Enantioselective Synthesis of exo -4-Nitroprolinates from Nitroalkenes and Azomethine Ylides Catalyzed by Chiral Phosphoramidite·Silver(I) or Copper(II) Complexes

Article abstract of DOI:10.1055/s-0034-1380158

Chiral complexes formed by privileged phosphoramidites derived from chiral binol and optically pure Davies' amines, and copper(II) triflate, silver(I) triflate or silver(I) benzoate are excellent catalysts for the general 1,3-dipolar cycloaddition between

Full text of DOI:10.1055/s-0034-1380158

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 934–943
psp
934
L. M. Castelló et al.
PSP
Synthesis
Enantioselective Synthesis of exo-4-Nitroprolinates from Nitro-
alkenes and Azomethine Ylides Catalyzed by Chiral Phosphor-
amidite·Silver(I) or Copper(II) Complexes
Luis M. Castellóa
Carmen Nájeraa
José M. Sansano*a
Olatz Larrañagab
Abel de Cózarb,c
Ph
O
P
N
O
R2
Ph
(5 mol%)
metal salt (5 mol%)
O2N
Fernando P. Cossíob,c
O2N
R2
R1
+
a Departamento de Química Orgánica, Instituto de
Síntesis Orgánica (ISO), and Centro de Innovación en
Química Avanzada (ORFEO-CINQA), Universidad de
Alicante, Apdo. 99, 03080-Alicante, Spain
b Departmento de Química Orgánica I, Facultad de
Química, and Centro de Innovación en Química
Avanzada (ORFEO CINQA), Universidad del País
Vasco, P. K. 1072, 20018 San Sebastián, Spain
c IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
jmsansano@ua.es
R1
Ar
Et3N (5 mol%)
PhMe, 25 °C, 17 h
N
H
CO2Me
Ar
N
CO2Me
exo
metal salt = Cu(OTf)2, AgOBz, AgOTf
Received: 14.01.2015
Accepted: 16.01.2015
N-Arylideneamino esters have been employed as
azomethine ylide precursors in the enantioselective 1,3-DC
with nitroalkenes employing both organocatalysts and
metal complexes as chiral catalysts for the construction of
exo-prolinates with 2,5-cis-4,5-trans arrangement.6 The
majority of contributions using α-imino esters to obtain
exo-adducts were achieved under the control of chiral met-
al complexes.7 Chiral Lewis acids formed by copper(I), cop-
per(II), gold(I), and nickel(II) complexes were the most ef-
fective.2 The only exception reported in all these examples
is the employment of a copper(II) triflate·pyridyl bis(imid-
azolidine) as chiral complex,8 and very interesting switch-
able chiral P,N-ferrocene ligands,9 which afforded the endo-
adducts.
Published online: 19.02.2015
DOI: 10.1055/s-0034-1380158; Art ID: ss-2015-z0029-psp
Abstract Chiral complexes formed by privileged phosphoramidites
derived from chiral binol and optically pure Davies’ amines, and cop-
per(II) triflate, silver(I) triflate or silver(I) benzoate are excellent cata-
lysts for the general 1,3-dipolar cycloaddition between nitroalkenes
and azomethine ylides generated from α-amino acid derived imino es-
ters. These three methods can be conducted at room temperature to
afford the exo-cycloadducts (4,5-trans-2,5-cis-4-nitroprolinates) with
high diastereoselectivity and high enantioselectivity. In general, the
three procedures are complementary but silver catalysts are more ver-
satile and less sensitive to sterically congested starting materials.
Key words dipolar cycloaddition, asymmetric catalysis, azomethine
ylides, phosphoramidite, copper, silver
Although silver(I) is traditionally the most suitable cat-
ion to stabilize a metallodipole derived from iminoesters
3,10 no efficient 1,3-DC between metallo-azomethine ylides
and β-nitroalkanes has been reported.11 Only Fukuzawa’s
group has published a highly effective asymmetric cycload-
dition using benzophenone-derived iminoglycinates and
nitroalkenes catalyzed by silver(I)·thioclickferrophos com-
plexes.12
Introduction
The straightforward synthesis of enantiomerically en-
riched polysubstituted exo-4-nitroprolinates can be
achieved through 1,3-dipolar cycloaddition (1,3-DC)1 be-
tween imino esters and nitroalkenes.2 The introduction of
the versatile nitro group at the 4-position of the pyrrolidine
skeleton enhances the interest of these chiral molecules.
Particularly, exo-4-nitroprolinates with a specific 2,5-cis-
4,5-trans-configuration have been used as leukocyte func-
tion associated antigen-1 antagonists during a cancer evo-
lution,3 with important activity as inhibitors of α4β1-integ-
rin-mediated hepatic melanoma metastasis and even for
the treatment of other diseases.4 Simpler exo-nitropro-
linates such as 4 have shown high efficiency as organocata-
lysts in asymmetric aldol reactions.5
Very recently, we showed that phosphoramidites13,14
derived from chiral binol-chiral Davies’ amines represent a
matched combination for the enantioselective 1,3-dipolar
cycloaddition (1,3-DC)15 between nitroalkenes and
16
azomethine ylides derived from imino esters. Cu(OTf)2
and silver(I) salts17 afforded exo-4-nitroprolinates in high
diastereomeric ratios and enantioselectivities. Seminal
works published on the asymmetric 1,3-CD of imino esters
and different dipolarophiles catalyzed by chiral phosphor-
amidite 1·silver(I) complexes supported this idea,18 with
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 934–943

935
L. M. Castelló et al.
PSP
Synthesis
enantiomerically enriched polysubstituted endo-proline
derivatives being obtained in good chemical yields and ex-
cellent diastereo- and enantioselectivities.
Herein, we wish to report a practical procedure for the
synthesis of exo-4-nitroprolinates 4 in which nitroalkenes
undergo copper(II)- and less known silver(I)-catalyzed 1,3-
dipolar cycloaddition with azomethine ylides obtained
from α-imino esters.
The influence of the aryl substituent of nitroalkene 3 on
the 1,3-DC with methyl benzylidene glycinate was investi-
gated and the results revealed that, in general, higher
chemical yields, exo-diastereoselectivities, and enantiose-
lections were obtained for products 4c–g when the reac-
tions were performed in the presence of (Sa,R,R)-1·AgOBz
rather than with the silver(I) or copper(II) triflates (Table 1,
entries 3–7). An exception was noted when meta-brominat-
ed nitrostyrene was employed as dipolarophile (Table 1, en-
try 6). In this example, (Sa,R,R)-1·Cu(OTf)2 complex was the
most effective catalyst, giving the cleanest crude compound
4f (90:10 dr, and 96:4 er). When the heteroaromatic moiety
was bonded to the nitro component (2-furyl) the use of the
chiral silver benzoate complex was more appropriate,
achieving 77% yield and 98% ee of exo-4h (Table 1, entry 8).
When nitroalkene 3, bearing an aliphatic cyclohexyl group,
was used, a reversal in diastereoselectivity was observed in
the 1,3-DC catalyzed by 1·AgOTf . The endo isomer was iso-
lated exclusively in 71% yield but as a racemic mixture.
However, an equimolar mixture of endo/exo diastereoiso-
mers, in 75% overall yield, was isolated in the analogous re-
action performed with AgOBz. Again, the adduct endo-4i
was separated as a racemate, whereas the exo-isomer 4i
was obtained in low 32% yield but with 96% ee (Table 1, en-
try 9). On the other hand, the 1,3-DC with nitroalkene 3
(R2 = Cy) failed with the Cu(OTf)2 complex.
When alanine, leucine, or phenylalanine derived imino
esters 2 were used as azomethine ylide precursors, an in-
crease in the proportion of endo-diastereoisomers 4j–l was
observed. This diastereoisomer was always obtained as a
racemic mixture (Table 1, entries 10–12). Alanine dipole
precursor 2 furnished very low proportions of exo-4j,
which was isolated with high optical purity in silver-cata-
lyzed processes (Table 1, entry 10). The other two quater-
nized pyrrolidines, exo-4k and exo-4l, were satisfactorily
isolated (>99:1 er) by employing (Sa,R,R)-1·Cu(OTf)2 cataly-
sis (Table 1, entries 11 and 12).
Scope and Limitations
The scope of the reaction was studied with different ni-
troalkenes 3, employing various arylideneimino esters 2
under the control of: (a) the catalyst formed by phosphor-
amidite (Sa,R,R)-1 and Cu(OTf)2 (Scheme 1, Procedure 1, Ta-
ble 1);16 (b) the catalyst generated from (Sa,R,R)-1 and Ag-
OTf (Scheme 1, Procedure 2, Table 1),17 and (c) the combina-
tion of phosphoramidite (Sa,R,R)-1 with AgOBz (Scheme 1,
Procedure 2, Table 1).17 Initially, the influence of the ester
moiety of imines 2 was surveyed. Compound 4a was ob-
tained as a very clear crude reaction product and with the
highest enantiomeric ratio in the presence of (Sa,R,R)-
1·AgOBz complex (Table 1, entry 1). When the isopropyl es-
ter of the corresponding dipole precursor was used instead
of the methyl ester, almost identical enantiomeric ratios for
the reactions catalyzed by the two chiral silver complexes
were obtained, with a slightly better exo-diastereoselection
for the isopropyl ester. The copper(II)-catalyzed process
gave better exo/endo ratios and similar enantiomeric ratios.
However, the lower yields (up to 70%) of the exo-product 4b
mixtures obtained in all of the reactions by using the iso-
propyl ester was consistent with the appearance of a pro-
portion of other unidentified diastereoisomers (ca. 20–28%
based on 1H NMR spectroscopic analysis of the crude prod-
uct; Table 1, entry 2). As a consequence, subsequent studies
on the scope of the reaction was undertaken with methyl
α-imino esters as metallo-azomethine ylide precursors.
procedure 1
R2
O2N
(Sa,R,R)-1 (5 mol%)
Cu(OTf)2 (5 mol%)
O2N
R2
O2N
R2
R1
3
R1
CO2Me
R1
Ar
Ar
Et3N (5 mol%)
PhMe, 25 °C, 17 h
N
H
N
CO2Me
Ph
N
H
Ar
N
CO2Me
O
O
exo-4
rac-endo-4
2
P
procedure 2
Ph
R2
O2N
(Sa,R,R)-1 (5 mol%)
AgOBz or AgOTf (5 mol%)
O2N
R2
O2N
R2
R1
3
(Sa,R,R)-1
R1
R1
Ar
Ar
Et3N (5 mol%)
PhMe, 25 °C, 17 h
N
H
N
CO2Me
CO2Me
H
Ar
N
CO2Me
exo-4
rac-endo-4
2
Scheme 1 General procedures for the synthesis of polysubstituted exo-nitroprolinates 4
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 934–943

936
L. M. Castelló et al.
PSP
Synthesis
Table 1 Scope of the Diastereo- and Enantioselective 1,3-DC between Imino Esters 2 and Nitroalkenes 3 Catalyzed by (Sa,R,R)-1·Cu(OTf)2,
(Sa,R,R)-1·AgOTf, and (Sa,R,R)-1·AgOBz
(Sa,R,R)-1·Cu(OTf)2
(Sa,R,R)-1·AgOTf
(Sa,R,R)-1·AgOBz
exo/endoa Yield (%)c erd
Entry
1
4
Structure
exo/endoa,b Yield (%)c erd
exo/endoa,b Yield (%)c erd
O2N
Ph
H
4a
4b
89:11
99:1
80
69
>99:1
>99:1
90:10
98:2
80
69
98:2
98:2
91:9
88
>99:1
Ph
N
H
CO2Me
O2N
Ph
Ph
2
3
93:7b
70
98:2
H
N
H
CO2Pri
O2N
Ph
4c
82:18
48
99:1
70:30
52
95:5
93:7
92
99:1
H
N
H
CO2Me
F
O2N
Ph
4
4d
82:12
73
96:4
89:11
74
98:2
92:8
88
>99:1
H
N
H
CO2Me
Br
O2N
5
4e
73:27
56
96:4
76:24
64
97:3
91:9b
76
96:4
H
Ph
N
H
CO2Me
Br
82:18b
61
94:6
O2N
6
4f
90:10
61
94:6
81:19
61
93:7
H
Ph
N
H
CO2Me
Br
O2N
7
4g
84:16
70
95:5
85:15
56
99:1
82:18
77
99:1
H
Ph
N
H
CO2Me
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 934–943

937
L. M. Castelló et al.
PSP
Synthesis
Table 1 (continued)
(Sa,R,R)-1·Cu(OTf)2
exo/endoa,b Yield (%)c erd
(Sa,R,R)-1·AgOTf
(Sa,R,R)-1·AgOBz
exo/endoa Yield (%)c erd
Entry
4
Structure
exo/endoa,b Yield (%)c erd
O
O2N
Ph
8
4h
77:23
41
91:9
68:32
50
97:3
84:16
50:50
77
99:1
H
N
H
CO2Me
O2N
Ph
33d
42e
9
4i
–
–
–
1:99
71e
rac
98:2f
H
N
H
CO2Me
O2N
Ph
Ph
14d
63e
21d
69e
10
11
12
4j
26:74
92:8
18
60
65
racf
21:79
92:8
93:7f
27:73
35:65
50:50b
96:4f
99:1f
Me
N
H
CO2Me
O2N
Ph
Ph
21d
53e
Bui
4k
4l
>99:1f
>99:1f
46
98:2
N
H
CO2Me
O2N
Ph
Ph
42d
40e
33d
33e
75:25
54:46
99:1f
>99:1f
Ph
N
H
CO2Me
O2N
Ph
H
13
14
4m
4n
59:41
79:21
51
61
75:25
90:10
56:44
76:24
33
65
91:9
94:6
75:25b
87:13
56
79
95:5
91:9
N
CO2Me
H
O2N
Ph
H
N
CO2Me
H
O2N
Ph
H
15
16
4o
4p
79:21
59
94:6
94:6
93:7
79
81
97:3
98:2
88:12b
90:10
60
75
97:3
96:4
N
CO2Me
H
O2N
Ph
H
–
–
–
N
CO2Me
H
MeO
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 934–943

938
L. M. Castelló et al.
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Synthesis
Table 1 (continued)
(Sa,R,R)-1·Cu(OTf)2
exo/endoa,b Yield (%)c erd
(Sa,R,R)-1·AgOTf
(Sa,R,R)-1·AgOBz
exo/endoa Yield (%)c erd
Entry
17
4
Structure
exo/endoa,b Yield (%)c erd
O2N
Ph
H
4q
4r
4s
87:13
89:11
86:14
70
76
70
99:1
88:12
91:9
72
77
70
>99:1
>99:1
92:8
88:12
94:6b
83
83
66
92
N
CO2Me
H
F
O2N
Ph
H
18
19
95:5
99:1
88:12
N
CO2Me
H
Br
O2N
Ph
H
85:15
86:14
80:20b
N
CO2Me
H
a Based on NMR spectroscopic analysis of the crude product.
b Other stereoisomers were detected in noticeable proportions.
c Isolated yield (for the exo-adduct) after purification by flash chromatography.
d For the exo-stereoisomer (HPLC).
e For the endo-isomer.
f The endo-isomer was obtained as a racemic mixture.
With respect to the reaction of different methyl
arylidene glycinates 2 with nitrostyrene, the more sterically
hindered o-tolyl imino group also favored the generation of
the endo-isomer 4m, but to a lesser extent in the case of
AgOBz (Table 1, entry 13). For the m-tolyl imino group de-
rivative, the benzoate counteranion gave the highest enan-
tioselectivities for compound exo-4n (Table 1, entry 14). It
seems that the lower the steric repulsion the higher the
proportion of exo-adduct and enantioselection. This gener-
al assumption can be supported by the transformations in-
volving para-substituted arylidene imino esters 2 (Table 1,
entries 15–18). Thus, better results for compounds 4o–r
were observed when (Sa,R,R)-1·AgOTf was the selected cata-
lyst, rather than the processes mediated by the silver ben-
zoate (Table 1, entries 15–18). Notably, compound exo-4p
could not be prepared through the copper(II)-catalyzed
method (Table 1, entry 16). Finally, in the reaction using
substrate 2 with a 2-naphthyl substituent, product exo-4s
was obtained with up to 72% de and 85% ee when AgOTf
was used, which was better than the results obtained with
Cu(OTf)2 and AgOBz (Table 1, entry 19).
tance is shorter. These results justify the use of the (Sa,R,R)-
1·Cu(OTf)2 complex in the reactions involving α-substituted
imino esters 2.
The influence of the benzoate anion versus the triflate
anion in the silver-catalyzed cycloaddition can be explained
by the assumption that benzoate, which has more steric
bulk than triflate, is oriented along the arylidene moiety of
the dipole. Thus, a small π-stacking interaction is observed
when 4 (R = H, Ar = Ph) is computed with the benzoate an-
ion, so we think that a variation of the aromatic moiety of
the imino group would increase the steric repulsion with
the bulkier benzoate anion rather than with triflate.19 In
this sense, the reaction of nitrostyrenes with 2 when R1 = H
and Ar = Ph, is optimally catalyzed by the (Sa,R,R)-1·AgOBz
complex. In contrast, when different aryl substituents are
bonded to the 1,3-dipole precursor, the employment of
(Sa,R,R)-1·AgOTf complex is desirable.
In conclusion, an efficient preparation of enantiomeri-
cally enriched polysubstituted exo-4-nitroprolinates has
been achieved through copper(II)- or silver(I)-catalyzed
1,3-DC between imino esters and nitroalkenes. These meth-
ods allows the preparation of pyrrolidines in larger scale
(0.5–0.8 g) at room temperature. (Sa,R,R)-1·AgOBz is the
best catalyst for cycloadditions starting from methyl ben-
zylideneglycinate, whereas (Sa,R,R)-1·Cu(OTf)2 complex is
more suitable for reactions involving α-substituted imino
esters 2. Finally, (Sa,R,R)-1·AgOTf catalyst is recommended
when imines derived from aromatic aldehydes other than
benzaldehyde are used.
In these efficient copper(II) or silver(I)-catalyzed cyclo-
additions of nitroalkenes, the influence of the position of
the anion in the transition state is crucial to explain the
diastereo- and enantioselectivity of the whole process be-
cause the anion blocks one of the two prochiral faces of the
1,3-dipole. DFT calculations16,17 indicate that the triflate an-
ion is closer to the copper(II) center than to the correspond-
ing silver(I) cation, whereas the silver(I) cation–dipole dis-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 934–943

939
L. M. Castelló et al.
PSP
Synthesis
Anhydrous solvents were freshly distilled under an argon atmosphere
and degassed by freeze–pump–thaw methodology. Aldehydes were
also distilled prior to use for the elaboration of the imino esters and
nitroalkenes. The substrates are known molecules and are easily pre-
pared.16,17 Copper salts were dried in a Kugelrohr apparatus and
stored under an argon atmosphere. All silver-mediated reactions
were run in the dark. Melting points were determined with a Reichert
Thermovar hot plate apparatus and are uncorrected. HPLC analyses
were performed with a JASCO-2000 series instrument equipped with
the indicated chiral column by using mixtures of n-hexane–isopropyl
alcohol as the mobile phase at 25 °C. Yields refer to isolated com-
pounds (after flash chromatography) estimated to be >95% pure as
determined by 1H NMR spectroscopic and HPLC analyses. Only the
structurally most important peaks of the IR spectra (recorded on a Ni-
colet 510 P-FT and on a Jasco FTIR 4100) are listed. 1H NMR (300
MHz) and 13C NMR (75 MHz) spectra were obtained on a Bruker AC-
300 using CDCl3 as solvent and Me4Si as internal standard, unless oth-
erwise stated. Low-resolution electron impact (EI) mass spectra were
obtained at 70eV on a Shimadzu QP-5000 and high-resolution mass
spectra were obtained on a Finnigan VG Platform. HRMS (EI) were re-
corded on a Finnigan MAT 95S. Microanalyses were performed on a
Perkin Elmer 2400 and a Carlo Erba EA1108.
1H NMR (300 MHz, CDCl3): δ = 2.71 (br s, 1 H, NH), 3.26 (s, 3 H, CH3),
4.35 (t, J = 7.8 Hz, 1 H, CHCO), 4.48 (d, J = 9.1 Hz, 1 H, CHPh), 4.73 (d,
J = 7.8 Hz, 1 H, CHPh), 5.19 (t, J = 8.0 Hz, 1 H, CHNO), 7.45–7.18 (m,
8 H, ArH), 7.56–7.52 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 51.8 (CH3), 53.7 (CHPh), 64.2 (CHCO),
67.5 (PhCHNH), 95.0 (CHNO2), 126.8, 127.8, 128.1, 128.7, 128.9, 129.0,
135.8, 137.6 (ArC), 171.8 (CO).
MS (EI): m/z (%) = 326 (0.1) [M]+, 279 (16), 220 (73), 193 (100), 178
(12), 115 (42).
Anal. Calcd for C18H18N2O4: C, 66.3; H, 5.6; N, 8.6. Found: C, 66.4; H,
5.3; N, 8.6.
(2S,3R,4R,5S)-Isopropyl 4-Nitro-3,5-diphenylpyrrolidine-2-car-
boxylate (4b)
Obtained according to P1.
Colorless needles (n-hexane–Et2O, 4:1); mp 130–132 °C; [α]D20 82.3 (c
1.02 CHCl3); >99:1 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–hex-
ane, 10:90; flow rate 1.0 mL/min): tR = 15.5 (major), 20.4 (minor) min.
IR (solid): 1265, 1551, 1731 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 0.58 (d, J = 6.3 Hz, 3 H, CH3), 1.06 (d, J =
6.3 Hz, 3 H, CH3), 2.75 (br s, 1 H, NH), 4.37 (dd, J = 8.9, 8.0 Hz, 1 H,
CHPh), 4.46 (d, J = 9.1 Hz, 1 H, CHCO), 4.65 [dt, J = 12.6, 6.3 Hz, 1 H,
CH(CH3)2], 4.75 (d, J = 8.3 Hz, 1 H, PhCHN), 5.20 (dd, J = 8.3, 8.3 Hz,
1 H, CHNO2), 7.19–7.30 (m, 5 H, ArH), 7.36–7.45 (m, 3 H, ArH), 7.54–
7.57 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 20.7 (CH3), 21.6 (CH3), 53.5 (CHPh), 64.1
(CHCO), 67.4 [CH(CH3)2], 69.1 (PhCHNH), 95.4 (CHNO2), 126.9, 128.1,
128.8, 128.9, 129.0, 129.4, 136.3, 137.6 (ArC), 170.8 (CO).
Copper-Catalyzed Synthesis of exo-Cycloadducts 4; General Proce-
dure 1 (P1)
To a solution of the chiral phosphoramidite (0.05 mmol) and Cu(OTf)2
(0.05 mmol) in anhydrous toluene (3 mL) under an argon atmosphere
was added a solution of imino ester (1 mmol) and nitroalkene (1
mmol) in toluene (5 mL). To the resulting suspension, Et3N (0.05
mmol, 7 μL) was added and the mixture was stirred at r.t. (25 °C) for
16–24 h. The crude reaction mixture was filtered through a small
Celite pad and the residue was purified by flash chromatography to
give the pure exo-cycloadducts. Solid products were recrystallized
from n-hexane–Et2O. Compounds 4a and 4f were also prepared on a 3
mmol scale, and the results were identical to those reported for the
model reaction.
MS (EI): m/z (%) = 356 (0.01) [M]+, 307 (10), 220 (100), 193 (80), 115
(28).
HRMS (EI): m/z calcd for C20H22N2O4 – NO2: 309.4021; found:
309.4028.
Anal. Calcd for C20H22N2O4: C, 67.8; H, 6.3; N, 7.9. Found: C, 67.4; H,
6.3; N, 8.3.
Silver-Catalyzed Synthesis of exo-Cycloadducts 4; General Proce-
dure 2 (P2-AgOTf) or (P2-AgOBz)
(2S,3S,4R,5S)-Methyl 4-Nitro-5-phenyl-3-(p-tolyl)-pyrrolidine-2-
carboxylate (4c)
To a solution of chiral phosphoramidite 1 (0.05 mmol) and AgX (0.05
mmol, triflate or benzoate) in anhydrous toluene (3 mL) under an ar-
gon atmosphere was added a solution of imino ester (1 mmol) and ni-
troalkene (1 mmol) in toluene (5 mL). To the resulting suspension,
Et3N (0.05 mmol, 7 μL) was added and the mixture was stirred at r.t.
(25 °C). The crude reaction mixture was filtered through a small
Celite pad and the residue was purified by flash chromatography to
give the pure exo-cycloadducts. Solid products were recrystallized
from n-hexane–Et2O. Compounds 4a and 4f were also prepared on a 3
mmol scale, and the results were identical to those reported for the
model reaction.
Obtained according to P2-AgOBz.
20
Colorless needles (n-hexane–Et2O, 5:1); mp 108–110 °C; [α]D 144.8
(c 1.0, CHCl3); 99:1 er; HPLC (Daicel Chiralpak AS-H; 2-propanol–
n-hexane, 5:95; flow rate 1.1 mL/min): tR = 23.2 (major), 24.2
(minor) min.
IR (neat): 1212, 1547, 1736, 2917 cm–1
1H NMR (300 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3C), 2.75 (br s, 1 H, NH),
3.32 (s, 3 H, OCH3), 4.35 (dd, J = 8.5 Hz, 1 H, CHTol), 4.48 (d, J = 9 Hz,
1 H, CHCO2Me), 4.76 (d, J = 8.3 Hz, 1 H, CHPh), 5.21 (dd, J = 8.2, 8.2 Hz,
1 H, CHNO2), 7.13 (m, 2 H, ArH), 7.40–7.45 (m, 4 H, ArH), 7.55–7.57
(m, 3 H, ArH).
.
(2S,3S,4R,5S)-Methyl 4-Nitro-3,5-diphenylpyrrolidine-2-carboxyl-
ate (4a)
13C NMR (75 MHz, CDCl3): δ = 21.0 (CH3C), 51.9 (CHC6H4Me), 53.5
(CH3), 64.2 (CHCO2Me), 67.5 (CHPh), 95.1 (CHNO2), 126.9 (CHCHCHC),
127.7, 129.0, 129.1, 129.4 (ArC), 132.53 (CH3C), 137.52 (CCHNH),
137.92 (CCHCHNH), 171.86 (CO).
Obtained ccording to P2-AgOBz.
Colorless needles (n-hexane–Et2O, 4:1); mp 104–105 °C; [α]D20 128 (c
1.1, CHCl3); >99:1 er; HPLC (Daicel Chiralpak AS-H; 2-propanol–hex-
ane, 20:80; flow rate 0.4 mL/min; 220 nm): tR = 25.2 (major), 27
(minor) min.
MS (EI): m/z (%) = 294 (9) [M+ – NO2], 234 (36), 207 (100), 129 (15).
HRMS (EI): m/z calcd for C19H20N2O4 – NO2: 294.1400; found:
IR (solid): 1265, 1551, 1731 cm–1
.
294.1399.
Anal. Calcd for C19H20N2O4: C, 67.0; H, 5.9; N, 8.2. Found: C, 67.3; H,
6.2; N, 7.9.
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(2S,3S,4R,5S)-Methyl 3-(4-Fluorophenyl)-4-nitro-5-phenylpyrroli-
dine-2-carboxylate (4d)
13C NMR (75 MHz, CDCl3): δ = 52.0 (CHC6H4Br), 53.0 (CH3), 64.1 (CH-
CO2Me), 67.4 (CHPh), 94.9 (CHNO2), 122.8 (CBr), 126.3, 126.9, 129.1,
129.1, 130.3, 131.2, 131.4, 137.5, 138.4 (ArC), 171.5 (CO).
MS (EI): m/z (%) = 360 (17) [M+-NO2], 358 (17), 298 (86), 270 (77), 192
(100), 117 (76).
Obtained according to P2-AgOBz.
Colorless prisms (n-hexane–Et2O, 5:1); mp 96.2–97 °C; [α]D20 108.1 (c
1, CHCl3); >99:1 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–n-hex-
ane, 10:90; flow rate 1.0 mL/min): tR = 21.0 (minor), 28.2 (major) min.
HRMS (EI): m/z calcd for C18H17BrN2O4 – NO2: 359.0338; found:
IR (solid): 1265, 1511, 1553, 1746 cm–1
.
359.0334.
1H NMR (300 MHz, CDCl3): δ = 2.58 (br s, 1 H, NH), 3.34 (s, 3 H, OCH3),
4.34–4.44 (m, 1 H, CHCHCO), 4.51 (d, J = 9.0 Hz, 1 H, CHCO2Me), 4.78
(d, J = 8.2 Hz, 1 H, CHPh), 5.16 (dd, J = 8.0, 8.0 Hz, 1 H, CHNO2), 6.99–
7.11 (m, 2 H, ArH), 7.23–7.32 (m, 2 H, ArH), 7.36–7.49 (m, 3 H, ArH),
7.58 (d, J = 7.5 Hz, 2 H, ArH).
Anal. Calcd for C18H17BrN2O4: C, 53.3; H, 4.2; N, 6.9. Found: C, 52.9; H,
4.1; N, 6.6.
(2S,3S,4R,5S)-Methyl 3-(4-Bromophenyl)-4-nitro-5-phenylpyrroli-
dine-2-carboxylate (4g)
13C NMR (75 MHz, CDCl3): δ = 51.9 (CHCHCO), 52.8 (CH3), 64.0 (CH-
CO), 67.3 (CHPh), 95.2 (CHNO2), 126.8, 128.9, 129.5, 129.6, 131.8,
137.6, 161.2, 163.4 (ArC), 171.6 (CO).
MS (EI): m/z (%) = 298 (10) [M+-NO2], 238 (55), 211 (100), 133 (19),
117 (18).
Obtained according to P2-AgOBz.
20
Colorless prisms (n-hexane–Et2O, 4:1); mp 89–91 °C; [α]D 96.0 (c
0.7, CHCl3); 99:1 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–
n-hexane, 10:90; flow rate 1.0 mL/min): tR = 19.4 (major), 26.8
(minor) min.
IR (solid): 1544, 1737, 2925 cm–1
.
HRMS (EI): m/z calcd for C18H17FN2O4 – NO2: 298.1181; found:
1H NMR (300 MHz, CDCl3): δ = 2.75 (br s, 1 H, NH), 3.34 (s, 3 H, CH3),
4.21–4.33 (m, 1 H, CHC6H4Br), 4.48 (d, J = 8.9 Hz, 1 H, CHCO2Me), 4.73
(d, J = 8.1 Hz, 1 H, CHPh), 5.08 (dd, J = 7.8, 7.8 Hz, 1 H, CHNO2), 7.12–
7.14 (m, 2 H, ArH), 7.37–7.44 (m, 5 H, ArH), 7.50–7.51 (m, 2 H, ArH).
298.1175.
Anal. Calcd for C18H17N2O4: C, 62.8; H, 5.0; N, 8.1. Found: C, 62.5; H,
5.2; N, 7.9.
(2S,3S,4R,5S)-Methyl 3-(2-Bromophenyl)-4-nitro-5-phenylpyrroli-
dine-2-carboxylate (4e)
13C NMR (75 MHz, CDCl3): δ = 52.0 (CHC6H4Br), 52.9 (CH3), 64.0 (CH-
CO2Me), 67.3 (CHPh), 95.1 (CHNO2), 122.3 (CBr), 126.8, 129.0, 129.1,
129.6, 132.0, 135.3, 137.6 (ArC), 171.5 (CO).
MS (EI): m/z (%) = 360 (15) [M+ – NO2], 359 (15), 300 (52), 298 (51),
273 (99), 271 (100), 219 (26), 192 (89), 117 (43), 115 (26).
Obtained according to P2-AgOBz.
Pale-yellow oil; [α]D20 57.7 (c 1.0 CHCl3); 95:5 er; HPLC (Daicel Chiral-
pak AD-H; 2-propanol–n-hexane, 10:90; flow rate 1.0 mL/min): tR
=
20.1 (major), 23.9 (minor) min.
HRMS (EI): m/z calcd for C18H17BrN2O4 – NO2: 359.0338; found:
IR (neat): 1549, 1736, 2926 cm–1
.
359.0330.
1H NMR (300 MHz, CDCl3): δ = 2.53 (br s, 1 H, NH), 3.29 (s, 3 H, CH3),
4.70 (d, J = 9.1 Hz, 1 H, CHPh), 4.83 (d, J = 8.6 Hz, 1 H, CHCO2Me), 4.98
(dd, J = 9.3, 9.3 Hz, 1 H, CHC6H4Br), 5.30 (dd, J = 9.0, 9.0 Hz, 1 H, CH-
NO2), 7.17 (dd, J = 7.7, 1.4 Hz, 1 H, ArH), 7.36–7.45 (m, 6 H, ArH), 7.55–
7.63 (m, 2 H, ArH).
Anal. Calcd for C18H17BrN2O4: C, 53.3; H, 4.2; N, 6.9. Found: C, 52.9; H,
4.2; N, 6.6.
(2S,3S,4R,5S)-Methyl 3-(Furan-2-yl)-4-nitro-5-phenylpyrrolidine-
2-carboxylate (4h).
13C NMR (75 MHz, CDCl3): δ = 51.9 (CHAr), 52.2 (CH3), 61.9 (CH-
CO2Me), 67.2 (CHPh), 92.9 (CHNO2), 127.1 (CBr), 127.2, 127.8, 128.6,
128.7, 129.1, 129.2, 133.3, 134.6, 137.3 (ArC), 172.2 (CO).
Obtained according to P2-AgOBz.
20
Yellow prisms (n-hexane–Et2O, 3:1); mp 60–62 °C; [α]D 89.0 (c 1,
CHCl3); 99:1 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–n-hexane,
10:90; flow rate 1.0 mL/min): tR = 15.4 (major), 18.8 (minor) min.
MS (EI): m/z (%) = 360 (28) [M+-NO2], 358 (28), 347 (11), 345 (11), 300
IR (neat): 1209, 1549, 1740, 2341, 2359 cm–1
.
(96), 298 (100), 273 (94), 271 (96), 219 (36), 192 (92).
1H NMR (300 MHz, CDCl3): δ = 2.77 (br s, 1 H, NH), 3.51 (s, 3 H, OCH3),
4.40 (d, J = 8.5 Hz, 1 H, CHCO), 4.50 (dd, J = 8.4, 7.2 Hz, 1 H, CHfuryl),
4.65 (d, J = 8.0 Hz, 1 H, CHPh), 5.23 (dd, J = 7.9, 7.0 Hz, 1 H, CHNO2),
6.20 (d, J = 3.1 Hz, 1 H, CCH), 6.29 (dd, J = 3.2, 1.8 Hz, 1 H, CCHCHCHO),
7.25–7.61 (m, 6 H, ArH and OCH).
HRMS (EI): m/z calcd for C18H17BrN2O4 – NO2: 359.0338; found:
359.0343.
Anal. Calcd for C18H17BrN2O4: C, 53.3; H, 4.2; N, 6.9. Found: C, 53.1; H,
4.1; N, 6.5.
(2S,3S,4R,5S)-Methyl 3-(3-Bromophenyl)-4-nitro-5-phenylpyrroli-
dine-2-carboxylate (4f)
13C NMR (75 MHz, CDCl3): 47.9 (CHfuryl), 52.2 (CH3), 63.2 (CHCO),
68.2 (CHPh), 93.6 (CHNO2), 108.4 (CCH), 110.5 (CCHCHCHO), 126.8,
128.6, 128.9, 137.2 (ArC), 142.8 (OCH), 148.9 (OC), 171.1 (CO).
Obtained according to P1.
MS (EI): m/z (%) = 270 (12) [M+ – NO2], 183 (100), 155 (10), 117 (12).
20
Pale-yellow prisms (n-hexane–Et2O, 5:1); mp 72–74 °C; [α]D = 60.5
(c 0.85, CHCl3); 94:6 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–
n-hexane, 5:95; flow rate 1.0 mL/min): tR = 41.5 (minor), 44.3
(major) min.
HRMS (EI): m/z calcd for C16H16N2O5: 316.1059; found: 316.1049.
(2S,3R,4S,5S)-Methyl 3-Cyclohexyl-4-nitro-5-phenylpyrrolidine-2-
carboxylate (4i)
IR (solid): 1547, 1735, 2928 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.73 (br s, 1 H, NH), 3.38 (s, 3 H, CH3),
4.33 (dd, J = 8.8, 7.8 Hz, 1 H, CHC6H4Br), 4.50 (d, J = 8.9 Hz, 1 H, CH-
CO2Me), 4.75 (d, J = 8.1 Hz, 1 H, CHPh), 5.13 (dd, J = 7.9, 7.9 Hz, 1 H,
CHNO2), 7.20–7.22 (m, 2 H, ArH), 7.41–7.55 (m, 5 H, ArH), 7.55–7.57
(m, 2 H, ArH).
Obtained according to P2-AgOBz.
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Synthesis
White needles (n-hexane–Et2O, 4:1); mp 125–127 °C; [α]D20 0.2 (c 1.0,
CHCl3); 52:48 er; HPLC (Chiralpak AD-H; 2-propanol–hexane, 10%;
flow rate 1.0 mL/min): tR = 14.5 (minor), 16.2 (major) min. exo-4i
(Chiralpak AD-H; 2-propanol–hexane, 10:90; flow rate 1.0 mL/min):
tR = 17.1 (major), 19.0 (minor) min.
HRMS (EI): m/z calcd for C22H26N2O4 – NO2: 321.1729; found:
321.1750.
Anal. Calcd for C22H26N2O4: C, 69.1; H, 6.9; N, 7.3. Found: C, 69.5; H,
6.8; N, 7.4.
IR (neat): 1202, 1544, 1737, 2927 cm–1
.
(2S,3R,4R,5S)-Methyl 2-Benzyl-4-nitro-3,5-diphenylpyrrolidine-2-
1H NMR (400 MHz, CDCl3): δ = 1.25–1.32 (m, 5 H, CH2), 1.58–1.67 [m,
1 H, CH(CH2)2], 1.72–1.86 (m, 5 H, CH2), 2.87 [td, J = 7, 2.4 Hz, 1 H,
CHCH(CH2)2], 3.28 (dd, J = 11.5, 10.7 Hz, 1 H, NH), 3.83 (m, 1 H, CH-
CO2Me), 3.86 (s, 3 H, Me), 4.47 (dd, J = 12.3, 5.9 Hz, 1 H, CHPh), 5.11
(dd, J = 5.9, 2.4 Hz, 1 H, CHNO2), 7.26–7.35 (m, 5 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 26.13 (CH2CH2CH2CH), 29.94 (2 ×
CH2CH2CH2CH), 31.51 (2 × CH2CH2CH2CH), 39.73 (CH2CH2CH2CH),
52.65 (CHCy), 57.09 (CH3), 63.10 (CHCO2Me), 67.73 (CHPh), 93.33
(CHNO2), 126.17, 128.46, 128.65, 134.26 (ArC), 172.38 (CO).
carboxylate (4l)
Obtained according to P1.
20
Colorless oil; [α]D = 25.2 (c 1.0, CHCl3); >99:1 er; HPLC (Daicel Chi-
ralpak AD-H; 2-propanol–n-hexane, 10:90; flow rate 1.0 mL/min):
tR = 20.8 (minor), 30.1 (major) min.
IR (neat): 1208, 1547, 1723, 2946 cm–1
1H NMR (300 MHz, CDCl3): δ = 2.49 (br s, 1 H, NH), 3.22 (s, 3 H, OCH3),
3.32 (d, J = 13.6 Hz, 1 H, CH2), 3.42 (d, J = 13.5 Hz, 1 H, CH2), 4.15 (d, J =
9.7 Hz, 1 H, CHCCC), 4.67 (d, J = 9.0 Hz, 1 H, CHPh), 5.23 (dd, J = 9.4,
9.4 Hz, 1 H, CHNO2), 7.15–7.56 (m, 15 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 42.8 (CH2), 51.9 (CHPh), 60.3 (CH3), 65.8
(NCHPh), 73.6 (qC), 95.1 (CHNO2), 127.0, 127.1, 127.9, 128.3, 128.3,
128.4, 129.0, 129.1, 130.5, 135.8, 136.0, 137.5 (ArC), 173.42 (CO).
.
MS (EI): m/z (%) = 285 (13) [M+ – NO2], 273 (16), 226 (82), 144 (100),
117 (28).
HRMS (EI): m/z calcd for C18H24N2O4: 332.3934; found: 332.3927.
(2S,3S,4S,5S)-Methyl 2-Methyl-4-nitro-3,5-diphenylpirrolidine-2-
carboxylate (4j)
MS (EI): m/z (%) = 326 (19) [M+ – Bn], 325 (97), 279 (20), 278 (100),
246 (76), 219 (41), 193 (20), 115 (29).
Obtained according to P2-AgOTf.
HRMS (EI): m/z calcd for C25H24N2O4 – CO2Me: 357.1608; found:
357.1604.
Yellow oil; [α]D20 –10.7 (c 1, CHCl3); 55:45 er; HPLC (Chiralpak AD-H;
2-propanol–hexane, 10:90; flow rate 1.0 mL/min): tR = 9.3 (minor),
15.6 (major) min. exo-4j (Chiralpak AD-H; 2-propanol–n-hexane,
10:90; flow 1.0 mL/min): tR = 9.1 (minor), 17.4 (major) min.
(2S,3S,4R,5S)-Methyl 4-Nitro-3-phenyl-5-(2-tolyl)pyrrolidine-2-
carboxylate (4m)
IR (neat): 1257, 1549, 1731 cm–1
.
Obtained according to P2-AgOBz.
1H NMR (300 MHz, CDCl3): δ = 1.19 (s, 3 H, CCH3), 3.25 (br, 1 H, NH),
3.86 (s, 3 H, CO2CH3), 4.52 (d, J = 6.1 Hz, 1 H, CHC), 5.08 (d, J = 7.4 Hz,
1 H, CHN), 5.65 (dd, J = 7.4, 6.1 Hz, 1 H, CHNO2), 7.23–7.49 (m, 10 H,
ArH).
13C NMR (75 MHz, CDCl3): δ = 22.0 (CCH3), 52.9 (CHC), 56.9 (OCH3),
64.9 (CHN), 68.8 (CCH3), 95.6 (CHNO2), 126.8 (ArC), 128.0 (ArC), 128.5
(ArC), 128.6 (ArC), 128.7 (ArC), 128.8 (ArC), 135.3 (ArC), 135.5 (ArC),
174.7 (CO).
Pale-yellow needles (n-hexane–Et2O, 5:1); mp 71–72 °C; [α]D20 108.2
(c 0.3, CHCl3); 95:5 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–
n-hexane, 10:90; flow rate 1.0 mL/min): tR = 20.4 (minor), 25.3
(major) min.
IR (solid): 1213, 1548, 1736 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.38 (s, 3 H, CCH3), 2.55 (br s, 1 H, NH),
3.28 (s, 3 H, OCH3), 4.43 (dd, J = 10.1, 7.1 Hz, 1 H, CHPh), 4.50 (d, J =
9.4 Hz, 1 H, CHCO), 5.10 (d, J = 8.8 Hz, 1 H, CHTol), 5.34 (dd, J = 8.7,
8.7 Hz, 1 H, CHNO2), 7.20–7.37 (m, 9 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 19.2 (CCH3), 51.8 (CHPh), 54.0 (OCH3),
63.3 (CHCO), 64.0 (CHTol), 93.8 (CHNO2), 125.6, 126.8, 127.7, 128.2,
128.6, 128.7, 130.9, 135.9, 135.6, 137.1 (ArC), 172.1 (CO).
MS (EI): m/z (%) = 281 (45) [M+ – NO2], 234 (100), 219 (17), 193 (37),
115 (21).
HRMS (EI): m/z calcd for C19H20N2O4: 340.1422, found: 281.1428.
(2S,3R,4R,5S)-Methyl 2-Isobutyl-4-nitro-3,5-diphenylpyrrolidine-
2-carboxylate (4k)
MS (EI): m/z (%) = 359 (21) [M+ – NO2], 340 (2), 293 (12), 234 (61), 207
(100), 191 (12), 131 (20), 115 (25).
Obtained according to P1.
Anal. Calcd for C19H20N2O4: C, 67.0; H, 5.9; N, 8.2. Found: C, 66.9; H,
5.5; N, 8.4.
Colorless prisms (n-hexane–Et2O, 4:1); mp 105–107 °C; [α]D20 59.0 (c
1, CHCl3); 99:1 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–
n-hexane, 10:90; flow rate 1.0 mL/min): tR = 9.9 (major), 14.5
(minor) min.
(2S,3S,4R,5S)-Methyl 4-Nitro-3-phenyl-5-(3-tolyl)pyrrolidine-2-
carboxylate (4n)
IR (solid): 1230, 1545, 1730 cm–1
.
Obtained according to P2-AgOBz.
1H NMR (300 MHz, CDCl3): δ = 0.81 (d, J = 6.7 Hz, 3 H, CH3), 1.04 (d, J =
6.7 Hz, 3 H, CH3), 1.57 (br s, 1 H, NH), 1.79 (td, J = 13.3, 6.7 Hz, 1 H,
CH), 1.96 (dd, J = 13.9, 5.7, Hz, 1 H, CH2), 2.15 (dd, J = 13.9, 6.9 Hz, 1 H,
CH2), 3.19 (s, 3 H, CH3), 4.00 (d, J = 9.9 Hz, 1 H, CHC), 4.75 (d, J = 9.2 Hz,
1 H, CHNH), 5.23 (dd, J = 9.2, 9.2 Hz, 1 H, CHNO2), 7.14–7.22 (m, 2 H,
ArH), 7.25–7.47 (m, 6 H, ArH), 7.54–7.61 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 22.8, 24.3 (2 × CH3), 25.6 (CH2), 46.2
(CHCH2), 51.8, 62.7 (2 × CHPh), 66.1 (CCO2), 73.2, 94.9 (CHNO2), 126.9,
127.7, 128.2, 128.6, 128.9, 129.1, 135.6, 137.2 (ArC), 174.5 (CO).
Pale-yellow prisms (n-hexane–Et2O, 5:1); mp 56–58 °C; [α]D20 99.8 (c
0.74, CHCl3); 95:5 er (after recrystallization). HPLC (Daicel Chiralpak
AD-H; 2-propanol–n-hexane, 10:90; flow rate 1.0 mL/min): tR = 15.1
(minor), 19.9 (major) min.
IR (solid): 1213, 1265, 1549, 1737 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.22 (br s, 1 H, NH), 2.39 (s, 3 H, CH3C),
3.30 (s, 3 H, OCH3), 4.40 (dd, J = 8.7, 8.7 Hz, 1 H, CHPh), 4.53 (d, J =
9.2 Hz, 1 H, CHCO), 4.77 (d, J = 8.5 Hz, 1 H, CHTol), 5.26 (dd, J = 8.4,
8.4 Hz, 1 H, CHNO2), 7.19–7.38 (m, 9 H, ArH).
MS (EI): m/z (%) = 337 (25) [M+ – NO2], 193 (100), 115 (20).
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Synthesis
13C NMR (75 MHz, CDCl3): δ = 21.5 (CCH3), 52.0 (CHPh), 53.7 (OCH3),
64.0 (CHCO), 67.4 (CHTol), 94.5 (CHNO2), 123.9, 127.6, 127.8, 128.2,
128.4, 128.8, 129.0, 129.4, 129.9, 138.9 (ArC), 171.6 (CO).
Pale-yellow oil; [α]D20 65.2 (c 1.2, CHCl3); 99:1 er; HPLC (Daicel Chiral-
pak AD-H; 2-propanol–n-hexane, 10:90; flow rate 1.0 mL/min): tR
=
16.9 (minor), 19.4 (major) min.
MS (EI): m/z (%) = 294 (21) [M+ – NO2], 234 (75), 207 (100), 131 (20),
IR (neat): 1221, 1509, 1548, 1736 cm–1
.
115 (29).
1H NMR (300 MHz, CDCl3): δ = 2.62 (br s, 1 H, NH), 3.30 (s, 3 H, OCH3),
4.41 (dd, J = 8.2, 8.2 Hz, 1 H CHPh), 4.50 (d, J = 9.1 Hz, 1 H, CHCO), 4.77
(d, J = 8.3 Hz, 1 H, CHN), 5.21 (dd, J = 8.2, 8.2 Hz, 1 H, CHNO2), 7.07–
7.16 (m, 2 H, ArH), 7.24–7.38 (m, 5 H, ArH), 7.56–7.62 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 51.8 (CHPh), 53.4 (OCH3), 64.0 (CHCO),
66.8 (CHN), 94.9 (CHNO2), 115.9, 127.8, 128.2, 128.7, 128.8, 133.7,
135.7, 161.7, 164.2 (ArC), 171.9 (CO).
HRMS (EI): m/z calcd for C19H20N2O4 – NO2: 294.1572; found:
294.1565.
Anal. Calcd for C19H20N2O4: C, 67.0; H, 5.9; N, 8.2. Found: C, 67.2; H,
6.0; N, 8.2.
(2S,3S,4R,5S)-Methyl 4-Nitro-3-phenyl-5-(4-tolyl)pyrrolidine-2-
carboxylate (4o)
MS (EI): m/z (%) = 297 (14) [M+ – NO2], 238 (74), 211 (100), 135 (23),
133 (20), 115 (21).
Obtained according to P2-AgOTf.
Pale-yellow prisms (n-hexane–Et2O, 8:1); mp 90–92 °C; [α]D20 81.9 (c
0.72, CHCl3); 97:3 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–
n-hexane, 10:90; flow rate 1.0 mL/min): tR = 22.3 (minor), 28.0
(major) min.
HRMS (EI): m/z calcd for C18H17FN2O4 – NO2: 297.1181; found:
297.1175.
(2S,3S,4R,5S)-Methyl 5-(4-Bromophenyl)-4-nitro-3-phenylpyrroli-
IR (solid): 1220, 1545, 1725 cm–1
.
dine-2-carboxylate (4r)
Obtained according to P2-AgOTf.
1H NMR (300 MHz, CDCl3): δ = 2.30 (s, 3 H, CH3C), 2.65 (br s, 1 H, NH),
3.21 (s, 3 H, OCH3), 4.29 (dd, J = 9.0, 9.0 Hz, 1 H, CHPh), 4.41 (d, J =
9.1 Hz, 1 H, CHCO), 4.64 (d, J = 8.4 Hz, 1 H, CHTol), 5.12 (dd, J = 8.1,
8.1 Hz, 1 H, CHNO2), 7.14–7.38 (m, 9 H, ArH).
Colorless prisms (n-hexane–Et2O, 3:1); mp 149–151 °C; [α]D20 66.4 (c
1, CHCl3); 99:1 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–n-hex-
ane, 10:90; flow rate 1.0 mL/min): tR = 23.6 (minor), 25.5 (major) min.
13C NMR (75 MHz, CDCl3): δ = 21.2 (CCH3), 51.8 (CHPh), 53.8 (OCH3),
64.2 (CHCO), 67.5 (CHTol), 95.1 (CHNO2), 126.9, 127.8, 128.1, 128.8,
129.2, 129.7, 134.5, 135.9 (ArC), 171.9 (CO).
MS (EI): m/z (%) = 294 (10) [M+ – NO2], 293 (25), 234 (85), 207 (100),
191 (16), 131 (26), 115 (26).
IR (solid): 1213, 1547, 1738 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 2.73 (br s, 1 H, NH), 3.31 (s, 3 H, OCH3),
4.40 (dd, J = 8.7 Hz, 1 H, CHPh), 4.53 (d, J = 9.1 Hz, 1 H, CHCO), 4.80 (d,
J = 8.4 Hz, 1 H, CHN), 5.23 (dd, J = 8.4, 8.4 Hz, 1 H, CHNO2), 7.17–7.29
(m, 2 H, ArH), 7.31–7.33 (m, 3 H, ArH), 7.44–7.51 (m, 2 H, ArH), 7.55–
7.61 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): δ = 52.0 (CHPh), 53.2 (OCH3), 63.8 (CHCO),
66.4 (CHN), 94.1 (CHNO2), 123.3, 127.7, 127.8, 128.9, 129.4, 132.3,
132.4, 134.9 (ArC), 171.4 (CO).
HRMS (EI): m/z calcd for C19H20N2O4 – NO2: 294.1572; found:
294.1562.
Anal. Calcd for C19H20N2O4: C, 67.0; H, 5.9; N, 8.2. Found: C, 66.8; H,
5.8; N, 7.9.
MS (EI): m/z (%) = 359 (21) [M+ – NO2], 357 (22), 300 (65), 298 (68),
273 (97), 271 (100), 219 (30), 218 (14), 197 (15), 195 (21), 192 (96),
191 (35), 115 (17), 114 (32).
(2S,3S,4R,5S)-Methyl 5-(4-Methoxyphenyl)-4-nitro-3-phenylpyr-
rolidine-2-carboxylate (4p)
HRMS (EI): m/z calcd for C18H17BrN2O4 – NO2: 359.0343; found:
Obtained according to P2-AgOTf.
359.0334.
20
Yellow oil; [α]D 95.2 (c 1.9, CHCl3); 98:2 er; HPLC (Chiralpak AD-H;
Anal. Calcd for C18H17BrN2O4: C, 53.3; H, 4.2; N, 6.9. Found: C, 52.9; H,
4.0; N, 6.8.
2-propanol–n-hexane, 30:70; flow rate 1.0 mL/min): tR = 19.9 (mi-
nor), 25.2 (major) min.
IR (neat): 1177, 1213, 1248, 1513, 1547, 1735 cm–1
.
(2S,3S,4R,5S)-Methyl 5-(Naphth-2-yl)-4-nitro-3-phenylpyrroli-
dine-2-carboxylate (4s)
1H NMR (300 MHz, CDCl3): δ = 3.29 (s, 3 H, PhOCH3), 3.83 (s, 3 H,
CO2CH3), 4.41 (dd, J = 8.4, 8.4 Hz, 1 H, CHPh), 4.50 (d, J = 9.2 Hz, 1 H,
CHCO), 4.74 (d, J = 8.5 Hz, 1 H, CHN), 5.22 (dd, J = 8.4, 8.4 Hz, 1 H,
CHNO2), 6.95 (d, J = 8.7 Hz, 2 H, ArH), 7.19–7.36 (m, 5 H, ArH), 7.50 (d,
J = 8.7 Hz, 2 H).
13C NMR (101 MHz, CDCl3): δ = 172.01, 160.07, 135.88, 129.53,
128.77, 128.14, 127.82, 127.70, 114.46, 113.86, 95.07, 77.34, 77.02,
76.70, 67.36, 64.18, 55.33, 53.67, 51.81.
Obtained according to P2-AgOTf.
20
Colorless prisms (n-hexane–Et2O, 5:1); mp 76–78 °C; [α]D 46.0 (c
0.6, CHCl3); 92:8 er; HPLC (Daicel Chiralpak AD-H; 2-propanol–
n-hexane, 10:90; flow rate 1.0 mL/min): tR = 19.9 (minor), 23.0
(major) min.
IR (solid): 1550, 1743 cm–1
.
MS (EI): m/z (%) = 309 (35) [M+ – NO2], 250 (100), 223 (88), 207 (39),
147 (47), 115 (28).
1H NMR (300 MHz, CDCl3): δ = 2.83 (br s, 1 H, NH), 3.33 (s, 3 H, OCH3),
4.46 (dd, J = 8.7, 8.7 Hz, 1 H CHPh), 4.60 (d, J = 9.1 Hz, 1 H, CHCO), 5.02
(d, J = 8.5 Hz, 1 H, CHNaph), 5.41 (dd, J = 8.4, 8.4 Hz, 1 H, CHNO2),
7.26–7.36 (m, 5 H, ArH), 7.51–7.53 (m, 2 H, ArH), 7.73 (dd, J = 8.5,
1.8 Hz, 1 H, ArH), 7.72–7.9 (m, 4 H, ArH).
Anal. Calcd for C19H20N2O5: C, 64.0; H, 5.7; N, 7.9. Found: C, 63.8; H,
5.8; N, 7.9.
13C NMR (75 MHz, CDCl3): δ = 52.0 (CHPh), 53.5 (OCH3), 64.0 (CHCO),
67.4 (CHNf), 94.1 (CHNO2), 123.9, 126.7, 127.8, 128.2, 128.4, 128.5,
128.6, 128.9, 129.3, 129.4, 133.2, 133.6, 134.9, 135.9 (ArC), 171.8 (CO).
(2S,3S,4R,5S)-Methyl 5-(4-Fluorophenyl)-4-nitro-3-phenylpyrroli-
dine-2-carboxylate (4q)
Obtained according to P2-AgOTf.
MS (EI): m/z (%) = 329 (38) [M+ – NO2], 271 (19), 270 (88), 244 (20),
243 (100), 227 (14), 167 (34), 165 (27), 115 (26).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 934–943

943
L. M. Castelló et al.
PSP
Synthesis
HRMS (EI): m/z calcd for C22H20N2O4: 376.1442; found: 376.1432.
(6) For recent reviews of asymmetric 1,3-DC, see: (a) Pellissier, H.
Tetrahedron 2007, 63, 3235. (b) Nájera, C.; Sansano, J. M. Top.
Heterocycl. Chem. 2008, 12, 117. (c) Stanley, L. M.; Sibi, M. P.
Chem. Rev. 2008, 108, 2887. (d) Álvarez-Corral, M.; Muñoz-
Dorado, M.; Rodríguez-García, I. Chem. Rev. 2008, 108, 3174.
(e) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132.
(f) Nájera, C.; Sansano, J. M.; Yus, M. J. Braz. Chem. Soc. 2010, 21,
377. (g) Kissane, M.; Maguire, A. R. Chem. Soc. Rev. 2010, 39, 845.
(h) Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784.
(i) Adrio, J.; Carretero, J. C. Chem. Commun. 2014, 50, 12434.
(7) The exo descriptor refers the approach of the dipolarophile in
which the electron-withdrawing group of the 1,3-dipole and
the nitro group are orientated in the opposite direction.
(8) Arai, T.; Mishiro, A.; Yokoyama, N.; Suzuki, K.; Sato, H. J. Am.
Chem. Soc. 2010, 132, 5338.
Anal. Calcd for C22H20N2O4: C, 70.2; H, 5.4; N, 7.4. Found: C, 69.8; H,
5.5; N, 7.4.
Acknowledgment
This work has been supported by the Spanish Ministerio de Ciencia e
Innovación (MICINN) (Consolider INGENIO 2010 CSD2007-00006,
CTQ2010-20387) and Ministerio de Economía
y Competitvidad
(MINECO) (CTQ2013-43446P, CTQ2014-51912-REDC), FEDER, Gener-
alitat Valenciana (PROMETEO/2009/039 and 2014/017), and by the
University of Alicante. L.M.C. thanks the MICINN for a FPI fellowship.
Financial support was also provided by the MICINN and FEDER (proj-
ects CTQ2010-16959/BQU), the University of the Basque Country
(UPV/EHU, UFI11/22QOSYC) and the Basque Government (GV/EJ,
grant IT-324-07). The authors thank the SGI/IZO-SGIker UPV/EHU and
the DIPC for generous allocation of computational resources.
(9) Yan, X.-X.; Peng, Q.; Zhang, Y.; Hong, W.; Hou, X.-L.; Wu, Y.-D.
Angew. Chem. Int. Ed. 2006, 45, 1979.
(10) Grigg, R.; Kilner, C.; Sarker, M. A. B.; Orgaz de la Cierva, C.;
Dondas, H. A. Tetrahedron 2008, 64, 8974.
(11) Silver-catalyzed processes have been attempted, but these
resulted in low diastereoselectivities and moderate to low, see:
(a) Shimizu, K.; Ogata, K.; Fukuzawa, S.-I. Tetrahedron Lett. 2010,
51, 5068. (b) Gu, X.; Xu, Z.-J.; Lo, V. K.-Y.; Che, C.-M. Synthesis
2012, 44, 3307.
References
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 934–943