 3a, which indicated that
two distinct pathways dominated at different temperatures
in the same catalytic system (Scheme 3). To gain insight into
Experimental Section
General synthesis of DA adduct 3 as major product: A mixture of b,g-un-
saturated a-ketoester (0.4 mmol), CuACHTUNRGTNEUNG(OTf)2 (0.8 mg, 0.002 mmol), and
N,N’-dioxide L3 (1.3 mg, 0.002 mmol) were added to a test tube under ni-
trogen and kept at ambient temperature for 0.5 h. Anhydrous CH2Cl2
(4.0 mL) was added and the solution was stirred at 258C for 0.5 h. Subse-
quently, cyclopentadiene (400 mL) was added at 258C and the reaction
mixture was stirred for an additional 15 min. The residue was purified by
flash chromatography on silica gel to afford the desired product.
Scheme 3. Control reaction of 3a and 5a.
General synthesis of HDA adduct 5 as major product: A mixture of b,g-
unsaturated a-ketoester (0.2 mmol), CuACHTNUTRGNEUNG(OTf)2 (1.1 mg, 0.003 mmol), and
the origin of the enantioselectivity, nonlinear effects[17] in
the present system were investigated. As shown in Figure 1,
strong positive nonlinear effects were observed for both
products, suggesting that the reaction system involved a
N,N’-dioxide L3 (2.0 mg, 0.003 mmol) were added to a test tube under ni-
trogen and kept at ambient temperature for 0.5 h. Anhydrous CH2Cl2
(2.0 mL) was added and the solution was stirred at 258C for 0.5 h. Subse-
quently, cyclopentadiene (200 mL) was added at À208C and the reaction
mixture was stirred for an additional 12 h at À208C. The residue was pu-
rified by flash chromatography on silica gel to afford the desired product.
polymeric L3–CuACHTUNGTRENNUNG(OTf)2 complex species. Moreover, the
strong positive nonlinear effect makes it possible that the
high enantioselectivity of the reaction can be achieved by
using only a moderate ee value for L3.
General procedure for the scale-up reaction (3a as major product): A
mixture of b,g-unsaturated a-ketoester 1a (5 mmol, 0.95 g), CuACHTUNGTRENNUNG(OTf)2
(16.2 mg, 0.025 mmol), and N,N’-dioxide L3 (9.0 mg, 0.025 mmol) were
added to a flask under nitrogen and kept at ambient temperature for
0.5 h. Anhydrous CH2Cl2 (50 mL) was added and the solution was stirred
at 258C for 0.5 h. Subsequently, cyclopentadiene (5.0 mL) was added at
258C and the reaction mixture was stirred for an additional 15 min. The
residue was purified by flash chromatography on silica gel (ethyl acetate/
petroleum ether 1:8) to afford 3a.
General procedure for the scale-up reaction (5a as major product): A
mixture of b,g-unsaturated a-ketoester 1a (5 mmol, 0.95 g), CuACHTUNGTRENNUNG(OTf)2
(16.2 mg, 0.025 mmol), and N,N’-dioxide L3 (9.0 mg, 0.025 mmol) were
added to a flask under nitrogen and kept at ambient temperature for
0.5 h. Anhydrous CH2Cl2 (50 mL) was added and the solution was stirred
at 258C for 0.5 h. Subsequently, cyclopentadiene (5.0 mL) was added
under À208C and the reaction mixture was stirred for an additional 24 h.
The residue was purified by flash chromatography on silica gel (ethyl
acetate/petroleum ether 1:8) to afford 5a.
General procedure for the control reaction: A mixture of HDA product
5a (0.1 mmol, 25.6 mg) and CuACTHNUTRGNE(UGN OTf)2 (0.6 mg, 0.002 mmol) were added
to a test tube. Anhydrous CH2Cl2 (1.0 mL) was added and the solution
was stirred at 258C for 12 h. Under the conditions of the reaction, no in-
terconversion of 3a into 5a was observed.
*
Figure 1. Nonlinear effects in the reaction. : DA adduct 3a obtained at
&
258C, : HDA adduct 5a obtained at À208C.
For the methods used to determine the relative and absolute configura-
tions of cycloadducts, see the Supporting Information.
Conclusion
We have developed a catalytic asymmetric cycloaddition re-
action between b,g-unsaturated a-ketoesters and cyclopenta-
diene that is promoted by an N,N’-dioxide–CuACTHNUGTRENUNG(OTf)2 com-
Acknowledgements
We appreciate the National Natural Science Foundation of China (nos.
20732003 and 20872097), PCSIRT (no.: IRT0846), and the National Basic
Research Program of China (973 Program: no.: 2010CB833300) for finan-
cial support. We also thank Sichuan University Analytical & Testing
Center for NMR spectroscopic analysis and State Key Laboratory of Bio-
therapy for HRMS analysis.
plex. Through regulating the reaction temperature, both
normal DA adducts and inverse-electron-demand HDA ad-
ducts were obtained in moderate to high chemoselectivity,
respectively, with good to excellent enantioselectivities (up
to >99% ee). The chemoselectivity for the DA adducts was
improved greatly when the reaction was performed at room
temperature (258C, up to 94%). In contrast, low tempera-
ture was favorable for the chemoselective formation of the
HDA adducts (À208C, up to 65%). The reaction also fea-
tured mild reaction conditions, a simple procedure, and re-
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Received: May 19, 2010
Published online: September 8, 2010
11968
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