Binap-silver salts as chiral catalysts for the enantioselective 1,3-dipolar cycloaddition of azomethine ylides and alkenes

Article abstract of DOI:10.1016/j.tetasy.2012.10.015

Binap-AgSbF₆ catalyzed 1,3-dipolar cycloadditions between azomethine ylides and electrophilic alkenes are described and compared with analogous transformations mediated by other Binap-silver(I) salt complexes. Maleimides and 1,2-bis(phenylsulfo

Full text of DOI:10.1016/j.tetasy.2012.10.015

Tetrahedron: Asymmetry 23 (2012) 1596–1606
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Tetrahedron: Asymmetry
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Binap-silver salts as chiral catalysts for the enantioselective 1,3-dipolar
cycloaddition of azomethine ylides and alkenes
Juan Mancebo-Aracil a, María Martín-Rodríguez a, Carmen Nájera a, José M. Sansano a, , Paulo R. R. Costa b,
⇑
Evanoel Crizanto de Lima b, Ayres G. Dias b
a Departamento de Química Orgánica e Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias, Universidad de Alicante, E-03080 Alicante, Spain
b Laboratório de Química Biorgânica, Núcleo de Pesquisas de Produtos Naturais, Centro de Ciencias da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária,
21941-590 Rio de Janeiro, Brazil
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 October 2012
Accepted 12 October 2012
Binap-AgSbF6 catalyzed 1,3-dipolar cycloadditions between azomethine ylides and electrophilic alkenes
are described and compared with analogous transformations mediated by other Binap-silver(I) salt com-
plexes. Maleimides and 1,2-bis(phenylsulfonyl)ethylene are suitable dipolarophiles for obtaining very
good enantioselectivities, even better values are generated by a multicomponent version. There are some
very interesting applications of the disulfonylated cycloadducts in the total synthesis of cis-2,5-disubsti-
tuted pyrrolidines, precursors of natural products, or valuable intermediates in the synthesis of antiviral
compounds.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
responsible for the enantiodiscrimination, the perchlorate anion
was weakly bonded to the central metal (2.41 Å).5b Based on these
Privileged chiral ligands1 are very efficient enantiomerically
pure molecules, incorporating a few core structures, and are used
as references for chemists working in the field of asymmetric catal-
ysis. Binap is one such example of this concept, which has been
used with ruthenium, rhodium, and palladium in many enantiose-
lective organic transformations.1 This chiral diphosphine was also
tested in the catalytic enantioselective 1,3-dipolar cycloaddition2
(1,3-DC) of azomethine ylides (derived from imino esters) and
electrophilic alkenes.3 In the first substoichiometric catalytic enan-
tioselective 1,3-DC of azomethine ylides reported by Zhang et al.,4
the combination of (S)-Binap-AgOAc (3 mol %) showed low ee val-
ues when dipoles derived from imino esters and dimethyl maleate
were used (up to 13% ee). The change of the counterion of the com-
plex was critical for the success of the reaction. (S)-Binap-AgClO4 1,
a very stable and recyclable complex, is very appropriate for the
1,3-DC of imino esters and maleimides (up to >99% ee).5 In addition
to silver(I), copper(I)6 and (II),7 gold(I)8–10 chiral Binap complexes
have been studied as catalysts in analogous 1,3-DCs using several
dipolarophiles.
data, we thought that the weakly coordinating hexafluoroantimo-
nate anion could be used as an alternative to perchlorate as cata-
lyst for this particular cycloaddition. An identical semi-empirical
model, but incorporating SbFꢀ6 instead of ClO4ꢀ, showed a longer
distance (2.46 Å) between the central silver atom and its counter-
ion.11 Herein we report how important this small distance differ-
ence is during the enantioselective catalyzed 1,3-DC between
imino esters and electron-deficient alkenes, and the scope of (S)-
Binap-AgSbF6 catalyst 2 versus other Binap complexes formed with
different silver(I) salts.12
PPh2
PPh2
PPh2
PPh2
·AgSbF6
·AgClO4
1
2
(Sa)-
(Sa)-
The reluctance of chemical companies to use perchlorate salts,
prompted us to search another poorly coordinated anion in order
to ensure or even improve upon the results obtained from using
the (S)-Binap-AgClO4 complex. Computational studies of this asyn-
chronous transformation also revealed that in the transition state
2. Results and discussion
2.1. Optimization of the reaction conditions
The model reaction selected between methyl benzylideneimi-
noglycinate 3aa and N-methylmaleimide (NMM) 4a was
performed in toluene at room temperature using 5 mol % of
⇑
Corresponding author. Tel./fax: +34 965903549.
E-mail address: jmsansano@ua.es (J.M. Sansano).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.10.015

J. Mancebo-Aracil et al. / Tetrahedron: Asymmetry 23 (2012) 1596–1606
1597
(S)-Binap and 5 mol % of AgI salt as the catalyst precursor
(Scheme 1 and Table 1). The reaction was carried out with equimo-
lar amounts of both (Sa)-Binap and several oxygenated silver(I)
salts with a weakly coordinating anion, such as AgOAc, AgOTfa
(Tfa = trifluoroacetate), AgOTf (Tf = trifluoromethanesulfonate)
AgNO3, or AgBF4, (5 mol %). When AgOAc was used, excellent re-
sults for compound 5aa were obtained by using triethylamine
rather than DABCO (Table 1, entries 1 and 2), but the crude reac-
tion product was not very clean. Silver trifluoroacetate also gave
excellent results for cycloadduct 5aa, but again the reaction crude
product was slightly impure (1H NMR) (Table 1, entry 3). This chi-
ral catalyst can work as an internal base, with the trifluoroacetate
anion being the most effective (Table 1, entry 4). In this case, the
enantioselection was excellent, although the reaction was slightly
slower and a few impurities were detected in the crude product.
The bifunctional behavior of acetate derived catalyst was not as
effective as the Tfa complex, affording lower yields of the cycload-
duct 5aa. Silver triflate afforded excellent enantioselection (99% ee)
but with a higher amount of the exo-diastereoisomer (Table 1, en-
try 5). The rest of the silver salts described in Table 1 were not able
to promote the 1,3-DC in the absence of an external base. AgBF4
and AgNO3 catalyzed the reactions but afforded lower chemical
yields, diastereo- and enantioselections (Table 1, entries 6 and 7).
Using AgSbF6 and Et3N as the base, the enantiomerically en-
riched cycloadduct 5aa (>99% ee) was isolated in very good yield
(90%) and with excellent endo-selectivity.13 This result, and the re-
sult obtained when the reaction was performed with AgClO4, were
almost identical (Table 1, entry 8). Other solvents, such as Et2O,
DCM, THF, and MeCN, were tested but neither the purity nor the
diastereo-/enantioselection of the final product 5aa were improved
upon. The 5 mol % catalyst loading was the most appropriate be-
cause the reaction became slower when a 3 mol % charge was used
instead (Table 1, entry 9). Bases such as 1,4-diazabicy-
clo[2.2.2]octane (DABCO) and diazabicyclo[5.4.0]undec-7-ene
(DBU) were evaluated in this reaction and afforded lower enantios-
elections with some unidentified products in the crude mixture
(Table 1, entries 10, and 11). However, when the reaction was car-
ried out with N,N-diisopropylethylamine (DIPEA), it was com-
pletely equivalent to the reaction carried out with triethylamine
(Table 1, compare entries 8 and 10). Using a different stoichiome-
try to 1:1 (Sa)-Binap:silver salt, such as 2:1 or 1:2, afforded lower
enantioselections and larger amounts of the exo-diastereoisomer
in both situations (Table 1, entries 13 and 14).
Thus it can be seen that when the reaction is carried out with
silver hexafluoroantimonate in the presence of a small amount of
thiethylamine, good chemical yields, excellent enantioselection
(>99%), and a very clean material that did not require any addi-
tional purification were obtained.
2.2. Characterization of the catalytic species
N
O
O
N
i
O
O
The reaction was also carried out with the isolated complex
formed by the addition of equimolar amounts of (S)-Binap and
AgSbF6; obtaining almost identical results to those described in
entry 8 of the Table 1. However, this AgSbF6 derived complex
became darker upon standing since it was much more unstable
than the identical complex generated by AgClO4. As a result, the
in situ generation of the catalytic complex, which avoided light
exposure during the whole process was preferred for all of the
transformations described herein.
Ph
N
CO2Me
3aa
Ph
CO2Me
N
H
4a
endo-5aa
Scheme 1. Reagents and conditions: (i) (Sa)-Binap (5 mol %), AgI salt (5 mol %), base
(5 mol %), toluene, 25 °C, 16 h.
The presumed catalytic monomeric species in the solution were
identical to those reported previously with triflate14 (Fig. 1) or
perchlorate anions.5b Complexes formed from silver triflate and
(R)- or (S)-Binap, were isolated at different temperatures and fur-
ther characterized by X-ray diffraction analysis by Yamamoto
et al. These studies revealed that the mixture of structures 6–8
Table 1
Optimization of the reaction of imino esters 3aa with NMM 4a
AgI salt
Base
Product 5aaa
endo:exoc
Yieldb (%)
eed (%)
1
2
3
4
5
6
7
8
AgOAc
AgOAc
AgOTfa
AgOTfa
AgOTf
AgNO3
AgBF4
Et3N
DABCO
Et3N
—
89
85
89
78
88
65
77
90 (89)
78 (80)
89 (89)
87 (88)
87 (80)
90 (90)
90 (91)
>98:2
>95:5
>98:2
>98:2
90:10
85:11
89:11
>98:2 (>98:2)
>98:2 (>98:2)
>98:2 (>98:2)
>90:10 (>90:10)
>90:10 (>90:10)
90:10 (90:10)
>98:2 (>98:2)
99e
94
99e
TfO-
99e
P
P
P
P
Et3N
Et3N
Et3N
Et3N
Et3N
DIPEA
DABCO
DBU
Et3N
Et3N
99
67
72
Ag+
*
P
P
P
P
AgOTf
AgSbF6
>99 (>99)
>99 (>99)
>99 (>99)
94 (92)e
90 (91)e
96 (98)e
56 (<50)e
f
PPh2
PPh2
9
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
=
6
*
*
10
11
12
13
14
P
AgOTf
-
O
O
O
g
Ag+
S
8
*
h
(R)-Binap
CF3
P
a
Conversions were higher than 95% (determined by 1H NMR spectroscopy of the
7
crude product).
b
Isolated yield after recrystallization. The yields of the analogous reaction per-
-
formed with AgClO4 are given in parenthesis.5
SbF6
P
P
c
Determined by 1H NMR spectroscopy of the crude product.
Determined by HPLC of the crude product employing chiral columns (Daicel
O
d
OMe
Ag+
*
Chiralpak AS). The ee of the analogous reaction performed with AgClO4 is given in
parenthesis.5Identical ee values were determined for the purified product in both
reaction sets.
N
e
Ph
Some unidentified impurities were detected in the crude product.
f
Reaction performed with 3 mol % of the catalyst.
9
g
Reaction performed with 2 equiv of Binap and 1 equiv of AgI salt.
h
Reaction performed with 1 equiv of Binap and 2 equiv of AgI salt.
Figure 1. [(R)-Binap]AgOTf complexes and catalyst-dipole complex 9.

1598
J. Mancebo-Aracil et al. / Tetrahedron: Asymmetry 23 (2012) 1596–1606
were in equilibrium, and at room temperature, the 1:1 complex 7
was the most abundant system (Fig. 1).14
The absolute configuration of these products 5, as well as all of
the compounds described herein, was determined by comparison
with the known data reported in the literature for identical
molecules.
The 1:1 (R)- or (S)-Binap and AgSbF6 complexes were character-
ized by ESI-MS experiments and 31P NMR. ESI-MS showed an M++1
signal at 730, and 732 corresponding to the monomeric Binap-AgI
complex (Sa)-2 and a tiny one at 1352 and 1354 corresponding to
the 2:1 Binap:AgSbF6 (similar to complex 6). The 31P NMR (CDCl3)
spectra of 1:1 (R)- or (S)-Binap and AgSbF6 (using 10% aqueous
polyphosphoric acid as an internal reference) afforded signals at
15.31 ppm and 15.45 ppm (2d, J = 242 Hz) (15.26, and 15.35 ppm
for the Binap-AgClO4 complex).
Calculations performed with the Binap-AgClO4 model, which
were comparable with the Binap-AgSbF6 model, supported the idea
that NMM was the best dipolarophile due to coordination of the
nitrogen atom to the metal center. The TS responsible for the enan-
tiodiscrimination was as expected, asynchronous. The steric inter-
action between one of the phenyl groups of the phosphine moiety
of the chiral ligand and the dipolarophile can be considered to be
crucial for explaining the experimental findings and providing a
rationale for the observed excellent asymmetric induction.
When different N-substituted maleimides were compared, we
found that N-ethylmaleimide (NEM) did not give any difference
with respect to those results obtained with the (S)-Binap-AgClO4.
However, when the reaction was carried out with N-phenylmale-
imide (NPM), it was much more enantioselective in the presence
of (S)-Binap-AgSbF6 complex than that obtained with a perchlorate
derived chiral complex (82% ee, vs 62% ee). Computational calcula-
tions justified this difference because of the existence of steric
hindrance between the phenyl group of the NPM and the Binap-
AgClO4 catalyst.5b The less coordinating anion in the catalyst
Binap-AgSbF6 released the steric congestion of the transition state.
In the examples carried out with N-benzylmaleimide, the
differences in the ee values of the product endo-8 were not impor-
tant (Scheme 3). Products endo-6, endo-7, and endo-8 were isolated
in more than a 98:2 endo:exo ratio independent of the chiral
catalyst employed.
2.3. General scope of the (Sa)-Binap-AgSbF6 catalyzed 1,3-DC
R
R
N
N
O
O
The optimized reaction conditions were employed in the diaste-
reo- and enantioselective transformation of several azomethine
ylides, generated from the corresponding methyl arylideneimino-
glycinates 3, and maleimides into the corresponding cycloadducts
endo-5. Reactions employing 5 mol % of an equimolar mixture of
(S)-Binap and AgSbF6 in the presence of toluene as a solvent and
a catalytic amount of triethylamine (5 mol %) were compared di-
rectly with the analogous results obtained with the (S)-Binap-Ag-
ClO4 complex5 (Scheme 2, and Table 2).
O
O
i
Ph
N
CO2Me
Ph
3aa
CO2Me
N
H
4
endo-6-8
Et
N
Ph
N
Bn
N
O
O
O
O
O
O
Ph
CO2Me Ph
CO2Me
Ph
CO2Me
N
H
N
H
N
H
N
O
O
N
i
endo-6
endo-7
endo-8
O
O
Ar
N
CO2R1
AgSbF6
AgClO4
84%, 99% ee
90%, 99% ee
86%, 82% ee
86%, 62% ee
82%, 98% ee
81%, 92% ee
CO2R1
Ar
3
N
H
4a
Scheme 3. Reagents and conditions: (i) (Sa)-Binap (5 mol %), AgI salt (5 mol %), Et3N
(5 mol %), toluene, 25 °C, 16 h.
endo-5
Scheme 2. Reagents and conditions: (i) (Sa)-Binap (5 mol %), AgI salt (5 mol %), Et3N
(5 mol %), toluene, 25 °C, 16 h.
The effect of a-substitution in the 1,3-dipole precursor was next
evaluated. Alanine, leucine, and phenylalaninates 9 were allowed
to react with NMM under the typical reaction conditions, requiring
48 h to reach complete conversions (Scheme 4). Cycloadducts
In general, we observed that the isolated chemical yields of
compounds 5 were identical to each other. For example, for
Ar = Ph, 2-naphthyl, and 2-thienyl, there was no difference in terms
of enantioselection between both catalytic complexes (Table 2, en-
tries 1, 6 and 12). These three entries were also repeated employ-
ing (S)-Binap-AgTfa with no added base; similar enantioselections
and lower chemical yields of slightly unpurified cycloadducts
endo-5 (not shown in Table 2) were obtained. When the reaction
was performed with (R)-Binap, the corresponding enantiomer of
endo-5aa was isolated in good yield and excellent enantioselectiv-
ity (Table 2, entry 2). Modification of the alkyl moiety of the ester
group caused a decrease of the diastereoselection, (Table 2, entries
3–5). In all of these cases, the enantioselectivity was lower than
that obtained for the methyl ester. For substituted aromatic imino
esters, the enantioselection was always higher when AgSbF6 was
selected as the co-catalyst, except when o-tolyl derivative 3ca
was used (Table 2, entries 7–10). Heteroaromatic groups attached
to the 1,3-dipole precursor, influenced the reaction course.
Whereas a 2-thienyl derivative furnished 5ha with very good
enantioselection, 3-pyridyl derivative 3ga was not suitable for this
particular transformation (Table 2, entries 11 and 12). Presumably,
the basic character of the nitrogen heterocycle promoted the non-
asymmetric process.
N
R
O
O
N
i
O
O
Ph
N
CO2Me
R
Ph
9
N
H
CO2Me
4a
endo-10
N
N
N
O
O
O
O
O
O
Ph
Ph
Ph
N
H
N
H
N
H
CO2Me
CO2Me
CO2Me
S
endo-10a
endo-10b
endo-10c
AgSbF6
AgClO4
84%, 99% ee
80%, 72% ee
78%, 91% ee
81%, 74% ee
86%, 99% ee
83%, 64% ee
Scheme 4. Reagents and conditions: (i) (Sa)-Binap (5 mol %), AgI salt (5 mol %), Et3N
(5 mol %), toluene, 25 °C, 48 h.

J. Mancebo-Aracil et al. / Tetrahedron: Asymmetry 23 (2012) 1596–1606
1599
R1
endo-10 were obtained in good yields when both chiral catalysts
PhO2S
Ar
SO2Ph
R1
CO2R2
were used, but the enantioselectivity achieved by (Sa)-Binap-
AgSbF6 was noticeably higher. This is further evidence of the ease
of the hexafluoroantimonate salt to perform cycloadditions with
sterically hindered components.
i
SO2Ph
Ar
N
CO2R2
PhO2S
9
11
N
H
We also found that dipolarophiles such as alkyl acrylates, dial-
kyl fumarates, dimethyl maleate, and acrylonitrile exhibited iden-
tical behavior with both silver salts, that is, very low
enantioselections and good chemical yields were obtained. More
polar solvents, such as acetone, acetonitrile, diethyl ether, ethanol,
and water were tested but the cycloaddition was not completed
and the crude reaction mixtures were notably impure. When small
amounts of cycloadducts were isolated, the enantioselections were
almost zero.
Large differences were detected when 1,2-bis(phenylsulfo-
nyl)ethylene was employed as low-LUMO alkene (Scheme 5 and Ta-
ble 3). Although toluene was used as the solvent, the reactions
could also be carried out in THF because we observed a very clean
reaction mixture, and the crude products endo-12 did not require
additional purification. When the reaction was performed with
(S)-Binap-AgClO4, we saw no improvement in the results generated
by intermediacy of (S)-Binap-AgSbF6. Phenyl- and 2-naphthyl sub-
stituents bonded to the imino group afforded high enantioselec-
tions of the products 12aaa and 12baa, respectively (Table 3,
entries 1–4). The effect of the methyl group in the azomethine ylide
caused lower enantioselections in the final products 12bba (Table 3,
entries 5 and 6). The introduction of a substituent in the arylidene
moiety of the imino ester was not very profitable because the ee
of the cycloadducts was very low, except in the case of para-methyl
substituted derivatives (Table 3, entries 7–14). The presence of an
isopropyl ester instead of a methyl group also gave poor enantiose-
lection in heterocycle 12fab (Table 3, entries 15 and 16). The 3-pyr-
idyl group was the most appropriate heterocycle (Table 3, entries
17 and 18) since the 2-thienyl and 2-thiazolyl imino esters did
not afford very high enantioselections despite producing excellent
yields (Table 3, entries 19–22). Sterically hindered imino esters
endo-12
Scheme 5. Reagents and conditions: (i) (Sa)-Binap (5 mol %), AgI salt (5 mol %), Et3N
(5 mol %), toluene or THF, 25 °C, 48 h.
Multicomponent reactions were attempted using the best re-
sults obtained in Tables 2 and 3. Thus, benzaldehyde/NMM 4a or
3-pyridinecarbaldehyde/disulfone 11, glycine methyl ester hydro-
chloride, triethylamine (1.05 equiv), (S)-Binap-AgSbF6 (5 mol %),
were put together in toluene and the resulting mixture was al-
lowed to react at 25 °C for 48 h. The results obtained for compound
endo-5aa or endo-12gaa were good (88% yield, >99% ee, or 86%
yield, 98% ee, respectively, Scheme 6). However, analogous reac-
N
O
O
N
O
O
4a
i
CHO
Ph
N
H
CO2Me
endo-5aa
88%, >99% ee
HCl·H2N
PhO2S
CO2Me
SO2Ph
CHO
PhO2S
SO2Ph
11
ii
CO2Me
N
H
N
N
such as ortho-substituted arylinenes, isopropyl esters, and
a-
endo-12gaa
86%, 98% ee
HCl·H2N
CO2Me
branched amino acid derivatives (alanine and leucine) furnished
lower endo:exo ratios, and this was more pronounced when
(S)-Binap-AgClO4 was employed (Table 3, entries 5–8, 15, 16, and
19–22).
Scheme 6. Reagents and conditions: (i) (Sa)-Binap (5 mol %), AgSbF6 (5 mol %), Et3N
(5 mol %), toluene, 25 °C, 16 h. (ii) (Sa)-Binap (5 mol %), AgSbF6 (5 mol %), Et3N
(5 mol %), toluene, 25 °C, 48 h.
Table 2
1.3-DC of iminoglycinates 3 and NMM 4a
Entry
N°
Ar
R1
Product endo-5
b,d
No.
Yielda,b (%)
endo:exob,c
eeendo (%)
1
2
3
4
5
6
7
8
3aa
3aae
3ab
3ac
3ad
3ba
3ca
3da
3ea
3fa
Ph
Ph
Ph
Ph
Me
Me
Et
5aa
ent-5aa
5ab
5ac
5ad
5ba
5ca
5da
5ea
5fa
90 (90)
90 (90)
81 (78)
80 (81)
81 (79)
89 (80)
85 (85)
85 (88)
85 (85)
84 (87)
77 (81)
84 (87)
>98:2
>98:2
95:5 (90:10)
90:10
80:20 (75:25)
>98:2
>98:2
>98:2
>98:2
>98:2
>99 (>99)
>99 (>99)
92 (91)
87 (72)
91 (92)
>99 (>99)
70 (75)
>99 (85)
99 (80)
94 (65)
40 (10)
Pri
Ph
But
Me
Me
Me
Me
Me
Me
Me
2-Naphthyl
2-CH3C6H4
2-ClC6H4
4-CH3C6H4
4-ClC6H4
3-Pyridyl
2-Thienyl
f
9
10
11
12
3ga
3ha
5ga
5ha
80:20
>98:2 (90:10)
93 (92)
a
b
c
d
e
f
Isolated yield after flash chromatography.
In brackets the result obtained previously with (S)-Binap-AgClO4 complex.5
Determined by chiral 1H NMR of the crude product.
Determined by HPLC of the crude product using chiral columns. Identical ee was determined after purification of 5.
Reaction performed with (R)-Binap-AgSbF6.
Reaction performed at ꢀ20 °C.

1600
J. Mancebo-Aracil et al. / Tetrahedron: Asymmetry 23 (2012) 1596–1606
Table 3
1.3-DC of iminoglycinates 9 and disulfone 11
Entry
Ar
R1
R2
Solvent
No
Product endo-12
endo:exob,c
b,d
Yielda,b (%)
eeendo (%)
1
2
3
4
5
6
7
8
Ph
Ph
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Pri
PhMe
THF
PhMe
THF
PhMe
THF
PhMe
THF
PhMe
PhMe
PhMe
THF
PhMe
THF
PhMe
THF
PhMe
THF
12aaa
12aaa
12baa
12baa
12bba
12bba
12caa
12caa
12daa
12daa
12eaa
12eaa
12faa
12faa
12fab
12fab
12gaa
12gaa
12hca
12hca
12ica
12ica
81 (80)
82
>98:2
>98:2
>98:2
>98:2
90:10
90:10
90:10
90:10
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
80:20
80:20
90 (88)
90
92 (80)
80
24 (10)
12
18 (16)
6
88 (28)
82
38 (28)
12
45 (27)
42
40 (30)
30
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-Naphthyl
2-CH3C6H4
2-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-Pyridyl
3-Pyridyl
2-Thienyl
2-Thienyl
2-Thiazolyl
2-Thiazolyl
91e (88)
90
95e (82)
91e
63 (79)
68
9
91e (78)
78
10
11
12
13
14
15
16
17
18
19
20
21
22
58 (60)
78
81 (85)
79
64 (71)
Pri
93e
Me
Me
Me
Me
Me
Me
83 (82)
92e
>98:2
>98:2
90:10 (75:25)
90:10 (75:25)
90:10 (75:25)
90:10 (75:25)
93 (78)
90
70 (12)
58
10 (8)
4
H
Bui
Bui
Bui
Bui
PhMe
PhMe
PhMe
PhMe
92 (<50)
95e
92e (<50)
93e
a
b
c
Isolated yield after flash chromatography.
In brackets, the result obtained previously with an (S)-Binap–AgClO4 complex.
Determined by chiral 1H NMR of the crude product.
d
e
Determined by HPLC of the crude product using chiral columns. Identical ee was determined after purification of 12.
No additional purification was required.
tions carried out in the presence of the (S)-Binap-AgClO4 complex
were unsuccessful. Although very activated aminomalonates have
been used as one of the three components of enantioselective
organocatalyzed 1,3-DC, this was the first occasion in which a
three-component transformation was performed enantioselective-
ly in the presence of a chiral Lewis acid.12 However, the employ-
ment of other substrates with these two dipolarophiles did not
afford either the expected enantioselections or good chemical
(Scheme 7). This low yield could be justified by the formation of
significant amounts of the pyrrole derivative after the
desulfonylation step.
(R)-(+)-Crispine A 17 and (R)-(+)-harmicine 18 are naturally
occurring molecules that are employed in traditional medicine.
The anticancer properties of the former and the anti-leishmaniasis
effects of the latter have attracted the attention of many scien-
tists.17,18 Following the approach of Coldham et al., which used a
1,3-DC with disulfone 11 (Scheme 8),19 new starting aromatic
precursors 19 and 20, that were suitably protected, were prepared.
yields. The introduction of the free
a-amino ester instead of the
corresponding hydrochloride did not improve the results.
2.4. Applications of (Sa)-Binap-AgX catalyzed 1,3-DC
Ph
CO2But
N
As a masked acetylene equivalent, disulfone 11 has been used in
this 1,3-DC for the preparation of Schramm’s C-azanucleoside,15
which is a promising trypanosomal nucleoside hydrolase inhibitor.
Herein the enantioselective synthesis of the exo-cycloadduct (of
type 12) was the key step of the total process, after which the
methoxycarbonyl group was reduced with lithium aluminum hy-
dride (LAH) followed by complete desulfonylation with sodium
amalgam. In our case, when the enantiomerically enriched endo-
12aaa was allowed to undergo this double reduction protocol
(LAH plus amalgam) a very complex reaction mixture was ob-
tained, with pyrrole being the major product observed. Several
conditions were tested and we found that the behavior of the
endo-diastereoisomer was very different to the exo one, even in
terms of stability upon flash chromatography.
The synthesis of 5-substituted prolines is another interesting
application because it gives access to biologically active com-
pounds, such as the nonpeptide cholecystokinin antagonist (+)-
RP 66803 13.16 The 5-phenylprolinate fragment was prepared
according to the route described in Scheme 7. Isomers 14 and 15
were obtained after desulfonylation with sodium amalgam (10%)
and the crude mixture, without purification, was submitted to
hydrogenation with Pt/C (10%). The enantiomeric excesses of both
prolinates remained unaltered with respect to the starting
disulfonylated heterocycle ones. The overall yield of 16 was 47%
O
O
NH
NH
13
(+)-RP 66803
PhO2S
Ph
SO2Ph
i
Ph
CO2Me
Ph
ii
CO2Me
N
H
N
H
CO2Me
N
H
14
15
7:5
12aaa
90% ee
Ph
CO2Me
N
H
16
47% overall yield, 90% ee
Scheme 7. Reagents and conditions: (i) Na(Hg), 10%, MeOH/THF (3/1), from 0 to
25 °C, 1 h. (ii) Pt/C (10%), H2 (1 atm), MeOH, 48 h, 25 °C.

J. Mancebo-Aracil et al. / Tetrahedron: Asymmetry 23 (2012) 1596–1606
1601
PhO2S
SO2Ph
SO2Ph
PhO2S
PhO2S
SO2Ph
PhO2S
MeO
MeO
11
MeO
MeO
CO2Me
PhO2S
i
N
N
N
H
CO2Me
N
H
N
N
CO2Me
OAc
OTBDMS
17
(R)-(+)-crispine
19
OTBDMS
20
PhO2S
SO2Ph
22
H
N
PhO2S
N
Scheme 10. Reagents and conditions: (i) (Sa)-Binap (10 mol %), AgTfa (10 mol %),
DABCO (10 mol %), toluene, 25 °C, 48 h.
N
CO2Me
N
H
OTBDMS
(R)-(+)-harmicine 18
Under the best reaction conditions described in Table 4, imino
ester 22 was submitted to cycloaddition with disulfone 11 to afford
cycloadduct 20 in 60% chemical yield with very poor enantioselec-
tivity Scheme 10 (12% ee).
20
Scheme 8. Retrosynthetic analysis of natural products 19 and 20.
Despite the low enantioselections obtained in the reaction per-
formed between imino ester 3aa and acrylates, the 1,3-DC of the
heterocyclic imino ester 23 and tert-butyl acrylate were attempted
(Scheme 11 and Table 5). As reported in previous works, molecule
24 is the key intermediate in the elaboration of 2nd generation GSK
inhibitors of the virus causing hepatitis C 25.9,21 AgClO4, AgTfa, and
AgSbF6 were tested (Table 5), and the reactions afforded good
chemical yields at 25 °C, for 48 h and with high enantioselections,
especially for the reaction carried out with silver perchlorate (88%
ee) (Table 5, entry 1). The reaction needed 10 mol % of both catalyst
loading and triethylamine to occur. Lowering the temperature and
using different solvents, bases did not improve upon the results de-
scribed in Table 5.
SO2Ph
PhO2S
PhO2S
SO2Ph
11
MeO
MeO
i
MeO
MeO
CO2Me
N
H
N
CO2Me
OAc
OAc
19
21
Scheme 9. Reagents and conditions: (i) (Sa)-Binap (10 mol %), AgI salt (10 mol %),
base (10 mol %), toluene, 20–25 °C, 48 h.
Table 4
3. Conclusion
Optimization of the reaction of imino ester 21 with 11
AgI salt
Base
Product 19
Yielda,b (%)
We conclude that a small variation in the structure of the
dipole-dipolarophile or in the reaction parameters can cause a
dramatic change in the final enantioselection of the chiral Binap-
silver(I) complexes when they catalyze enantioselective 1,3-dipo-
lar cycloadditions between azomethine ylides and electrophilic
alkenes. Replacing perchlorate salts with other different anions is
also desirable from an industrial point of view. Silver hexafluoro-
antimonate can efficiently catalyze cycloadditions dealing with
maleimides and 1,2-bis(phenylsulfonyl)ethylene and the best re-
sults were obtained when using sterically hindered dipole precur-
sors. It should be noted that multicomponent transformations
could be carried out in the presence of AgSbF6 while the analogous
reaction, mediated by silver(I) perchlorate, was unsuccessful. How-
ever, silver trifuoroacetate was much more effective, or as effective
as silver(I) perchlorate, in the applications of this methodology into
the synthesis of natural (crispine or harmicine precursors) or bio-
logically attractive compounds (e.g. antiviral precursors).
eec (%)
1
2
3
4
5
6
7
8
AgSbF6
AgOAc
AgTfa
AgTfa
AgTfa
AgSbF6
AgTfa
AgTfa
AgTfa
AgTfa
AgTfa
Et3N
Et3N
Et3N
DIPEA
DABCO
DABCO
DBU
Cinchonine
Cinchonidine
Quinine
Quinidine
55
45
55
80
59
50
63
87
81
71
77
32
30
35
30
50
30
24
40
40
9
10
11
45
ꢀ12
a
b
c
Isolated yield of the endo-product after flash chromatography.
The endo/exo ratio could not be determined from the crude product.
Determined by HPLC of the crude product employing chiral column (Daicel
Chiralpak AD).
The reaction of imine 21 (obtained from the corresponding
aldehyde20 and methyl glycinate) and disulfone 11 was accom-
plished at 20–25 °C using toluene as the solvent with 10 mol % of
catalyst loading (formed by chiral Binap and a silver salt) and in
the presence or absence of a base (Scheme 9 and Table 4). AgSbF6,
AgTfa, and AgOAc were tested and the best results were obtained
when the trifluoroacetate salt was combined with triethylamine
(10 mol %) as the base (Table 4, entries 1–3). Other bases such as
DIPEA, DABCO, or DBU were tested and we found a noticeable in-
crease in the enantioselection with AgTfa/DABCO mixture (up to
50% ee) (Table 4, entries 4–7). Quinuclidine based alkaloids were
tested next for double chiral induction, but the results never over-
took 45% ee (Table 4, entries 8–11). The transformations carried out
with these silver salts in the absence of base were unsuccessful.
Cycloadduct 19 (up to 32% ee) was obtained with poor enantios-
elections and in moderate chemical yields (55–65%).
4. Experimental
4.1. General
All reactions were carried out in the absence of light. Anhydrous
solvents were freshly distilled under an argon atmosphere. Alde-
hydes were also distilled prior to use for the elaboration of the imi-
no esters. Melting points were determined with
a Reichert
Thermovar hot plate apparatus and are uncorrected. Only the
structurally most important peaks of the IR spectra (recorded on
a Nicolet 510 P-FT) are listed. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were obtained on a Bruker AC-300 using CDCl3
as the solvent and TMS as the internal standard, unless otherwise
stated. Optical rotations were measured on a Perkin Elmer 341
polarimeter. HPLC analyses were performed on a JASCO 2000-

1602
J. Mancebo-Aracil et al. / Tetrahedron: Asymmetry 23 (2012) 1596–1606
tBuO2C
R
tBuO2C
i
(ref 9)
N
N
CO2H
CO2Me
N
N
H
N
S
N
CO2Me
S
Ar
O
S
24
23
25
Scheme 11. Reagents and conditions: (i) (Sa)-Binap (10 mol %), AgX (10 mol %), Et3N (10 mol %), toluene, 25 °C, 48 h.
Table 5
Methyl (1S,3R,3aS,6aR)-3-(4-chlorophenyl)-5-methyl-4,6-dioxo
octahydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-5fa.5a
Methyl (1S,3R,3aS,6aR)-3-(3-pyridyl)-5-methyl-4,6-dioxoocta
hydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-5ga.22
Methyl (1S,3R,3aS,6aR)-5-methyl-4,6-dioxo-3-(2-thienyl)octa
hydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-5ha.5a
Methyl (1S,3R,3aS,6aR)-5-ethyl-4,6-dioxo-3-phenyloctahydro
pyrrolo[3,4-c]pyrrole-1-carboxylate endo-6.23
Synthesis of antiviral agent precursor 24
Entry
AgX
Product 24
Yielda,b (%)
eec (%)
1
2
3
AgClO4
AgTfa
AgSbF6
78
75
79
88
88
72
a
b
c
Isolated yield of the endo-product after flash chromatography.
The endo/exo ratio was >98:2 (1H NMR).
Determined by HPLC of the crude product employing chiral column (Daicel
Methyl (1S,3R,3aS,6aR)-4,6-dioxo-3,5-diphenyloctahydro pyr-
rolo[3,4-c]pyrrole-1-carboxylate endo-7.23
Chiralpak AD).
Methyl (1S,3R,3aS,6aR)-5-benzyl-4,6-dioxo-3-phenyloctahydro
pyrrolo[3,4-c]pyrrole-1-carboxylate endo-8. Pale yellow oil;
½
a 2D0
ꢁ
¼ þ69:4 (c 1, CHCl3) 98% ee from HPLC; IR mmax 1740–1705,
3260 cmꢀ1
;
1H NMR dH: 2.10 (s, 1H, NH), 3.33, 3.58 (2ꢂdeform.
d, J = 7.0, Hz, 2H, CH2Ph), 3,40 (d, J = 7,5 Hz, 1H, CCH), 3,58 (dd,
J = 9.1, and 7.6 Hz, 1H, CHCHCO2CH3), 3.76 (s, 3H, CO2Me), 3.58
(d, J = 7.1 Hz, 1H, CHCO2CH3), 4.25 (d, J = 6.8 Hz, 1H, CHAr), 7.27–
7.48 (m, 10H, ArH); 13C NMR dC: 46.2 (CH2Ph), 47.1, 48.9
(2 ꢂ CHCON), 51.9 (CH3), 61.4, 66.2 (2 ꢂ CHN), 128.1, 128.5,
125.9, 140.5, 126.9, 128.6, 126.7, 136.5 (ArC), 176.4, 176.0, 171.6
(3 ꢂ CO); MS (EI-GC) m/z: 364 (M++1, 2%), 273 (100), 91 (47), 68
series equipped with a chiral column (detailed for each compound
in the main text), using mixtures of n-hexane/isopropyl alcohol as
mobile phase, at 25 °C. Low-resolution electron impact (EI) mass
spectra were obtained at 70 eV on a Shimadzu QP-5000 and
high-resolution mass spectra were obtained on a Finnigan VG Plat-
form. HRMS (EI) were recorded on a Finnigan MAT 95S. Microanal-
yses were performed on a Perkin Elmer 2400 and a Carlo Erba
EA1108. Analytical TLC was performed on Schleicher & Schuell
F1400/LS silica gel plates and the spots were visualized under UV
light (k = 254 nm). For flash chromatography, we employed Merck
silica gel 60 (0.040–0.063 mm).
(11); HRMS calculated for
C21H20N2O4: 364.1423, found:
364.1430; HPLC (Chiralpak AS, 1 mL/min, n-hexane/i-PrOH: 20/
80, k 225 nm), tRmaj = 10.5 min, tRmin = 26.7 min.
Methyl (1S,3R,3aS,6aR)-1,5-dimethyl-4,6-dioxo-3-phenylocta-
hydro pyrrolo[3,4-c]pyrrole-1-carboxylate endo-10a.5b
Methyl
(1S,3R,3aS,6aR)-1-isobutyl-5-methyl-4,6-dioxo-3-(2-
4.2. 1,3-Dipolar cycloaddition of imino esters 3, 9, 21, 22, or 23
and dipolarophiles. General procedure
thienyl) octahydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-10b.5b
Methyl (1S,3R,3aS,6aR)-1-benzyl-5-methyl-4,6-dioxo-3-phenyl
octahydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-10c.5b
Methyl (2R,3R,4R,5S)-5-phenyl-3,4-bis(phenylsulfonyl)pyrroli-
A solution of the imino ester (1 mmol) and dipolarophile
(1 mmol) in toluene (5 mL) was added to a suspension containing
(R)- or (S)-Binap (0.05 mmol, 31 mg) and AgX (0.05 mmol) in tolu-
ene (5 mL). To the resulting suspension triethylamine (0.05 mmol,
dine-2-carboxylate endo-12aaa. Sticky oil,
CH2Cl2) 90% ee from HPLC; IR (neat)
½
a 2D0
ꢁ
¼ þ1:2 (c 1,
m
max: 3311, 1753 cmꢀ1
;
1H
NMR dH: 2.80 (br s, 1H, NH), 3.68 (s, 3H, CO2Me), 4.33 (m, 1H,
PhCHCHSO2Ph), 4.41 (dd, J = 2.4, 6.3 Hz, 1H, NCCHSO2Ph), 4.47
(dd, J = 2.4, 6.0 Hz, 1H, CHCO2Me), 4.64 (m, 1H, PhCHN), 7.28–
7.26 (m, 2H, ArH), 7.34–7.32 (m, 2H, ArH), 7.46–7.42 (m, 2H,
ArH), 7.61–7.52 (m, 3H, ArH), 7.72–7.65 (m, 6H, ArH); 13C NMR
dC: 38.3 (Me) 48.6 (CHCO2Me), 49.1, 52.7 (2 ꢂ CHS), 56.0 (CHPh),
112.3, 112.9, 113.2, 113.3, 113.7, 113.9 114.1, 114.2, 119.2, 121.9,
122.8, 123.1 (ArC), 152.4 (CO); MS (EI) m/z (%): 485 (M+, <1%),
284 (11), 203 (15), 202 (100), 170 (18), 144 (27), 143 (60), 115
(14), 77 (14); HRMS calculated for C24H23NO6S2: 485.0967, found:
485.0990; HPLC (Chiralpak IA, 1 mL/min, n-hexane/i-PrOH: 80/20,
k 224 nm), tRmaj = 50.23 min, tRmin = 30.92 min.
7 lL) was added and the mixture was stirred at room temperature
and in the absence of the light for 16–48 h (see main text). The pre-
cipitate was filtered and the complex was recovered. The organic
filtrate was directly evaporated and the residue was purified by
recrystallization or by flash chromatography yielding pure endo-
cycloadducts.
Methyl (1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-dioxooctahydro
pyrrolo [3,4-c]pyrrole-1-carboxylate endo-5aa.5b
Ethyl (1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-dioxooctahydro
pyrrolo[3,4-c]pyrrole-1-carboxylate endo-5ab.5b
Isopropyl
(1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-dioxoocta
hydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-5ac.5b
Methyl (2R,3R,4R,5S)-5-(naphth-2-yl)-3,4-bis(phenylsulfonyl)
tert-Butyl
(1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-dioxoocta
pyrrolidine-2-carboxylate endo-12baa. Sticky oil, ½a D20
¼ þ17:1 (c
ꢁ
hydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-5ad.5b
Methyl (1S,3R,3aS,6aR)-5-methyl-3-(2-naphthyl)-4,6-dioxoocta
hydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-5ba.5a
Methyl (1S,3R,3aS,6aR)-5-methyl-4,6-dioxo-3-o-tolyloctahydro
pyrrolo[3,4-c]pyrrole-1-carboxylate endo-5ca.5b
0.5; CH2Cl2) 92% ee from HPLC; IR (neat) m ;
max: 1741, 3340 cmꢀ1
1H NMR dH: 2.20 (br s, 1H, NH), 3.69 (s, 3H, CO2Me); 4.38 (m, 1H,
ArCHCHSO2Ph), 4.45 (dd, J = 2.4, 6.4 Hz, 1H, NCCHSO2Ph), 4.49
(dd, J = 2.4, 6.0 Hz, 1H, CHCO2Me), 4.79 (m, 1H, CHAr), 7.39–7.35
(m, 2H, ArH), 7.56–7.45 (m, 6H, ArH), 7.72–7.60 (m, 7H, ArH),
7.81–7.77 (m, 2H, ArH); 13C NMR dC: 38.5 (Me), 48.6 (CHCO2Me),
49.1, 52.7 (2 ꢂ CHSO2), 55.9 (ArCH), 109.3, 111.2, 111.3, 112.0,
112.4, 112.5, 112.9, 113.0, 113.3, 113.4, 113.5, 113.8, 114.2,
Methyl (1S,3R,3aS,6aR)-3-(2-chlorophenyl)-5-methyl-4,6-dioxo
octahydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-5da.5a
Methyl (1S,3R,3aS,6aR)-5-methyl-3-(4-methylphenyl)-4,6-di-
oxo octahydropyrrolo[3,4-c]pyrrole-1-carboxylate endo-5ea.5a

J. Mancebo-Aracil et al. / Tetrahedron: Asymmetry 23 (2012) 1596–1606
1603
114.3, 119.2, 120.0, 121.1, 121.3 (ArC), 152.5 (CO); MS (EI) m/z (%):
535 (M+, <1%), 394 (26), 392 (11), 391 (35), 359 (28), 268 (21), 267
(19), 266 (17), 253 (19), 252 (100), 251 (31), 250 (13), 220 (31), 219
(31), 194 (35), 193 (62), 192 (22), 191 (31), 190 (41), 167 (15), 166
(11), 165 (47), 164 (13), 163 (15), 155 (11), 153 (11), 152 (22), 142
(11), 127 (17), 125 (14), 78 (20), 77 (46), 51 (15); HRMS calculated
for C28H25NO6S2: 535.1123; found: 535.1110; HPLC (Chiralpak AD,
1 mL/min, n-hexane/i-PrOH: 75/25, k 227 nm), tRmaj = 57.01 min,
tRmin = 51.97 min.
99.0, 113.4, 113.5, 114.2, 114.3, 119.2, 119.5, 120.8, 121.9, 122.2,
123.0, 144.4 (ArC), 152.4 (CO); MS (EI) m/z (%): 515 (M+, <1%),
375 (17), 374 (77), 233 (17), 232 (100), 231 (14), 200 (31), 199
(16), 174 (27), 173 (46), 172 (11), 159 (11), 158 (23), 130 (11),
78 (10), 77 (29); HRMS required for C25H25NO7S2: 515.1072;
found: 515.1082; HPLC (Chiralpak AD, 1 mL/min, n-hexane/i-PrOH:
70/30, k 230 nm), tRmaj = 38.85 min, tRmin = 43.96 min.
Methyl (2R,3R,4R,5S)-5-(4-chlorophenyl)-3,4-bis(phenylsulfo-
nyl) pyrrolidine-2-carboxylate endo-12faa: Colorless viscous oil,
Methyl (2R,3R,4R,5S)-2-methyl-5-(naphth-2-yl)-3,4-bis(phenyl
sulfonyl)pyrrolidine-2-carboxylate endo-12bba: Colorless oil,
½
a 2D0
ꢁ
¼ þ91:6 (c 1, CH2Cl2) 45% ee from HPLC; IR (neat) mmax
:
1750, 3341 cmꢀ1 1H NMR dH: 2.40 (br s, 1H, NH), 3.67 (s, 3H,
;
½
a 2D0
ꢁ
¼ þ5:2 (c 1, CH2Cl2) 24% ee from HPLC; IR (neat)
m
max: 1748
CO2Me); 4.30 (dd, J = 2.3, 6.3 Hz, 1H, ArCHCHSO2Ph), 4.34 (m, 1H,
NCCHSO2Ph), 4.38 (dd, J = 2.3, 5.9 Hz, 1H, CHCO2Me), 4.66–4.61
(m, 1H, ArCH), 7.30–7.21 (m, 3H, ArH), 7.53–7.43 (m, 4H, ArH),
7.71–7.59 (m, 7H, ArH); 13C NMR dC: 37.5 (Me); 45.2 (CHCO2Me),
48.9, 52.6 (2 ꢂ CHSO2), 55.9 (ArCH), 113.2, 113.5, 113.8, 113.9,
114.2, 114.3, 114.5, 114.8, 119.2, 119.5, 121.7, 123.0 (ArC), 152.3
(CO); MS (EI) m/z (%): 519 (M+, <1%), 238 (32), 237 (17), 236
(100), 235 (12), 204 (19), 203 (15), 179 (17), 178 (19), 177 (48),
143 (21), 140 (14), 125 (16), 115 (13), 77 (29), 152 (13); HRMS re-
quired for C24H22ClNO6S2: 519.0577; found: 519.0585; HPLC (Chir-
3341 cmꢀ1 1H NMR dH: 1.80 (s, 3H, CH3), 3.79 (s, 3H, CO2Me),
;
3.46–3.43 (m, 1H, NH), 4.48 (d, J = 3.9 Hz, 1H, ArCHCHSO2Ph),
4.61 (dd, J = 3.9, 7.2 Hz, 1H, NCCHSO2Ph), 4.83–4.77 (m, 1H, ArCH),
7.28–7.12 (m, 5H, ArH), 7.51–7.43 (m, 5H, ArH),7.73–7.57 (m, 6H,
ArH), 7.90–7.87 (m, 1H, ArH); 13C NMR dC: 25.2 (CH3), 39.2
(CO2Me), 49.0, 52.1 (2 ꢂ CHSO2), 56.9 (ArCH), 73.5 (CMe), 111.7,
112.0, 112.5, 112.9, 113.0, 124.0, 126.3, 126.4, 127.5, 127.6,
128.0, 128.2, 128.8, 129.0, 129.1, 129.4, 134.1, 134.4 (ArC), 171.0
(CO); MS (EI) m/z (%): 549 (M+, <1%), 408 (22), 348 (15), 267
(20), 266 (100), 234 (31), 208 (39), 207 (91), 206 (27), 193 (19),
165 (20), 77 (14). HRMS required for C29H27NO6S2: 549.1280;
found: 549.1301; HPLC (Chiralpak AD, 1 mL/min, n-hexane/i-PrOH:
60/40, k 227 nm), tRmaj = 18.21 min, tRmin = 39.37 min.
alpak AD, 1 mL/min, n-hexane/i-PrOH: 70/30,
tRmaj = 41.08 min, tRmin = 34.69 min.
k
220 nm),
Isopropyl (2R,3R,4R,5S)-5-(4-chlorophenyl)-3,4-bis(phenylsul-
fonyl) pyrrolidine-2-carboxylate endo-12fab: Colorless needles,
Methyl (2R,3R,4R,5S)-3,4-bis(phenylsulfonyl)-5-(o-tolyl)pyrrol-
mp 178 °C (CH2Cl2/n-hexane); ½a D20
ꢁ
¼ þ37:0 (c 0.7, CHCl3) 40% ee
idine-2-carboxylate endo-12caa: Colorless sticky oil, ½a D20
ꢁ
¼ þ1:7
from HPLC; IR (KBr) m ;
max: 1735, 3328 cmꢀ1 1H NMR dH: 1,33,
(c 0.9, CH2Cl2) 18% ee from HPLC; IR (neat) mmax
:
1749,
1.41 [2 ꢂ d, J = 6.2 Hz, 6H, CO2CH(CH3)2], 2.42 (br s, 1H, NH), 4.30
(dd, J = 2.3, 6.3 Hz, 1H, ArCHCHSO2Ph), 4.34 (m, 1H, NCCHSO2Ph),
4.38 (dd, J = 2.3, 5.9 Hz, 1H, CHCO2Me), 4.66–4.61 (m, 1H, ArCH),
5.20 (m, 1H, CHMe2); 7.21–7.81 (m, 7 Hz, 14H, ArH); 13C NMR dC:
21.6, 21.9 [CH(CH3)2], 45.2 (CHCO2), 47.5, 48.9 (2 ꢂ CHSO2), 55.9
(ArCH), 62.0 [CH(CH3)2], 113.2, 113.5, 113.7, 113.9, 114.0, 114.1,
114.5, 114.6, 119.4, 119.5, 121.7, 123.0 (ArC), 152.3 (CO); MS (EI)
m/z (%): 513 (M+, 2%), 229 (100), 140 (14); HRMS calculated for
3341 cmꢀ1 1H NMR dH: 2.42 (s, 3H, ArCH3); 2.90 (br s, 1H, NH),
;
3.64 (s, 3H, CO2Me), 4.32 (s, 1H, ArCHCHSO2Ph), 4.48 (dd, J = 2.7,
6.2 Hz, 1H, NCCHSO2Ph), 4.65 (dd, J = 2.7, 6.9 Hz, 1H, CHCO2Me),
4.97 (s, 1H, ArCH), 7.25–7.16 (m, 2H, ArH), 7.41 (t, J = 7.6 Hz,
8.0 Hz, 2H, ArH), 7.58–7.54 (m, 5H, ArH), 7.71–7.67 (m, 5H, ArH),
13C NMR dC: 37.4 (OMe), 44.3 (ArMe), 50.0 (CHCO2Me), 53.0, 55.5
(2 ꢂ CHSO2), 57.8 (ArCH), 110.9, 111.9, 113.1, 113.3, 114.2, 114.3,
115.5, 119.1, 119.2, 120.8, 122.0, 122.1, 123.1, 124.6, (ArC),152.3
(CO); MS (EI) m/z (%): 499 (M+, <1%), 298 (10), 217 (16), 216
(100), 184 (18), 158 (29), 157 (49), 156 (20), 143 (12), 129 (11),
77 (23); HRMS calculated for C25H25NO6S2: 499.1123; found:
499.1134; HPLC (Chiralpak AD, 1 mL/min, n-hexane/i-PrOH: 80/
20, k 227 nm), tRmaj = 35.89 min, tRmin = 43.91 min.
C
C
17H20N2O4: 513.11280; found: 513,11289; Microanalysis for
26H27NO6 S2: C, 60.8; H, 5.3; N, 2.8%, found: C, 60.5; H, 5.3; N,
2.5; HPLC (Chiralpak OD-H, 1 mL/min, n-hexane/i-PrOH: 80/20, k
215 nm), tRmaj = 20.5 min, tRmin = 38.4 min.
Methyl
pyrrolidine-2-carboxylate endo-12gaa: Colorless sticky oil,
¼ ꢀ63:9 (c 1.2, CH2Cl2) 92% ee from HPLC; IR (neat) mmax
1753, 3310 cmꢀ1 1H NMR dH: 2.25 (br s, 1H, NH), 3.68 (s, 3H,
(2R,3R,4R,5S)-3,4-bis(phenylsulfonyl)-5-(pyrid-3-yl)
Methyl (2R,3R,4R,5S)-3,4-bis(phenylsulfonyl)-5-(p-tolyl)pyrrol-
½
a 2D0
ꢁ
:
idine-2-carboxylate 12daa: Colorless sticky oil, ½a D20
ꢁ
¼ þ2:3 (c 1,
;
CH2Cl2) 88% ee from HPLC; IR (neat)
m
max: 1747, 3341 cmꢀ1
;
1H
Me); 4.33 (dd, J = 2.3, 6.4 Hz, 1H, ArCHCHSO2Ph), 4.35 (s, 1H,
NCCHSO2Ph), 4.43 (dd, J = 2.3, 5.9 Hz, 1H, CHCO2Me), 4.66 (d,
J = 6.4 Hz, 1H, ArCH), 7.46 (t, J = 7.7 Hz, 8.0 Hz, 2H, ArH), 7.53 (t,
J = 7.4 Hz, 2H, ArH), 7.61–7.65 (m, 3H, ArH), 7.70 (t, J = 7.4 Hz, 5H,
ArH), 8.36 (s, 1H, ArH), 8.52 (s, 1H, ArH); 13C NMR dC: 34.6, 37.5
(CHCO2Me), 48.9, 52.4 (2 ꢂ CHSO2), 55.7 (ArCH), 108.7, 113.3,
113.4, 114.3, 114.6, 119.3, 119.6, 119.8, 120.1, 121.5, 122.5 134.0,
134.7 (ArC), 152.3 (CO); MS (EI) m/z (%): 289 (M+, 18%); HRMS cal-
culated for C23H22N2O6S2: 289.1062; found: 289.1064; HPLC (Chir-
NMR dH: 2.30 (s, 3H, ArCH3); 2.20 (br s, 1H, NH), 3.66 (s, 3H,
CO2Me), 4.31–4.27 (m, 1H, ArCHCHSO2Ph), 4.35 (dd, J = 2.4,
6.4 Hz, 1H, NCCHSO2Ph), 4.41 (dd, J = 2.4, 6.0 Hz, 1H, CHCO2Me),
4.61–4.57 (m, 1H, ArCH), 7.06 (d, J = 8.1 Hz, 1H, ArH), 7.20 (d,
J = 8.1 Hz, 1H, ArH), 7.54–7.40 (m, 6H, ArH), 7.64–7.57 (m, 2H,
ArH), 7.70–7.66 (m, 4H, ArH), 13C NMR dC: 21.2 (CH3Ar), 53.6
(OMe), 63.5, 64.2 (2 ꢂ CHSO2), 67.9 (CHCO2Me), 71.2 (ArCH),
127.3, 128.5, 128.6, 129.1, 129.3, 129.4, 129.5, 134.3, 135.0,
138.2, 138.3 (ArC), 167.6 (CO); MS (EI) m/z (%): 499 (M+, <1%),
358 (24), 217 (15), 216 (100), 184 (22), 158 (22), 157 (48), 156
(14), 77 (15); HRMS required for C25H25NO6S2: 499.1123; found:
499.1122; HPLC (Chiralpak AD, 1 mL/min, n-hexane/i-PrOH: 75/
25, k 220 nm), tRmaj = 50.08 min, tRmin = 26.11 min.
alpak AD, 1 mL/min, n-hexane/i-PrOH: 50/50,
tRmaj = 15.05 min, tRmin = 7.91 min.
k
222 nm),
Methyl
(2R,3R,4R,5S)-2-isobutyl-3,4-bis(phenylsulfonyl)-5-
(thien-2-yl)pyrrolidine-2-carboxylate endo-12hca: Pale yellow
oil, ½a 2D0
ꢁ
¼ 7:1 (c 1, CH2Cl2) 70% ee from HPLC; IR (neat) mmax
:
Methyl (2R,3R,4R,5S)-5-(4-methoxyphenyl)-3,4-bis(phenylsul-
fonyl) pyrrolidine-2-carboxylate endo-12eaa: Colorless sticky oil,
1779, 3338 cmꢀ1 1H NMR dH: 0.88 [d, J = 6.7 Hz, 3H, CH(CH3)2],
;
1.08 [d, J = 6.4 Hz, 3H, CH(CH3)2], 1.84–1.74 [m, 1H, CH(CH3)2],
1.98 [dd, J = 6.4, 14.6 Hz, 1H, CH2CH(CH3)2], 2.22 [dd, J = 5.7 Hz,
14.6 Hz, 1H, CH2CH(CH3)2], 3.10 (br s, 1H, NH), 3.82 (s, 3H, CO2Me),
4.40 (d, J = 3.9 Hz, 1H, ArCHCHSO2Ph), 4.46 (dd, J = 3.9 Hz, 7.2 Hz,
1H, NCCHSO2Ph), 4.88 (m, 1H, ArCH), 7.21–7.13 (m, 2H, ArH),
7.36–7.26 (m, 4H, ArH), 7.54–7.45 (m, 4H, ArH), 7.65–7.61 (m,
1H, ArH), 7.76–7.23 (m, 1H, ArH), 7.90 (d, J = 7.3 Hz, 1H, ArH); 13C
NMR dC: 24.4, 24.6 [CH(CH3)2], 28.4 [CH(CH3)2], 37.7 (CH2), 39.5,
½
a 2D0
ꢁ
¼ ꢀ4:5 (c 1, CH2Cl2) 38% ee from HPLC; IR (neat)
mmax: 1747,
3341 cmꢀ1
;
1H NMR dH: 2.70 (br s, 1H, NH), 3.68, 3.80 (2 ꢂ s, 6H,
CO2Me); 4.31 (s, 1H, ArCHCHSO2Ph), 4.35 (dd, J = 2.4, 6.4 Hz, 1H,
NCCHSO2Ph), 4.44 (dd, J = 2.4, 6.0 Hz, 1H, CHCO2Me), 4.61 (s, 1H,
ArCH), 7.29–7.24 (m, 2H, ArH), 7.47–7.43 (m, 2H, ArH), 7.63–7.52
(m, 5H, ArH), 7.72–7.66 (m, 5H, ArH); 13C NMR dC: 37.4, 40.1
(2 ꢂ OMe), 45.3 (CHCO2Me), 49.0, 52.7 (2 ꢂ CHSO2), 56.0 (ArCH),

1604
J. Mancebo-Aracil et al. / Tetrahedron: Asymmetry 23 (2012) 1596–1606
43.7, 57.8 (OMe and 2 ꢂ CHSO2), 58.4, 58.9 (CCO, NCH), 110.2,
110.5, 111.1, 111.7, 113.0, 114.0, 114.2, 118.9, 119.2, 123.2,
123.3, 125.7, (ArC), 155.2 (CO). MS (EI) m/z (%): 547 (M+, < 1%),
488 (13), 406 (13), 348 (28), 346 (22), 317 (12), 316 (66), 265
(16), 264 (100), 232 (22), 208 (26), 207 (25), 206 (26), 205 (57),
176 (26), 175 (12), 162 (43), 150 (13), 149 (30), 121 (14), 77
(0.040 g, 0.33 mmol), and Et3N (2.35 ml, 16.6 mmol) were added
in this order. The mixture was then stirred for 4 h. Next, water
(5 mL) and ethyl acetate (3 ꢂ 6 ml) were added, and the resulting
organic layers were washed with brine. The crude product was em-
ployed in the next step without purification. This aldehyde [2-(2-
acetoxyethyl)-4,5-dimethoxybenzaldehyde]20 (252 mg, 1 mmol),
glycine methyl ester hydrochloride (126 mg, 1 mmol), Et3N
(1.1 mmol), and MgSO4 (100 mg) were suspended in chloroform
and the mixture was refluxed for 16 h. The mixture was then fil-
tered and the resulting organic phase was washed with water
(2 ꢂ 5 mL). The organic layer was dried (MgSO4) and evaporated
in vacuo to obtain imine 21 in 96% yield.
(20); HRMS calculated for
C26H29NO6S3: 547.1157; found:
547.1151. HPLC (Chiralpak AD, 1 mL/min, n-hexane/i-PrOH: 70/
30, k 233 nm), tRmaj = 19.67 min, tRmin = 23.43 min.
Methyl
(thiazol-2-yl)pyrrolidine-2-carboxylate endo-12ica: Sticky oil,
¼ þ4:1 (c 1, CH2Cl2) 10% ee from HPLC; IR (neat) max: 1735,
(2R,3R,4R,5S)-2-isobutyl-3,4-bis(phenylsulfonyl)-5-
½
a 2D0
ꢁ
m
3328 cmꢀ1. 1H NMR dH: 0.87, 1.07 [2 ꢂ d, J = 6.7 Hz, 6H, CH(CH3)2],
1.86–1.73 [m, 1H, CH(CH3)2], 1.98 (dd, J = 6.4 Hz, 14.6 Hz, 1H, CH2),
2.22 (dd, J = 5.7 Hz, 14.6 Hz, 1H, CH2), 3.79 (s, 3H, OMe), 4.40 (d,
J = 4.1 Hz, 1H, ArCHCHSO2Ph), 4.97 (dd, J = 7.1 Hz, 12.2 Hz, 1H,
NCCHSO2Ph), 5.11 (dd, J = 4.1 Hz, 7.1 Hz, 1H, ArCH), 7.26–7.19 (m,
3H, ArH), 7.38–7.33 (m, 2H, ArH), 7.62–7.50 (m, 5H, ArH), 7.74–
7.68 (m, 1H, ArH), 7.88–7.85 (m, 2H, ArH); 13C NMR dC: 24.5,
24.7 [CH(CH3)2], 28.0 [CH(CH3)2], 37.9 (CH2), 39.9, 43.9, 57.2
(OMe and 2 ꢂ CHSO2), 58.4, 58.4 (CCO, NCH), 110.2, 110.5, 111.7,
113.4, 114.4, 114.2, 118.4, 119.2, 123.1, 123.3, 125.9, (ArC), 155.8
(CO); MS (EI) m/z (%): 548 (M+, <1%), 491 (26), 489 (19), 407
(13), 351 (13), 347 (28), 317 (53), 266 (15), 265 (87), 233 (50),
221 (12), 209 (35), 208 (71), 207 (52), 206 (100), 205 (10), 178
(11), 177 (79), 176 (13), 164 (13), 163 (65), 151 (19); 150 (17),
141 (11), 125 (16), 123 (17), 122 (13), 94 (10), 86 (10), 80 (12),
78 (13), 77 (44), 59 (11); HRMS calculated for C25H28N2O6S2:
548.1109; found: 548.1118. HPLC (Chiralpak AD, 1 mL/min, n-hex-
ane/i-PrOH: 70/30, k 220 nm), tRmaj = 21.63 min, tRmin = 12.69 min.
Methyl (E)-2-{[(2-(2-acetoxyethyl)-4,5-dimethoxybenzylidene]
amino}acetate 21: Pale yellow oil; IR (neat)
tmax: 1741, 1731,
1634 cmꢀ1 1H NMR dH: 1.96 (s, 3H, CH3CO2), 3.05 (t, J = 7.3 Hz,
;
2H, AcOCH2), 3.61 (s, 3H, CO2CH3), 3.84, 3.85 (2 ꢂ s, 6H, 2 ꢂ OCH3),
4.16 (t, J = 7.3 Hz, 2H, PhCH2), 4.36 (s, 2H, NCH2), 6.61 (s, 1H, ArH),
7.46 (s, 1H, ArH), 8.48 (s, 1H, NCH); 13C NMR dC: 20.9 (CH3CO), 31.3
(CH2Ar), 52.0, 55.8, 56.0 (3 ꢂ OMe), 62.1, 65.0 (CH2CO, CH2O),
109.7, 112.8, 126.5, 131.3, 148.1, 151.4 (ArC), 162.9 (CN), 170.7,
170.9 (2 ꢂ CO); MS (EI) m/z (%): 323.2 (M+, 5%), 264 (21), 263
(26), 262 (100), 190 (13), 176 (14), 175 (59); HRMS calculated
for C16H21NO6: 323.1369; found: 323.1361.
4.6. Synthesis of cycloadduct 19
A suspension of silver(I) salt (0.01 mmol), and (S)-Binap (6 mg,
0.01 mmol) in toluene was stirred at 25 °C for 30 min avoiding
exposure to light. Next, imine 21 (32 mg, 0.1 mmol), 1,2-bis(phen-
ylsulfonyl)ethylene (31 mg, 0.1 mmol) and the corresponding base
(0.01 mmol, see Table 4) were added in this order. The reaction was
stirred for 48 h at 25 °C after which water (5 ml) and the aqueous
phase extracted with ethyl acetate (2 ꢂ 5 ml). The organic layer
was dried (MgSO4) and evaporated in vacuo to obtain cycloadduct
19.
4.3. Multicomponent 1,3-dipolar cycloaddition of glycine
methyl ester hydrochloride. General procedure
To a suspension containing (R)- or (S)-Binap (0.05 mmol, 31 mg)
and AgSbF6 (17 mg, 0.05 mmol) in toluene (3 mL), triethylamine
Methyl
(2R,3S,4S,5S)-5-[2-(2-acetoxyethyl)-4,5-dimethoxy-
(6.6
lL, 0.05 mmol), the corresponding dipolarophile (1 mmol)
phenyl]-3,4-bis(phenylsulfonyl)pyrrolidine-2-carboxylate 19: Col-
and glycine methyl ester hydrochloride (126 mg, 1 mmol) were
added in this order at 25 °C. The reaction mixture was then stirred
at the same temperature for 16 or 48 h (see Scheme 6). The solvent
was evaporated in vacuo and the residue was purified by flash
chromatography yielding products endo-5aa or endo-12gaa.
orless needles, mp 92–94 °C (n-hexane/ethyl acetate);
½
a 2D0
ꢁ
¼ ꢀ25:3 (c 1, CHCl3) 50% ee from HPLC; IR (KBr)
tmax: 1148,
1309, 1738, 3306 cmꢀ1 1H NMR dH: 2.05 (s, 3H, CH3CO2), 2.30
;
(br s, 1H, NH), 2.85, 3.18 (2 m, 2H, PhCH2), 3.60 (s, 3H, CO2CH3),
3.88, 3.91 (2s, 6H, 2 ꢂ OCH3), 4.25–4.28 (m, 4H, AcOCH2, CHS,
CHCO2Me), 4.60 (dd, J = 6.3, 1.9 Hz, 1H, CHS), 5.04 (d, J = 6.3 Hz,
1H, PhCH), 6.63 (s, 1H, ArH), 7.31 (s, 1H, ArH), 7.43–7.74 (m, 10H,
ArH); 13C NMR dC: 21.0 (CH3CO), 31.9 (CH2Ar), 45.6, 49.9, 52.4,
55.9, 56.1, 58.6 (CHCO2Me 3xOMe and 2 CHS), 64.4, 64.8 (CH2CO,
CH2O), 68.5 (ArCH), 109.8, 112.8, 128.1, 128.4, 129.1, 129.3,
129.5, 134.2, 135.5, 137.3, 137.4, 137.5, 138.3, 148.7 (ArC), 167.4,
171.0 (2 ꢂ CO); MS (EI) m/z (%): 631.1 (M+, 0.1%), 348 (16), 347
(79), 272 (13), 256 (17), 255 (25), 254 (21), 229 (17), 228 (100),
227 (55), 215 (17), 214 (11), 213 (11), 212 (16), 200 (14), 197
(12), 196 (13), 184 (13); Microanalysis for C30H33NO10 S2: C,
57.0; H, 5.3; N, 2.2%, found: C, 57.3; H, 5.3; N, 2.5; HPLC (Chiralpak
AD, 1 mL/min, n-hexane/i-PrOH: 70/30, k 217 nm), tRmaj = 28.20 -
min, tRmin = 21.53.
4.4. Synthesis of pyrrolidine 16
To a solution of methyl (2R,3S,4S,5S)-5-phenyl-3,4-bis(phenyl-
sulfonyl)
pyrrolidine-2-carboxylate
endo-12aaa,
(22.0 mg,
0.04 mmol), in a 3:1 mixture of MeOH/THF (3 ml), 10% Na(Hg)
(69.3 mg) and Na2HPO4 (22.4 mg, 0.16 mmol) were sequentially
added at 0 °C. After stirring for 1 h at room temperature, ethyl ace-
tate (10 ml) was added, and the resulting suspension was filtered
and washed with water (2 ꢂ 5 ml). The aqueous phase was ex-
tracted with ethyl acetate (2 ꢂ 5 ml) and the combined organic
phases were washed with brine (5 ml), dried, and concentrated.
The residue (7:5 mixture of 14 and 15) was then dissolved in meth-
anol (3 ml) and Pt/C (10%) (30 mg) was added. The reaction was
stirred for 48 h under a hydrogen atmosphere (1 atm) at 25 °C
and the final mixture was filtered over a Celite pad. The remaining
solution was evaporated in vacuo and the residue was purified by
flash chromatography to give product 16a in 47% overall yield.
Methyl 5-phenylpyrrolidine-2-carboxylate 16a.16
4.7. Synthesis of imine 2224
To a cooled solution (0 °C) of tryptophol (0.5 g, 3.1 mmol) and
imidazole (0.46 g, 6.8 mmol) in DMF (3 mL), TBDMCl (0.51 g,
3.4 mmol) was added, and the reaction mixture was stirred for
16 h at 26 °C. Ethyl acetate was then added (10 mL) and the organic
phase was washed with brine (3 ꢂ 4 ml). The organic phase was
dried over MgSO4 and evaporated in vacuo. The residue was puri-
fied by flash chromatography to obtain the silyl-protected deriva-
tive (0.84 g, 99%). A solution of this derivative (0.84 g, 3.1 mmol)
4.5. Synthesis of imine 21
To
a solution of 3,4-dimethoxyphenethyl alcohol (3.0 g,
16.6 mmol) in pyridine (4 ml), Ac2O (1.6 ml, 16.6 mmol), DMAP

J. Mancebo-Aracil et al. / Tetrahedron: Asymmetry 23 (2012) 1596–1606
1605
in anhydrous DMF (3 ml) was slowly added at 0 °C to a suspension
4.9. Synthesis of the antiviral precursor 2425
of 60% NaH (0.19 g, 9.5 mmol) in anhydrous DMF (2 ml) and stir-
ring was continued at 25 °C for 30 min. Next, PhSO2Cl (0.53 ml,
4 mmol) was added in one portion and the reaction was main-
tained at the same temperature for another 19 h. A saturated solu-
tion of ammonium chloride was poured out (10 ml) and the
aqueous phase was extracted with diethyl ether (3 ꢂ 15 ml). The
combined organic phases were dried over MgSO4 and evaporated
in vacuo. The residue was purified by flash chromatography to ob-
tain the N-phenylsulfonyl derivative (0.79 g, 81%). The final formy-
lation was achieved by preparing a solution of the last compound
(0.79 g, 1.90 mmol) in anhydrous THF (2 mL), which was cooled
to ꢀ78 °C and treated with 1.6 M solution of BuLi in hexanes
(2.14 mL). After 2 h, the temperature was slowly increased to
25 °C and then immediately cooled to ꢀ78 °C. Next, DMF
(0.77 ml, 1 mmol) was added and the temperature again was al-
lowed to rise to 25 °C. A saturated solution of ammonium chloride
was poured out (10 mL) and the aqueous phase was extracted with
ethyl acetate (3 ꢂ 15 mL). The combined organic phases were dried
over MgSO4 and evaporated in vacuo. The residue was purified by
flash chromatography to obtain the desired aldehyde (0.63 g,
75%).24b
Compound 24 was prepared according to the procedure de-
scribed earlier (see Section 4.2).
tert-Butyl methyl (2S,4S,5R)-2-isobutyl-5-(thiazol-2-yl)pyrroli-
dine-2,4-dicarboxylate 24: ½a D20
¼ þ38 (c 1, CH2Cl2) 99% ee by HPLC
ꢁ
Lit.25
½
a 2D0
ꢁ
¼ þ43 (c 1, CH2Cl2) 99% ee by HPLC.
Acknowledgments
This work has been supported by the Spanish Ministerio de
Ciencia e Innovación (MICINN) through the Hispano-Brazilian pro-
ject PHB2008-0037-PC and CNPq-2878, Consolider INGENIO 2010
CSD2007-00006, CTQ2010-20387, FEDER, Generalitat Valenciana
(PROMETEO/2009/039), and by the University of Alicante. MM-R
thanks MEC for a predoctoral fellowship. EC thanks CNPq for a pre-
doctoral Doutorado Sanduíche stay.
References
1. Privileged Chiral Ligands and Catalysts; Qi-Lin Zhou, Ed.; Wiley-VCH: New York,
2011.
2. For the pioneering catalytic enantioselective 1,3-DC work carried out by Grigg
et al., see (a) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32, 5817–5820; (b)
Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475–2486.
Imine 22 was prepared in 95% pure crude yield as described for
21 (see above).
3. The enantioselective 1,3-DC of azomethine ylides is a prolific area in organic
synthesis and is frequently reviewed. For selected recent examples, see: (a)
Pellissier, H. Tetrahedron 2007, 63, 3235–3285; (b) Nájera, C.; Sansano, J. M. In
Topics in Heterocyclic Chemistry; Hassner, A., Ed.; Springer: Berlin, Heidelberg,
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2887–2902; (d) Álvarez-Corral, M.; Muñoz-Dorado, M.; Rodríguez-García, I.
Chem. Rev. 2008, 108, 3174–3198; (e) Naodovic, M.; Yamamoto, H. Chem. Rev.
2008, 108, 3132–3148; (f) Nájera, C.; Sansano, J. M.; Yus, M. J. Braz. Chem. Soc.
2010, 21, 377–412; (g) Kissane, M.; Maguire, A. R. Chem. Soc., Rev. 2010, 39,
845–883; (h) Adrio, J.; Carretero, J. C. Chem. Commun. 2011, 47, 6784–6794.
4. Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400–13401.
5. (a) Nájera, C.; Retamosa, M. G.; Sansano, J. M. Org. Lett. 2007, 9, 4025–4028; (b)
Nájera, C.; Retamosa, M. G.; Sansano, J. M.; de Cózar, A.; Cossío, F. P.
Tetrahedron: Asymmetry 2008, 19, 2913–2923.
(E)-Methyl 2-{[3-(2-[(tert-butyldimethylsilyloxy)ethyl]-1-(phe-
nyl sulfonyl)-1H-indol-2-yl]methylene}aminoacetate 22: Orange
sticky oil; IR (neat) t ;
max: 1747, 1631, 1371, 1170 cmꢀ1 1H NMR
dH: ꢀ0.17, 0.02 (2 ꢂ s, 6H, 2 ꢂ SiCH3), 0.87 [s, 9H, SiC(CH3)3], 2.88
(t, J = 6.7 Hz, 2H, CCH2), 3.31 (t, J = 6.7 Hz, 2H, OCH2), 3.81 (s, 3H,
CO2CH3), 4.53 (s, 2H, NCH2), 7.41–8.00 (m, 9H, ArCH), 8.84 (s, 1H,
NCH); 13C NMR dC: ꢀ2.8, ꢀ2.6, 18.2, 25.8, 28.5, 52.0, 62.5, 63.2,
113.6, 115.3, 119.5, 120.3, 121.3, 123.0, 124.1, 124.5, 126.6,
128.9, 129.1, 133.5, 158.6, 170.9; MS (EI) m/z (%): 514 (M+, 1%),
359 (16), 358 (59), 233 (11), 217 (11), 216 (51), 200 (16), 199
(100). HRMS calculated for
514.1967.
C26H34N2O5SSi: 514.1958; found:
6. (R)-Binap-Cu(MeCN)4ClO4 catalyzed the reaction with phenyl vinyl sulfone (up
to 26% ee). Llamas, T.; Gómez-Arrayás, R.; Carretero, J. C. Org. Lett. 2006, 8,
1795–1798.
7. (R)-Binap-Cu(OTf)2 catalyzed the reaction with maleimides (up to 64–65% ee of
the corresponding exo-adduct). Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.;
Kasano, Y.; Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043–5046.
8. [(Sa)-Binap-AuTFA]2 catalyzed the reaction with maleimides, maleates,
acrylates, vinylic sulfones, etc. (up to 99% ee). (a) Martín-Rodríguez, M.;
Nájera, C.; Sansano, J. M.; Wu, F. L. Tetrahedron: Asymmetry 2010, 21, 1184–
1186. and corringendum, 2010, 21, 2559; (b) Martín-Rodríguez, M.; Nájera, C.;
Sansano, J. M.; de Cózar, A.; Cossío, F. P. Chem. Eur. J. 2011, 17, 14224–14233.
9. The reactivity of the dimeric gold complex [(Sa)-Binap-AuTFA]2 has been
studied and compared with several silver complexes in the elaboration of the
key precursor of the 2nd generation GSK-inhibitors of the virus responsible for
hepatitis C: Martín-Rodríguez, M.; Nájera, C.; Sansano, J. M.; de Cózar, A.;
Cossío, F. P. Beilstein J. Org. Chem. 2011, 7, 988–996.
4.8. Synthesis of cycloadduct 20
A suspension of silver(I) trifluoroacetate (3 mg, 0.01 mmol), and
(S)-Binap (6 mg, 0.01 mmol) in toluene was stirred at 25 °C for
30 min while avoiding exposure to light. Next, imine 22 (51 mg,
0.1 mmol), 1,2-bis(phenylsulfonyl)ethylene (31 mg, 0.1 mmol),
and DABCO (2 mg, 0.01 mmol) were added in this order. The reac-
tion was stirred for 48 h at 25 °C and water (5 mL) and the aqueous
phase extracted with ethyl acetate (2 ꢂ 5 mL). The organic layer
was dried (MgSO4) and evaporated in vacuo to obtain cycloadduct
20.
10. For enantioselective gold(I)-catalyzed cycloadditions dealing with azlactones
see: (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, 133, 3517–3527; (c) Martín-Rodríguez, M.;
Nájera, C.; Sansano, J. M. Synlett 2012, 62–65.
Methyl
(2R,3R,4R,5S)-5-{3-[2-((tert-butyldimethylsi-
lyl)oxy)ethyl]-1-(phenylsulfonyl)-1H-indol-2-yl}-3,4-bis(phenyl-
sulfonyl)pyrrolidine-2-carboxylate 20: Colorless needles, mp
11. Unpublished estimated data calculated by F. P. Cossío and A. de Cózar
(University of the Basque Country).
155 °C (n-hexane/ethyl acetate); ½a D20
ꢁ
¼ ꢀ4:5 (c 1, CHCl3) 12% ee
from HPLC; IR (KBr) t ;
max: 1142, 1309, 1765, 3286 cmꢀ1 1H NMR
12. For
a preliminary communication, see: Martín-Rodríguez, M.; Nájera, C.;
Sansano, J. M.; Costa, P. R. R.; de Lima, E. C.; Dias, A. G. Synlett 2010, 962–967.
13. The endo descriptor refers the approach of the electron-withdrawing group to
the metalodipole before the cycloaddition.
14. Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5360–5361.
15. López-Pérez, A.; Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2008, 130, 10084–
10085.
16. See, for example: van Esseveldt, B. C. J.; Vervoort, P. W. H.; van Delft, F. L.;
Rutjes, P. J. T. J. Org. Chem. 2005, 70, 1791–1795.
17. Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795–6798.
18. Kam, T.; Sim, K. Phytochemistry 1997, 47, 145–147.
19. Coldham, I.; Jana, S.; Watson, L.; Martin, N. G. Org. Biomol. Chem. 2009, 7, 1674–
1679.
20. Ammendola, S.; Mosca, L.; Bovicelli, P. Arkivoc 2008, VIII, 105–115.
21. Nájera, C.; Sansano, J. M. Org. Biomol. Chem. 2009, 7, 4567–4581.
22. Nájera, C.; Retamosa, M. G.; Martín-Rodríguez, M.; Sansano, J. M.; de Cózar, A.;
Cossío, F. P. Eur. J. Org. Chem. 2009, 5622–5634.
dH: ꢀ0.137, ꢀ0.04 (2 ꢂ s, 6H, 2 ꢂ SiCH3), 0.79 [s, 9H, SiC(CH3)3],
2.81 (t, J = 6.6 Hz, 2H, OTBDMSCH2), 3.02 (td, J = 6.6, 1.9 Hz, 2H,
CCH2), 3.76–3.79 (m, 5H, CO2CH3, SCH, CHCO2CH3), 4.26 (d,
J = 7.1 Hz, 1H, NCH2), 4.87 (dd, J = 7.1, 4.7 Hz, 1H, CHN), 5.40 (s,
1H, NH), 7.07–8.01 (m, 19H, ArCH); 13C-NMR dC: ꢀ5.5,ꢀ5.3, 18.0,
29.9, 30.0, 30.6, 48.4, 51.9, 52.5, 62.5, 64.1, 108.7, 115.8, 115.9,
116.8, 116.9, 117.6, 125.6, 125.7, 126.9, 127.0, 128.00, 128.46,
128.73, 129.13, 129.86, 133.59, 134.09, 134.92, 136.96, 140.37,
171.5; MS (ESI) m/z (%): 822 (M+, 2%). Microanalysis for
C40H46N2O9 S3Si: C, 58.4; H, 5.6; N, 3.4%, found: C, 58.3; H, 5.3;
N, 3.5; HPLC (Chiralpak OD-H, 1 mL/min, n-hexane/i-PrOH: 93/7,
k 222 nm), tRmaj = 24.5 min, tRmin = 27.8 min.

1606
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M. Org. Lett. 2003, 5, 5043–5046; (b) Dogan, Ö.; Koyuncu, H.; Garner, P.; Bulut,
A.; Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8, 4687–4690.
Cascieri, M.; Strader, C. J. Am. Chem. Soc. 1993, 115, 12550–12568; (b) Kuethe,
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24. (a) Hirschmann, R.; Nicolau, K.; Pietranico, S.; Leahy, E.; Salvino, J.; Arison, B.;
Cichy, M.; Spoors, P.; Shakespeare, W.; Sprengeler, P.; Hamley, P.; Smith, A.;
Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.; Freidinger, R.;
25. Martín-Rodríguez, M.; Nájera, C.; Sansano, J. M.; de Cózar, A.; Cossío, F. P.
Beilstein J. Org. Chem. 2011, 7, 988–996.