Chiral squaramides catalyzed diastereo- and enantioselective Michael addition of α-substituted isocyanoacetates to N-aryl maleimides

Article abstract of DOI:10.1016/j.tet.2013.09.084

An efficient diastereo- and enantioselective Michael addition of α-substituted isocyanoacetates to N-aryl maleimides catalyzed by quinine or cyclohexane-1,2-diamine derived squaramide catalysts has been disclosed, affording the corresponding adducts in go

Full text of DOI:10.1016/j.tet.2013.09.084

Tetrahedron 69 (2013) 10763e10771
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Chiral squaramides catalyzed diastereo- and enantioselective
Michael addition of
maleimides
a-substituted isocyanoacetates to N-aryl
,
a
a
a,b,
*
Mei-Xin Zhao a , Fei-Hu Ji , Deng-Ke Wei , Min Shi
*
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Mei Long Road, Shanghai
200237, PR China
b State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai
200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2013
Received in revised form 14 September 2013
Accepted 27 September 2013
Available online 3 October 2013
An efficient diastereo- and enantioselective Michael addition of a-substituted isocyanoacetates to N-aryl
maleimides catalyzed by quinine or cyclohexane-1,2-diamine derived squaramide catalysts has been
disclosed, affording the corresponding adducts in good yields (up to 99%), high diastereoselectivities (up
to >20:1 dr) and good to excellent enantioselectivities (up to 94% ee) under mild conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Isocyanoacetates
Maleimides
Michael addition
Squaramides
Organocatalysis
1. Introduction
Isocyanides were found to be irreplaceable building blocks for
the synthesis of numerous important classes of nitrogen hetero-
Hydrogen bonding promoted asymmetric organocatalysis has
attracted intense research efforts in the past decade. Chiral ureas
and thioureas, diols, and phosphoric acids dominated the field of
hydrogen bonding, and the thiourea framework has been consid-
ered as a gold mine in H-bonding involved bifunctional activation
processes.1 However, chiral squaramide catalysts, pioneered by
Rawal’s group and later developed by other groups with in-
corporating the squaramide moiety as a powerful hydrogen bond
donor in different chiral scaffolds, have been identified as another
complementary or even superior H-bond donor catalyst in asym-
metric organocatalysis in the past several years.2 Squaramide’s dual
binding ability, structural rigidity, further apart H-bond spacing and
lower pKa values of the NeH protons, may lead to a broader sub-
strate scope, improved recognitions, better stereoinduction or rate-
enhancement compared to the thiourea or urea analogues in some
cases.
cyclic compounds due to the unique divalent features of the iso-
cyano group that make isocyanides react smoothly with both
electrophiles and nucleophiles.3 Isocyanoacetates 1, which com-
bined several potential reaction centers, such as an isocyano group,
an acidic CH fragment, and a protected carboxylic acid, have shown
exceptional reaction diversity and broad synthetic potential.4 In
light of the pioneering works by Ito and Hayashi,5 Gong6 et al.,
organo- and organometallic complex catalyzed asymmetric addi-
tion of isocyanoacetates to many carbonecarbon, carbon-
eheteroatom multiple bonds electrophiles, including nitroolefins,6
carbonyl compounds,7 imines,8 azodicarboxylates,9 and
a,b-un-
saturated carbonyl compounds,10 have been intensively studied in
recent years. In most cases, chiral cyclic compounds were obtained.
As part of our ongoing interest in the enantioselective addition
reactions of
pounds,7d,9b,10f we have developed a highly diastereo- and enan-
-aryl isocyanoacetates
a-aryl isocyanoacetates to unsaturated com-
tioselective [3þ2] cycloaddition reaction of
a
to maleimides cooperative catalyzed by bifunctional cinchona
alkaloids-based squaramide/AgSbF6 (Scheme 1).10f However, dif-
ferent from those organocatalyzed enantioselective addition re-
actions of isocyanoacetates to nitroolefin6 or carboneheteroatom
multiple bonds electrophiles,7a,d,8,9 Michael adducts 5 rather than
* Corresponding authors. Tel.: þ86 21 64252995; fax: þ86 21 34201699 (M.-X.Z.);
tel.: þ86 21 54925137 (M.S.); e-mail addresses: mxzhao@ecust.edu.cn (M.-X. Zhao),
Mshi@mail.sioc.ac.cn (M. Shi).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.084

10764
M.-X. Zhao et al. / Tetrahedron 69 (2013) 10763e10771
Table 1
the expected [3þ2] cycloaddition products 4 were obtained in the
absence of silver salts. Considering that substituted maleimides are
important structural motifs, which widely present in numerous
biologically interesting molecules and pharmaceuticals11 and the
asymmetric Michael addition to maleimides is also an effective
strategy for the construction of vicinal quaternaryetertiary ster-
eocenters,12 which are ubiquitous and structural moieties in com-
plex natural products and pharmaceuticals, we described herein
chiral squaramides catalyzed highly diastereo- and enantiose-
Catalysts screeninga
lective Michael addition of a-aryl isocyanoacetates to maleimides.
Despite Wang et al. have reported the chiral tertiary aminee-
thiourea catalyzed asymmetric Michael addition of iso-
cyanoacetates to maleimdes,10c there are still several challenging
issues, such as substrate generality, efficiency of catalyst, and re-
action time, need to be addressed. Therefore, the development of
other new, more efficient catalytic systems is still highly desirable.
Entry
Cat. 3
Yieldb (%)
drc
ee (%)d
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
50
61
62
58
57
36
72
54
74
73
56
34
8:1
6:1
8:1
6:1
2.4:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
56
52
ꢀ61
ꢀ50
15
82
73
61
ꢀ56
ꢀ81
ꢀ70
ꢀ75
9
Scheme 1. Asymmetric reactions of a-aryl isocyanoacetates 1 with maleimides 2.
10
11
12
3j
3k
3l
2. Results and discussion
a
All of reactions were carried out with 1a (0.24 mmol), 2a (0.20 mmol), and cat. 3
(0.02 mmol) in DCM (2.0 mL) at rt for 24 h.
b
Isolated yield.
On the basis of the earlier successes of bifunctional catalysts
possessing both H-bond donor and acceptor moieties in many
maleimides involved enantioselective reactions13 and cinchona al-
c
The dr value of the purified product was determined by 1H NMR spectroscopy.
d
The ee value was determined by chiral HPLC analysis.
kaloids catalyzed asymmetric additions of
a
-aryl isocyanoacetates
-phenyl
1,6,7a,d,8,9b,10e the initial studies were carried out using
a
In view of the higher yield and enantioselectivity, efforts were
taken to further optimize the reaction conditions by examining other
parameters, such as solvent, temperature, reactant concentrations,
and additives (Table 2; For more details see Table S1 in the Supple-
mentary data). It was found that the ratio of 1a/2a was crucial for the
yieldand enantioselectivity; higher yieldwasobtained by using2:1 of
1a/2a without impairing the enantioselectivity (Table 2, entries 1 vs 2
and Table 1, entry 6). Of the various solvents screened, dichloro-
methane was the best solvent for this Michael addition, despite that
high dr values, similar level of enantioselectivities in other chlori-
nated solvents (Table 2, entries 3 and 4). Moderate ee values and low
yields were obtained in toluene and xylene (Table 2, entries 5 and 6).
Ethers and polar solvents, such as acetone, methanol, and acetonitrile
were not suitable for this reaction, giving 5a with low enantiose-
lectivities (Table 2, entries 7e11). Prolonging the reaction time can
significantly improve the yield and ee value, and the lower concen-
tration led to the formation of 5a in a similar ee value but in lower
yield (Table 2, entries 12e14). Further examination of temperature
effect revealed that lowering the reaction temperature produced 5a
in lower yield and ee value (Table 2, entry 15); elevating the reaction
temperature could improve the yield of 5a, but decreased the enan-
isocyanoacetate (1a) and N-phenyl maleimide (2a) as substrate and
quinine derived thiourea 3a as catalyst. When the reaction was
carried out in dichloromethane at room temperature using
10 mol % of catalyst 3a, the corresponding Michael adduct 5a, rather
than the expected [3þ2] cycloaddition product, was obtained in
moderate yield, diastereoselectivity, and enantioselectivity (50%,
8:1 dr, 56% ee) (Table 1, entry 1). Encouraged by this result, a series
of cinchona alkaloid thioureas 3bee were used as catalysts to ex-
amine the reaction outcome (Table 1). Generally, most thiourea
catalysts could effectively promote this reaction, giving the corre-
sponding adduct 5a in moderate yields and stereoselectivities
(Table 1, entries 2e5). Among of these, quinine thiourea catalyst
bearing sulfonamide as multiple H-bond donors 3e, which has
shown good catalytic activities in the enantioselective Michael
addition of N-Boc-3-aryloxindoles to phenyl vinyl sulfone14 and
formal [3þ2] cycloaddition of isocyanoacetates to isatins,7d was not
effective catalyst for this reaction, providing 5a in moderate yield
along with low stereoselectivity (Table 1, entry 5). Cinchona
alkaloid-based squaramides 3fel can serve as better bifunctional
organocatalysts, and they showed much higher stereoselectivities
than those of above mentioned thiourea catalysts (Table 1, entries
6e12). Of the cinchona alkaloid squaramides screened, quinine
derived squaramide 3f was the best catalyst, giving 5a in high
diastereo- and enantioselectivity, albeit with much lower yield
(Table 1, entry 6).
ꢀ
tioselectivity (Table 2, entry 16). Moreover, the addition of 4 A mo-
lecular sieves could further improve the enantioselectivity, affording
5a in good yield with up to 90% ee (Table 2, entry 17); Reducing the
catalyst loading from 10 mol % to 5 mol %, leads to similar yield and
much lower ee values (Table 2, entry 18).

M.-X. Zhao et al. / Tetrahedron 69 (2013) 10763e10771
10765
Table 2
yields (70e94%), high diastereoselectivities (up to >20:1) and good
enantioselectivities (85e92% ee) (Table 3, entries 1e7). However,
low yield and moderate enantioselectivity was afforded for N-alkyl
substituted maleimide 2h (Table 3, entries 8). Further examination
Optimization of the reaction conditions for the asymmetric Michael addition of
a-
phenyl isocyanoacetate 1a with N-phenyl maleimide 2a catalyzed by 3fa
Entry
Solvent
T (ꢁC)
Time (h)
Yieldb (%)
drc
ee (%)d
1
CH2Cl2
CH2Cl2
CHCl3
20
20
20
20
20
20
20
20
20
20
20
20
20
20
0
24
24
24
24
24
24
24
24
24
24
24
72
72
72
72
30
72
72
51
63
51
67
33
27
69
33
69
53
36
74
85
55
45
95
88
91
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
83
67
81
73
53
57
17
55
4
of substituent effect of isocyanoacetates revealed that most a-aryl
2e
isocyanoacetates, whether bearing electron-donating or electron-
withdrawing group on para- or meta-position of the phenyl
group, could give the desired adducts in good to excellent yields
(60e95%), excellent stereoselectivities (up to >20:1 dr and 94% ee)
(Table 3, entries 9e16), albeit isocyanoacetates with an electron-
withdrawing group gave the desired products with slightly
higher enantioselectivities than those of isocyanoacetates without
substituent or with electron-donating groups (Table 3, entries 9e12
and 15 vs 1, 13, 14 and 16). It should be also noted that as for more
sterically hindered substrate, such as ortho-tolyl derived iso-
cyanoacetate (1i), the reaction became sluggish and no desired
adduct was detected under the optimal conditions (Table 3, entry
3
4
5
6
7
8
9
DCE
Toluene
Xylene
THF
Et2O
Acetone
CH3OH
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
11
12
13f
14g
15f
16f
17f,h
18f,h,i
0
5
86
86
86
84
81
90
88
30
20
20
17). Different from benzyl
a-phenyl isocyanoacetate (1j), which
afforded the similar result to methyl isocyanoacetate (1a), tert-
butyl isocyanoacetate (1k) led to the formation of the desired
product 5s in low yield (41%) and diastereoselectivity (1:1 dr) as
well as comparable ee value (86% ee) even with prolonged reaction
time to 7 days, presumably due to steric effect (Table 3, entries 18
and 19). Moreover, a-alkyl isocyanoacetate 1l is not suitable for this
reaction; trace product 5t was detected due to its low reactivity
(Table 3, entry 20).
It is not surprising that the above Michael addition catalyzed by
3f proceeded slowly and was not applicable to less reactive alkyl-
substituted maleimides and isocyanoacetates probably due to the
inefficient basicity of cinchona alkaloid derivatives. Recently, Wang
et al. reported chiral cyclohexane-1,2-diamine derived bifunctional
tertiary-amine thiourea can efficiently catalyze this enantiose-
lective Michael addition10c and chiral cyclohexane-1,2-diamine
derived bifunctional tertiary amineesquaramides have found
a
Unless otherwise noted, all of reactions were carried out with isocyanoacetate
1a (0.30 mmol), maleimide 2a (0.15 mmol), and cat. 3f (0.015 mmol) in DCM
(1.5 mL).
b
Isolated yield.
c
The dr value of the purified product was determined by 1H NMR spectroscopy.
d
The ee value was determined by chiral HPLC analysis.
The ratio of 1a/2a was 1:2.
CH2Cl2 (1.0 mL) was used.
CH2Cl2 (3.0 mL) was used.
MS (30 mg of 4 A) was added.
Cat. 3f (5 mol %) was used.
e
f
g
h
ꢀ
i
With the optimal conditions in hand, we explored the substrate
scope of this Michael addition. As shown in Table 3, with respect to
3-phenyl isocyanoacetate (1a), a variety of N-aryl maleimides
worked well and the corresponding adducts were obtained in good
Table 3
Enantioselective asymmetric Michael addition of isocyanoacetate 1 with N-substituted maleimides 2 catalyzed by squaramides 3f or 3na
Entry
1 (R1/R2)
2 (R3)
t (h)
5 (ent-5)
Yieldb (%)
drc
ee (%)d
1
2
3
4
5
6
7
8
1a (Ph/Me)
1a (Ph/Me)
1a (Ph/Me)
1a (Ph/Me)
1a (Ph/Me)
1a (Ph/Me)
1a (Ph/Me)
1a (Ph/Me)
1b (4-FC6H4/Me)
1c (4-ClC6H4/Me)
1d (4-BrC6H4/Me)
1d (4-BrC6H4/Me)
1e (4-MeC6H4/Me)
1f (4-MeOC6H4/Me)
1g (3-FC6H4/Me)
1h (3-MeC6H4/Me)
1i (2-MeC6H4/Me)
1j (Ph/Bn)
2a (Ph)
72 (4)
72 (9)
72 (4)
72 (4)
72 (4)
72 (4)
72 (4)
72 (4)
72 (4)
72 (4)
72 (4)
72
72 (4)
72 (4)
72 (4)
72 (7)
72
5a (ent-5a)
5b (ent-5b)
5c (ent-5c)
5d (ent-5d)
5e (ent-5e)
5f (ent-5f)
5g (ent-5g)
5h (ent-5h)
5i (ent-5i)
5j (ent-5j)
5k (ent-5k)
5l
5m (ent-5m)
5n (ent-5n)
5o (ent-5o)
5p (ent-5p)
5q
88 (99)
70 (92)
82 (98)
86 (98)
81 (99)
81 (99)
94 (99)
25 (71)
71 (99)
90 (99)
77 (99)
95
66 (98)
60 (92)
95 (98)
85 (99)
n.r.
>20:1 (>20:1)
>20:1 (>20:1)
20:1 (20:1)
>20:1 (>20:1)
20:1 (20:1)
>20:1 (>20:1)
>20:1 (>20:1)
>20:1 (>20:1)
>20:1 (>20:1)
>20:1 (>20:1)
>20:1 (>20:1)
>20:1
>20:1 (>20:1)
20:1 (>20:1)
>20:1 (>20:1)
>20:1 (>20:1)
n.d.
90 (90)
86 (85)
87 (91)
88 (86)
85 (88)
87 (88)
92 (90)
76 (65)
94 (89)
92 (90)
90 (91)
91
90 (86)
88 (88)
93 (84)
86 (86)
n.d.
2b (4-FC6H4)
2c (4-BrC6H4)
2d (4-MeC6H4)
2e (4-MeOC6H4)
2f (3-ClC6H4)
2g (3-MeOC6H4)
2h (Bn)
2a (Ph)
2a (Ph)
2a (Ph)
2g (3-MeOC6H4)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
2a (Ph)
9
10
11
12
13
14
15
16
17
18
19
20
21
72
5r
95
10:1
1:1 (3:1)
n.d. (2.4:1)
(1.4:1)
90
1k (Ph/t-Bu)
1l (Bn/Me)
1m (H/Et)
168 (24)
120 (72)
(72)
5s (ent-5s)
5t (ent-5t)
(ent-5u)
41 (93)
Trace (20)
(15)
86, 0 (85, 51)e
n.d. (46, 33)e
(20, 15)e
a
All of reactions were carried out with isocyanoacetates 1 (0.30 mmol), maleimides 2 (0.15 mmol), catalyst 3f or 3n (10 mol %), and 30 mg of 4 A MS in DCM (1.0 mL) at 20 ꢁC,
ꢀ
the data in parenthesis was obtained by using the catalyst 3n.
b
Isolated yield.
c
The dr value of the purified product was determined by 1H NMR spectroscopy.
d
The ee value was determined by chiral HPLC analysis.
The second data was the ee value for minor isomer.
e

10766
M.-X. Zhao et al. / Tetrahedron 69 (2013) 10763e10771
wide applications in organocatalyzed asymmetric reactions.2iel
Inspired by these new results and to further expand the use of bi-
functional squaramide catalysts in this asymmetric Michael addi-
tion, we synthesized the 1,2-diaminocyclohexane derived
squaramide catalysts 3meo to evaluate their catalytic activity for
this reaction. It was found that the substituent on nitrogen atoms of
the tertiary amine has played an important role in determining the
reaction outcome. Under the above optimal conditions, pyrrolidine
substituted catalyst 3n showed better catalytic activity than those
of the corresponding dimethyl and piperidine substituted catalysts
3m and 3o, affording 5a in almost quantitative yield, excellent
diastereoselectivity and up to 90% ee value after just 4 h (Table 3,
entry 1).15 Although the result is comparable to those of quinine-
derived squaramide 3f (3 d, 88%, >20:1 dr, 90% ee) and cyclohex-
ane-1,2-diamine derived thiourea catalyst of Wang (18 h, 93%, 99:1
dr and 94% ee),10c the yield was improved and the reaction time was
greatly shortened. Further examination of the substrate scope
revealed that this conjugate addition mediated by catalyst 3n is
isocyanoacetate through si-face to attack the maleimide from the
si-face or re-face, affording the adduct 5a and ent-5a with (R,R)- and
(S,S)-configuration, respectively.
3. Conclusion
In conclusion, we have developed quinine- or cyclohexane-1,2-
diamine derived squaramides catalyzed highly diastereo- and
enantioselective Michael addition of
a-aryl isocyanoacetates to N-
aryl maleimides under mild conditions. A variety of
a
-aryl
substituted isocyanoacetates, as well as N-aryl maleimides, with
different electron property of substituent were tolerated in this
catalytic enantioselective Michael addition, affording the corre-
sponding adducts in good yields (up to 99%), high diaster-
eoselectivities (up to >20:1 dr), and good to excellent
enantioselectivities (up to 94% ee). Compared with quinine derived
squaramide catalyst 3f, cyclohexane-1,2-diamine derived squar-
amide catalyst 3n exhibited the higher catalytic reactivity; the
yields were improved, and the reaction times were greatly short-
applicable to a variety of N-aryl maleimides and a-aryl-substituted
isocyanoacetates, excellent yields as well as good to excellent
stereoselectivities were generally attainable (Table 3, entries 2e11
and 13e16). For sterically bulky tert-butyl isocyanoacetate (1k),
excellent yield, moderate diastereoselectivity and good ee value
were obtained (Table 3, entry 19). However, to our disappointment,
less reactive alkyl-substituted isocyanoacetates and N-alkyl
substituted maleimide still could not give satisfactory results. N-
Benzyl maleimide 2h reacted smoothly with isocyanoacetate 1a to
give the desired product in moderate yield, high diaster-
ened. Investigations on the asymmetric addition of a-aryl iso-
cyanoacetates to other electrophiles are currently ongoing in our
laboratory.
4. Experimental section
4.1. General method
NMR spectra were recorded on a Bruker AVANCE III 400 MHz
spectrometer for solution in CDCl3 with tetramethylsilane (TMS) as
an internal standard; J-values are in Hertz. Infrared spectra were
recorded on a Bio-Rad FTS-185. Chiral HPLC was performed on
a SHIMADZU SPD-10A series with chiral columns. Mass spectra
were recorded by EI and HRMS (EI, ESI) was measured on a Finnigan
MAþ instrument. Optical rotations were determined at 589 nm
(sodium D line) using a PerkineElmer-341 MC digital polarimeter;
eoselectivity and moderate ee value (Table 3, entry 8); whereas a-
benzyl or hydrogen atom substituted isocyanoacetates 1l and 1m
gave only low yields and low stereoselectivities (Table 3, entries 20
and 21).
The absolute configuration of 5 and ent-5 has been assigned as
(R,R) and (S,S) by comparing the specific rotation with the reported
ones10c and X-ray crystal analysis of product ent-5c (Fig. 1),16 re-
spectively. The absolute configurations of the other products were
assigned as well.
[a g
]D-values are given in units of 10ꢀ1 deg cm2 ꢀ1. Melting points
were measured with a digital melting point apparatus. Flash col-
umn chromatography was performed using silica gel
(300e400 mesh). Unless otherwise noted, all commercially ob-
tained reagents were used without further purification. All re-
actions were carried out under an atmosphere of air in a closed
system. a
-Aryl isocyanoacetate 1,17 N-substituted maleimides 2,18
and catalyst 319 were prepared using literature method. Racemic
Michael adducts for chiral HPLC analysis were prepared from the
corresponding isocyanoacetates 1 (0.24 mmol) and maleimides 2
(0.20 mmol) in the presence of DABCO (20 mol %) in 2.0 mL of DCM
at room temperature for 2 h.
4.2. General procedure for the asymmetric Michael addition
of a-isocyanoacetates 1 with N-substituted maleimides 2
catalyzed by 3f
A solution of isocyanoacetates 1 (0.30 mmol), N-substituted
ꢀ
maleimides 2 (0.15 mmol), cat. 3f (8.9 mg, 0.015 mmol), and 4 A MS
(30 mg) in DCM (1.0 mL) was stirred at 20 ꢁC for 3 d. And then the
reaction mixture was concentrated and the residue was directly
subjected to flash column chromatography on silica gel (petroleum
ether/ethyl acetate¼4:1) to furnish the corresponding products 5.
Fig. 1. X-ray crystallography of compound ent-5c.
A plausible transition-state model is proposed based on the
above results and general accepted mechanism for squaramides
catalyst (Scheme 2). The carbonyl of maleimide is H-bonded to the
squaramide motif, while isocyanoacetate is deprotonated and
resulted in a single H-bonding interaction between the OH group of
the enolized isocyanoacetate and the tertiary amine. Additionally,
a weak H-bonding interaction might be formed concurrently be-
tween the OMe group of the enolized isocyanoacetate and the NH
in the squaramide moiety, which forcing the enolized
4.2.1. (R)-Methyl 2-((R)-2,5-dioxo-1-phenyl pyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (5a).10c Yellow solid (45.3 mg, 88%); mp
172.9e174.7 ꢁC. >20:1 dr. ½a 2D5
ꢀ41.4 (c 1.01, CH2Cl2); 90% ee
ꢂ
(Chiralpak OD-H; hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
tmajor¼18.84 min, tminor¼31.05 min). 1H NMR (400 MHz, CDCl3):
d
¼7.65 (dd, J¼8.0, 1.6 Hz, 2H, ArH), 7.52e7.40 (m, 6H, ArH), 7.31 (d,
J¼8.4 Hz, 2H, ArH), 4.44 (dd, J¼9.6, 6.0 Hz, 1H, CH), 3.88 (s, 3H,

M.-X. Zhao et al. / Tetrahedron 69 (2013) 10763e10771
10767
N
O
O
O
O
O
Ph
N
CO2Me
(R)NC
Ar
N
H
N
H
(R)
Ar
N
H
N
H
N
O
Ph
CN
O
Ph
H
MeO
Ph
N
O
(S)
MeO2C
(S)
H
N
Ph
H
O
MeO
O
O
Ph
N
CN
O
Ph
(R)
O
ent-5a
Ph
N
MeO2C (R)
NC
through Si-face
NC
O
Ph
N
O
Ph
O
Si-face attack
through Si-face
Re-face attack
5a
Ar = 4-CF3C6H4
Ar = 3,5-(CF3)2C6H3
Scheme 2. Proposed transition state model.
OCH3), 2.80 (dd, J¼18.4, 9.6 Hz, 1H, CH), 2.53 (dd, J¼18.8, 6.4 Hz, 1H,
CH) ppm. 13C NMR (100 MHz, CDCl3):
¼173.6, 173.1, 166.6, 164.3,
131.8, 131.1, 129.9, 129.4, 129.2, 129.0, 126.5, 125.4, 71.0, 54.4, 48.2,
30.6 ppm. IR (film):
¼2131, 1751, 1713, 1499, 1384, 1245, 1182, 1038,
1018 cmꢀ1
(46.1 mg, 81%); mp 179.5e181.9 ꢁC. 20:1 dr. ½a D25
ꢂ
ꢀ46.7 (c 1.0,
d
CH2Cl2); 85% ee (Chiralpak AD-H; hexane/2-propanol, 60:40;
1.0 mL/min; 230 nm; tmajor¼30.90 min, tminor¼17.81 min). 1H NMR
n
(400 MHz, CDCl3):
d
¼7.64 (d, J¼6.8 Hz, 2H, ArH), 7.52e7.45 (m, 3H,
.
ArH), 7.22 (d, J¼8.8 Hz, 2H, ArH), 6.98 (d, J¼8.8 Hz, 2H, ArH), 4.42
(dd, J¼9.6, 6.0 Hz, 1H, CH), 3.88 (s, 3H, OCH3), 3.83 (s, 3H, OCH3),
2.78 (dd, J¼18.8, 9.6 Hz, 1H, CH), 2.51 (dd, J¼18.8, 6.0 Hz, 1H,
4.2.2. (R)-Methyl 2-((R)-1-(4-fluorophenyl)-2,5-dioxopyrrolidin-3-
yl)-2-isocyano-2-phenylacetate (5b).10c Pale-yellow solid (38.6 mg,
CH) ppm. 13C NMR (100 MHz, CDCl3):
d¼173.8, 173.4, 166.7, 164.4,
a 25
ꢁ
70%); mp 163.7e165.8 C. >20:1 dr. ½ ꢂD ꢀ37.0 (c 0.8, CH2Cl2); 86%
ee (Chiralcel OD-H; hexane/2-propanol, 80:20; 1.0 mL/min;
230 nm; tmajor¼17.88 min, tminor¼34.64 min). 1H NMR (400 MHz,
159.9, 132.0, 130.0, 129.6, 127.8, 125.5, 123.8, 114.6, 71.2, 55.5, 54.5,
48.3, 30.6 ppm. IR (film):
¼2358, 2132, 1752, 1712, 1511, 1391, 1247,
1166, 1023 cmꢀ1
n
.
CDCl3):
d
¼7.65e7.62 (m, 2H, ArH), 7.52e7.45 (m, 3H, ArH),
7.33e7.28 (m, 2H, ArH), 7.20e7.14 (m, 2H, ArH), 4.43 (dd, J¼9.6,
6.0 Hz, 1H, CH), 3.89 (s, 3H, OCH3), 2.81 (dd, J¼18.4, 9.6 Hz, 1H, CH),
2.52 (dd, J¼18.4, 6.4 Hz, 1H, CH) ppm. 13C NMR (100 MHz, CDCl3):
4.2.6. (R)-Methyl 2-((R)-1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-
yl)-2-isocyano-2-phenylacetate (5f). White solid (46.5 mg, 81%);
mp 125.3e127.1 ꢁC. >20:1 dr. ½a 2D5
ꢀ46.0 (c 0.75, CH2Cl2); 87% ee
ꢂ
d
¼173.5,173.0,166.5,164.4,162.5 (d, J¼247.7 Hz),131.8,130.0,129.6,
(Chiralcel OD-H; hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
128.5 (d, J¼8.6 Hz), 127.0 (d, J¼3.4 Hz), 125.4, 116.4 (d, J¼22.1 Hz),
tmajor¼15.68 min, tminor¼28.32 min). 1H NMR (400 MHz, CDCl3):
71.1, 54.5, 48.3, 30.6 ppm. 19F NMR (376 MHz, CDCl3):
d
¼7.64 (dd, J¼8.0, 1.6 Hz, 2H, ArH), 7.52e7.45 (m, 3H, ArH),
d
¼ꢀ111.5 ppm. IR (film):
n
¼2132, 1752, 1716, 1509, 1391, 1238,
7.43e7.41 (m, 2H, ArH), 7.36 (d, J¼1.6 Hz, 1H, ArH), 7.25e7.23 (m,
1H, ArH), 4.44 (dd, J¼9.6, 6.0 Hz, 1H, CH), 3.89 (s, 3H, OCH3), 2.81
(dd, J¼18.8, 9.6 Hz, 1H, CH), 2.53 (dd, J¼18.8, 6.0 Hz, 1H, CH) ppm.
1190 cmꢀ1
.
HRMS (ESI-TOF): calcd for C20H16FN2O4 [MþH]þ
367.1094; found 367.1096.
13C NMR (100 MHz, CDCl3):
d¼173.1, 172.6,166.5, 164.5, 134.8, 132.2,
4.2.3. (R)-Methyl 2-((R)-1-(4-bromophenyl)-2,5-dioxopyrrolidin-3-
131.8, 130.2, 130.0, 129.5, 129.3, 126.7, 125.4, 124.7, 71.0, 54.5, 48.3,
yl)-2-isocyano-2-phenylacetate (5c).10c Pale-yellow solid (53.2 mg,
30.6 ppm. IR (film):
n
¼2133, 1752, 1717, 1478, 1450, 1383, 1247,
82%); mp 187.0e190.3 ꢁC. 20:1 dr. ½a D25
ꢂ
ꢀ41.4 (c 1.0, CH2Cl2); 87% ee
1186 cmꢀ1. HRMS (ESI-TOF): calcd for C20H16ClN2O4 [MþH]þ
(Chiralcel OD-H; hexane/2-propanol, 60:40; 1.0 mL/min; 230 nm;
383.0799; found 383.0801.
tmajor¼10.76 min, tminor¼19.57 min). 1H NMR (400 MHz, CDCl3):
d
¼7.64e7.59 (m, 4H, ArH), 7.55e7.47 (m, 3H, ArH), 7.24e7.20 (m,
4.2.7. (R)-Methyl 2-isocyano-2-((R)-1-(3-methoxyphenyl)-2,5-
2H, ArH), 4.43 (dd, J¼9.6, 6.0 Hz, 1H, CH), 3.88 (s, 3H, OCH3), 2.80
(dd, J¼18.8, 9.6 Hz, 1H, CH), 2.52 (dd, J¼18.8, 6.0 Hz, 1H, CH) ppm.
dioxopyrrolidin-3-yl)-2-phenylacetate (5g). Yellow solid (53.4 mg,
94%); mp 140.6e143.2 ꢁC. >20:1 dr. ½a D25
ꢀ43.9 (c 1.0, CH2Cl2); 92%
ꢂ
13C NMR (100 MHz, CDCl3):
d¼173.2, 172.7, 166.5, 164.4, 132.5, 131.8,
ee (Chiralpak OD-H; hexane/2-propanol, 70:30; 0.8 mL/min;
130.1, 130.0, 129.6, 128.0, 125.4, 123.0, 71.0, 54.6, 48.3, 30.6 ppm. IR
(film):
¼2361, 2342, 2131, 1751, 1716, 1489, 1384, 1245, 1177,
1035 cmꢀ1
230 nm; tmajor¼17.28 min, tminor¼25.94 min). 1H NMR (400 MHz,
n
CDCl3):
d
¼7.64 (dd, J¼8.0, 1.6 Hz, 2H, ArH), 7.52e7.46 (m, 3H), 7.39
.
(t, J¼7.6 Hz, 1H, ArH), 6.96 (dd, J¼8.0, 2.0 Hz, 1H, ArH), 6.89 (d,
J¼7.6 Hz, 1H, ArH), 6.83 (d, J¼2.0 Hz, 1H, ArH), 4.43 (dd, J¼7.2,
6.0 Hz, 1H, CH), 3.88 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 2.79 (dd,
4.2.4. (R)-Methyl 2-((R)-2,5-dioxo-1-(p-tolyl)pyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (5d).10c Yellow solid (46.6 mg, 86%); mp
J¼18.8, 9.6 Hz, 1H, CH), 2.52 (dd, J¼18.8, 6.0 Hz, 1H, CH) ppm. 13
C
166.6e168.7 ꢁC. >20:1 dr. ½a 2D5
ꢂ
ꢀ45.3 (c 1.02, CH2Cl2); 88% ee
NMR (100 MHz, CDCl3):
d
¼173.4, 173.0, 166.6, 164.4, 160.1, 132.1,
(Chiralcel OD-H; hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
131.9, 130.0, 129.9, 129.5, 125.4, 118.7, 115.1, 112.2, 71.0, 55.4, 54.5,
tmajor¼16.77 min, tminor¼29.27 min). 1H NMR (400 MHz, CDCl3):
48.3, 30.6 ppm. IR (film):
n
¼2133, 1752, 1717, 1478, 1450, 1383, 1247,
d
¼7.64 (dd, J¼8.0, 2.0 Hz, 2H, ArH), 7.52e7.46 (m, 3H, ArH), 7.28 (d,
1186 cmꢀ1
.
HRMS (ESI-TOF): calcd for C21H19N2O5 [MþH]þ
J¼8.0 Hz, 2H, ArH), 7.18 (d, J¼8.4 Hz, 2H, ArH), 4.42 (dd, J¼9.2,
6.0 Hz, 1H, CH), 3.88 (s, 3H, OCH3), 2.79 (dd, J¼18.8, 9.6 Hz, 1H, CH),
2.52 (dd, J¼18.8, 6.0 Hz, 1H, CH), 2.38 (s, 3H, CH3) ppm. 13C NMR
379.1294; found 379.1293.
4.2.8. (R)-methyl 2-((R)-1-benzyl-2,5-dioxopyrrolidin-3-yl)-2-
(100 MHz, CDCl3):
d
¼173.6, 173.2, 166.6, 164.3, 139.2, 131.9, 129.9,
isocyano-2-phenylacetate (5h).10c Yellow solid (13.4 mg, 25%); mp
129.5, 128.5, 126.3, 125.4, 71.1, 54.5, 48.3, 30.6, 21.2 ppm. IR (film):
71.6e73.8 ꢁC. >20:1 dr. ½a 2D5
ꢀ9.5 (c 0.5, CH2Cl2); 76% ee (Chiralpak
ꢂ
n
¼2132, 1754, 1717, 1514, 1389, 1246, 1193 cmꢀ1. HRMS (ESI-TOF):
OD-H; hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
calcd for C21H19N2O4 [MþH]þ 363.1345; found 363.1343.
tmajor¼16.19 min, tminor¼19.17 min). 1H NMR (400 MHz, CDCl3):
d
¼7.57 (d, J¼8.0 Hz, 2H, ArH), 7.48e7.43 (m, 5H, ArH), 7.39 (d,
4.2.5. (R)-Methyl 2-isocyano-2-((R)-1-(4-methoxyphenyl)-2,5-
J¼6.8 Hz,1H, ArH), 7.34e7.28 (m, 2H, ArH), 4.71 (dd, J¼30.0,14.0 Hz,
2H, CH2), 4.25 (dd, J¼9.2, 6.4 Hz, 1H, CH), 3.90 (s, 3H, OCH3), 2.60
dioxopyrrolidin-3-yl)-2-phenylacetate
(5e).10c Yellow
solid

10768
M.-X. Zhao et al. / Tetrahedron 69 (2013) 10763e10771
(dd, J¼18.4, 9.6 Hz, 1H, CH), 2.35 (dd, J¼18.4, 6.4 Hz, 1H, CH) ppm.
13C NMR (100 MHz, CDCl3):
¼173.9, 173.6, 166.7, 164.3, 135.1, 132.0,
129.9, 129.5, 128.8, 128.7, 128.2, 125.3, 70.6, 54.5, 48.3, 42.9,
30.5 ppm. IR (film):
¼2133, 1751, 1717, 1504, 1389, 1253, 1200,
1022 cmꢀ1
1752, 1717, 1606, 1491, 1387, 1257, 1196, 1077, 1094, 1010 cmꢀ1
.
d
HRMS (ESI-TOF): calcd for
found 457.0396.
C
21H18BrN2O5 [MþH]þ 457.0399;
n
.
4.2.13. (R)-Methyl 2-((R)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
isocyano-2-(p-tolyl)acetate (5m). White solid (35.8 mg, 66%); mp
4.2.9. (R)-Methyl 2-((R)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-(4-
fluorophenyl)-2-isocyanoacetate (5i). White solid (39.1 mg, 71%);
208.5e211.3 ꢁC. >20:1 dr. ½a 2D5
ꢀ50.5 (c 0.9, CH2Cl2); 90% ee
ꢂ
(Chiralcel OD-H; hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
mp 185.5e186.9 ꢁC. >20:1 dr. ½a 2D5
ꢂ
ꢀ40.7 (c 0.77, CH2Cl2); 94% ee
tmajor¼16.52 min, tminor¼41.30 min). 1H NMR (400 MHz, CDCl3):
(Chiralcel OD-H; hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
d
¼7.52e7.42 (m, 5H, ArH), 7.32e7.27 (m, 4H, ArH), 4.42 (dd, J¼9.6,
tmajor¼17.69 min, tminor¼31.46 min). 1H NMR (400 MHz, CDCl3):
6.0 Hz, 1H, CH), 3.87 (s, 3H, OCH3), 2.81 (dd, J¼18.4, 9.6 Hz, 1H, CH),
d
¼7.66e7.62 (m, 2H, ArH), 7.51e7.43 (m, 3H, ArH), 7.31 (d, J¼8.0 Hz,
2.53 (dd, J¼18.8, 6.0 Hz, 1H, CH), 2.39 (s, 3H, CH3) ppm. 13C NMR
2H, ArH), 7.19 (td, J¼8.0, 2.0 Hz, 2H, ArH), 4.39 (dd, J¼9.6, 6.0 Hz,1H,
CH), 3.89 (s, 3H, OCH3), 2.81 (dd, J¼18.4, 9.6 Hz, 1H, CH), 2.53 (dd,
(100 MHz, CDCl3):
d
¼173.6, 173.1, 166.7, 164.1, 140.1, 131.2, 130.1,
129.3, 129.1, 129.0, 126.5, 125.3, 70.9, 54.4, 48.2, 30.7, 21.0 ppm. IR
J¼18.4, 6.0 Hz, 1H, CH) ppm. 13C NMR (100 MHz, CDCl3):
d
¼173.3,
(film):
n
¼2132, 1751, 1716, 1500, 1388, 1247, 1189, 1040, 1020 cmꢀ1
.
172.9, 166.5, 164.8, 163.4 (d, J¼250.1 Hz), 130.1, 129.3, 129.1, 127.8 (d,
J¼3.6 Hz), 127.6 (d, J¼9.2 Hz), 126.5, 116.6 (d, J¼21.7 Hz), 70.5, 54.6,
48.3, 30.5 ppm. 19F NMR (376 MHz, CDCl3, non-decoupled):
HRMS (ESI-TOF): calcd for C21H19N2O4 [MþH]þ 363.1345; found
363.1342.
d
¼ꢀ111.1 (m) ppm. IR (film):
n
¼2360, 2341, 2132, 1751, 1705,
4.2.14. (R)-Methyl 2-((R)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
1450, 1432, 1398, 1344, 1244, 1168 cmꢀ1. HRMS (ESI-TOF): calcd for
isocyano-2-(4-methoxyphenyl)acetate
(5n). Pale-yellow
solid
C
20H16FN2O4 [MþH]þ 367.1094; found 367.1091.
(34.2 mg, 60%); mp 201.3e202.8 ꢁC. 20:1 dr. ½a D25
ꢂ
ꢀ45.3 (c 0.45,
CH2Cl2); 88% ee (Chiralcel OD-H; hexane/2-propanol, 70:30;
4.2.10. (R)-Methyl 2-(4-chlorophenyl)-2-((R)-2,5-dioxo-1-
1.0 mL/min; 230 nm; tmajor¼18.38 min, tminor¼43.58 min). 1H NMR
phenylpyrrolidin-3-yl)-2-isocyanoacetate
(5j). Yellow
solid
(400 MHz, CDCl3):
d
¼7.54 (dd, J¼6.8, 2.0 Hz, 2H, ArH), 7.50e7.41 (m,
(51.6 mg, 90%); mp 187.6e191.0 ꢁC. >20:1 dr. ½a D25
ꢂ
ꢀ53.1 (c 1.01,
3H, ArH), 7.31 (d, J¼8.4 Hz, 2H, ArH), 6.98 (dd, J¼7.2, 2.0 Hz, 2H,
ArH), 4.39 (dd, J¼9.6, 6.0 Hz, 1H, CH), 3.87 (s, 3H, OCH3), 3.85 (s, 3H,
OCH3), 2.81 (dd, J¼18.8, 9.2 Hz, 1H, CH), 2.54 (dd, J¼18.8, 6.0 Hz, 1H,
CH2Cl2); 92% ee (Chiralpak AD-H; hexane/2-propanol, 70:30;
1.0 mL/min; 230 nm; tmajor¼23.97 min, tminor¼15.45 min). 1H NMR
(400 MHz, CDCl3):
d
¼7.59 (d, J¼8.8 Hz, 2H, ArH), 7.50e7.42 (m, 5H,
CH) ppm. 13C NMR (100 MHz, CDCl3):
d
¼173.6, 173.1, 166.8, 164.0,
ArH), 7.30 (d, J¼7.6 Hz, 1H, ArH), 4.38 (dd, J¼9.6, 6.0 Hz, 1H, CH),
160.6, 131.2, 129.3, 129.1, 126.8, 126.5, 123.7, 114.7, 70.7, 55.4, 54.4,
3.88 (s, 3H, OCH3), 2.80 (dd, J¼18.8, 9.6 Hz, 1H, CH), 2.51 (dd, J¼18.4,
48.2, 30.7 ppm. IR (film):
n
¼2132, 1750, 1713, 1511, 1500, 1386, 1257,
6.0 Hz, 1H, CH) ppm. 13C NMR (100 MHz, CDCl3):
d¼173.2, 172.7,
1182, 1029 cmꢀ1. HRMS (ESI-TOF): calcd for C21H19N2O5 [MþH]þ
166.3, 165.1, 136.4, 131.1, 130.5, 130.0, 129.7, 129.2, 127.0, 126.4, 70.6,
54.6, 48.3, 30.6 ppm. IR (film):
¼2131, 1749, 1713, 1598, 1508, 1500,
379.1294; found 379.1292.
n
1386, 1238, 1188, 1165, 1015 cmꢀ1. HRMS (ESI-TOF): calcd for
4.2.15. (R)-Methyl 2-((R)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-(3-
C
20H16ClN2O4 [MþH]þ 383.0799; found 383.0797.
fluoro-phenyl)-2-isocyanoacetate
(5o). Pale-yellow
solid
(52.4 mg, 95%); mp 158.3e160.2 ꢁC. >20:1 dr. ½a D25
ꢂ
ꢀ36.1 (c 1.1,
4.2.11. (R)-Methyl 2-(4-bromophenyl)-2-((R)-2,5-dioxo-1-
CH2Cl2); 93% ee (Chiralpak AD-H; hexane/2-propanol, 70:30;
phenylpyrrolidin-3-yl)-2-isocyanoacetate
(5k). Yellow
solid
1.0 mL/min; 230 nm; tmajor¼22.76 min, tminor¼16.70 min). 1H
(49.0 mg, 77%); mp 189.6e193.0 ꢁC. >20:1 dr. ½a D25
ꢂ
ꢀ48.5 (c 1.02,
NMR (400 MHz, CDCl3):
d
¼7.51e7.37 (m, 6H, ArH), 7.31 (d,
CH2Cl2); 90% ee (Chiralpak AD-H; hexane/2-propanol, 80:20;
J¼7.2 Hz, 2H, ArH), 7.20e7.16 (m, 1H, ArH), 4.38 (dd, J¼9.6, 6.0 Hz,
1H, CH), 3.90 (s, 3H, OCH3), 2.82 (dd, J¼18.8, 9.6 Hz, 1H, CH), 2.53
(dd, J¼18.8, 6.0 Hz, 1H, CH) ppm. 13C NMR (100 MHz, CDCl3):
1.0 mL/min; 230 nm; tmajor¼42.01 min, tminor¼25.66 min). 1H NMR
(400 MHz, CDCl3):
d¼7.63 (d, J¼8.4 Hz, 2H, ArH), 7.54e7.41 (m, 5H,
ArH), 7.31 (d, J¼8.0 Hz, 1H, ArH), 4.38 (dd, J¼9.2, 6.0 Hz, 1H, CH),
d
¼173.2, 172.8, 166.2, 165.1, 163.0 (d, J¼247.1 Hz), 134.3 (d,
3.89 (s, 3H, OCH3), 2.81 (dd, J¼18.8, 9.6 Hz, 1H, CH), 2.51 (dd,
J¼7.5 Hz), 131.3 (d, J¼8.8 Hz), 131.1, 129.3, 129.2, 126.5, 121.2 (d,
J¼2.7 Hz), 117.2 (d, J¼21.6 Hz), 113.2 (d, J¼25.1 Hz), 70.6, 54.7,
J¼18.4, 6.0 Hz, 1H, CH) ppm. 13C NMR (100 MHz, CDCl3):
¼173.2,
d
172.8, 166.2, 165.1, 132.7, 131.1, 131.0, 129.3, 129.2, 127.2, 126.5,
48.4, 30.5 ppm. 19F NMR (376 MHz, CDCl3):
d
¼ꢀ109.5 ppm. IR
124.6, 70.7, 54.7, 48.2, 30.5 ppm. IR (film):
n
¼2134, 1752, 1716,
(film):
1246, 1189, 1069, 1017 cmꢀ1
20H15FN2O4 [M]þ 366.1016; found 366.1013.
n
¼2360, 2131, 1752, 1713, 1593, 1500, 1489, 1437, 1386,
1499, 1489, 1388, 1246, 1183, 1010 cmꢀ1. MS (EI) m/z: 428 [(Mþ2)þ,
27%], 426 (Mþ, 27), 386 (17), 384 (19), 222 (44), 196 (30), 194 (26),
141 (100), 140 (48), 119 (41), 115 (39), 114 (34), 91 (33), 59 (30);
HRMS (EI-TOF): calcd for C20H16BrN2O4 [M]þ 426.0215; found
426.0216.
.
HRMS (EI-TOF): calcd for
C
4.2.16. (R)-Methyl 2-((R)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
isocyano-2-(m-tolyl)acetate (5p). Pale-yellow solid (46.2 mg, 85%);
mp 180.7e184.3 ꢁC. >20:1 dr. ½a 2D5
ꢀ33.7 (c 1.0, CH2Cl2); 86% ee
ꢂ
4.2.12. (R)-Methyl 2-(4-bromophenyl)-2-isocyano-2-((R)-1-(3-
(Chiralpak AD-H; hexane/2-propanol, 70:30; 1.0 mL/min; 230 nm;
methoxyphenyl)-2,5-dioxopyrrolidin-3-yl)acetate (5l). Yellow solid
tmajor¼35.22 min, tminor¼14.87 min). 1H NMR (400 MHz, CDCl3):
(65.3 mg, 95%); mp 164.1e166.6 ꢁC. >20:1 dr. ½a D25
ꢂ
ꢀ46.1 (c 1.04,
d
¼7.51e7.44 (m, 5H, ArH), 7.42e7.31 (m, 3H, ArH), 7.27e7.26 (m,1H,
CH2Cl2); 91% ee (Chiralpak AD-H; hexane/2-propanol, 70:30;
ArH), 4.43 (dd, J¼9.6, 6.0 Hz, 1H, CH), 3.88 (s, 3H, OCH3), 2.81 (dd,
J¼18.4, 9.6 Hz, 1H, CH), 2.54 (dd, J¼18.8, 6.0 Hz, 1H, CH), 2.43 (s, 3H,
1.0 mL/min; 230 nm; tmajor¼41.40 min, tminor¼23.80 min). 1H
NMR (400 MHz, CDCl3):
d
¼7.63 (d, J¼8.4 Hz, 2H, ArH), 7.52 (d,
CH3) ppm. 13C NMR (100 MHz, CDCl3):
d
¼173.5, 173.1, 166.6, 164.2,
J¼8.8 Hz, 2H, ArH), 7.39 (t, J¼8.0 Hz, 1H, ArH), 6.97 (dd, J¼8.4,
2.0 Hz, 1H, ArH), 6.88 (d, J¼8.8 Hz, 1H, ArH), 6.82 (t, J¼2.0 Hz, 1H,
ArH), 4.37 (dd, J¼9.6, 6.0 Hz, 1H, ArH), 3.89 (s, 3H, OCH3), 3.81 (s,
3H, OCH3), 2.80 (dd, J¼18.8, 9.6 Hz, 1H, CH), 2.51 (dd, J¼18.4,
139.6, 131.8, 131.2, 130.7, 129.4, 129.3, 129.1, 126.5, 126.0, 122.5, 71.0,
54.5, 48.3, 30.7, 21.6 ppm. IR (film):
n
¼2133, 1752, 1716, 1500, 1388,
1247, 1191 cmꢀ1. HRMS (ESI-TOF): calcd for C21H19N2O4 [MþH]þ
363.1345; found 363.1342.
6.0 Hz, 1H, CH) ppm. 13C NMR (100 MHz, CDCl3):
d
¼173.2, 172.7,
166.3, 165.0, 160.2, 132.7, 132.0, 131.0, 130.1, 127.2, 124.6, 118.7,
115.1, 112.2, 70.6, 55.4, 54.7, 48.2, 30.5 ppm. IR (film):
¼2132,
4.2.17. (R)-Benzyl 2-((R)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (5r). White solid (60.5 mg, 95%); mp
n

M.-X. Zhao et al. / Tetrahedron 69 (2013) 10763e10771
10769
161.8e164.2 ꢁC. 10:1 dr. ½a 2D5
ꢂ
ꢀ21.8 (c 1.0, CH2Cl2); 90% ee (Chir-
hexane/2-propanol, 60:40; 1.0 mL/min; 230 nm; tminor¼8.05 min,
tmajor¼11.47 min).
alpak AD-H; hexane/2-propanol, 70:30; 1.0 mL/min; 230 nm;
tmajor¼52.98 min, tminor¼29.16 min). 1H NMR (400 MHz, CDCl3):
d
¼7.63e7.61 (m, 2H, ArH), 7.52e7.43 (m, 6H, ArH), 7.34e7.31 (m,
4.3.5. (S)-Methyl 2-isocyano-2-((S)-1-(4-methoxyphenyl)-2,5-
5H, ArH), 7.28e7.25 (m, 2H, ArH), 5.27 (s, 2H, CH2), 4.45 (dd, J¼9.6,
6.0 Hz, 1H, CH), 2.81 (dd, J¼18.8, 9.6 Hz, 1H, CH), 2.54 (dd, J¼18.8,
dioxopyrrolidin-3-yl)-2-phenylacetate
(ent-5e). Yellow
solid
(63.4 mg, 99%); 20:1 dr. ½a D25
þ42.9 (c 0.5, CH2Cl2); 88% ee (Chir-
ꢂ
6.0 Hz, 1H, CH) ppm. 13C NMR (100 MHz, CDCl3):
d
¼173.3, 173.0,
alpak AD-H; hexane/2-propanol, 60:40; 1.0 mL/min; 230 nm;
165.7, 164.3, 134.2, 131.8, 131.2, 129.9, 129.5, 129.3, 129.2, 129.07,
129.06, 128.9, 128.7, 128.5, 128.1, 128.0, 126.53, 126.47, 125.5, 125.4,
tmajor¼14.37 min, tminor¼23.15 min).
71.3, 69.3, 48.0, 30.7 ppm. IR (film):
n
¼2132, 1752, 1714, 1499, 1450,
4.3.6. (S)-Methyl 2-((S)-1-(3-chlorophenyl)-2,5-dioxopyrrolidin-3-
1383, 1182 cmꢀ1. HRMS (ESI-TOF): calcd for C26H21N2O4 [MþH]þ
yl)-2-isocyano-2-phenylacetate (ent-5f). White solid (60.0 mg,
425.1501; found 425.1500.
99%); >20:1 dr. ½a D25
þ46.6 (c 0.35, CH2Cl2); 88% ee (Chiralcel OD-H;
ꢂ
hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm; tminor¼14.12 min,
tmajor¼23.19 min).
4.2.18. (R)-tert-Butyl 2-((R)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (5s). Pale-yellow solid (24.2 mg, 41%);
mp 126.2e130.2 ꢁC. 1:1 dr. ½a D25
ꢂ
ꢀ10.0 (c 1.0, CH2Cl2); 86% ee for
4.3.7. (S)-Methyl 2-isocyano-2-((S)-1-(3-methoxyphenyl)-2,5-
major isomer (Chiralpak AD-H; hexane/2-propanol, 80:20;
dioxopyrrolidin-3-yl)-2-phenylacetate
(ent-5g). Yellow
solid
1.0 mL/min; 230 nm; tmajor¼41.08 min, tminor¼35.01 min). 1H
(57.4 mg, 99%); >20:1 dr. ½a D25
þ48.7 (c 2.7, CH2Cl2); 90% ee (Chir-
ꢂ
NMR (400 MHz, CDCl3):
d
¼7.62 (d, J¼6.8 Hz, 1H, ArH), 7.58 (d,
alpak OD-H; hexane/2-propanol, 70:30; 0.8 mL/min; 230 nm;
J¼6.8 Hz, 1H, ArH), 7.52e7.35 (m, 6H, ArH), 7.32 (d, J¼7.6 Hz, 1H,
ArH), 7.23 (d, J¼7.2 Hz, 1H, ArH), 4.41 (dd, J¼9.6, 6.0 Hz, 0.5H,
CH), 4.09 (dd, J¼8.8, 6.0 Hz, 0.5H, CH), 3.18 (dd, J¼18.8, 9.6 Hz,
0.5H, CH), 2.88 (dd, J¼18.8, 4.8 Hz, 0.5H, CH), 2.79 (dd, J¼18.8,
9.6 Hz, 0.5H, CH), 2.50 (dd, J¼18.8, 6.0 Hz, 0.5H, CH), 1.48 (s,
4.5H, 3ꢃ CH3), 1.47 (s, 4.5H, 3ꢃ CH3) ppm. 13C NMR (100 MHz,
tminor¼17.85 min, tmajor¼24.67 min).
4.3.8. (S)-Methyl 2-((S)-1-benzyl-2,5-dioxopyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (ent-5h). Yellow solid (38.5 mg, 71%);
>20:1 dr. ½a 2D5
ꢂ
þ105.0 (c 0.2, CH2Cl2); 65% ee (Chiralpak OD-H;
hexane/2-propanol,
80:20; 1.0 mL/min; 230 nm;
CDCl3):
d
¼173.5, 173.32, 173.28, 172.6, 164.7, 164.4, 163.5, 163.3,
tminor¼15.12 min, tmajor¼18.16 min).
132.54, 132.46, 131.3, 129.7, 129.4, 129.34, 129.29, 129.1, 129.0,
128.93, 128.88, 126.7, 126.5, 125.29, 125.26, 85.9, 85.3, 72.3, 71.7,
4.3.9. (S)-Methyl 2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-(4-
47.8, 32.6, 30.9, 29.6, 27.5 ppm. IR (film):
n
¼2360, 2342, 2131,
fluorophenyl)-2-isocyanoacetate (ent-5i). White solid (54.2 mg,
1717, 1450, 1383, 1371, 1259, 1186, 1149 cmꢀ1. HRMS (ESI-TOF):
99%); >20:1 dr. ½a D25
þ37.0 (c 0.25, CH2Cl2); 89% ee (Chiralcel OD-H;
ꢂ
calcd for C23H23N2O4 [MþH]þ 391.1658; found 391.1656.
hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm; tminor¼17.65 min,
tmajor¼28.57 min).
4.3. General procedure for the asymmetric Michael addition
4.3.10. (S)-Methyl 2-(4-chlorophenyl)-2-((S)-2,5-dioxo-1-
of
a
-isocyanoacetates 1 with N-substituted maleimides 2
phenylpyrrolidin-3-yl)-2-isocyanoacetate (ent-5j). Yellow solid
catalyzed by 3n
(52.8 mg, 99%); >20:1 dr. ½a D25
þ53.8 (c 0.6, CH2Cl2); 90% ee
ꢂ
(Chiralpak AD-H; hexane/2-propanol, 70:30; 1.0 mL/min; 230 nm;
To a solution of isocyanoacetates 1 (0.30 mmol), cat. 3n (7.1 mg,
0.015 mmol), and 4 A MS (30 mg) in DCM (1.0 mL) was added N-
tmajor¼15.46 min, tminor¼23.72 min).
ꢀ
substituted maleimides 2 (0.15 mmol). The resulting mixture was
stirred at 20 ꢁC for 4e72 h. Then the reaction mixture was con-
centrated and the residue was directly subjected to flash column
chromatography on silica gel (petroleum ether/ethyl acetate¼4:1)
to furnish the corresponding products ent-5.
4.3.11. (S)-Methyl 2-(4-bromophenyl)-2-((S)-2,5-dioxo-1-
phenylpyrrolidin-3-yl)-2-isocyanoacetate (ent-5k). Yellow solid
(71.2 mg, 99%); >20:1 dr. ½a D25
þ32.2 (c 0.35, CH2Cl2); 91% ee
ꢂ
(Chiralpak AD-H; hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
tmajor¼24.39 min, tminor¼40.37 min).
4.3.1. (S)-Methyl 2-((S)-2,5-dioxo-1-phenyl pyrrolidin-3-yl)-2-
4.3.12. (S)-Methyl 2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (ent-5a). Yellow solid (52.1 mg, 99%);
isocyano-2-(p-tolyl)acetate (ent-5m). White solid (53.4 mg, 98%);
>20:1 dr. ½a 2D5
ꢂ
þ44.4 (c 0.4, CH2Cl2); 90% ee (Chiralpak OD-H;
>20:1 dr. ½a 2D5
ꢂ
þ52.2 (c 0.40, CH2Cl2); 86% ee (Chiralcel OD-H;
hexane/2-propanol,
80:20; 1.0 mL/min; 230 nm;
hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
tminor¼16.55 min, tmajor¼27.68 min).
tminor¼16.86 min, tmajor¼38.42 min).
4.3.2. (S)-Methyl 2-((S)-1-(4-fluorophenyl)-2,5-dioxopyrrolidin-3-
4.3.13. (S)-Methyl 2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
yl)-2-isocyano-2-phenylacetate
(ent-5b). Pale-yellow
þ43.9 (c 0.3, CH2Cl2); 85% ee
solid
isocyano-2-(4-methoxyphenyl)acetate (ent-5n). Pale-yellow solid
(50.5 mg, 92%); >20:1 dr. ½a D25
ꢂ
(52.2 mg, 92%); >20:1 dr. ½a D25
þ45.5 (c 0.25, CH2Cl2); 88% ee
ꢂ
(Chiralcel OD-H; hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
(Chiralcel OD-H; hexane/2-propanol, 70:30; 1.0 mL/min; 230 nm;
tminor¼15.41 min, tmajor¼27.13 min).
tminor¼18.60 min, tmajor¼42.10 min).
4.3.3. (S)-Methyl 2-((S)-1-(4-bromophenyl)-2,5-dioxopyrrolidin-3-
4.3.14. (S)-Methyl 2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-(3-
yl)-2-isocyano-2-phenylacetate
(ent-5c). Pale-yellow
þ43.7 (c 0.3, CH2Cl2); 91% ee
solid
fluoro-phenyl)-2-isocyanoacetate
(ent-5o). Pale-yellow
solid
(63.0 mg, 98%); >20:1 dr. ½a D25
ꢂ
(54.0 mg, 98%); >20:1 dr. ½a D25
þ37.3 (c 0.25, CH2Cl2); 84% ee
ꢂ
(Chiralcel OD-H; hexane/2-propanol, 60:40; 1.0 mL/min; 230 nm;
(Chiralpak AD-H; hexane/2-propanol, 70:30; 1.0 mL/min; 230 nm;
tminor¼8.91 min, tmajor¼13.60 min).
tmajor¼18.68 min, tminor¼25.87 min).
4.3.4. (S)-Methyl 2-((S)-2,5-dioxo-1-(p-tolyl)pyrrolidin-3-yl)-2-
4.3.15. (S)-Methyl 2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (ent-5d). Yellow solid (53.3 mg, 98%);
isocyano-2-(m-tolyl)acetate (ent-5p). Pale-yellow solid (59.0 mg,
>20:1 dr. ½a 2D5
ꢂ
þ39.7 (c 0.35, CH2Cl2); 86% ee (Chiralcel OD-H;
99%); >20:1 dr. ½a D25
þ49.8 (c 1.0, CH2Cl2); 86% ee (Chiralpak AD-H;
ꢂ

10770
M.-X. Zhao et al. / Tetrahedron 69 (2013) 10763e10771
hexane/2-propanol, 70:30; 1.0 mL/min; 230 nm; tmajor¼16.68 min,
tminor¼41.41 min).
References and notes
1. For selected reviews, see: (a) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107,
5713e5743; (b) Yu, X.; Wang, W. Chem.dAsian J. 2008, 3, 516e532; (c) Akiyama,
T. Chem. Rev. 2007, 107, 5744e5758; (d) Connon, S. J. Chem.dEur. J. 2006, 12,
5418e5427; (e) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520e1543; (f) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3, 719e724; (g)
Schreiner, P. R. Chem. Soc. Rev. 2003, 32, 289e296.
4.3.16. (S)-tert-Butyl 2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
isocyano-2-phenylacetate (ent-5s). Pale-yellow solid (54.2 mg,
93%); 3:1 dr. ½a 2D5
þ24.8 (c 0.25, CH2Cl2); 85% ee and 51% ee
ꢂ
(Chiralpak AD-H; hexane/2-propanol, 80:20; 1.0 mL/min; 230 nm;
ꢁ
2. For recent review and references cited therein, see: (a) Aleman, J.; Parra, A.;
tminoreminor¼13.49
min,
tminoremajor¼14.65
min
Jiang, H.; Jørgensen, K. A. Chem.dEur. J. 2011, 17, 6890e6899 For selected recent
examples, see: (b) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc.
2008, 130, 14416e14417; (c) Dai, L.; Wang, S.-X.; Chen, F.-E. Adv. Synth. Catal.
2010, 352, 2137e2141; (d) Yang, W.; Du, D.-M. Org. Lett. 2010, 12, 5450e5453;
(e) Wang, Y.-F.; Chen, R.-X.; Wang, K.; Zhang, B.-B.; Li, Z.-B.; Xu, D.-Q. Green
Chem. 2012, 14, 893e895; (f) Ling, J.-B.; Su, Y.; Zhu, H.-L.; Wang, G.-Y.; Xu, P.-F.
Org. Lett. 2012, 14, 1090e1093; (g) Wang, X.; Yao, W.; Yao, Z.; Ma, C. J. Org. Chem.
2012, 77, 2959e2965; (h) Yang, W.; Du, D.-M. Chem. Commun. 2011,
12706e12708; (i) Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H. Org. Lett.
2010, 12, 2028e2031; (j) Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.; Zhao, J.; Rawal, V. H.
Chem. Commun. 2010, 3004e3006; (k) Yang, W.; Du, D.-M. Adv. Synth. Catal.
2011, 353, 1241e1246; (l) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int.
Ed. 2010, 49, 153e156.
tmajoremajor¼28.85 min, tmajoreminor¼35.08 min).
4.3.17. (R)-Methyl 2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
isocyano-3-phenylpropanoate
(ent-5t).10c Pale-yellow
solid
(10.7 mg, 20%); mp 122.8e124.6 ꢁC. 2.4:1 dr. ½a D25
ꢂ
þ12.4 (c 0.15,
CH2Cl2); 46% and 33% ee (Chiralpak AD-H; hexane/2-propanol,
80:20; 1.0 mL/min; 230 nm; tmajoremajor¼21.43 min,
tmajoreminor¼31.35
min,
tminoremajor¼29.70
min,
¼7.54e7.47
tminoreminor¼16.63 min). 1H NMR (400 MHz, CDCl3):
d
3. For recent review and references cited therein, see: Lygin, A. V.; de Meijere, A.
Angew. Chem., Int. Ed. 2010, 49, 9094e9124.
(m, 3H, ArH), 7.45e7.40 (m, 1.5H, ArH), 7.38e7.29 (m, 10H, ArH),
3.89 (d, J¼13.6 Hz, 0.45H, CH), 3.78 (s, 3H, OCH3), 3.74 (s, 1.4H,
OCH3), 3.69 (dd, J¼9.6, 6.4 Hz, 1H, CH), 3.65e3.57 (m, 0.9H, 2ꢃ CH),
3.34 (dd, J¼20.8, 9.6 Hz, 2H, 2ꢃ CH), 3.12 (dd, J¼18.4, 9.2 Hz, 1H,
CH), 3.08 (dd, J¼18.4, 9.2 Hz, 0.45H, CH), 2.93 (dd, J¼18.4, 6.0 Hz,1H,
CH), 2.72 (dd, J¼18.4, 4.8 Hz, 0.45H, CH) ppm. 13C NMR (100 MHz,
4. For recent review on isocyanoacetates, see: Gulevich, A. V.; Zhdanko, A. G.;
Orru, R. V. A.; Nenajdenko, V. G. Chem. Rev. 2010, 110, 5235e5331.
5. (a) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem. Soc. 1986, 108, 6405e6406; (b)
Ito, Y.; Sawamura, M.; Hayashi, T. Tetrahedron Lett. 1987, 28, 6215e6218; (c)
Hayashi, T.; Uozumi, Y.; Yamazaki, A.; Sawamura, M.; Hamashima, H.; Ito, Y.
Tetrahedron Lett. 1991, 32, 2799e2802.
CDCl3):
d
¼173.4, 173.2, 173.03, 172.97, 167.1, 166.7, 163.6, 163.4,
6. Guo, C.; Xue, M.-X.; Zhu, M.-K.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47,
3414e3417.
132.8, 132.0, 131.3, 130.2, 130.0, 129.3, 129.2, 129.1, 129.0, 128.70,
128.65, 128.4, 128.2, 126.7, 126.5, 70.3, 69.4, 53.9, 53.8, 46.0, 45.1,
7. For recent examples, see: (a) Xue, M.-X.; Guo, C.; Gong, L.-Z. Synlett 2009,
2191e2197; (b) Sladojevich, F.; Trabocchi, A.; Guarna, A.; Dixon, D. J. J. Am.
Chem. Soc. 2011, 133, 1710e1713; (c) Kim, H. Y.; Oh, K. Org. Lett. 2011, 13,
1306e1309; (d) Zhao, M.-X.; Zhou, H.; Tang, W.-H.; Qu, W.-S.; Shi, M. Adv. Synth.
Catal. 2013, 355, 1277e1283.
8. For recent examples, see: (a) Zhang, Z.-W.; Lu, G.; Chen, M.-M.; Lin, N.; Li, Y.-B.;
Hayashi, T.; Chan, A. S. C. Tetrahedron: Asymmetry 2010, 21, 1715e1721; (b)
Nakamura, S.; Maeno, Y.; Ohara, M.; Yamamura, A.; Funahashi, Y.; Shibata, N.
Org. Lett. 2012, 14, 2960e2963.
42.60, 42.58, 32.0, 31.2 ppm. IR (film):
n
¼2140, 1715, 1497, 1393,
1260, 1089, 1018 cmꢀ1. HRMS (ESI-TOF): calcd for C21H18N2O4Na
[MþNa]þ 385.1164; found 385.1143.
4.3.18. (R)-Methyl 2-((S)-2,5-dioxo-1-phenylpyrrolidin-3-yl)-2-
isocyanoacetate (ent-5u). White viscous solid (6.5 mg, 15%);
9. (a) Monge, D.; Jensen, K. L.; Marín, I.; Jørgensen, K. A. Org. Lett. 2011, 13,
328e331; (b) Zhao, M.-X.; Bi, H.-L.; Zhou, H.; Yang, H.; Shi, M. J. Org. Chem. 2013,
78, 9377e9382.
1.4:1 dr. ½a 2D5
þ4.5 (c 0.4, CH2Cl2); 20% and 15% ee (Chiralpak AD-
ꢂ
H; hexane/2-propanol, 70:30; 1.0 mL/min; 234 nm;
tmajoreminor¼11.49 min, tmajoremajor¼14.89 min, tminoreminor
¼23.48 min, tminoremajor¼25.00 min). 1H NMR (400 MHz, CDCl3):
ꢁ
ꢁ
10. For recent examples, see: (a) Arroniz, C.; Gil-Gonzalez, A.; Semak, V.; Escolano,
C.; Bosch, J.; Amat, M. Eur. J. Org. Chem. 2011, 3755e3760; (b) Song, J.; Guo, C.;
Chen, P.-H.; Yu, J.; Luo, S.-W.; Gong, L.-Z. Chem.dEur. J. 2011, 17, 7786e7790; (c)
Bai, J.-F.; Wang, L.-L.; Peng, L.; Guo, Y.-L.; Jia, L.-N.; Tian, F.; He, G.-Y.; Xu, X.-Y.;
Wang, L.-X. J. Org. Chem. 2012, 77, 2947e2953; (d) Padilla, S.; Adrio, J.; Carre-
tero, J. C. J. Org. Chem. 2012, 77, 4161e4166; (e) Wang, L.-L.; Bai, J.-F.; Peng, L.; Qi,
L.-W.; Jia, L.-N.; Guo, Y.-L.; Luo, X.-Y.; Xu, X.; Wang, L.-X. Chem. Commun. 2012,
5175e5177; (f) Zhao, M.-X.; Wei, D.-K.; Ji, F.-H.; Zhao, X.-L.; Shi, M. Chem.
dAsian. J. 2012, 7, 2777e2781.
11. (a) Ahmed, S. Drug Des. Discovery 1996, 14, 77e89; (b) Curtin, M. L.; Garland, R. B.;
Heyman, H. R.; Frey, R. R.; Michaelides, M. R.; Li, J.; Pease, L. J.; Glaser, K. B.;
Marcotte, P. A.; Davidsen, S. K. Bioorg. Med. Chem. Lett. 2002, 12, 2919e2923; (c)
Pohlmann, J.; Lampe, T.; Shimada, M.; Nell, P. G.; Pernerstorfer, J.; Svenstrup, N.;
Brunner, N. A.; Schiffer, G.; Freiberg, C. Bioorg. Med. Chem. Lett. 2005, 15,
1189e1192.
12. For reviews and references cited therein, see: (a) Peterson, E. A.; Overman, L. E.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 11943e11948; (b) Trost, B. M.; Jiang, C.
Synthesis 2006, 369e396; (c) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur. J.
Org. Chem. 2007, 5969e5994; (d) Bella, M.; Gasperi, T. Synthesis 2009,
1583e1614; (e) Das, J. P.; Marek, I. Chem. Commun. 2011, 4593e4623; (f)
Chauhan, P.; Kaur, J.; Chimni, S. S. Chem. -Asian. J. 2013, 8, 328e346. For selected
examples of related stereoselective construction of vicinal quaternaryetertiary
carbon centers, see: (g) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125,
11204e11205; (h) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.; MacMillan, D.
W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482e5487; (i) Li, H.; Wang, Y.; Tang,
L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005,
44, 105e108; (j) Poulsen, T. B.; Alemparte, C.; Saaby, S.; Bella, M.; Jørgensen, K.
A. Angew. Chem., Int. Ed. 2005, 44, 2896e2899; (k) Lalonde, M. P.; Chen, Y.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 6366e6370; (l) van Steenis, D. J.
V. C.; Marcelli, T.; Lutz, M.; Spek, A. L.; van Maarseveen, J. H.; Hiemstra, H. Adv.
Synth. Catal. 2007, 349, 281e286; (m) Ogawa, S.; Shibata, N.; Inagaki, J.; Na-
kamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2007, 46, 8666e8669; (n)
Tsubogo, T.; Saito, S.; Seki, K.; Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc.
2008, 130, 13321e13332.
d
¼7.52e7.40 (m, 5H, ArH), 7.31e7.27 (m, 3.5H, ArH), 5.08 (d,
J¼3.2 Hz, 1H, CH), 4.90 (d, J¼3.6 Hz, 0.7H, CH), 4.36 (q, J¼7.2 Hz,
2H, OCH2), 4.35 (q, J¼7.2 Hz, 1.4H, OCH2), 3.70e3.63 (m,
1Hþ0.7H, CH), 3.16 (dd, J¼16.4, 9.6 Hz, 0.7H, CH), 3.05 (dd,
J¼16.4, 9.6 Hz, 1H, CH), 2.92 (dd, J¼16.4, 5.6 Hz, 1H, CH), 2.83 (dd,
J¼16.4, 5.6 Hz, 0.7H, CH), 1.37 (t, J¼7.2 Hz, 3H, CH3), 1.35 (t,
J¼7.2 Hz, 2.1H, CH3) ppm. 13C NMR (100 MHz, CDCl3):
¼173.8,
d
173.42, 173.36, 173.2, 164.2, 163.9, 163.8, 163.1, 131.3, 131.2, 129.3,
129.2, 129.1, 129.0, 126.4, 126.3, 63.8, 55.9, 42.3, 42.1, 31.2, 29.5,
13.92, 13.86 ppm. IR (film):
n
¼2147, 1715, 1501, 1390, 1187,
1031 cmꢀ1. MS (EI): m/z (%)¼286 (86) [M]þ, 259 (37), 213 (100),
174 (92), 119 (22), 91 (12). HRMS (EI-TOF): calcd for C15H14N2O4
[M]þ 286.0954; found 286.0955.
Acknowledgements
We gratefully acknowledge National Natural Science Foundation
of China (20772030, 21072056, 21272067) and the Fundamental
Research Funds for the Central Universities for the financial
support.
Supplementary data
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Detailed optimization reaction conditions, copies of NMR
spectra of new compounds, HPLC traces for the determination of
the enantiomeric excess for compounds 5 and X-ray crystal data of
product ent-5c (CCDC 932205) have been provided. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.09.084.

M.-X. Zhao et al. / Tetrahedron 69 (2013) 10763e10771
14. Zhao, M.-X.; Tang, W.-H.; Chen, M.-X.; Wei, D.-K.; Dai, T.-L.; Shi, M. Eur. J. Org. For the synthesis of
10771
a
-aryl isocyanoacetates 1bei, see: (b) Jacobsen, E. J.; Stelzer,
Chem. 2011, 6078e6084.
L. S.; Belonga, K. L.; Carter, D. B.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Von-
Voigtlander, P. F.; Petke, J. D. J. Med. Chem. 1996, 39, 3820e3836; (c) Matsumoto,
K.; Suzuki, M.; Miyoshi, M. J. Org. Chem. 1978, 38, 2094e2096.
15. Under the optimized reaction conditions, ent-5a was obtained in moderate ee
values by using catalyst 3m (12 h, 98%, >20:1 dr, 76% ee) and 3o (12 h, 93%,
>20:1 dr, 47% ee). Moreover, the (S,S)-cyclohexane-1,2-diamine derived
catalyst ent-3n was also screened and gave lower stereoselectivity of 5a (3 h,
99%, 10:1 dr, 77% ee).
18. Cava, M. P.; Deana, A. A.; Muth, K.; Mitchell, M. J. Organic Syntheses, 1973,
Collect. Vol. No. 5, p 944; Cava, M. P.; Deana, A. A.; Muth, K.; Mitchell, M. J.
Organic Syntheses, 1961, Collect. Vol. No. 41, p 93.
16. The structure of product ent-5 was determined by X-ray crystal structure
analysis. CCDC 932205 (ent-5c) contains the supplementary crystallographic
data for this paper.
19. For the synthesis of cinchona alkaloid thiourea catalysts 3aee, see: (a) Ye, J.;
Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481e4483; (b) Vakulya, B.;
ꢁ
Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005, 7, 1967e1969; (c) Ref. 14; For the
17. For the synthesis of
a
-phenyl isocyanoacetates 1a, 1jek and
a
-alkyl substituted
synthesis of cinchona alkaloid squaramide catalyst 3fel, see: Refs. 2bed. (d) For
the synthesis of squaramide 3meo, see: Refs. 2jel.
isocyanoacetates 1l, see: (a) Bon, R. S.; Hong, C.; Bouma, M. J.; Schmitz, R. F.; de
Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Orru, R. V. A. Org. Lett. 2003, 5, 3759e3762