Au-catalyzed asymmetric formal [3 + 2] cycloaddition of isocyanoacetates with maleimides

Article abstract of DOI:10.1021/jo3003425

An efficient protocol for the Au^I-catalyzed asymmetric formal [3 + 2] cycloaddition of isocyanoacetates with phenylmaleimide has been developed. In the presence of cationic Au^I/DTBM-segphos complex, excellent diastereoselectivity and high levels of enantioselectivity (up to 97% ee) have been attained with a variety of α-substituted isocyanoacetates. The synthetic potential of the resulting enantioenriched 1-pyrrolines has been demonstrated by the preparation of highly substituted pyrrolidines bearing a quaternary stereocenter.

Full text of DOI:10.1021/jo3003425

Note
pubs.acs.org/joc
Au-Catalyzed Asymmetric Formal [3 + 2] Cycloaddition of
Isocyanoacetates with Maleimides
Silvia Padilla, Javier Adrio,* and Juan C. Carretero*
́ ́
Departamento de Química Organica, Facultad de Ciencias, Universidad Autonoma de Madrid, Cantoblanco, 28049 Madrid, Spain
S
* Supporting Information
ABSTRACT: An efficient protocol for the AuI-catalyzed
asymmetric formal [3 + 2] cycloaddition of isocyanoacetates
with phenylmaleimide has been developed. In the presence of
cationic AuI/DTBM-segphos complex, excellent diastereoselec-
tivity and high levels of enantioselectivity (up to 97% ee) have
been attained with a variety of α-substituted isocyanoacetates.
The synthetic potential of the resulting enantioenriched 1-
pyrrolines has been demonstrated by the preparation of highly
substituted pyrrolidines bearing a quaternary stereocenter.
OH-Mop complex as catalyst led to the corresponding 2-
he cyclization reaction of isocyanides with carbon−carbon
Tand carbon−heteroatom multiple bonds has proved to be pyrrolines with high yields and excellent enantioselectivities (up
a powerful tool for the preparation of substituted aromatic five-
membered heterocycles, such as pyrroles, 1,3-azoles, and 1,2,4-
triazoles.1 In particular, isocyanoacetates, which contain a more
acidic proton in the α-position, offer additional synthetic
possibilities. For instance, the formal [3 + 2] cycloaddition of
isocyanoacetates with electron-deficient olefins can be
envisaged as one of the most convergent approaches for the
preparation of pyrrolines (Scheme 1), which are versatile
building blocks in the synthesis of natural products and
biologically active compounds.2
to 98% ee), albeit with moderate diastereoselectivities (3:1 to
5:1 trans/cis mixtures). Shortly after, Escolano and co-workers
demonstrated that the combination of a cinchona alkaloid
derived bifunctional catalyst and a silver salt is able to promote
the cycloaddition of isocyanoacetates and α,β-unsaturated
ketones in moderate enantioselectivities.7
Despite these significant advances, the scope of the
enantioselective reaction with regard to both reaction partners
is still rather limited. For example, as far as we are aware, cyclic
activated alkenes such as maleimides have not been yet applied
in this asymmetric formal [3 + 2] cycloaddition.8 It is
interesting to note that this type of alkenes led to 1-pyrrolines
instead of the 2-pyrrolines obtained in the previously reported
catalytic asymmetric versions.
Scheme 1. [3 + 2] Cycloaddition of Isocyanoacetates with
Electron-Deficient Olefins
Herein, we describe the AuI/DTBM-segphos9,10 catalyzed
highly diastereoselective and enantioselective synthesis of 1-
pyrrolines by reaction of isocyanoacetates with phenyl-
maleimide. Some aspects of the synthetic utility of the resulting
1-pyrrolines are also presented.
As model reaction we chose the cycloaddition of methyl
isocyanoacetate (1a) with N-phenylmaleimide (2). After
screening a variety of metal salts and chiral ligands,11 we
found that the reaction catalyzed by 10 mol % of (R)-DTBM-
segphos(AuCl)2 (4a) and 10 mol % of AgSbF6 in CH2Cl2
as solvent and Et3N as base, afforded the desired adduct 3a with
moderate yield, a relatively good diastereoselectivity (cis/trans
80/20), and a promising 50% ee (Table 1, entry 1). Further
optimization of the reaction conditions was then carried out.
After surveying different solvents (entries 2−4), we observed a
significant improvement in the reactivity and selectivity in THF
(71% yield, excellent cis-selectivity and 70% ee, entry 4).
This reaction can be greatly accelerated either in the
presence of a base or a metal complex. However, since the
pioneering work by Saegusa in 1971, using Cu2O as catalyst,3
this type of formal [3 + 2] cycloaddition has received limited
attention.4
Regarding the development of catalytic asymmetric proto-
cols, the first procedure was described by Gong and co-workers
in the reaction of α-phenyl isocyanoacetate with nitroolefins
catalyzed by cinchona alkaloids.5 Very recently, in 2011, the
same research group succeeded in performing the silver-
catalyzed enantioselective reaction of α-aryl isocyanoacetates
with α,β-unsaturated ketoesters.6 The use of a chiral silver−
12
13
Received: February 20, 2012
Published: March 29, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Table 1. Optimization of the Reaction Conditions for the
Model Reaction
Table 2. Scope of the Process with α-Substituted
Isocyanoacetates
a
b
entry
R
R1
product
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
Ph
Me
Me
Me
Me
Et
3b
3c
3d
3e
3f
55
60
65
71
54
70
62
69
68
92
87
85
87
83
95
97
96
m-MeC6H4
Me
Et
b
c
Au
yield
(%)
ee (cis)
CH2Ph
i-Pr
a
entry
base
Et3N
complex
solvent
cis/trans
(%)
Me
Me
Me
Me
3g
3h
3i
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
CH2Cl2
CH3CN
toluene
THF
80/20
80/20
55
35
50
71
50
35
71
70
s-Bu
Et3N
Et3N
Et3N
t-Bu
c
>95/<5
>95/<5
CH2SCH2Ph
3j
80 (95)
a
b
c
Isolated yield. Determined by HPLC . ee after recrystallization.
THF
iPr2EtN
DBU
Cs2CO3
Et3N
THF
>95/<5
60/40
65
69
63
70
68
29
65
79
this catalyst system can be also applied to α-alkyl-substituted
isocyanoacetates (entries 3−8), which has been seldom applied
in this type of asymmetric cycloaddition.18 A particularly high
enantioselectivity resulted from substrates having a sterically
demanding substituent (i-Pr, s-Bu and t-Bu, 95−97% ee, entries
6−8). A functionalized sulfur-substituted substrate was also
tested (entry 9). In this case, the enantiopurity of the adduct
cis-3j was enhanced to 95% ee by simple recrystallization with i-
PrOH. The absolute and relative configuration of pyrroline 3j
was unequivocally established by X-ray diffraction analysis.19
These enantioenriched pyrrolines are very appealing
synthetic intermediates and can be transformed into a variety
of different substituted pyrrolidines using standard imine
chemistry (Scheme 2). For example, reduction of the double
THF
THF
>95/<5
>95/<5
d
9
THF
e
10
Et3N
THF
f d
11 ,
Et3N
THF
80/20
70
70
61
55
78
54
d
12
Et3N
THF
>95/<5
>95/<5
g,d
13
Et3N
THF
a
Determined by 1H NMR; cis/trans relationship refers to the
b
c
stereochemistry at C1−C6a. Isolated yield. Determined by HPLC.
d
e
Reaction performed at 0 °C. The reaction was carried out in the
f
g
absence of silver salt. 20 mol % of AgSbF6 was used. 5 mol % of
catalyst
Regarding the base partner, we first confirmed that the reaction
did not proceed in the absence of an external base14 (entry 5),
while the use of other bases instead of Et3N resulted in a similar
reactivity but lower enantioselectivity (entries 6−8). We also
studied the effect of the temperature, observing a moderate
enhancement in the enantioselectivity when the reaction was
carried out at 0 °C (79% ee, entry 9).
Scheme 2. Synthetic Transformations of Pyrroline 3g
We also established that the in situ formation of the cationic
gold complex is critical, since no reaction was observed in the
absence of the silver salt (entry 10). Interestingly, the presumed
dicationic gold complex which would be formed by treatment
with 20 mol % of AgSbF6 provided a poorer diastereoselectivity
and enantioselectivity15 (entry 11). With this result in hand, we
were intrigued by the possibility of using the more atom-
economical monometallic complex 4b instead of the digold
complex 4a. Pleasingly, we observed that when 10 mol % of this
complex and 10 mol % of the silver salt were used, the
corresponding 1-pyrroline was formed with comparable yield
and enantioselectivity16 (entry 12). The attempt to reduce the
catalyst loading to 5 mol % resulted in a similar reactivity, albeit
with a significant drop in the enantioselectivity (54% ee, entry
13).
bound of pyrroline 3g with NaBH4 afforded the corresponding
pyrrolidine 5 in 60% yield. For the formation of a new C−C
bond, the introduction of a heterocyclic moiety at C-3 via
Friedel−Crafts reaction was next studied.20 Thus, the reaction
of pyrroline 3g with indole and pyrrole in the presence of
AgBF4 afforded the corresponding 5-indolyl and 5-pyrrylpyrro-
lidines 6 and 7 in reasonable yields (54−57% yield) and with
almost complete diastereoselectivity.21
Under these optimized conditions,17 we next examined the
reaction with substituted isocyanoacetates, which would lead to
1-pyrrolines bearing a quaternary stereocenter at C-5 (Table 2).
To our delight, the reaction of α-aryl-substituted isocyanoace-
tates provided the 1-pyrroline adduct as a single diastereomer
and with higher enantiocontrol (87−92% ee, entries 1 and 2)
than that observed in the model reaction. It is worth noting that
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Note
7.14 (m, 1H), 5.26 (q, J = 2.6 Hz, 1H), 4.35 (ddd, J = 1.2, 2.7, 8.4 Hz,
1H), 3.96 (dd, J = 2.6, 8.4 Hz, 1H), 3.78 (s, 3H). 13C NMR (75 MHz,
CDCl3): 175.3, 171.1, 169.7, 162.8, 131.1, 129.3, 129.1, 126.3 (2C),
78.6, 59.0, 53.3, 45.4, 29.7. HRMS (FAB+): calcd for C14H12N2O4 [M
+ H] 273.0875, found 273.0867.
In summary, we have described an efficient procedure for the
catalytic asymmetric formal [3 + 2] cycloaddition of
isocyanoacetates with maleimides.22 Using cationic AuI/
DTBM-segphos complex as the catalyst system, a variety of
1-pyrrolines containing a quaternary stereocenter at C-1 were
prepared with almost complete cis diastereoselectivity and high
enantioselectivity (up to 97% ee). This methodology has been
applied to the preparation of highly substituted pyrrolidines.
(1S,3aR,6aS)-Methyl 4,6-Dioxo-1,5-diphenyl-1,3a,4,5,6,6a-
hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3b). Following the
typical procedure, the reaction of isocyanoacetate 1b (32 mg, 0.18
mmol) with N-phenylmaleimide (47 mg, 0.27 mmol), AgSbF6 (6.2
mg, 0.018 mmol), (R)-DTBM-SEGPHOS(AuCl) complex (30 mg,
0.018 mmol), and Et3N (8 μL, 0.055 mmol), in THF (1.5 mL) at 0 °C
afforded, after purification by silica gel flash chromatography (hexane−
EtOAc 1:1), cis-3b (35 mg, 55%, white solid). Mp: 174.3−179.3 °C.
[α]20D: +25.0 (c = 0.9, CH2Cl2), 92% ee. HPLC: Daicel Chiralpak IB,
i-PrOH−hexane 15/85, flow rate 0.7 mL/min, tR 12.2 min
EXPERIMENTAL SECTION
■
General Procedures. All anaerobic and moisture-sensitive
manipulations were carried out in anhydrous solvents and under
nitrogen. THF was dried and stored over microwave-activated 4 Å
molecular sieves. Melting points were taken in open-end-capillary
tubes. Reactions were monitored by thin-layer chromatography carried
out on 0.25 mm silica gel plates (230−400 mesh). Flash column
chromatography was performed using silica gel (230−400 mesh).
NMR spectra were recorded on a 300 MHz instrument and calibrated
using residual undertreated solvent (CDCl3) as internal reference.
Acetic formic anhydride was prepared by stirring 1 equiv of acetic
anhydride and 1.2 equiv of formic acid for 2 h at 55 °C. Other
commercially available reagents were used without further purification.
Isocyanides 1b,23 1d, 1e, 1f,241g, 1h, and 1j25 were prepared according
to literature procedures. Because of their lability, all the isocyanides,
once isolated and purified, were immediately used in the [3 + 2]
cycloaddition.
1
(1S,3aR,6aS)-isomer and 22.1 min (1R,3aS,6aR)-isomer, 254 nm. H
NMR (300 MHz, CDCl3): 7.92 (d, J = 1.5 Hz, 1H), 7.54 (dd, J = 1.3,
8.3 Hz, 2H), 7.46−7.21 (m, 8H), 4.32 (dd, J = 1.5, 9.2 Hz, 1H), 3.82
(d, J = 9.2 Hz, 1H), 3.57 (s, 3H). 13C NMR (75 MHz, CDCl3): 174.3,
171.1, 161.7, 140.7, 131.5 (3C), 129.3, 128.5(3C), 128.2, 127.0 (2C),
126.6 (2C), 90.5, 59.9, 54.1, 53.7.HRMS (FAB+): calcd for
C20H16N2O4 [M + H] 349.1188, found 349.1178.
(1S,3aR,6aS)-Methyl 4,6-dioxo-5-phenyl-1-m-tolyl-1,3a,4,5,6,6a-
hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3c). Following the
typical procedure, the reaction of isocyanoacetate 1c (60 mg, 0.32
mmol) with N-phenylmaleimide (83 mg, 0.48 mmol), AgSbF6 (10 mg,
0.032 mmol), (R)-DTBM-SEGPHOS(AuCl) complex (45 mg, 0.032
mmol), and Et3N (13 μL, 0.096 mmol) in THF (2.0 mL) at 0 °C
afforded, after purification by silica gel flash chromatography (hexane−
EtOAc 2:1), cis-3c (68.9 mg, 60%, white solid). Mp: 110.2−112.8 °C
[α]20D: +114.0 (c = 0.5, CH2Cl2), 87% ee. HPLC: Daicel Chiralpak IA,
i-PrOH-hexane 15/85, flow rate 0.7 mL/min, tR 39.6 min
Typical Procedure for the Synthesis of Isocyanides: Methyl 2-
Isocyano-2-m-tolylacetate (1c). To a stirred suspension of methyl 2-
formamido-2-m-tolylacetate (441 mg, 2.1 mmol) in dry THF (5 mL)
at −78 °C was added Et3N (2.8 mL, 19.8 mmol). Then POCl3 (253
μL, 2.6 mmol) in dry THF (5 mL) was added dropwise, and the
reaction mixture was allowed to warm to 0 °C. After the mixture was
stirred for 2 h, ice-cold water was added, and the mixture was extracted
with Et2O (3 × 20 mL). The combined organic layers were washed
with brine (25 mL), dried with MgSO4, and concentrated in vacuo.
The resulting residue was purified by silica gel flash chromatography
(hexane−EtOAc 2:1) to afford isocyanoacetate 1c (274 mg, 64%,
1
(1R,3aS,6aR)-isomer and 51.9 min (1S,3aR,6aS)-isomer, 254 nm. H
NMR (300 MHz, CDCl3): 8.01 (d, J = 1.3 Hz, 1H), 7.49 (dd, J = 7.0,
15.2 Hz, 2H), 7.46−7.39 (m, 3H), 7.36−7.30 (m, 3H), 7.18 (t, J = 6.7
Hz, 2H), 4.41 (dd, J = 1.4, 9.4 Hz, 1H), 3.92 (d, J = 9.3 Hz, 1H), 3.66
(s, 3H), 2.40 (s, 3H). 13C NMR (75 MHz, CDCl3): 174.3, 171.1,
170.1, 161.5, 140.6, 138.2, 133.3, 131.6, 129.3, 128.9, 128.4, 127.5,
126.5 (2C), 126.2, 124.1, 90.5, 59.9, 53.9, 53.6, 21.5. HRMS (FAB+):
calcd for C21H18N2O4 [M + H] 363.1345, found 363.1342.
(1R,3aR,6aS)-Methyl 1-Methyl-4,6-dioxo-5-phenyl-1,3a,4,5,6,6a-
hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3d). Following the
typical procedure, the reaction of isocyanoacetate 1d (40 mg, 0.35
mmol) with N-phenylmaleimide (92 mg, 0.48 mmol), AgSbF6 (12 mg,
0.035 mmol), (R)-DTBM-SEGPHOS(AuCl) complex (49 mg, 0.035
mmol), and Et3N (15 μL, 0.10 mmol) in THF (2.0 mL) at 0 °C
afforded, after purification by silica gel flash chromatography (hexane−
EtOAc 4:1), cis-3d (65.0 mg, 65%, yellow oil). [α]20D: +47.5 (c = 0.2,
CH2Cl2), 85% ee. HPLC: Daicel Chiralpak IA, i-PrOH−hexane 15/85,
flow rate 0.7 mL/min, tR 31.6 min (1S,3aS,6aR)-isomer and 39.0 min
(1R,3aR,6aS)-isomer, 254 nm. 1H NMR (300 MHz, CDCl3): 7.74 (d,
J = 1.2 Hz, 1H), 7.50−7.43 (m, 2H), 7.42 (t, J = 1.51 Hz, 1H), 7.22
(dd, J = 1.5, 7.0 Hz, 2H), 4.43 (dd, J = 1.3, 8.7 Hz, 1H), 3.70 (s, 3H),
3.41 (d, J = 8.7 Hz, 1H), 1.70 (s, 3H). 13C NMR (75 MHz,
CDCl3):174.2, 171.0, 170.4, 160.1, 131.4, 129.3 (2C), 129.0, 126.4
(2C), 84.1, 59.4, 53.0, 52.0, 25.9. HRMS (FAB+): calcd for
C15H14N2O4 [M + H] 287.1032, found 287.1036.
1
orange oil). H NMR (300 MHz, CDCl3): 7.39−7.23 (m, 4H), 5.37
(s, 1H), 3.83 (s, 3H), 2.43 (s, 3H). 13C NMR (75 MHz): 166.2, 161.4,
139.2, 131.7, 130.4, 129.1, 127.2, 123.8, 60.2, 53.7, 21.4. HRMS (EI+):
calcd for C11H11NO2 [M]+ 189.0790, found 189.0795.
Methyl 3-(Benzylthio)-2-isocyanopropanoate (1j). Following the
typical procedure, the reaction of methyl 3-(benzylthio)-2-formami-
dopropenoate (1.8 g, 7.1 mmol) with POCl3 (850 μL, 1.3 mmol) in
dry THF (34 mL) at 0 °C afforded isocyanoacetate 1j (1.0 g, 60%,
1
yellow oil). H NMR (300 MHz, CDCl3): 7.38−7.24 (m, 5H), 4.35
(dd, J = 5.1, 7.0 Hz, 1H), 3.84 (s, 2H), 3.78 (s, 3H), 2.91 (dq, J = 6.1,
14.3 Hz, 2H) 13C NMR (75 MHz): 165.8, 161.8, 137.2, 129.1, 128.7,
128.6, 127.5, 127.2, 56.8, 53.6, 36.7, 33.4. HRMS (EI+): calcd for
C12H13NO2S [M]+ 235.0667, found 235.0635.
Typical Procedure for Asymmetric formal [3 + 2] Cycloadditions:
(1R,3aR,6aS)-Methyl 4,6-Dioxo-5-phenyl-1,3a,4,5,6,6a-
hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3a). (R)-DTBM-
SEGPHOS(AuCl) complex (34 mg, 0.024 mmol) and AgSbF6 (8.4
mg, 0.024 mmol) were dissolved in THF (0.5 mL), and the mixture
was stirred during 1 h under nitrogen atmosphere at room
temperature. Then methyl isocyanoacetate 1a (24 mg, 0.24 mmol)
in THF (0.5 mL) and Et3N (10 μL, 0.073 mmol) were successively
added. The reaction mixture was cooled to 0 °C, and N-
phenylmaleimide (63 mg, 0.36 mmol) in THF (0.5 mL) was added.
The mixture was stirred overnight and filtered through a plug of Celite
with the aid of CH2Cl2 (5.0 mL). The organic layer was concentrated,
and the resulting residue was purified by silica gel flash
chromatography (hexane−EtOAc 2:1) to afford cis-3a (46 mg, 70%,
white solid). Mp: 151.2−153.9 °C. [α]20D: +24.2 (c = 0.2, CH2Cl2),
79% ee. HPLC: Daicel Chiralpak ASH, i-PrOH−hexane 15/85, flow
rate 0.7 mL/min, tR 18.0 min (1S,3aS,6aR)-isomer and 21.4 min
(1R,3aR,6aS)-isomer, 254 nm. 1H NMR (300 MHz, CDCl3): 7.71 (d,
J = 1.2 Hz, 1H), 7.45−7.29 (m, 3H), 7.18 (d, J = 3.4 Hz, 1H), 7.16−
(1R,3aR,6aS)-Methyl 1-Ethyl-4,6-dioxo-5-phenyl-1,3a,4,5,6,6a-
hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3e). Following the
typical procedure, the reaction of isocyanoacetate 1e (50 mg, 0.39
mmol) with N-phenylmaleimide (102 mg, 0.59 mmol), AgSbF6 (13
mg, 0.039 mmol), (R)-DTBM-SEGPHOS(AuCl) complex (55 mg,
0.039 mmol), and Et3N (16 μL, 0.12 mmol) in THF (2.0 mL) at 0 °C
afforded, after purification by silica gel flash chromatography (hexane−
EtOAc 1:1), cis-3e (83 mg, 71%, white solid). Mp: 83.2−85.1 °C.
[α]20D: +70.0 (c = 4, CH2Cl2), 87% ee. HPLC: Daicel Chiralpak IB, i-
PrOH−hexane 15/85, flow rate 0.7 mL/min, tR: 9.2 min (1R,3aR,6aS)-
1
isomer and 11.3 min (1S,3aS,6aR)-isomer, 254 nm. H NMR (300
MHz, CDCl3): 7.82 (d, J = 1.1 Hz, 1H), 7.51−7.38 (m, 4H), 7.22 (dd,
J = 1.5, 6.9 Hz, 1H), 4.35 (dd, J = 1.2, 8.7 Hz, 1H), 3.70 (s, 3H), 3.44
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Note
(d, J = 8.7 Hz, 1H), 2.26 (qd, J = 7.3, 14.7 Hz, 1H), 2.26 (dt, J = 7.3,
14.6 Hz, 1H), 1.21 (t, 3H). 13C NMR (75 MHz, CDCl3): 174.4, 171.0,
170,1, 160.5, 131.4, 129.3 (2C), 129.0, 126.4 (2C), 87.9, 59.6, 52.8,
49.7, 31.2, 7.9. HRMS (FAB+): calcd for C16H16N2O4 [M + H]
301.1188, found 301.1190.
NMR (300 MHz, CDCl3): 7.89 (d, J = 1.9 Hz, 1H), 7.50−7.36 (m,
3H), 7.24−7.19 (m, 2H), 4.33 (dd, J = 2.2, 8.9 Hz, 1H), 3.71 (d, J =
9.1 Hz, 1H), 3.59 (s, 3H), 1.22 (s, 9H). 13C NMR (75 MHz,
CDCl3):174.8, 171.2, 168.6, 160.3, 131.5, 129.2 (2C), 128.9, 126.2
(2C), 93.9, 60.1, 52.3, 47.3, 37.3, 25.7 (3C). HRMS (FAB+): calcd for
C18H20N2O4 [M + H] 329.1501, found 329.1495.
(1R,3aR,6aS)-Ethyl 1-Benzyl-4,6-dioxo-5-phenyl-1,3a,4,5,6,6a-
hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3f). Following the
typical procedure, the reaction of isocyanoacetate 1f (50 mg, 0.24
mmol) with N-phenylmaleimide (64 mg, 0.37 mmol), AgSbF6 (8.2
mg, 0.024 mmol), (R)-DTBM-SEGPHOS(AuCl) complex (34 mg,
0.024 mmol), and Et3N (10 μL, 0.074 mmol) in THF (2.0 mL) at 0
°C afforded, after purification by silica gel flash chromatography
(hexane−EtOAc 2:1), cis-3f (48 mg, 54%, yellow oil). [α]20D: +15.0 (c
= 0.1, CH2Cl2), 83% ee. HPLC: Daicel Chiralpak ASH, i-PrOH−
hexane 15/85, flow rate 0.7 mL/min, tR 27.5 min (1S,3aR,6aS)-isomer
(1R,3aR,6aS)-Methyl 1-(Benzylthiomethyl)-4,6-dioxo-5-phenyl-
1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3j).
Following the typical procedure, the reaction of isocyanoacetate 1j
(50 mg, 0.21 mmol) with N-phenylmaleimide (55 mg, 0.32 mmol),
AgSbF6 (7.4 mg, 0.021 mmol), (R)-DTBM-SEGPHOS(AuCl)
complex (29 mg, 0.021 mmol), and Et3N (8.8 μL, 0.063 mmol) in
THF (1.5 mL) at 0 °C afforded, after purification by silica gel flash
chromatography (hexane−EtOAc 2:1), cis-3j (58.3 mg, 68%, white
solid). Mp: 100.2−101.8 °C. [α]20D: +30.0 (c = 0.2, CH2Cl2), 80% ee.
HPLC: Daicel Chiralpak IB, i-PrOH−hexane 15/85, flow rate 0.7 mL/
min, tR 13.2 min (1R,3aR,6aS)-isomer and 24.5 min (1S,3aS,6aR)-
1
and 43.5 min (1R,3aS,6aR)-isomer, 254 nm. H NMR (300 MHz,
CDCl3): 7.65 (d, J = 1.2 Hz, 1H), 7.47−7.35 (m, 2H), 7.31−7.23 (m,
3H), 7.19−7.12 (m, 5H), 4.22 (ttd, J = 7.1, 10.7, 14.2 Hz, 2H), 3.56
(d, J = 8.6 Hz, 1H), 3.51 (s, 2H), 3.31 (dd, J = 1.2, 8.6 Hz, 1H), 1.23
(t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3):173.4, 169.9, 168.8,
160.5, 133.5, 130.3, 130.1 (2C), 128.2 (2C), 127.9, 127.3 (2C), 126.3,
125.3 (2C), 85.8, 61.4, 58.6, 47.9, 41.4, 12.9. HRMS (FAB+): calcd for
C22H20N2O4 [M + H] 377.1501, found 377.1506.
1
isomer, 254 nm. H NMR (300 MHz, CDCl3): 7.83 (d, J = 1.3 Hz,
1H), 7.54−7.40 (m, 3H), 7.35−7.27 (m, 5H), 7.23−7.17 (m, 2H),
4.42 (dd, J = 1.4, 8.8 Hz, 1H), 3.73 (s, 2H), 3.69 (s, 3H), 3.46 (d, J =
8.8 Hz, 1H), 3.24 (d, J = 14.3 Hz, 1H), 3.16 (d, J = 14.3 Hz, 1H). 13C
NMR (75 MHz, CDCl3): 174.3, 170.9, 169.4, 162.5, 137.8, 131.3,
129.3 (2C), 129.1, 129.0 (2C), 128.7 (2C), 127.4, 126.4 (2C), 87.9,
60.7, 53.2, 49.8, 38.8, 37.5. HRMS (FAB+): calcd for C22H20N2O4S
[M + H] 409.1222, found 409.1219.
(1R,3aR,6aS)-Methyl 4,6-Dioxo-5-phenyloctahydropyrrolo[3,4-c]-
pyrrole-1-carboxylate (5). To a suspension of NaBH4 (6.0 mg, 0.16
mmol) in THF (1.0 mL) under nitrogen atmosphere was added a
solution of pyrroline cis-3g (50 mg, 0.159 mmol) in THF (0.8 mL).
After being stirred for 24 h at room temperature, the mixture was
filtered through a plug of Celite with the aid of CH2Cl2 (2 mL), and
the solvent was removed under reduced pressure. The residue was
purified by silica gel flash chromatography (hexane−EtOAc 2:1) to
afford 5 (30 mg, 60%, yellow oil). [α]20D: −14.5 (c = 0.3, CH2Cl2). 1H
NMR (300 MHz, CDCl3): 7.46 (t, J = 7.8 Hz, 1H), 7.38 (t, J = 7.4 Hz,
2H), 7.28 (d, J = 7.5 Hz, 3H), 3.76 (s, 3H), 3.59 (dt, J = 5.6, 8.5 Hz,
1H), 3.53−3.43 (m, 2H), 2.37−2.30 (m, 1H), 1.61 (bs, 1H), 1.09 (dd,
J = 6.8, 11.6 Hz, 6H). 13C NMR (75 MHz, CDCl3): 176.9, 175.3,
175.0, 131.9, 129.1 (2C), 128.7, 126.5 (2C), 77.9, 52.7, 52.1, 49.1,
47.8, 34.5, 18.0, 17.8. HRMS (FAB+): calcd for C17H20N2O4 [M + H]
317.1501, found 317.1503.
(1R,3aR,6aS)-Methyl 1-Isopropyl-4,6-dioxo-5-phenyl-
1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3g).
Following the typical procedure, the reaction of isocyanoacetate 1g
(50 mg, 0.35 mmol) with N-phenylmaleimide (92.1 mg, 0.59 mmol),
AgSbF6 (12.2 mg, 0.035 mmol), (R)-DTBM-SEGPHOS(AuCl)
complex (49.4 mg, 0.035 mmol), and Et3N (14.6 μL, 0.105 mmol)
in THF (2.0 mL) at 0 °C afforded, after purification by silica gel flash
chromatography (hexane−EtOAc 1:1), cis-3g (76.9 mg, 70%, white
solid). Mp: 107.6−108.7 °C. [α]20D: +33 (c = 0.3, CH2Cl2), 95% ee.
HPLC: Daicel Chiralpak IB, i-PrOH−hexane 15/85, flow rate 0.7 mL/
min, tR 23.3 min (1R,3aR,6aS)-isomer and 34.6 min (1S,3aS,6aR)-
1
isomer, 254 nm. H NMR (300 MHz, CDCl3): 7.83 (d, J = 1.5 Hz,
1H), 7.50−7.35 (m, 4H), 7.25 (dd, J = 1.5, 6.9 Hz, 1H), 4.29 (dd, J =
1.4, 8.8 Hz, 1H), 3.71 (s, 3H), 3.49 (d, J = 8.8 Hz, 1H), 2.74 (td, J =
6.7, 13.4 Hz, 1H), 0.98 (m, 6H). 13C NMR (75 MHz, CDCl3): 174.7,
171.1, 170.0, 160.8, 131.4, 129.2 (2C), 128.9, 126.4 (2C), 91.8, 59.8,
52.8, 47.6, 34.1, 17.6, 16.7. HRMS (FAB+): calcd for C17H18N2O4 [M
+ H] 315.1345, found 315.1339.
(1R,3S,3aR,6aS)-Methyl 3-(1H-Indol-3-yl)-1-isopropyl-4,6-dioxo-
5-phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (6). To a
mixture of pyrroline cis-3g (50 mg, 0.159 mmol) and AgBF4 (37
mg, 0.191 mmol) in THF (0.7 mL) under nitrogen atmosphere was
added indole (37 mg, 0.318 mmol) in THF (1.5 mL). The mixture
was stirred at room temperature for 24 h, filtered through a plug of
Celite with the aid of CH2Cl2 (2 mL), and washed with a saturated
aqueous solution of NH4Cl (2 × 5 mL). The organic layer was dried
over Na2SO4 and the solvent evaporated under reduced pressure. The
residue was purified by silica gel flash chromathography (hexane−
EtOAc 2:1) to afford 6 (37 mg, 54%, yellow oil). [α]20D: −50.0 (c =
0.2, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 8.18 (bs, 1H), 7.99 (d, J
= 7.9 Hz, 1H), 7.52 (t, J = 7.7 Hz, 2H), 7.43 (dd, J = 7.6, 12.7 Hz,
4H), 7.33 (d, J = 2.0 Hz, 1H), 7.26 (t, J = 7.2, 10.1 Hz, 1H), 7.18 (t, J
= 7.5 Hz, 1H), 4.85 (d, J = 7.2 Hz, 1H), 3.82 (s, 3H), 3.74 (dd, J = 7.2,
10.1 Hz, 1H), 3.65 (d, J = 10.2 Hz, 1H), 2.50 (td, J = 6.8, 13.5 Hz,
1H), 1.61 (bs, 1H), 1.31 (d, J = 6.8 Hz, 3H), 1.25 (d, J = 6.8 Hz, 3H).
13C NMR (75 MHz, CDCl3):176.2, 174.8, 173.2, 136.9, 132.4, 129.1
(1R,3aR,6aS)-Methyl 1-(S)-sec-Butyl-4,6-dioxo-5-phenyl-
1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3h).
Following the typical procedure, the reaction of isocyanoacetate 1h
(100 mg, 0.64 mmol) with N-phenylmaleimide (133 mg, 0.77 mmol),
AgSbF6 (22 mg, 0.064 mmol), (R)-DTBM-SEGPHOS(AuCl)
complex (90 mg, 0.064 mmol), and Et3N (26 μL, 0.19 mmol), in
THF (3.5 mL) at 0 °C afforded, after purification by silica gel flash
chromatography (hexane−EtOAc−CH2Cl2 2:1:2), cis-3h (130.1 mg,
62%, yellow oil). [α]20D: +65.6 (c = 0.8, CH2Cl2), 97% ee. HPLC:
Daicel Chiralpak OD, i-PrOH−hexane 15/85, flow rate 0.7 mL/min,
tR 30.5 min (1R,3aR,6aS)-isomer and 37.0 min (1S,3aS,6aR)-isomer,
1
254 nm. H NMR (300 MHz, CDCl3): 7.84 (d, J = 1.2 Hz, 1H),
7.51−7.35 (m, 3H), 7.27−7.20 (m, 2H), 4.29 (dd, J = 71.2, 8.9 Hz,
1H), 3.71 (s, 3H), 3.49 (d, J = 8.9 Hz, 1H), 2.45 (m, 1H), 1.54 (m,
2H), 1.32 (d, J = 7.67 Hz, 3H), 0.98 (t, J = 7.42 Hz, 3H). 13C NMR
(75 MHz, CDCl3):174.6, 171.1, 170.1, 160.7, 131.5, 129.2 (2C), 128.9,
126.4 (2C), 92.4, 59.8, 52.8, 47.9, 41.1, 24.8, 13.3, 12.2. HRMS (FAB
+): calcd for C18H20N2O4 [M + H] 329.1501, found 329.1500.
(1S,3aR,6aS)-Methyl 1-tert-Butyl-4,6-dioxo-5-phenyl-
1,3a,4,5,6,6a-hexahydropyrrolo[3,4-c]pyrrole-1-carboxylate (3i).
Following the typical procedure, the reaction of isocyanoacetate 1i
(50 mg, 0.32 mmol) with N-phenylmaleimide (83 mg, 0.48 mmol),
AgSbF6 (11 mg, 0.032 mmol), (R)-DTBM-SEGPHOS(AuCl)
complex (45 mg, 0.032 mmol), and Et3N (13 μL, 0.096 mmol) in
THF (1.5 mL) at 0 °C afforded, after purification by silica gel flash
chromatography (hexane−EtOAc 2:1), cis-3i (72.5 mg, 69%, yellow
oil). [α]20D: +12.5 (c = 0.5, CH2Cl2), 96% ee. HPLC: Daicel Chiralpak
ASH, i-PrOH−hexane 15/85, flow rate 0.7 mL/min, tR 21.3 min
(2C), 128.4, 126.6 (2C), 125.5, 122.8, 122.5, 120.1, 119.7, 115.9,
111.5, 76.4, 56.5, 52.6, 52.4, 48.8, 33.6, 18.5, 17.2. HRMS (FAB+):
calcd for C25H25N3O4 [M + H] 432.1923, found 432.1913.
(1R,3S,3aR,6aS)-Methyl 1-isopropyl-4,6-dioxo-5-phenyl-3-(1H-
pyrrol-2-yl)octahydropyrrolo[3,4-c]pyrrole-1-carboxylate (7). To a
mixture of pyrroline cis-3g (50 mg, 0.159 mmol) and AgBF4 (37 mg,
0.191 mmol) in THF (0.7 mL) under nitrogen atmosphere was added
pyrrole (21 mg, 0.318 mmol) in THF (1.5 mL). The mixture was
stirred at room temperature for 24 h, filtered through a plug of Celite
with the aid of CH2Cl2 (2 mL), and washed with a saturated aqueous
solution of NH4Cl (2 × 5 mL). The organic layer was dried over
1
(1S,3aR,6aS)-isomer and 42.8 min (1R,3aS,6aR)-isomer, 254 nm. H
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The Journal of Organic Chemistry
Note
Na2SO4 and the solvent evaporated under reduced pressure. The
residue was purified by silica gel flash chromathography (hexane−
EtOAc 1:1) to afford 7 (34 mg, 57%, yellow oil). [α]20D: −83.3 (c =
0.2, CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 8.83 (bs, 1H), 7.50 (t, J
= 7.9 Hz, 2H), 7.41 (dt, J = 0.8, 8.0 Hz, 3H), 6.80 (ddd, J = 1.3, 2.6,
3.7 Hz, 1H), 6.20−6.14 (m, 2H), 4.56 (d, J = 7.0 Hz, 1H), 3.76 (s,
3H), 3.47−3.38 (m, 2H), 2.57 (bs, 1H), 2.41 (td, J = 6.7, 13.4 Hz,
1H), 1.17 (t, J = 6.7 Hz, 6H). 13C NMR (75 MHz, CDCl3): 176.6,
174.7, 172.7, 132.2, 131.1, 129.2 (2C), 128.6, 126.5 (2C), 118.0, 108.3,
104.5, 76.7, 56.7, 52.9, 52.7, 48.7, 33.4, 18.5, 16.9. HRMS (FAB+):
calcd for C21H23N3O4 [M + H] 382.1767, found 382.1769.
(6) Song, J.; Guo, C.; Chen, P.-H.; Yu, J.; Luo, S.-W.; Gong, L.-Z.
Chem.Eur. J. 2011, 17, 7786−7790.
(7) Arroniz, C.; Gil-Gonzalez, A.; Semak, V.; Escolano, C.; Bosch, J.;
́
́
Amat, M. Eur. J. Org. Chem. 2011, 3755−3760.
(8) For a racemic example of the reaction of isocyanoacetates with N-
phenylmaleimide, see ref 4b.
(9) Hayashi and co-workers established for the first time the
efficiency of chiral gold Lewis acids in the activation of isocyano esters
in the aldol reaction. Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem.
Soc. 1986, 108, 6405−6406.
(10) Interesting examples of Au(I)-catalyzed enantioselective cyclo-
additions of azomethine ylides with activated olefins have been
recently reported. (a) Melhado, A. D.; Luparia, M.; Toste, F. D. J. Am.
Chem. Soc. 2007, 129, 12638−12639. (b) Melhado, A. D.; Amarante,
G. W.; Wang, Z. J.; Luparia, M.; Toste, F. D. J. Am. Chem. Soc. 2011,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds, copies of
HPLC traces used to determine enantiomeric purity, and X-ray
crystallographic data of compounds 3j and 7 (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
133, 3517−3527. (c) Martín-Rodriguez, M.; Naj
Feng-Liu, W. Tetrahedron:Asymmetry 2010, 21, 1184−1186. (d) Mar-
tín-Rodriguez, M.; Najera, C.; Sansano, J. M.; de Cozar, A.; Cossío, F.
́
era, C.; Sansano, J. M.;
́
́
P. Chem.Eur. J. 2011, 17, 14224−14233.
(11) See the Supporting Information for catalyst optimization
studies.
AUTHOR INFORMATION
(12) For a recent review on asymmetric gold catalysis, see:
(a) Sengupta, S.; Shi, X. ChemCatChem 2010, 2, 609−619. For
recent examples on the use of DTBM-segphos(AuCl)2 in asymmetric
catalysis, see: (b) Bandini, M; Monari, M.; Romaniello, A.; Tragni, M.
Chem.Eur. J. 2010, 16, 14272−14277. (c) Murai, M.; Uenishi, J.;
Uemura, M. Org. Lett. 2010, 12, 4788−4791. (d) LaLonde, R. L.;
Wang, Z. J.; Mba, M.; Lackner, A. D.; Toste, F. D. Angew. Chem., Int.
Ed. 2010, 49, 598−601.
■
Corresponding Author
*E-mail: javier.adrio@uam.es, juancarlos.carretero@uam.es.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(13) The use of other silver sources such as AgBF4, AgClO4, or
AgOTf did not produce significant improvements either in reactivity
or selectivity.
Financial support of this work by the Ministerio de Ciencia e
Innovacion
́
of Spain (MICINN, CTQ2009-07791), CAM
(project AVANCAT; S2009/PPQ-1634), and CAM-UAM
(CCG-10-UAM/PPQ-5853) is gratefully acknowledged. S.P.
thanks the MICINN for a predoctoral contract. We thank
Takasago Co. (Dr. Taichiro Touge) for generous loans of
Segphos and DTBM-Segphos chiral ligands.
(14) The reaction did not occur using a silver salt with a more basic
counterion such as AgOAc or AgOBz.
(15) Presumed dicationic gold complexes formed in situ by reaction
of chloride gold complexes with silver salts have proved to be excellent
Lewis acids in previously reported catalyzed asymmetric trans-
formations (see ref 12).
(16) We also studied the possibility of performing the reaction in
absence of gold species. However, the use of AgSbF4/DTBM-segphos
complex as catalyst led to the corresponding pyrroline with
significantly lower diastereoselectivity (cis/trans 4:1) and enantiose-
lectivity (55% ee).
(17) Under these optimized Au-catalyzed reaction conditions, we
also tested several acyclic activated alkenes. Unfortunately, we did not
observe reaction of 1a with methyl acrylate, (E)-β-nitrostyrene, or
trans-chalcone, and only traces of the cycloaddut were detected in the
reaction of 1a or 1g with dimethyl fumarate.
(18) As far as we know, only two isolated examples of reaction of α-
benzyl isocyanoacetate with methyl and ethyl vinyl ketone (16% and
36% ee, respectively) have been previously reported; see ref 6.
(19) See the Supporting Information for details on the X-ray
structure of enantiopure cis-3j.
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