Asymmetric formal [3+2] cycloaddition reaction of α-aryl isocyanoesters with N-aryl maleimides by bifunctional cinchona alkaloids-based squaramide/AgSbF6 cooperative catalysis

Article abstract of DOI:10.1002/asia.201200686

It is better to be cooperative: A highly diastereo- and enantioselective asymmetric [3+2] cycloaddition reaction of α-aryl isocyanoacetates with N-aryl maleimides through cooperative catalysis of cinchona alkaloid-derived squaramide/AgSbF₆ was

Full text of DOI:10.1002/asia.201200686

DOI: 10.1002/asia.201200686
Asymmetric Formal [3+2] Cycloaddition Reaction of a-Aryl Isocyanoesters
with N-Aryl Maleimides by Bifunctional Cinchona Alkaloids-Based
Squaramide/AgSbF6 Cooperative Catalysis
Mei-Xin Zhao,*[a] Deng-Ke Wei,[a] Fei-Hu Ji,[a] Xiao-Li Zhao,[b] and Min Shi*[a, c]
Cooperative catalysis, which combines two or more cata-
lytic species that operate together within the same molecu-
lar environment to achieve an overall transformation
through synergistic activation of reaction partners, have
been shown to possess distinguished advantages in develop-
ing new chemical transformations or improving the efficien-
cy and stereoselectivity of existing transformations.[1] The
organo/metal mixed system, as one of the three main cate-
gories of cooperative systems, has been widely used in reac-
tions such as a-functionalization of aldehydes or imines,
conjugate addition to a,b-unsaturated carbonyl compounds,
and carbonyl and imine 1,2-addition via the merger of en-
amine or imine catalysis and metal catalysis.[1j] Moreover,
cinchona alkaloid scaffolds have proven to be privileged sys-
tems in the cooperative catalysis owing to their facile prepa-
ration, excellent stereoselective induction, commercial avail-
ability, and presence of multiple sites for further functionali-
zation. Cinchona alkaloid-derived ethers, esters, amides, and
thioureas have been widely applied in nucleophilic additions
of aldehydes, imines, and olefins, through their Brønsted/
Lewis basic property, to activate pro-nucleophiles via depro-
tonation or coordination, and ketene cycloaddition reactions
by using them as Lewis basic/nucleophilic catalyst.[1k]
catalysis in the past several years.[2] Squaramideꢀs dual bind-
ing ability, structural rigidity, different H-bond spacing, and
lower pKa values of the N-H protons, may lead to a broader
substrate scope, improved recognition, better stereoinduc-
tion, or rate enhancement compared to the thiourea or urea
analogues in some cases. However, to the best of our knowl-
edge, no example of organo/metal cooperative catalysis in-
volving squaramide has been reported.
The cyclization reaction of isocyanides with carbon-
carbon and carbon-heteroatom multiple bonds has proved
to be a powerful tool for the synthesis of numerous impor-
tant classes of nitrogen heterocyclic compounds due to the
unique divalent features of the isocyano group that make
isocyanides react smoothly with both electrophiles and nu-
cleophiles.[3] Isocyanoacetates, owing to an acidic proton in
the a-position originating from the ester group, have exhib-
ited an exceptional reaction diversity and high synthetic po-
tential. In light of the pioneering work by Ito and Hayashi,
using chiral AuI or AgI complexes as catalysts to promote
the asymmetric addition of isocyanoacetates to aldehydes,[4]
this type of addition had been widely used in the synthesis
of some bioactive molecules and natural products in the
1980s.[5] However, this kind of asymmetric reaction was
overlooked and received limited attention in the following
twenty years[6,7] until Gong and co-workers described the
first organocatalytic asymmetric reaction of a-aryl isocya-
noacetates with nitroolefins in the presence of cinchona al-
kaloids.[8] Since then, organo- or organometallic-catalyzed
asymmetric additions of isocyanoacetates with many electro-
philes, such as aldehydes,[9] imines,[10] azodicarboxylates,[11]
a,b-unsaturated carbonyl compounds,[12] and maleimides,[13]
have been intensively investigated.
As part of our ongoing interest in the enantioselective ad-
dition reactions of a-aryl isocyanoacetates to unsaturated
compounds, we have developed a highly diastereo- and
enantioselective Michael addition reaction of a-aryl isocya-
noacetates to N-aryl maleimides using quinine-derived
squaramide as catalyst (Scheme 1).[13c] Different from those
addition reactions of isocyanoacetates to nitroolefins or a,b-
unsaturated carbonyl compounds, Michael adducts 4 rather
than expected [3+2] cycloaddition products 5 were obtained
in this reaction. Considering that silver acetate is an efficient
catalyst for the cycloaddition reaction of isocyanoacetates
with various Michael acceptors[14] and encouraged by the de-
velopment in the field of cooperative catalysis using cincho-
While the thiourea framework has been considered a gold
mine in H-bonding involved bifunctional activation process-
es, squaramides has become another complementary or
even superior H-bond donor catalyst in asymmetric organo-
[a] Dr. M.-X. Zhao, D.-K. Wei, F.-H. Ji, Prof. Dr. M. Shi
Key Laboratory for Advanced Materials and Institute of Fine Chemi-
cals
East China University of Science and Technology
130 Meilong Road, Shanghai, 200237 (P. R. China)
Fax : (+86)21-34201699
E-mail: mxzhao@ecust.edu.cn
Mshi@mail.sioc.ac.cn
[b] Dr. X.-L. Zhao
Department of Chemistry
East China Normal University
3663 N. Zhongshan Road, Shanghai, 200062 (P. R. China)
[c] Prof. Dr. M. Shi
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201200686.
Chem. Asian J. 2012, 00, 0 – 0
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COMMUNICATION
Table 1. Screening of catalysts for the asymmetric [3+2] cycloaddition of
a-phenyl isocyanoacetate 1a with N-phenyl maleimide 2a.[a]
Scheme 1. Asymmetric reactions of a-aryl isocyanoacetates 1 with malei-
mides 2.
Entry[a]
Catalyst 3
Yield [%][b]
d.r.[c]
ee [%][d]
na alkaloid derivatives in combination with metal ion-
s,[1k,9b,12a] we envisioned that cinchona alkaloid derivatives/
AgI salt cooperative catalysis could facilitate the [3+2] cy-
cloaddition reaction of isocyanoacetates with N-aryl malei-
mides, affording the expected optically active, substituted
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
3g
3h
75
82
80
82
90
90
85
72
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
6
4
41[e]
40[e]
46[e]
63
67
65
1,3a,4,5,6,6a-hexahydropyrroloACTHNUGRTNEUNG[3,4-c]pyrrole derivatives 5.
While one example has been reported very recently for the
catalytic asymmetric [3+2] cycloaddition of a-substituted
isocyanoacetates with N-phenyl maleimides using a cationic
AuI/DTBM-segphos complex as catalyst,[13b] to the best of
our knowledge, no example of an organo/metal cooperative
catalytic system for this kind of reaction has been reported.
Herein, we wish to report our studies on this subject.
[a] Unless noted otherwise, all reactions were carried out with 1a
(0.2 mmol), 2a (0.1 mmol), AgOAc (0.02 mmol), and 3 (0.01 mmol) in
CH2Cl2 (2 mL) at 208C for 2 h. [b] Yield of isolated product. [c] The d.r.
of the purified product was determined by 1H NMR spectroscopy.
[d] The ee was determined by HPLC on a chiral stationary phase. [e] The
opposite enantiomer was obtained.
In our initial attempt we examined the reaction outcome
of the asymmetric [3+2] cycloaddition reaction of a-phenyl
isocyanoacetate 1a with N-phenyl maleimide 2a in dichloro-
methane at 208C. A variety of bifunctional cinchona alka-
loid-derived thioureas or squaramides, in combination with
20 mol% of AgOAc, were examined in these model reac-
tions, and the results of these experiments are summarized
in Table 1. Quinidine- or cinchonine-derived thiourea cata-
lysts 3a and 3b exhibited high catalytic activity, affording
the desired adduct 5a in high yield and good diastereoselec-
tivity but with low enantioselectivity (Table 1, entries 1–2).
However, the use of quinine- or quinidine-derived squara-
mides as organocatalyst significantly improved the enantio-
selectivity along with similar diastereoselectivity and yield
(Table 1, entries 3–8). It should be noted that different from
the cinchona alkaloid-derived squaramide-catalyzed asym-
metric Michael addition of a-aryl isocyanoacetates to malei-
mides, in which quinine-derived squaramide 3c gave the
best results, quinidine-derived squaramide catalysts 3 f–3h
in combination with AgOAc resulted in a better enantiose-
lectivity as compared to that obtained with the correspond-
ing quinine-derived squaramide catalysts 3c–3e. Catalyst 3g
turned out to be a good catalyst for this reaction, affording
the corresponding product 5a in 85% yield with >20:1 d.r.
and 67% ee (Table 1, entry 7).
Lewis acid, temperature, reaction concentrations, and cata-
lyst loading; representative results are summarized in
Table 2 (for further details, see Table S1 in the Supporting
Information). It was found that this [3+2] cycloaddition re-
action can proceed smoothly in most of less polar solvents
to give 5a with moderate enantioselectivity (Table 2, en-
tries 1–6). Dichloromethane and ethyl acetate (EA) gave
the best stereoselecitivity with similar yield at 158C when
3g was used as an organocatalyst (Table 2, entries 1 and 6).
Using ethyl acetate as solvent, the enantioselectivity and
yield can be further improved by lowering the reactant con-
centration and adding 3 ꢂ molecular sieves as additive, re-
spectively (Table 2, entries 7–8). Among the various Lewis
acids screened (see Table S1 in the Supporting Information),
AgSbF6 was found to be the best metal catalyst (Table 2,
entry 9).[15] Further screening with cinchonine-derived squar-
amide catalysts 3i and 3j revealed that 3i afforded 5a with
a higher yield and enantioselecitivity than 3g and 3j
(Table 2, entries 10 vs. 9 and 11). Considering that dichloro-
methane was another suitable solvent for this reaction, we
next re-examined the cooperative catalytic system 3i/
AgSbF6 in CH2Cl2. Different from 3g/AgOAc, no obvious
temperature effect was observed (Table 1, entries 12 and
13). Reducing the ratio of 1a/2a from 2:1 to 1.5:1 still af-
forded similar enantioselectivity and a reasonable yield
(Table 1, entry 14). Further examination of catalyst loading
To improve the enantioselectivity, further efforts were un-
dertaken by examining other parameters, such as solvents,
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Asymmetric Formal [3+2] Cycloaddition Reaction
Table 2. Optimization of the reaction conditions for the asymmetric [3+2] cycloaddi-
tion reaction of a-phenyl isocyanoacetate 1a with N-phenyl maleimide 2a.[a]
and 7). Substrate 2g, bearing an electron-donating
group at the meta position, afforded the corre-
sponding product 5g in much higher enantioseleci-
tivity than substrate 2e, which bears an electron-do-
nating group at the para position (Table 3, entries 7
vs. 5). For the less reactive N-alkyl-substituted mal-
eimides 2h and 2i, the cycloaddition adducts 5h
and 5i were obtained in good yield, high diastereo-
Entry
3
Ag (I)
Solvent T [8C] t [h] Yield [%][b] d.r.[c]
ee [%][d]
1
3g AgOAc CH2Cl2 15
2
77
80
81
86
90
92
80
90
93
92
67
98
98
86
94
95
86
86
58
62
>20:1 71
2
3
4
5
3g AgOAc CHCl3
3g AgOAc DCE
3g AgOAc Et2O
3g AgOAc THF
3g AgOAc EA
3g AgOAc EA
3g AgOAc EA
3g AgSbF6 EA
15
15
15
15
15
15
15
15
15
15
2
2
2
2
2
2
2
2
>20:1 63
>20:1 66
>20:1 66
>20:1 62
>20:1 72
>20:1 77
>20:1 76
>20:1 77
>20:1 81
>20:1 73
>20:1 85
>20:1 85
>20:1 86
>20:1 88
>20:1 89
>20:1 89
>20:1 89
>20:1 84
>20:1 73
selectivity,
(Table 3, entries 8 and 9).
and
moderate
enantioselectivity
To broaden the substrate scope, a variety of iso-
cyanoacetates bearing a variety of substituents with
different electronic and steric proerties were also
evaluated (Table 4). Generally, most of the reac-
tions using these a-aryl isocyanoacetates reacted
smoothly to afford the corresponding cycloaddition
adducts in high yield and excellent diastereoselec-
tivity. The enantioselectivity varied depending on
the substituentꢀs electronic property. a-Aryl-substi-
tuted isocyanoacetates bearing an electron-with-
drawing group on the aromatic ring led to a better
enantioselectivity than those bearing an electron-
donating group (Table 4, entries 1–3, 5, and 7 vs. 4,
6, and 8). In the case of ortho-substituted isocya-
noacetates 1h and 1i, which cannot react with mal-
eimide 2a in a Michael addition under catalysis of
3c,[13c] the corresponding products 5p and 5q were
also formed in high yield and good enantioselectivi-
ty (Table 4, entries 7 and 8). Different from benzyl
a-phenyl isocyanoacetate 1j, which could provide
the corresponding adduct 5r in high yield and good
stereoselectivity, t-butyl a-phenyl isocyanoacetate
1k afforded the product 5s in moderate yield and
similiar stereoselectivity, even after prolonged reac-
tion times, presumably owing to steric hindrance
6
7[e]
8[e,f]
9[e,f]
10[e,f]
11[e,f]
12[f,g]
13[f,g]
14[f,g,h]
15[f,g,h,i]
16[f,g,h,j]
17[f,g,h,k]
18[f,g,h,l]
3i
3j
3i
3i
3i
3i
3i
3i
3i
AgSbF6 EA
AgSbF6 EA
2
2
AgSbF6 CH2Cl2 15
AgSbF6 CH2Cl2 25
AgSbF6 CH2Cl2 25
AgSbF6 CH2Cl2 25
AgSbF6 CH2Cl2 25
AgSbF6 CH2Cl2 25
AgSbF6 CH2Cl2 25
AgSbF6 CH2Cl2 25
AgSbF6 CH2Cl2 25
0.5
0.5
0.5
0.8
1.5
1.5
1.5
1.5
1.5
19[f,g,h,m] 3i
20[f,g,h,n]
3i
[a] Unless noted otherwise, all reactions were carried out with 1a (0.2 mmol), 2a
(0.1 mmol), 3 (10 mmol%), and AgOAc or AgSbF6 (20 mol%) in 2 mL of solvent.
[b] Yield of isolated product. [c] The d.r. of the purified product was determined by
1H NMR spectroscopy. [d] The ee was determined by HPLC on a chiral stationary
phase. [e] Ethyl acetate (4 mL) was used. [f] 3 ꢂ MS (30 mg) was added. [g] CH2Cl2
(4 mL) was used. [h] The ratio of 1a/2a was 1.5:1. [i] 3i (10 mmol%) and AgSbF6
(10 mol%) were used. [j] 3i (5 mmol%) and AgSbF6 (10 mol%) were used. [k] 3i
(5 mmol%) and AgSbF6 (5 mol%) were used. [l] 3i (5 mmol%) and AgSbF6
(1 mol%) were used. [m] 3i (3 mmol%) and AgSbF6 (1 mol%) were used. [n] 3i
(1 mmol%) and AgSbF6 (1 mol%) were used.
revealed that reducing the equivalent of AgSbF6 from
20 mol% to 1 mol% still afforded 5a with high enantiose-
lectivity, albeit with lower yield after a longer reaction time
(Table 2, entries 15–18). However, upon reduction of the or-
ganocatalyst loading from 5 mol% to 1 mol%, a lower yield
of 5a along with a lower enantioselectivity was obtained
(Table 2, entries 19–20). Considering both the yield and
enantioselectivity, we identified 5 mol% of 3i and 10 mol%
of AgSbF6 as the optimal catalyst loading.
With the optimized reaction conditions in hand, the scope
of maleimides 2 was examined next; the results of these ex-
periments are summarized in Table 3. Generally, most of the
N-aryl substituted maleimides can undergo the [3+2] cyclo-
addition reaction smoothly to give the desired adducts 5a–g
in high yield (90–96%), excellent diastereoselectivity (>
20:1), and good enantioselectivity (74–89%). Both the elec-
tronic property of the substituents and the position of substi-
tution play an important role in determining the reaction
outcome. N-Aryl maleimides bearing with an electron-with-
drawing group on the aromatic ring yielded the desired
products in slightly lower enantioselectivity as compared to
the corresponding substrates with no substituents or with
electron-donating groups (Table 3, entries 2–3, 6 vs. 1, 4, 5,
Table 3. Scope of N-substituted maleimides 2 for the asymmetric [3+2]
cyclo- addition of isocyanoacetate 1a.[a]
Entry 2 (R)
5
t [h] Yield [%][b] d.r.[c]
ee [%][d]
>20:1 89
1
2
3
4
5
6
7
8
9
2a (Ph)
5a 1.5
5b 0.5
5c 0.5
5d 0.5
95
90
91
92
92
96
92
84
76
2b (4-FC6H4)
2c (4-BrC6H4)
2d (4-MeC6H4)
2e (4-MeOC6H4) 5e 0.5
2 f (3-ClC6H4) 5 f 0.5
2g (3-MeOC6H4) 5g 0.5
>20:1 74
>20:1 78
>20:1 81
>20:1 77
>20:1 77
>20:1 86
>20:1 65
>20:1 53
2h (Bn)
2i (Me)
5h 30
5i 10
[a] All reactions were carried out with a-phenyl isocyanoacetate 1a
(0.225 mmol), maleimide (0.15 mmol), 3i (5 mol%), and AgSbF6
(10 mol%) in CH2Cl2 (4.0 mL) at room temperature. [b] Yield of isolated
product. [c] The diastereoisomeric ratio of the purified product was de-
termined by H NMR spectroscopy. [d] The ee was determined by HPLC
on a chiral stationary phase.
2
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Min Shi et al.
COMMUNICATION
Table 4. Scope of isocyanoacetates 1 for the asymmetric [3+2] cycloaddi-
tion with N-phenyl maleimide 2a.[a]
Entry 1 (R1/R2)
5
t [h] Yield [%][b] d.r.[c]
ee [%][d]
1
1b (4-FC6H4/OMe)
5j 0.5 93
>20:1 90
2
3
4
5
6
7
8
9
10
11
12
13
1c (4-ClC6H4/OMe) 5k 0.5 93
>20:1 90
>20:1 92
>20:1 74
>20:1 89
>20:1 81
1d (4-BrC6H4/OMe) 5l
1e (4-MeC6H4/OMe) 5m
0.5 91
5 71
1 f (3-FC6H4/OMe)
5n 0.5 93
Scheme 2. Proposed transition-state model.
1g (3-MeC6H4/OMe) 5o
1h (2-BrC6H4/OMe) 5p 24
1i (2-MeC6H4/OMe) 5q 48
2
97
98
91
95
50
85
83
67
10:1
86
>20:1 79
>20:1 80
>20:1 80
>20:1 10
>20:1 10
>20:1 13
1j (Ph/OBn)
1k (Ph/OtBu)
1l (iPr/OMe)
1m (Bn/OMe)
1n (H/OEt)
5r 12
5s 24
5t 96
5u 44
quently, a 5-endo-dig cyclization would take place assisted
by electrophilic silver isocyanide activation. The third ste-
reocenter is formed as S-configuration after the cyclization
step.
5v
4
In summary, we have developed the first example of a cin-
chona alkaloid-derived squaramide/AgSbF6 cooperative cat-
alytic system for the highly diastereo- and enantioselective
formal [3+2] cycloaddition of a-aryl isocyanoacetates with
N-aryl maleimides. A wide variety of N-aryl-substituted mal-
eimides and a-aryl isocyanoacetates, with different electron-
ic and steric properties, were tolerated in this catalytic enan-
tioselective [3+2] cycloaddition reaction, leading to optically
[a] All reactions were carried out with a-phenyl isocyanoacetate
1 (0.225 mmol), maleimide 2a (0.15 mmol), 3i (5 mol%), and AgSbF6
(10 mol%) in CH2Cl2 (4.0 mL) at room temperature. [b] Yield of isolated
product. [c] The diastereoisomeric ratio of the purified product was de-
termined by H NMR spectroscopy. [d] The ee was determined by HPLC
on a chiral stationary phase.
1
(Table 4, entries 9 vs. 10). Moreover, a-alkyl- or non-substi-
tuted isocyanoacetates 1l, 1m, and 1n are not suitable for
this asymmetric [3+2] cycloaddition, affording the desired
products 5t–v in good yield, high diastereoselectivity along
with very low stereoselectivity (only ca. 10% ee; Table 4, en-
tries 11–13).
active 1,3a,4,5,6,6a-hexahydropyrroloACTHNUTRGNE[UNG 3,4-c]pyrrole deriva-
tives in high yield along with good to excellent diastereo-
and enantioselectivities. Investigations aimed at fully under-
standing the reaction mechanism and expanding this kind of
bifunctional organo/metal cooperative catalysis with cincho-
na alkaloid scaffolds to other valuable transformations are
currently ongoing in our laboratory.
The absolute and relative configuration of 5 was unambig-
uously assigned by X-ray crystallographic analysis of the op-
tically pure compound 5l,[16] which was obtained by recrys-
tallization from a mixture of dichloromethane and hexanes
(Table 4, entry 3). The structure allowed the (1R, 3aS, 6aR)
assignment of the newly formed stereogenic centers in 5l
(see Figure S1 in the Supporting Information). The configu-
rations of other adducts were then assigned by analogy.
Although the mechanism of these reactions reported here
remains to be clarified, a plausible transition-state model,
based on the experimental results and commonly accepted
mechanisms, is proposed in Scheme 2. In this model, one
carbonyl group of maleimide 2a is hydrogen-bonded to the
squaramide motif, while the a-proton of isocyanoacetate 1a
is easily deprotonated by the quinuclidine nitrogen of cata-
lyst 3i due to the activation of AgI chelating to the terminal
carbon of the isocyano group. A single hydrogen bond is
then formed between the OH group of the enolized isocya-
noacetate and the tertiary amine of quinine. A weak hydro-
gen bond between the OMe group of the enolized isocya-
noacetate and the NH in the squaramide moiety, as well as
an interaction between AgI and the other carbonyl group of
the maleimide might be formed concurrently, thus forcing
the isocyanoacetate enolate to attack the maleimide from
the Re-face, thereby leading to the formation of two newly
generated stereocenters with (R, R)-configuration. Subse-
Experimental Section
General procedure for the asymmetric [3+2] cycloaddition of
isocyanoacetates 1 with maleimides 2 under the cooperative catalysis by
3i/AgSbF6
A solution of isocyanoacetate 1 (0.225 mmol), 3i (4.5 mg, 0.0075 mmol),
AgSbF6 (5.2 mg, 0.015 mmol), and 3 ꢂ MS (30 mg) in CH2Cl2 (4 mL) was
stirred at room temperature for 10 min, followed by addition of malei-
mide 2 (0.15 mmol). The resulting mixture was stirred at room tempera-
ture for 0.5–96 h until the reaction was complete (monitored by TLC).
Subsequently, the mixture was concentrated and purified by flash chro-
matography on silica gel (petroleum ether/ethyl acetate=4:1) to furnish
the corresponding cycloaddition product 5.
(1R,3aS,6aR)-Methyl-1-(4-fluorophenyl)-4,6-dioxo-5-phenyl-
1,3a,4,5,6,6a-hexahydropyrroloACTHNUTRGENUGN[3,4-c]pyrrole-1-carboxylate (5j)
Yellow solid, yield: 50.8 mg (93%); d.r.>20:1; m.p. 192.2–193.78C;
½aꢀ2D5 =ꢁ110.1 (c=1.0, CH2Cl2); 90% ee (Chiralpak AD-H; hexane/2-
propanol, 3:2; 0.8 mLminꢁ1; 230 nm; tmajor =14.48 min, tminor =24.83 min);
1H NMR (400 MHz, CDCl3): d=8.02 (d, J=1.6 Hz, 1H, =CH), 7.61–7.58
(m, 2H, ArH), 7.50 (t, J=7.2 Hz, 2H, ArH), 7.44 (d, J=7.2 Hz, 1H,
ArH), 7.32 (dd, J=7.2, 1.2 Hz, 2H, ArH), 7.11 (t, J=8.4 Hz, 2H, ArH),
4.44 (dd, J=9.2, 1.2 Hz, 1H, CH), 3.85 (d, J=9.2 Hz, 1H, CH), 3.65 ppm
(s, 3H, OCH3); 13C NMR (100 MHz, CDCl3): d=174.2, 170.9, 169.8,
162.3 (d, J=245.2 Hz), 162.0, 136.4 (d, J=2.3 Hz), 131.4, 129.3, 129.0,
128.8 (d, J=8.2 Hz), 126.5, 115.3 (d, J=21.8 Hz), 89.8, 59.9, 54.1,
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ÝÝ These are not the final page numbers!

Asymmetric Formal [3+2] Cycloaddition Reaction
53.7 ppm; 19F NMR (376 MHz, CDCl3): d=ꢁ113.7 ppm. IR (film): n˜ =
1713, 1509, 1383, 1226, 1192 cmꢁ1; HRMS (ESI): calcd. for C20H16FN2O4
[M+H]+ 367.1094; found: 367.1093.
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Acknowledgements
We are grateful for financial support from the National Natural Science
Foundation of China (20772030, 21072056, 21272067), the Fundamental
Research Funds for the Central Universities, Scientific Research Founda-
tion for the Returned Overseas Chinese Scholars, and State Education
Ministry and Shanghai Rising-Star Program (10QA1402000).
Keywords:
ACHTUNGTRENNUNG[3+2] cycloaddition · cooperative catalysis ·
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isocyanoacetates · maleimides · synthetic methods
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simplified the purification of the desired cycloaddition product 5a.
[16] CCDC 887265 (for 5l) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif. Empirical formula: C20H15BrN2O4; formula
mass: 427.25; temperature: 296 (2) K; crystal system: Monoclinic;
space Group: P2(1); lattice parameters: a=10.839(2), b=
7.8459(16), c=11.009(2) ꢂ, a=90.00, b=104.222(6), g=90.008, V=
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2799–2802.
907.5(3) ꢂ3; Z=2; 1cald =1.564 gcmꢁ3
2.294 mmꢁ1; F
(000)=432; crystal dimensions: 0.47ꢆ0.16ꢆ0.08 mm;
2q range: 1.91–24.998; goodness of fit on F2: 1.030; data/restraints/
parameters: 2757/1/244; final Indices [I>2s(I)]: R1 =0.0317,
wR2 =0.0817; R Indices (all data): R1 =0.0357, wR2 =0.0841.
;
absorption coefficient:
AHCTUNGTRENNUNG
R
[5] a) Y. Ito, M. Sawamura, T. Hayashi, Tetrahedron Lett. 1988, 29, 239–
240; b) A. Togni, S. D. Pastor, G. Rihs, Helv. Chim. Acta 1989, 72,
1471–1478; c) M. D. Bachi, A. Melman, J. Org. Chem. 1997, 62,
1896–1898.
Received: July 28, 2012
Revised: August 16, 2012
Published online: && &&, 0000
Chem. Asian J. 2012, 00, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
5
&
&
&
These are not the final page numbers! ÞÞ

COMMUNICATION
Cooperative Catalysis
Mei-Xin Zhao,* Deng-Ke Wei,
Fei-Hu Ji, Xiao-Li Zhao,
Min Shi*
&&&& — &&&&
Asymmetric Formal [3+2] Cycloaddi-
tion Reaction of a-Aryl Isocyanoesters
with N-Aryl Maleimides by Bifunc-
tional Cinchona Alkaloids-Based
Squaramide/AgSbF6 Cooperative
Catalysis
It is better to be cooperative: A highly
diastereo- and enantioselective asym-
metric [3+2] cycloaddition reaction of
a-aryl isocyanoacetates with N-aryl
maleimides through cooperative catal-
ysis of cinchona alkaloid-derived
tuted 1,3a,4,5,6,6a-hexahydropyrrolo-
AHCTUNGTRENNG[UN 3,4-c] pyrrole derivatives was obtained
in high yields (up to 98%), high diaste-
reoselectivities (>20:1 d.r.), and good
to excellent enantioselectivities (up to
92% ee) under mild reaction condi-
tions.
squaramide/AgSbF6 was developed. A
wide range of optically active, substi-
&
&
&6
&
www.chemasianj.org
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!