Silver-catalysed multicomponent 1,3-dipolar cycloaddition of 2-oxoaldehydes-derived azomethine ylides

Article abstract of DOI:10.1016/j.tet.2015.09.039

The silver-catalysed multicomponent reaction between ethyl glyoxylate, 2,2-dimethoxyacetaldehyde, or phenylglyoxal as aldehyde components with a α-amino ester hydrochloride and a dipolarophile in the presence of triethylamine is described. This domino pro

Full text of DOI:10.1016/j.tet.2015.09.039

Tetrahedron 71 (2015) 8804e8816
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Silver-catalysed multicomponent 1,3-dipolar cycloaddition of
2-oxoaldehydes-derived azomethine ylides
,
,
b
,
y
a
,
a,b,
*
Juan Mancebo-Aracil a y, Alberto Cayuelas a , Carmen Najera , Jose M. Sansano
*
ꢀ
ꢀ
a
ꢀ
Department of Organic Chemistry and Centro de Innovacion en Química Avanzada (ORFEO-CINQA), Faculty of Sciences, University of Alicante,
E-03080 Alicante, Spain
b
ꢀ
Instituto de Síntesis Organica, Faculty of Sciences, University of Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2015
Received in revised form 14 September 2015
Accepted 16 September 2015
Available online 25 September 2015
The silver-catalysed multicomponent reaction between ethyl glyoxylate, 2,2-dimethoxyacetaldehyde, or
phenylglyoxal as aldehyde components with a -amino ester hydrochloride and a dipolarophile in the
presence of triethylamine is described. This domino process takes place at room temperature by in situ
liberation of the -amino ester followed by the formation of the imino ester, which is the precursor of
a
a
a metalloazomethine ylide. The cycloaddition of this species and the corresponding dipolarophile affords
polysubstituted proline derivatives. Ethyl glyoxylate reacts with glycinate, alaninate, phenylalaninate and
phenylglycinate at room temperature in the presence of representative dipolarophiles affording endo-
2,5-cis-cycloadducts in good yields and high diastereoselection. In addition, 2,2-dimethoxyacetaldehyde
is evaluated with the same amino esters and dipolarophiles, under the same mild conditions, generating
the corresponding endo-2,5-cis-cycloadducts with higher diastereoselections than the obtained in the
same reactions using ethyl glyoxylate. In the case of phenylglyoxal the corresponding 5-benzoyl-endo-
2,5-cis cycloadducts are obtained in short reaction times and similar diasteroselection.
Ó 2015 Elsevier Ltd. All rights reserved.
Dedicated to Professor Max Malacria on the
occasion of his 65th birthday
Keywords:
Multicomponent
Cycloaddition
Azomethine ylide
Catalysis
Silver
1. Introduction
situ by imine formation from the corresponding aldehyde and the
a
-amino ester. Second, the metal catalyst fixes the geometry of the
Multicomponent process1-atom economy2-catalysis3 consti-
tutes three paramount milestones in organic chemistry today.
Methodologies involving them constitute a clear trend of in-
novation in both laboratory and industrial scale. Many reactions do
not waste atoms during their whole process, cycloadditions being
the most frequently employed.4 In addition, a large number of
domino/multicomponent cycloadditions are found in the literature
with very interesting perspectives and applications, especially
when a multifunctionalization can be introduced in the final
structure. 1,3-Dipolar cycloadditions (1,3-DC)5,6 involving metallo-
azomethine ylides and electrophilic alkenes are appropriate to
execute this three concepts with high efficiency.7 With this
favourable features, examples of multicomponent 1,3-DC of azo-
methine ylides are frequently described nowadays.8,9 Firstly, the
1,3-dipole precursor (normally an imino ester) can be obtained in
dipole favouring a high stereocontrol during the dipolarophile ap-
proach and operates under milder reaction conditions. The result of
these cycloadditions are polysubstituted pyrrolidines or proline
derivatives with an aromatic or heteroaromatic ring at the 5-
position, which are very interesting molecules in many scientific
areas.10 In addition, the synthesis of pyrrolizidine alkaloids has
been achieved, employ a 1,3-dipolar cycloaddition (1,3-DC) using
mainly nitrones11 or azomethine ylides.12,13
In a preliminary work14 the thermal multicomponent 1,3-DC of
diethyl aminomalonate or a-amino esters with ethyl glyoxylate and
dipolarophiles could be performed by in situ formation of the imino
ester.14e16 In order to improve the diastereoselectivity, the lowering
of the temperature by the employment of metal salts for the
enantioselective multicomponent 1,3-DC of imino esters and dif-
ferent dipolarophiles can be achieved.17 In this work we described
the use of silver salts as catalysts for the room temperature mul-
ticomponent 1,3-DC of ethyl glyoxylate and also other 2-
oxoaldehydes such as 2,2-dimethoxyacetaldehyde and phenyl-
glyoxal for the synthesis of prolinates with different carbonyl
groups at the 5-position of the pyrrolidine ring.
* Corresponding authors. Fax: þ34 965903549; e-mail addresses: cnajera@ua.es
ꢀ
(C. Najera), jmsansano@ua.es (J.M. Sansano).
y
Fax: þ34 965903549.
http://dx.doi.org/10.1016/j.tet.2015.09.039
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
8805
2. Results and discussion
absence the reaction failed at room temperature (Table 1, entry 1).
When the reaction was performed in toluene, compound 1a was
obtained as a 3:1 cis/trans pure mixture independently of the silver
salt employed (Table 1, entries 2e7). All the silver salts tested such
as AgSbF6, AgOTf (OTf¼triflate), AgOTfa (OTfa¼trifluoroacetate),
AgOBz, and Ag2CO3 afforded good conversions with very pure
crude products. In this sense, AgOAc was selected due to the high
conversion achieved (>98%, Table 1, entry 5). The effect of the re-
action temperature in the diastereomeric ratio of the product 1a
was also surveyed finding identical dr at 25 ꢀC than at 0 ꢀC (Table 1,
compare entries 5 and 8). This crude mixture was not so pure when
the reaction was run in DCM, THF, Et2O, or EtOH (Table 1, entries
9e12). Copper(II) perchlorate and triflate can be also used although
secondary unidentified products were also formed (Table 1, entries
13 and 14).
2.1. 1,3-DC with ethyl glyoxylate
For the optimization studies, ethyl glyoxylate, N-methyl-
maleimide (NMM) and glycine ethyl ester hydrochloride were
allowed to react in the presence of triethylamine (1.1 equiv) and
silver salt (5 mol %) in toluene at room temperature (Scheme 1,
Table 1). The presence of silver salt was crucial because in its
With the selected reaction conditions in hand we study the
scope of this multicomponent silver-catalysed process starting
from ethyl glyoxylate, different maleimides and ethyl glycinate
(Scheme 2 and Table 2, entries 1e3). N-Benzylmaleimide (NBM)
Scheme 1. Optimization of the 1,3-DC between ethyl glycinate, ethyl glyoxylate, and
NMM catalysed by silver salts in different solvents.
Table 1
Optimization of the 1,3-DC between ethyl glycinate, ethyl glyoxylate, and NMM
catalysed by silver saltsa
Scheme 2. Silver-catalysed 1,3-DC of
dipolarophiles.
a-amino esters and ethyl glyoxylate with
Entry
AgX
Solvent
Conv. (%)b
cis-1/trans-1c
1
2
3
4
5
6
7
8
d
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMee
DCM
THF
EtOH
Et2O
PhMe
PhMe
<5
86d
89d
91d
>98d
95d
95d
95d
95f
d
AgSbF6
AgOTf
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
3/1
2.5/1
3/1
<3/1
<3/1
afforded a cis/trans 3:1 pure mixture of 1b in excellent yield (Table
2, entry 2). In both examples (NMM and NBM), chemical yields
and diastereomeric ratios were higher than under thermal re-
actions.14 However, with N-phenylmaleimide (NPM) the same
diastereomeric ratio in 1c was identified (cis/trans 4:1) in-
dependently of the thermal or silver-catalysed used method being
the chemical yield sensibly higher for the last reaction conditions
(Table 2, entry 3). The relative stereochemistry of the stereoiso-
mers 1aec involving reactions with ethyl glyoxylate was drawn
according to the comparison with previously published data (X-
ray diffraction analysis and NMR experiments). The control of the
geometry of the 1,3-metallodipole by the silver cation is notice-
able in this reaction allowing the reaction course through a W,W-
shape metallodipole A, which afforded 2,5-cis-adducts 1 rather
than the W,S-shape metallodipole A giving 2,5-trans-adducts 1
(Scheme 3).
AgOTfa
AgOAc
AgOBz
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Cu(ClO4)2
Cu(OTf)2
9
10
11
12
13
14
92f
89f
95d
90f
90f
a
Ethyl glyoxylate (50% w solution in toluene), ethyl aminoglycinate hydrochlo-
ride and NMM (1:1:1), triethylamine (1.1 equiv) and the silver salt (5 mol %) were
dissolved in toluene and the mixture allowed to react at 25 ꢀC for 19 h.
b
Obtained by analysis of crude 1H NMR spectra.
c
Determined by 1H NMR analysis.
d
Crude product was very pure by 1H NMR.
e
Reaction performed at 0 ꢀC.
f
Several impurities were observed by 1H NMR.
Table 2
Scope of the silver catalysed 1,3-DC between ethyl glyoxylate with different
a
-imino esters and dipolarophilesa
Product
Entry
R1
R2
Dipolarophile
Yield (%)b, drc
1
H
Et
NMM
84, 3/1 (80, 2/1)
2
H
Et
NBM
95, 3/1 (64, 1/1)
(continued on next page)

8806
J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
Table 2 (continued )
Entry
R1
R2
Dipolarophile
Product
Yield (%)b, drc
3
H
Et
NPM
85, 4/1 (71, 4/1)
4
Me
Me
NMM
59 (85)
5
6
Me
Me
Me
Me
Dimethyl fumarate
55 (70)
65 (66)
BPSEd
7
8
Me
Bn
Me
Et
Methyl acrylate
53, 1/1/1.5 (60, 1/1/1.5)
NMM
83 (96)
9
Bn
Bn
Et
Et
NBM
NPM
68 (75)
85 (80)
10
11
12
Bn
Bn
Et
Et
Dimethyl fumarate
38 (80)
48 (60)
BPSEd
13
14
Ph
Ph
Me
Me
NMM
90, 2.5/1 (87, 2/1)
Methyl acrylate
45, 2/1 (67, 1/1)

J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
8807
Table 2 (continued )
Entry
R1
R2
Dipolarophile
Product
Yield (%)b, drc
15
Ph
Me
Dimethyl fumarate
45, 2/3 (87, 1/1)
16
Ph
Me
BPSEd
25 (68)
a
Ethyl glyoxylate (50% w solution in toluene), amino ester hydrochloride and the dipolarophile (1:1:1), triethylamine (1.1 equiv) and the silver salt (5 mol %) were dissolved
in toluene and the mixture allowed to react at 25 ꢀC for 1 d.
Isolated yield after column chromatography.
In brackets data of the process performed under thermal conditions (Ref. 14).
BDSE 1,2-bis(phenylsulfonyl)ethylene.
b
c
d
as dipolarophiles, lower chemical yields were obtained than under
thermal conditions. The reaction was diastereoselective affording
exo-cis-cycloadduct 3d and endo-cis-cycloadduct 3e, respectively
(Scheme 2, Table 2, entries 11 and 12). With all this information W,W-
shape type metallodipole B (Scheme 4) should be mainly generated
during the reaction course employing the phenylalaninate.
Scheme 3. Metallodipole conformations derived from glycine ethyl ester and ethyl
In the case of phenylglycine methyl ester, the major endo-cis
compound 4a was obtained through a W,W-shape metallodipole B
geometry (Scheme 4). The chemical yield of the reaction carried out
with methyl acrylate was 45% affording a 1:1 mixture of the cis- and
trans-adducts 4f, which demonstrated a higher proportion of the
Sg-shape metallodipole B during the reaction course (Schemes 2
and 4, Table 2, entry 14). In both examples, the diastereomeric ra-
tio was slightly higher than the originally reported for the analo-
gous thermal processes14 2.5:1 versus 2:1 and 2:1 versus 1:1,
respectively. E-1,2-Disubstituted electrophilic alkenes were not
very appropriate substrates for the cycloaddition using silver-cat-
alysed conditions. In both diastereoselective transformations
chemical yields were lower than the results obtained for the ther-
mal processes.14 The exo-adducts 4d and 4e predominated (Scheme
2, Table 2, entries 15 and 16). The bulkier phenylsulfonyl group,
presumably preferred to react through the S-shape metallodipoles
B rather than W-shaped one (Scheme 4).
glyoxylate.
Due to the importance of the quaternary
scientific areas, the multicomponent 1,3-DC employing several
substituted -amino esters were tested. When alanine methyl ester
a-amino acids in many
a
-
a
hydrochloride was allowed to react with ethyl glyoxylate and NMM
under the optimized reaction conditions endo-cis-cycloadduct 2a
was isolated in 59% yield as unique diastereoisomer with lower
yield than the obtained in the thermal process14 (Scheme 2, Table 2,
entry 4). No difference was observed in the reactions (thermal14 or
silver-catalysed) involving methyl acrylate, dimethyl fumarate, and
1,2-bis(phenylsulfonyl)ethylene (Scheme 2, Table 2, entries 5e7).
The diastereoselective transformation occurred for both (E)-con-
figured alkenes furnishing endo-cis-2d and endo-cis-2e in 55 and
65% yields, respectively (Table 2, entries 5 and 6). A mixture of three
stereoisomers (cis- and trans-2f and 2f0) was obtained in 45% yield
in the case of methyl acrylate and alanine methyl ester hydro-
chloride (Scheme 2, Table 2, entry 7). According to these results
W,W-shape metallodipole B (Scheme 4) is mainly originated by the
silver cation. We can assume that the preferred attack occurred
We anticipate that working with different ester groups at 2- and
5- positions as occurred in final
a-substituted prolines 2, and 4
would allow to transform chemoselectively one of them (less ste-
rically hindered) leaving the other ester group unaltered.
through the less hindered
employed as dipolarophile.
g-position when methyl acrylate was
2.2. 1,3-DC with 2,2-dimethoxyacetaldehyde
Following the same strategy and with the idea to introduce
a new protected formyl group at the 5-position of the pyrrolidine
ring, we next evaluated the scope of the multicomponent process
using 2,2-dimethoxyacetaldehyde as imine precursor. Ethyl glyci-
nate, maleimides and 2,2-dimethoxyacetaldehyde was an appro-
priate combination to be catalysed by AgOAc (Scheme 5 and
Table 3). Again the presence of the silver salt was crucial for
Scheme 4. Metallodipole conformations derived from a-substituted amino esters and
ethyl glyoxylate.
Phenylalanine ethyl ester hydrochloride smoothly reacted with
maleimides at room temperature using ethyl glyoxylate and silver
acetate (5 mol %). Again, endo-cis cycloadducts 3aec were isolated
diastereoselectively in good chemical yields (Scheme 2, Table 2, en-
tries 8e10). However, when more sterically hindered dimethyl fu-
marate and 1,2-bis(phenylsulfonyl)ethylene (BPSE) were employed
Scheme 5. Silver-catalysed 1,3-DC of a-amino esters and 2,2-dimethoxyacetaldehyde
with dipolarophiles.

Table 3
Scope of the silver catalysed 1,3-DC between 2,2-dimethoxyacetaldehyde with different
a
-imino esters and dipolarophilesa
Product
Entry
R1
R2
Dipolarophile
Yield (%)b
1
H
Et
NMM
74c,d
2
3
H
H
Et
Et
NBM
NPM
73d
71d
4
Me
Me
NMM
89d
5
6
Me
Me
Me
Me
Dimethyl fumarate
Methyl acrylate
43d
85
7
8
9
Bn
Bn
Bn
Et
Et
Et
NMM
NBM
NPM
87d
96d
85d
10
Bn
Et
Et
Dimethyl fumarate
66
70d
11
CO2Et
NMM
a
2,2-Dimethoxyacetaldehyde, amino ester hydrochloride and the dipolarophile (1:1:1), triethylamine (1.1 equiv) and the silver salt (5 mol %) were dissolved in toluene and
the mixture allowed to react at 25 ꢀC for 1 d.
b
Isolated yield after column chromatography.
c
Thermal MW-reaction afforded a 2:1 mixture of diastereoisomers (see text).
d
dr>50:1, determined by 1H NMR analysis.

J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
8809
obtaining total reaction conversions. In general, the reaction was
diastereoselective (>50:1 ratio by 1H NMR) and the chemical yields
of endo-2,5-cis-adducts 5 were satisfactory (71e74%) (Scheme 5,
Table 3, entries 1e3). These results indicated that stabilization of
the W,W-shape metallodipole type-C during the reaction course is
very important, probably due to a stronger coordination between
the two methoxy groups rather than the carbonyl group of the
glyoxylate (Scheme 6). The unfruitful multicomponent reaction of
acetaldehyde, glycine methyl ester hydrochloride and NMM con-
firmed the important role of this extra-coordination of dipole C.
cis-stereoisomers 6f, together with an unidentified diastereoisomer
was obtained. Stereoisomers 6f were isolated after purification in
85% yield (Scheme 5, Table 3, entry 6).
Phenylalanine ethyl ester derivative afforded endo-cis-com-
pounds 7aec in very good chemical yields and excellent diaster-
eoselections upon domino reaction with a maleimide and 2,2-
dimethoxyacetaldehyde (Scheme 5, Table 3, 7e9). The crude re-
action 1H NMR spectra revealed that any other stereoisomer was
formed.
Besides, a considerable lower diastereoselection was obtained
when dimethyl fumarate was employed as dipolarophile. The 3:1
endo-cis-7d:exo-cis-7d ratio was determined by 1H NMR and the
relative configuration assigned according to NOE experiments
(Scheme 5, entry 10). At this point the reaction with 1,2-
bis(phenylsulfonyl)ethylene completely failed, which confirms the
low chemical yield observed in precedent reactions possibly due to
steric reasons. The reactions dealing with phenylglycine derivative
were surveyed obtaining very complex crude reaction products
with many side products.
Unlike the behaviour observed with ethyl glyoxylate, 2,2-
dimethoxyacetaldehyde reacted in the presence of NMM and
diethyl aminomalonate in good yield (70%) and high di-
astereomeric ratio affording mainly all-cis compound 8 (Scheme 5,
Table 3, entry 11).
Scheme 6. Metallodipole conformation derived from 1,3-DC of a-substituted amino
esters and 2,2-dimethoxyacetaldehyde.
In addition, the microwave-assisted reaction at 110 ꢀC was
performed using NMM as example. This thermal transformation
produced a 2:1 mixture of cis:trans endo-cycloadducts 5a in 65%
yield (Scheme 7). In this last example, the thermal [1,2]-prototropy
did not control the geometry of the dipole as expected due to the
existence of S-dipole D in high proportions (Scheme 8). The con-
trast of this low diastereoselection with the good result achieved in
the silver-catalysed process prompted us to discard a parallel study
of the thermal reaction conditions.
2.3. 1,3-DC with phenylglyoxal
The benzoyl group was introduced at the 5-position of the
pyrrolidine ring by employing phenylglyoxal as aldehyde compo-
nent.16 The reactions were carried out under identical conditions
described in the two previous sections, silver salt being necessary
for the success of the process (Scheme 9 and Table 4).
Scheme 9. Silver-catalysed 1,3-DC of
a-amino esters and phenylglyoxal with
dipolarophiles.
Table 4
Scheme 7. Thermal 1,3-DC of ethyl glycinate, NMM and 2,2-dimethoxyacetaldehyde.
Scope of the silver catalysed 1,3-DC between phenylglyoxal with different
a
-imino
esters and dipolarophilesa
Entry R1
R2 Dipolarophile
Me NMM
Product
Yield (%)b
1
2
H
H
55c
Scheme 8. Dipole conformation for thermal 1,3-DC of ethyl glycinate, NMM and 2,2-
dimethoxyacetaldehyde.
Me NBM
48
70
Almost complete diastereoselection was detected when alanine
derivative and 2,2-dimethoxyacetaldehyde were allowed to react
with NMM and dimethyl fumarate. Compound endo-2,5-cis-6a was
isolated in 89% yield whilst endo-2,5-cis-6d was obtained in a lower
43% yield (Scheme 5, Table 3, entries 4 and 5). In this last reaction,
apart from starting reagents, small amounts of other secondary
products were hardly detected. When methyl acrylate was tested as
dipolarophile an equimolar mixture of endo-2,5-cis- and exo-2,5-
3
H
Mr NPM
(continued on next page)

8810
J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
Table 4 (continued )
aldehydes such as ethyl glyoxylate, 2,2-dimethoxyacetaldehyde, or
Entry R1
R2 Dipolarophile
Product
Yield (%)b
phenylglyoxal was successfully accomplished. In general, in the
catalysed process with ethyl glyoxylate the endo-2,5-cis-diaster-
eoselections and chemical yields were in general better than those
obtained under thermal conditions. When the reaction was per-
formed with 2,2-dimethoxyacetaldehyde or phenylglyoxal the sil-
ver-catalysed conditions for the cycloaddition gave the best results.
In this case, higher 2,5-cis-diastereoselections than in the reactions
involving ethyl glyoxylate were obtained, possibly due to the most
favoured W,W-metallodipole geometry.
4
5
Me
Me Maleimide
64
Bn
Et NMM
78
97
4. Experimental section
4.1. General
The structurally most important peaks of the IR spectra (recor-
6
7
Bn
Bn
Et NPM
ded using a Nicolet 510 P-FT) are listed. 1H NMR (300 MHz) and 13
C
NMR (75 MHz) spectra were obtained using a Bruker AC-300 with
CDCl3 as solvent and TMS as internal standard unless otherwise
stated. Low-resolution electron impact (GC-EI) mass spectra were
obtained at 70 eV using a Shimadzu QP-5000, and high-resolution
mass spectra were obtained using a Finnigan VG Platform. Ana-
lytical TLC was performed using Schleicher & Schuell F1400/LS
silica gel plates, and the spots were visualized under UV light
Et Dimethyl
fumarate
47
40
(
l
¼254 nm). Melting points were determined with a Reichert
Thermovar hot plate apparatus and are uncorrected. For flash
chromatography, Merck silica gel 60 (0.040e0.063 mm) was
employed.
8
CO2Et Et NMM
a
4.2. General procedure for the synthesis of cycloadducts
Phenylglyoxal, amino ester hydrochloride and the dipolarophile (1:1:1),
triethylamine (1.1 equiv) and the silver salt (5 mol %) were dissolved in toluene
and the mixture allowed to react at 25 ꢀC for 1 d.
Isolated yield after column chromatography.
A small amount (5%) of exo-cis-9a was isolated.
Ethyl glyoxylate (100
m
L, 0.5 mmol, 50% in toluene) or 2,2-
L, 0.5 mmol, 50% in water), or phe-
L, 0.5 mmol); diethyl aminomalonate
b
c
dimethoxyacetaldehyde (75
nylglyoxal monohydrate (58
m
m
The reactions involving glycine methyl ester hydrochloride and
hydrochloride or the amino acid ethyl ester hydrochloride
(0.5 mmol), the corresponding dipolarophile (0.5 mmol), AgOAc
(4.1 mg, 0.025 mmol) and triethylamine (90 mL, 0.55 mmol) were
maleimides afforded cycloadducts endo-2,5-cis-9 in moderate to
good chemical yields (Table 4, entries 1e3). Alanine or phenylala-
nine derivatives and maleimides also gave the expected 2,5-cis-
products 10a, 11a and 11c, in good yields and excellent endo-dia-
stereoselection (Table 4, entries 4e6). Methyl fumarate reacted in
the presence of the phenylalanine giving compound 11d as unique
stereoisomer in 47% yield. The multicomponent reaction of NMM
and diethyl aminomalonate occurred in moderate yield (40%) and
high diastereomeric ratio affording mainly all-cis compound 12
(Scheme 9, Table 4, entry 8). In some examples we observed a slight
decomposition of the cycloadducts during the chromatographic
separation and a deactivation of flash silica-gel was previously done
with triethylamine.
dissolved in toluene (4 mL). The reaction vessel was covered with
an aluminium foil in order to prevent the light exposure. Once the
reaction was judged complete after a TLC test the solvent was
evaporated under reduced pressure and the residue was dissolved
in ethyl acetate, washed with brine and dried over MgSO4. After
evaporation the residue was purified by flash chromatography
(silica gel) to afford the corresponding product. The reaction in-
volving ethyl glyoxylate and 2,2-dimethoxyacetaldehyde were
scaled up 10 times to afford endo-cis-3a and endo-cis-5a in 80% and
75%, respectively.
The intermediacy of the W,W-metallodipole F as intermediate
species (Fig. 1) can justify the relative cis-configuration between
two and five substituents.
4.2.1. Diethyl (1R*,3S*,3aR*,6aS*)-5-methyl-4,6-dioxooctahydro pyr-
rolo[3,4-c]pyrrole-1,3-dicarboxylate (endo-cis-1a).14 Sticky yellow
oil; IR (neat) nmax 2984, 1699, 1595 cmꢁ1 1H NMR dH: 1.33 (t,
;
J¼7.2 Hz, 6H, 2ꢂCO2CH2CH3), 2.94 (s, 3H, NCH3), 3.57 [m, 2H,
2ꢂCHCH(CO2Et)NH], 3.97 [m, 2H, 2ꢂCH(CO2Et)NH], 4.30 (q,
J¼7.2 Hz, 4H, 2ꢂCO2CH2CH3), NH nd; 13C NMR dC
: 14.2
(2ꢂCO2CH2CH3), 25.5 (NCH3), 50.0 [2ꢂCHCH(CO2Et)NH], 61.9
(2ꢂCO2CH2CH3), 63.1 [2ꢂCH(CO2Et)NH], 169.0 (2ꢂCO2CH2CH3),
175.0 (2ꢂCON); MS (EI-GC) m/z: 298 (Mþþ1, 1%), 226 (12), 225
(100), 179 (32), 151 (53), 94 (44), 67 (12); HRMS calcd for
C13H18N2O6: 298.1155, found: 298.1148.
Fig. 1. Metallodipole conformations derived from
a-substituted amino esters and
phenylglyoxal.
4.2.2. Diethyl (1R*,3R*,3aR*,6aS*)-5-methyl-4,6-dioxooctahydro pyr-
rolo[3,4-c]pyrrole-1,3-dicarboxylate (endo-trans-1a).14 Sticky yel-
low oil; IR (neat) nmax 2984, 1774, 1731, 1595 cmꢁ1; 1H NMR dH: 1.33
(t, J¼7.2 Hz, 3H, CO2CH2CH3), 1.35 (t, J¼7.2 Hz, 3H, CO2CH2CH3), 2.98
(s, 3H, NCH3), 3.56 [deform. dd, J¼8.0, 8.0 Hz, 1H, CHCH(CO2Et)NH],
3.64 [dd, J¼8.0, 1.2 Hz, 1H, CHCH(CO2Et)NH], 4.13 [d, J¼8.0 Hz, 1H,
3. Conclusions
The silver catalysed endo-diastereoselective multicomponent
1,3-DC using -amino esters, dipolarophiles and functionalized
a

J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
8811
CH(CO2Et)NH], 4.24 (q, J¼7.2 Hz, 2H, CO2CH2CH3), 4.27e4.35 [m,
3H, CO2CH2CH3 and CH(CO2Et)NH], NH nd; 13C NMR dC: 14.2, 14.3
(2ꢂCO2CH2CH3), 25.5 (NCH3), 47.6 [CHCH(CO2Et)NH], 48.8 [CHCH
(CO2Et)NH], 61.8, 62.0 (2ꢂCO2CH2CH3), 62.2 [CH(CO2Et)NH], 62.4
[CH(CO2Et)NH], 169.7, 171.7 (2ꢂCO2), 175.4, 176.6 (2ꢂCON); MS (EI-
GC) m/z: 298 (Mþþ1, 1%), 226 (12), 225 (100), 179 (17), 151 (40), 94
(40), 68 (10), 67 (13),; HRMS calcd for C13H18N2O6: 298.1155, found:
298.1148.
3H, C(CO2CH3)CH3], 2.93 (s, 3H, NCH3), 3.25 [d, J¼8.0 Hz, 1H,
CHC(CO2Me)CH3], 3.37 (d, J¼12.5 Hz, 1H, NH), 3.63 [deform. dd,
J¼8.0, 8.0 Hz, 1H, CHCH(CO2Et)NH], 3.83 (s, 3H, CO2CH3), 4.14 [dd,
J¼12.5, 8.0 Hz, 1H, CH(CO2Et)NH], 4.30 (q, J¼7.2 Hz, 2H,
CO2CH2CH3); 13C NMR dC: 14.2 (CO2CH2CH3), 24.6 [C(CO2CH3)CH3],
25.4 (NCH3), 50.4 [CHCH(CO2Et)NH], 53.1 [CHC(CO2Me)CH3], 62.0
(CO2CH3), 62.1 (CO2CH2CH3), 69.4 [CH(CO2Me)CH3], 169.5, 171.7
(2ꢂCO2), 175.0, 175.2 (2ꢂCON); MS (EI-GC) m/z: 298 (Mþþ1, <1%),
239 (67), 225 (39), 165 (100), 108 (43), 81 (10), 80 (21); HRMS calcd
for C13H18N2O6: 298.1165, found: 298.1163.
4.2.3. Diethyl (1R*,3S*,3aR*,6aS*)-5-benzyl-4,6-dioxooctahydro pyr-
rolo[3,4-c]pyrrole-1,3-dicarboxylate (endo-cis-1b).14 Sticky yellow
oil; IR (neat) nmax 2984, 1740, 1705 cmꢁ1
;
1H NMR dH: 1.28 (t,
4.2.8. 5-Ethyl 2,3,4-trimethyl (2S*,3S*,4S*,5R*)-2-methylpyrrolidine-
J¼7.1 Hz, 6H, 2ꢂCO2CH2CH3), 3.54 [m, 2H, CHCH(CO2Et)NH], 3.94
2,3,4,5-tetracarboxylate (endo-cis-2d).14 Pale yellow oil; IR (neat)
[m, 2H, CH(CO2Et)NH], 4.24 (q, J¼7.1 Hz, 4H, 2ꢂCO2CH2CH3), 4.58 (s,
nmax 2986, 2954, 2907, 1730, 1729 cmꢁ1 1H NMR dH: 1.27 (t,
;
2H, CH2Ph), 7.18e7.38 (m, 5H, ArH); 13C NMR dC
:
14.1
J¼7.1 Hz, 3H, CO2CH2CH3), 1.60 [s, 3H, C(CO2CH3)CH3], 3.24 [d,
J¼10.0 Hz, 1H, CHC(CO2Me)Me], 3.64, 3.68, 3.74 (3s, 3H, CO2CH3),
3.78 [dd, J¼10.0, 8.1 Hz, 1H, CHCH(CO2Et)NH], 4.02 [d, J¼8.1 Hz, 1H,
CH(CO2Et)NH], 4.15 (q, J¼7.1 Hz, 2H, CO2CH2CH3), NH nd; 13C NMR
dC: 14.2 (CO2CH2CH3), 24.9 [C(CO2CH3)CH3], 49.6 [CHC(CO2Me)Me],
52.3, 52.6 52.7 (3ꢂCO2CH3), 56.8 [CHCH(CO2Et)NH], 61.7
[CH(CO2Et)NH], 61.8 (CO2CH2CH3), 68.4 [C(CO2Me)Ph], 170.6, 172.3,
173.0, 173.8 (4ꢂCO2); MS (EI-GC) m/z: 331 (Mþþ1, <2%), 272 (65),
258 (19), 262 (19), 241 (10), 240 (82), 226 (99), 212 (80), 198 (60),
180 (10), 167 (11), 166 (100), 154 (25), 140 (72), 139 (10), 136 (10),
122 (10), 108 (58), 94 (11), 81 (22), 80 (27), 59 (24); HRMS calcd for
(2ꢂCO2CH2CH3), 43.0 (CH2Ph), 49.8 [2ꢂCHCH(CO2Et)NH], 62.0
(2ꢂCO2CH2CH3), 63.0 [2ꢂCH(CO2Et)NH], 128.1, 128.6, 128.7, 135.2
(ArC), 168.8 (2ꢂCO2CH2CH3), 174.6 (CON); MS (EI-GC) m/z: 374
(Mþþ1, 2%), 302 (18), 301 (100), 227 (50), 94 (23), 91 (47), 68 (11);
HRMS calcd for C19H22N2O6: 374.1478, found: 374.1470.
4.2.4. Diethyl (1R*,3R*,3aR*,6aS*)-5-benzyl-4,6-dioxooctahydro pyr-
rolo[3,4-c]pyrrole-1,3-dicarboxylate (endo-trans-1b).14 Sticky yel-
low oil; IR (neat) nmax 2990, 1740, 1700 cmꢁ1; 1H NMR dH: 1.23e1.38
(m, 6H, 2ꢂCO2CH2CH3), 3.64 (dd, J¼8.0, 1.4 Hz,1H, CHCH(CO2Et)
NH), 4.10e4.33 [m, 6H, CHCH(CO2Et)NH and CH(CO2Et)NH and
2ꢂCO2CH2CH3], 4.52e4.69 (m, 3H, CH2Ph and CH(CO2Et)NH),
7.18e7.40 (m, 5H, ArH); 13C NMR dC: 14.2, 14.3 (2ꢂCO2CH2CH3), 43.1
(CH2Ph), 48.8 [CHCH(CO2Et)NH], 49.9 [CHCH(CO2Et)NH], 61.8, 62.0
(2ꢂCO2CH2CH3), 62.2 [CH(CO2Et)NH], 62.5 [CH(CO2Et)NH], 128.1,
128.8, 129.1, 135.4 (ArC), 169.6, 171.7 (2ꢂCO2CH2CH3), 175.0, 176.3
(2ꢂCON); MS (EI-GC) m/z: 374 (Mþþ1, 2%), 302 (18), 301 (100), 227
(31), 94 (20), 91 (44), 68 (13); HRMS calcd for C19H22N2O6: 374.1478,
found: 374.1470.
C14H21NO8: 331.1267, found: 331.1274.
4.2.9. 5-Ethyl 2-methyl (2R*,3R*,4R*,5S*)-2-methyl-3,4-
bis(phenylsulfonyl)pyrrolidine-2,5-dicarboxylate
(endo-cis-2e).14
Orange oil; IR (neat) nmax 2985, 2956, 2905, 1735, 1710, 1308,
1146 cmꢁ1
;
1H NMR dH: 1.00 (t, J¼7.1 Hz, 3H, CO2CH2CH3), 1.72 [s,
3H, C(CO2CH3)CH3], 3.72 (s, 3H, CO2CH3), 3.94 (q, J¼7.1 Hz, 2H,
CO2CH2CH3), 4.27 [d, J¼6.5 Hz, 1H, CH(CO2Et)NH], 4.28 [d, J¼4.5 Hz,
1H, CHC(CO2Me)Me], 5.01 [dd, J¼6.5, 4.5 Hz, 1H, CHCHCO2Et],
7.51e7.71 (m, 6H, ArH), 7.81e8.02 (m, 4H, ArH), NH nd; 13C NMR dC
:
4.2.5. Diethyl (1R*,3S*,3aR*,6aS*)-4,6-dioxo-5-phenyloctahydro pyr-
14.0 (CO2CH2CH3), 23.7 [CHC(CO2Me)CH3], 52.7 [CH(CO2Et)NH],
61.5 (CO2CH3), 62.2 (CO2CH2CH3), 69.4 [C(CO2Me)Me], 69.5
[CHC(CO2Me)Me], 73.0 [CHCH(CO2Et)NH],128.4,128.9,129.3,129.4,
134.2,134.4,138.1, 140.4 (ArC), 170.1, 171.2 (2ꢂCO2); MS (EI-GC) m/z:
495 (Mþþ1, <1%), 294 (32), 279 (21), 248 (39), 237 (14), 236 (100),
222 (26), 221 (10), 156 (11), 128 (17), 125 (11), 108 (23), 96 (26), 95
(10), 94 (11), 81 (46), 80 (21), 77 (14); HRMS calcd for C22H25NO8S2:
495.1022, found: 495.1015.
rolo[3,4-c]pyrrole-1,3-dicarboxylate
(endo-cis-1c).14 Colourless
needles, mp¼123e125 ꢀC (from hexane/CDCl3); IR (neat) nmax 2980,
1741, 1732, 1708 cmꢁ1
;
1H NMR dH: 1.32 (t, J¼7.2 Hz, 6H,
2ꢂCO2CH2CH3), 3.05 (t, J¼12.7 Hz, 1H, NH), 3.71 [m, 2H,
2ꢂCHCH(CO2Et)NH], 4.06 [m, 2H, CH(CO2Et)NH], 4.29 (q, J¼7.2 Hz,
4H, 2ꢂCO2CH2CH3), 7.19e7.22 (m, 2H, ArH), 7.37e7.46 (m, 3H, ArH);
13C NMR dC: 14.0 (2ꢂCO2CH2CH3), 49.9 [2ꢂCHCH(CO2Et)NH], 62.1
(2ꢂCO2CH2CH3), 63.4 [2ꢂCH(CO2Et)NH], 126.5, 128.9, 129.2, 131.3
(ArC), 169.0 (2ꢂCO2CH2CH3), 174.1 (2ꢂCON); MS (EI-GC) 360 m/z
(Mþþ1, 3%), 288 (19), 287 (100), 94 (45), 68 (13), 67 (11); HRMS
calcd for C18H20N2O6: 360.1301, found: 360.1291.
4.2.10. 2-Ethyl 3,5-dimethyl (2R*,3S*,5S*)-5-methylpyrrolidine-2,3,5-
tricarboxylate (endo-cis-2f).14 Yellowish oil; IR (neat) nmax 2983,
2954, 1731, 1725, 1700 cmꢁ1
;
1H NMR dH: 1.26 (t, J¼7.2 Hz, 3H,
CO2CH2CH3), 1.49 [s, 3H, C(CO2CH3)CH3], 2.01 [dd, J¼12.9, 9.8 Hz,
1H, CHHC(CO2Me)CH3], 2.64 [dd, J¼12.9, 8.3 Hz, 1H, CHHC(CO2Me)
CH3], 3.19 [ddd, J¼9.8, 8.3, 7.1 Hz,1H, CH(CO2Me)], 3.71, 3.73 (2s, 3H,
CO2CH3), 3.77 [d, J¼7.1 Hz, 1H, CH(CO2Et)NH], 4.16 (q, J¼7.2 Hz, 2H,
4.2.6. Diethyl (1R*,3R*,3aR*,6aS*)-4,6-dioxo-5-phenyloctahydro pyr-
rolo[3,4-c]pyrrole-1,3-dicarboxylate
endo-trans-1c).14 Colourless
needles mp¼105e107 ꢀC (from hexane/CDCl3); IR (neat) nmax 2976,
1712 cmꢁ1
;
1H NMR dH: 1.20e1.32 (m, 6H, 2ꢂCO2CH2CH3), 2.85
CO2CH2CH3), NH nd; 13C NMR dC
: 14.3 (CO2CH2CH3), 25.9
(br s, 1H, NH), 3.68 [deform. dd, J¼8.1, 8.1 Hz, 1H, CHCH(CO2Et)NH],
3.83 [d, J¼8.1, 1H, CHCH(CO2Et)NH], 4.25 [m, 5H, 2ꢂCO2CH2CH3 and
CH(CO2Et)NH], 4.42 [s, 1H, CH(CO2Et)NH], 7.23e7.27 (m, 2H, ArH),
7.38e7.47 (m, 3H, ArH); 13C NMR dC: 14.0, 14.1 (2ꢂCO2CH2CH3), 47.6
[CHCH(CO2Et)NH], 49.9 [CHCH(CO2Et)NH], 61.9, 62.1 (2ꢂCO2CH2
CH3), 62.3 [CH(CO2Et)NH], 62.9 [CH(CO2Et)NH], 126.4, 128.8, 129.1,
131.5 (ArC), 169.8, 171.4 (2ꢂCO2CH2CH3), 174.6, 175.6 (2ꢂCON); MS
(EI-GC) 360 m/z: (Mþþ1, 4%), 67 (10), 68 (13), 94 (40), 287 (100),
288 (17); HRMS calcd for C18H20N2O6: 360.1301, found: 360.1291.
[C(CO2CH3)CH3], 40.7 [CH2C(CO2Me)CH3], 47.4 [CHCH(CO2Et)NH],
52.4, 52.7 (2ꢂCO2CH3), 61.6 (CO2CH2CH3), 63.0 [CH(CO2Et)NH], 66.3
[C(CO2Me)CH3], 172.8, 173.5, 176.3 (3ꢂCO2); MS (EI-GC) m/z: 273
(Mþþ1, <2%), 215 (11), 214 (100), 200 (30), 168 (13), 140 (33), 108
(19), 82 (21); HRMS calcd for C12H19NO6: 273.1212, found: 273.1214.
4.2.11. 2-Ethyl 3,5-dimethyl (2R*,3S*,5R*)-5-methylpyrrolidine-2,3,5-
tricarboxylate (endo-trans-2f).14 Yellowish oil; IR (neat) nmax 2983,
2953, 1732, 1725, 1703 cmꢁ1
;
1H NMR dH: 1.25 (t, J¼7.2 Hz, 3H,
CO2CH2CH3), 1.37 [s, 3H, C(CO2CH3)CH3], 2.01 [dd, J¼13.5, 8.0 Hz,1H,
CHHC(CO2Me)CH3], 2.68 [dd, J¼13.5, 7.2 Hz, 1H, CHHC(CO2Me)CH3],
3.30 [ddd, J¼8.0, 7.2, 7.0 Hz, 1H, CHCH(CO2Et)], 3.62, 3.73 (2s, 3H,
CO2CH3), 4.03 [d, J¼7.0 Hz, 1H, CH(CO2Et)NH], 4.15 (q, J¼7.2 Hz, 2H,
4.2.7. 3-Ethyl 1-methyl (1S*,3R*,3aS*,6aR*)-1,5-dimethyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate
endo-cis-
2a).14 Sticky pale yellow oil; IR (neat) nmax 2983, 2955, 1777, 1735,
1697 cmꢁ1
;
1H NMR dH: 1.36 (t, J¼7.2 Hz, 3H, CO2CH2CH3), 1.49 [s,
CO2CH2CH3), NH nd; 13C NMR dC
: 14.2 (CO2CH2CH3), 28.3

8812
J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
[C(CO2CH3)CH3], 39.1 [CH2C(CO2Me)CH3], 47.1 [CHCH(CO2Et)NH],
53.3, 53.4 (2ꢂCO2CH3), 61.4 (CO2CH2CH3), 62.8 [CH(CO2Et)NH], 65.4
[C(CO2Me)CH3], 172.3, 173.6, 176.4 (3ꢂCO2); MS (EI-GC) m/z: 273
(Mþþ1, <2%), 215 (12), 214 (100), 200 (33), 140 (62), 108 (20), 99
(24), 82 (23); HRMS calcd for C12H19NO6: 273.1212, found: 273.1215.
m/z: 450 (Mþþ1, <1%), 377 (14), 360 (22), 359 (100), 207 (44), 166
(40),156 (10),119 (10), 94 (13), 91 (45); HRMS calcd for C25H26N2O6:
450.1791, found: 450.1801.
4.2.16. 5-Ethyl 2,3,4-trimethyl (2S*,3S*,4S*,5R*)-2-benzylpyrrolidine-
2,3,4,5-tetracarboxylate (endo-cis-3d).14 Colourless oil; IR (neat)
nmax 2983, 2954, 2906, 1732, 1727 cmꢁ1; 1H NMR dH: 1.22, 1.26 (2t,
J¼7.1 Hz, 3H, CO2CH2CH3), 3.13, 3.37 (2d, J¼13.8 Hz, 2H, CH2Ph),
3.34 [d, J¼10.1 Hz, 1H, CHC(CO2Et)Bn], 3.65 [dd, J¼10.1, 8.5 Hz, 1H,
CHCH(CO2Et)NH], 3.70, 3.78 (2s, 3H, CO2CH3), 3.86 [d, J¼8.5 Hz, 1H,
CH(CO2Et)NH], 4.05e4.25 (m, 4H, 2ꢂCO2CH2CH3), 7.24e7.36 (m,
5H, ArH), NH nd; 13C NMR dC: 14.0, 14.2 (2ꢂCO2CH2CH3), 42.6
(CH2Ar), 49.3 [CHC(CO2Et)Bn], 52.4, 52.6 (2ꢂCO2CH3), 54.8
[CHCH(CO2Et)NH], 61.6 [CH(CO2Et)NH], 62.0, 61.7 (2ꢂCO2CH2CH3),
72.3 [C(CO2Et)Bn], 127.1, 128.3, 130.9, 135.9 (ArC), 170.5, 171.9, 172.3,
172.9 (4ꢂCO2); MS (EI-GC) m/z: 407 (Mþþ1, <1%), 348 (18), 330
(48), 316 (44), 298 (100), 166 (32), 138 (11), 91 (60); HRMS calcd for
4.2.12. 5-Ethyl 2,3-dimethyl (2S*,3R*,5R*)-2-methylpyrrolidine-2,3,5-
tricarboxylate (endo-cis-2f0).14 Yellowish oil; IR (neat) nmax 2983,
2955, 1730, 1726, 1700 cmꢁ1
;
1H NMR dH: 1.26 (t, J¼7.1 Hz, 3H,
CO2CH2CH3), 1.51 [s, 3H, C(CO2CH3)CH3], 2.29e2.57 [m, 2H,
CH2CH(CO2Et)], 2.87 [dd, J¼9.5, 8.1 Hz, 1H, CHC(CO2Me)CH3], 3.65,
3.66 (2s, 3H, CO2CH3), 3.87 [dd, J¼8.6, 7.6 Hz, 1H, CH(CO2Et)NH],
4.15 (q, J¼7.1 Hz, 2H, CO2CH2CH3), NH nd; 13C NMR dC: 14.3
(CO2CH2CH3), 25.5 [CHC(CO2Me)CH3], 32.3 [CH2CH(CO2Et)NH],
52.0, 52.1 (2ꢂCO2CH3), 52.5 [CHC(CO2Me)Me], 58.0 [CH(CO2Et)NH],
61.4 (CO2CH2CH3), 68.3 [C(CO2Me)Me], 171.6, 172.2, 174.3 (3ꢂCO2);
MS (EI-GC) m/z: 273 (Mþþ1, <2%), 215 (12), 214 (100), 200 (32), 140
(62), 108 (20), 99 (27), 82 (23); HRMS calcd for C12H19NO6:
273.1212, found: 273.1214.
C20H25NO8: 407.1580, found: 407.1586.
4.2.17. Diethyl
(2R*,3S*,4S*,5S*)-2-benzyl-3,4-bis(phenylsulfonyl)
4.2.13. Diethyl (1S*,3R*,3aS*,6aR*)-1-benzyl-5-methyl-4,6-
pyrrolidine-2,5-dicarboxylate (exo-cis-3e).14 Pale yellow prisms,
mp: 85e86 ꢀC (from n-hexane/ethyl acetate); IR (neat) nmax 2971,
dioxooctahydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate
(endo-cis-
3a).14 Sticky pale yellow oil; IR (neat) nmax 3030, 2982, 2936, 1779,
1741, 1235, 1149 cmꢁ1
;
1H NMR dH: 1.04 (t, J¼7.2 Hz, 1H,
1734, 1699 cmꢁ1
;
1H NMR dH: 1.32, 1.34 (2t, J¼7.2 Hz, 3H,
CO2CH2CH3), 1.21 (t, J¼7.2 Hz, 1H, CO2CH2CH3), 3.29, 3.40 (2ꢂd,
J¼14.2 Hz, 2H, CH2Ph), 3.88e4.29 (m, 4H, 2ꢂCO2CH2CH3), 4.20
[CH(CO2Et)NH], 4.43 (br s, 1H, NH), 4.51 [d, J¼5.2 Hz, 1H,
CHC(CO2Et)Bn], 4.89 [deform. dd, J¼5.2, 5.2 Hz, 1H, CHCH(CO2Et)
NH], 7.18e7.33 (m, 5H, ArH), 7.44e7.82 (m, 8H, ArH), 7.88e7.98 (m,
2H, ArH); 13C NMR dC: 13.8, 14.0 (2ꢂCO2CH2CH3), 41.0 (CH2Ph), 61.1,
62.2 (2ꢂCO2CH2CH3), 62.3 [CHCH(CO2Et)NH], 69.4 [CHCBn(CO2Et)
NH], 72.0 [CH(CO2Et)NH], 73.8 [CBn(CO2Et)NH], 127.4, 128.4, 128.8,
129.1,129.2,129.4,130.7,134.3,134.4,134.7,138.5,139.5 (ArC),169.6,
169.6 (2ꢂCO2); MS (EI-GC) m/z: 585 (Mþþ1, <1%), 512 (10), 494
(34), 370 (14), 353 (13), 352 (69), 306 (33), 298 (10), 280 (26), 235
(10), 234 (82), 157 (13), 156 (23), 141 (10), 125 (15), 112 (11), 94 (16),
91 (100), 80 (12), 77 (29); HRMS calcd for C29H31NO8S2eC3H5O2:
512.1202, found: 512.1215.
CO2CH2CH3), 2.88, 3.30 (2d, J¼13.8 Hz, 2H, CH2Ph) 2.92 (s, 3H,
NCH3), 3.38 [d, J¼8.0 Hz, 1H, CHC(CO2Et)Bn], 3.55 [deform. dd,
J¼8.4, 8.0 Hz,1H, CHCH(CO2Et)NH], 4.09 [d, J¼8.4 Hz, 1H, CH(CO2Et)
NH], 4.24 (q, J¼7.2 Hz, 2H, CO2CH2CH3), 4.26 (q, J¼7.2 Hz, 2H,
CO2CH2CH3), NH nd; 13C NMR dC: 14.0 (2ꢂCO2CH2CH3), 25.4 (NCH3),
42.2 (CH2Ar), 50.4 [CHCH(CO2Et)NH], 56.6 [CHC(CO2Et)Bn], 62.0
[CH(CO2Et)NH], 62.1 (CO2CH2CH3), 62.3 (CO2CH2CH3) 73.6
[C(CO2Et)Bn], 127.2, 128.3, 130.4, 135.7 (ArC)169.6, 170.1 (2ꢂCO2),
175.0, 175.1 (2ꢂCON); MS (EI-GC) m/z: 388 (Mþþ1, <1%), 315 (13),
298 (14), 297 (100), 223 (11), 166 (45), 94 (11), 91 (17); HRMS calcd
for C20H24N2O6: 388.1634, found: 388.1631.
4.2.14. Diethyl (1S*,3R*,3aS*,6aR*)-1,5-dibenzyl-4,6-dioxoocta hy-
dropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate
(endo-cis-3b).14
Colourless prisms, mp¼127e130 ꢀC (from hexane/CDCl3); IR (neat)
nmax 3030, 2989,1741,1719,1699 cmꢁ1; 1H NMR dH: 1.23 (t, J¼7.2 Hz,
3H, CO2CH2CH3), 1.28 (t, J¼7.2 Hz, 3H, CO2CH2CH3), 2.89, 3.31 (2d,
J¼13.9 Hz, 2H, CH2Ph), 3.38 [d, J¼7.8 Hz, 1H, CHC(CO2Et)Bn], 3.55
[deform. dd, J¼7.8, 7.8 Hz, 1H, CHCH(CO2Et)NH], 4.03e4.27 [m, 5H,
2ꢂCO2CH2CH3 and CH(CO2Et)NH], 4.54, 4.60 (d, J¼14.3 Hz, 2H),
7.20e7.35 (m, 10H, 2ꢂCH2Ph), NH nd; 13C NMR dC: 14.0, 14.1
(2ꢂCO2CH2CH3), 42.2, 43.0 (2ꢂCH2Ph), 50.4 [CHCH(CO2Et)NH],
56.6 [CHCH(CO2Et)NH], 61.9, 62.1 (2ꢂCO2CH2CH3), 62.3 [CH(CO2Et)
NH], 73.7 [CBn(CO2Et)NH], 127.2, 128.0, 128.3, 128.6, 128.7, 130.5,
135.2, 135.8 (ArC), 169.4, 169.9 (2ꢂCO2CH2CH3), 174.6, 174.7
(2ꢂCON); MS (EI-GC) m/z: 464 (Mþþ1, <1%), 391 (14), 374 (22), 373
(100), 166 (22), 91 (73); HRMS calcd for C26H28N2O6eC7H7:
373.1400, found: 373.1401.
4.2.18. 3-Ethyl 1-methyl (1R*,3R*,3aS*,6aR*)-5-methyl-4,6-dioxo-1-
phenyloctahydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate (endo-cis-
4a).14 Sticky pale yellow oil; IR (neat) nmax 2982, 2954, 1779, 1736,
1698 cmꢁ1
;
1H NMR dH: 1.25 (t, J¼7.2 Hz, 3H, CO2CH2CH3), 2.91 (s,
3H, NCH3), 3.37 [deform. dd, J¼8.5, 7.5 Hz, 1H, CHCHCO2Et], 3.69 (s,
3H, CO2CH3), 3.76 [d, J¼8.5, 1H, CH(CO2Et)NH], 3.96 [d, J¼7.5 Hz, 1H,
CH(CO2Me)Ph], 4.20 (qd, J¼7.2, 1.1 Hz, 2H, CO2CH2CH3), 7.22e7.36
(m, 3H, ArH), 7.58e7.63 (m, 2H, ArH), NH nd; 13C NMR dC: 14.2
(CO2CH2CH3), 25.5 (NCH3), 50.3 [CHCH(CO2Et)NH], 53.4
[CHC(CO2Me)Ph], 56.5 (CHCO2Et), 61.6 (CO2CH3), 62.1 (CO2CH2CH3),
74.8 [C(CO2Me)Ph], 127.4, 128.5, 128.7, 138.1 (ArC), 169.6, 170.2
(2ꢂCO2), 175.1, 175.4 (2ꢂCON); MS (EI-GC) m/z: 360 (Mþþ1, <1%),
302 (17), 301 (100), 228 (14), 227 (72), 170 (19), 143 (18), 142 (27);
HRMS calcd for C18H20N2O6: 360.1321, found: 360.1322.
4.2.15. Diethyl (1S*,3R*,3aS*,6aR*)-1-benzyl-4,6-dioxo-5-phenyl oc-
4.2.19. 3-Ethyl 1-methyl (1S*,3R*,3aS*,6aR*)-5-methyl-4,6-dioxo-1-
phenyloctahydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate (endo-trans-
4a).14 Sticky pale yellow oil; IR (neat) nmax 2983, 2954, 2926, 1781,
tahydropyrrolo[3,4-c]pyrrole-1,3-dicarboxylate
(endo-cis-3c).14
Colourless prisms, mp¼169e172 ꢀC (from hexane/CDCl3); IR (neat)
nmax 2979, 2937, 1729, 1714 cmꢁ1
;
1H NMR dH: 1.25e1.30 (m, 6H,
1729, 1702 cmꢁ1
;
1H NMR dH: 1.39 (t, J¼7.2 Hz, 3H, CO2CH2CH3),
2ꢂCO2CH2CH3), 2.96, 3.36 (2ꢂd, J¼13.9 Hz, 2H, CH2Ph), 3.51 (s, 1H,
NH), 3.55 [d, J¼7.8 Hz, 1H, CHC(CO2Et)Bn], 3.73 [deform. dd, J¼7.8,
7.8 Hz, 1H, CHCH(CO2Et)NH], 4.15e4.30 [m, 5H, 2ꢂCO2CH2CH3 and
CH(CO2Et)NH], 7.15e7.49 (m, 10H, ArH); 13C NMR dC: 13.9, 14.0
(CO2CH2CH3), 42.3 (CH2Ph), 50.4 [CHCH(CO2Et)NH], 56.6
[CHCH(CO2Et)NH], 62.1, 62.2 (2ꢂCO2CH2CH3), 62.3 [CH(CO2Et)NH],
74.1 [CBn(CO2Et)NH], 126.6, 127.2, 128.0, 128.2, 128.9, 129.2, 130.4,
135.6 (ArC), 169.7, 170.1 (2ꢂCO2), 174.0, 174.2 (2ꢂCON); MS (EI-GC)
2.79 (s, 3H, NCH3), 3.08 (d, J¼3.5 Hz, 1H, NH), 3.55 [deform. dd,
J¼7.6, 7.6 Hz, 1H, CHCHCO2Et], 3.79 (s, 3H, CO2CH3), 3.86 [dd, J¼7.6,
3.5 Hz, 1H, CH(CO2Et)NH], 4.25 [d, J¼7.6 Hz, 1H, CHC(CO2Me)Ph],
4.30e4.41 (m, 2H, CO2CH2CH3), 7.33e7.41 (m, 3H, ArH), 7.47e7.54
(m, 2H, ArH); 13C NMR dC: 14.2 (CO2CH2CH3), 25.2 (NCH3), 45.3
[CHCH(CO2Et)NH], 50.4 [CHC(CO2Me)Ph], 53.7 (CHCO2Et), 59.8
(CO2CH3), 61.7 (CO2CH2CH3), 74.1 [C(CO2Me)Ph], 126.0, 128.5, 128.9,
135.4 (ArC), 169.3, 173.5 (2ꢂCO2), 174.1, 175.6 (2ꢂCON); MS (EI-GC)

J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
8813
m/z: 360 (Mþþ1, <1%), 302 (18), 301 (100), 228 (13), 227 (63), 170
(20), 143 (22), 142 (30), 115 (15); HRMS calcd for C18H20N2O6:
360.1321, found:360.1336.
4e).14 Orange oil; Rf 0.10 (n-hexane/ethyl acetate 7/3); IR (neat)
nmax 2981, 2954, 2926, 1738, 1692, 1309, 1147 cmꢁ1 1H NMR dH
;
:
1.04 (t, J¼7.2 Hz, 3H, CO2CH2CH3), 3.74 (s, 3H, CO2CH3), 4.01 (q,
J¼7.2 Hz, 2H, CO2CH2CH3), 4.35 [d, J¼5.0 Hz,1H, CH(OMe)2NH], 3.40
[dd, J¼7.6, 4.8 Hz,1H, CHCH(OMe)2NH], 3.42, 3.54 (2s, 6H, 2ꢂOCH3),
3.51 [deform. dd, J¼7.9, 7.6 Hz, 1H, CHCH(CO2Et)NH], 3.85 [d,
J¼7.6 Hz,1H, CH(CO2Et)NH], 4.30 (q, J¼7.2 Hz, 2H, CO2CH2CH3), 4.69
[d, J¼4.8 Hz, 1H, CH(OMe)2]; 13C NMR dC: 14.2 (CO2CH2CH3), 25.2
(NCH3), 45.5 [CHCH(OMe)2NH], 49.1 [CHCH(CO2Et)NH], 55.8, 56.0
(2ꢂOCH3), 61.7 (CO2CH2CH3), 62.3 [CH(CH(OMe)2)NH], 63.4
[CH(CO2Et)NH], 102.6 [CH(OMe)2], 169.6 (CO2Et), 175.6, 175.9
(2ꢂCON); MS (EI-GC) m/z: 300 (Mþ, <1%), 269 (13), 225 (27), 195
(34), 179 (10), 151 (18), 94 (16), 75 (100); HRMS calcd for
4 . 2 . 2 0 . 5 - E t hyl 2 , 3 , 4 - t r i m e t hyl ( 2 R * , 3 S * , 4 S * , 5 R * ) - 2 -
phenylpyrrolidine-2,3,4,5-tetracarboxylate
(endo-cis-4d).14
Colourless oil; IR (neat) nmax 2984, 2954, 1735, 1716, 1713,
1700 cmꢁ1; 1H NMR dH: 1.14 (t, J¼7.1 Hz, 3H, CO2CH2CH3), 3.64, 3.67,
3.75 (3s, 3H, CO2CH3), 3.82 [dd, J¼10.1, 8.5 Hz,1H, CHCH(CO2Et)NH],
3.98 [d, J¼8.5 Hz, 1H, CH(CO2Et)NH], 4.04 (q, J¼7.1 Hz, 2H,
CO2CH2CH3), 4.38 [d, J¼10.1 Hz, 1H, CHC(CO2Me)Ph], 7.26e7.38 (m,
2H, ArH), 7.51 (dd, J¼8.5, 2.8 Hz,1H, ArH), 7.70 (dd, J¼8.5, 2.8 Hz, 2H,
ArH), NH nd; 13C NMR dC: 14.0 (CO2CH2CH3), 51.1, 52.3, 52.6
(3ꢂCO2CH3), 53.3 [CHC(CO2Me)Ph], 53.5 [CHCH(CO2Et)NH], 60.7
[CH(CO2Et)NH], 61.4 (CO2CH2CH3), 75.0 [C(CO2Me)Ph], 127.0, 128.1,
128.3,140.9 (ArC),170.8,171.3,171.7,172.8 (4ꢂCO2); MS (EI-GC) m/z:
393 (Mþþ1, <2%), 335 (19), 334 (100), 302 (24), 288 (11), 274 (35),
260 (25), 242 (13), 228 (51), 202 (25), 201 (11), 170 (11), 143 (26),
115 (16); HRMS calcd for C19H23NO8: 393.1424, found: 393.1421.
C13H20N2O6þ1: 301.1399, found: 301.1399.
4.2.25. Ethyl (1S*,3R*,3aS*,6aR*)-3-(dimethoxymethyl)-5-methyl-
4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (endo-cis-
5a). Yellow prisms, mp: 105e108 ꢀC (from hexane/CH2Cl2); IR
(neat) nmax 2980, 1719, 1696 cmꢁ1
;
1H NMR dH: 1.35 (t, J¼7.2 Hz,
3H, CO2CH2CH3), 2.50 (br s, 1H, NH), 2.95 (s, 3H, NCH3), 3.27
[deform. dd, J¼7.9, 7.6 Hz, 1H, CHCH(CH(), 3.56, 3.69, 3.72 (3s, 3H,
CO2CH3)], 3.64 [deform. dd, J¼6.9, 6.7 Hz, 1H, CHCH(CO2Et)NH],
3.89 [d, J¼6.7 Hz, 1H, CHC(CO2Me)Ph], 4.17 [d, J¼6.9 Hz, 1H,
CH(CO2Et)NH], 4.26 (q, J¼7.1 Hz, 2H, CO2CH2CH3), 7.28e7.38 (m,
2H, ArH), 7.51 (dd, J¼7.0, 2.3 Hz, 1H, ArH), 7.70 (dd, J¼7.0, 2.3 Hz,
2H, ArH), NH nd; 13C NMR dC: 14.3 (CO2CH2CH3), 51.8, 52.6, 52.8
(3ꢂCO2CH3), 53.6 [CHC(CO2Me)Ph], 54.7 [CHCH(CO2Et)NH], 61.6
[CH(CO2Et)NH], 61.9 (CO2CH2CH3), 75.2 [C(CO2Me)Ph], 126.4,
128.1, 128.2, 139.7 (ArC), 171.1, 171.6, 172.0, 172.1 (4ꢂCO2); MS (EI-
GC) m/z: 393 (Mþþ1, <1%), 335 (19), 334 (100), 303 (11), 302
(60), 274 (14), 260 (25), 242 (11), 228 (27), 202 (21), 170 (56), 143
(24), 115 (14); HRMS calcd for C19H23NO8: 393.1424, found:
393.1426.
4 . 2 . 21. 5 - E t hyl 2 , 3 , 4 - t r i m e t hyl ( 2 R * , 3 R * , 4 R * , 5 R * ) - 2 -
phenylpyrrolidine-2,3,4,5-tetracarboxylate
(exo-cis-4d).14
Colourless oil; IR (neat) nmax 2990, 2950, 1748, 1733, 1730,
1715 cmꢁ1; 1H NMR dH: 1.30 (t, J¼7.1 Hz, 3H, CO2CH2CH3 CO2Et)NH],
4.86 [d, J¼5.3 Hz, 1H, CHC(CO2Me)Ph], 4.91 [deform. dd, J¼5.3,
5.0 Hz, 1H, CHCHCO2Et], 7.35e8.05 (m, 15H, ArH), NH nd; 13C NMR
dC: 14.0 (CO2CH2CH3), 53.2 [CH(CO2Et)NH], 60.9 (CO2CH3), 62.3
(CO2CH2CH3), 69.4 [CHCH(CO2Et)NH], 74.6 [CHC(CO2Me)Ph], 75.1
[C(CO2Me)Ph], 128.2, 128.3, 128.6, 128.8, 128.9, 129.2, 129.3, 134.0,
134.3, 136.8, 138.6, 140.1 (ArC), 170.0, 170.1 (2ꢂCO2); MS (EI-GC) m/
z: 557 (Mþþ1, <1%), 357 (11), 356 (51), 342 (10), 310 (15), 299 (11),
298 (54), 284 (17), 283 (21), 215 (37), 158 (11), 157 (11), 144 (11), 143
(100), 142 (11), 115 (24), 77 (11); HRMS calcd for
C
27H27NO8S2:557.1168, found: 557.1173.
4.2.26. Ethyl (1S*,3R*,3aS*,6aR*)-5-benzyl-3-(dimethoxymethyl)-4,6-
4.2.22. 5-Ethyl 2,3-dimethyl (2R*,3R*,5R*)-2-phenylpyrrolidine-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(endo-cis-
2,3,5-tricarboxylate (endo-cis-4f).14 Yellowish oil; IR (neat) nmax
5b). Sticky pale yellow oil; IR (neat) nmax 2968, 2308, 1716,
1695 cmꢁ1; 1H NMR dH: 1.32 (t, J¼7.2 Hz, 3H, CO2CH2CH3), 2.50 (br s,
1H, NH), 3.16, 3.47 (2s, 6H, 2ꢂOCH3), 3.25 [deform. dd, J¼8.0, 7.7 Hz,
1H, CHCH(CH(OMe)2)NH], 3.40 [dd, J¼8.0, 4.0 Hz, 1H, CHCH(O-
Me)2NH], 3.51 [deform. dd, J¼7.7, 7.6 Hz, 1H, CHCH(CO2Et)NH], 3.87
[d, J¼7.6 Hz, 1H, CH(CO2Et)NH], 4.29 (q, J¼7.2 Hz, 2H, CO2CH2CH3),
4.54 (d, J¼14.3 Hz, 1H, NCHHPh), 4.65 [d, J¼4.0 Hz, 1H, CH(OMe)2],
4.68 (d, J¼14.3 Hz, 1H, NCHHPh) 7.23e7.34 (m, 5H, ArH); 13C NMR
dC: 14.2 (CO2CH2CH3), 42.7 (NCH2Ph), 46.8 [CHCH(CH(OMe)2)NH],
49.4 [CHCH(CO2Et)NH], 55.4, 55.7 (2ꢂOCH3), 61.6 (CO2CH2CH3),
62.7 [CH(CH(OMe)2)NH], 63.7 [CH(CO2Et)NH], 102.0 [CH(OMe)2],
127.9, 128.5, 128.6, 135.6 (ArC), 169.4 (CO2Et), 175.3, 175.5 (2ꢂCON);
MS (EI-GC) m/z: 376 (Mþ, <1%), 301 (29), 271 (15), 243 (10), 227
(18), 94 (10), 75 (100); HRMS calcd for C19H24N2O6þ1: 377.1712,
found: 377.1701.
2985, 2953, 1734, 1700 cmꢁ1
;
1H NMR dH: 1.29 (t, J¼7.1 Hz, 3H,
CO2CH2CH3), 2.29e2.36 [m, 2H, CH2CH(CO2Et)], 3.51 [dd, J¼7.6,
4.5 Hz, 1H, CHC(CO2Me)Ph], 3.68, 3.70 (2s, 3H, CO2CH3), 3.85 [dd,
J¼9.0, 5.7 Hz, 1H, CH(CO2Et)NH], 4.23 (q, J¼7.1 Hz, 2H, CO2CH2CH3),
7.25e7.35 (m, 3H, ArH), 7.73e7.77 (m, 2H, ArH), NH nd; 13C NMR dC
:
14.3 (CO2CH2CH3), 33.8 [CH2CH(CO2Et)NH], 52.2, 52.9 (2ꢂCO2CH3),
54.0 [CHC(CO2Me)Ph], 58.6 [CH(CO2Et)NH], 61.5 (CO2CH2CH3), 75.5
[C(CO2Me)Ph], 126.9, 128.1, 128.4, 140.2 (ArC), 172.2, 173.1, 173.6
(3ꢂCO2); MS (EI-GC) m/z: 335 (Mþþ1, <2%), 277 (18), 276 (100),
262 (19), 202 (41), 170 (19), 144 (20), 143 (14), 115 (10), 99 (15);
HRMS calcd for C17H21NO6: 335.1369, found:335.1313.
4.2.23. 5-Ethyl 2,3-dimethyl (2S*,3R*,5R*)-2-phenylpyrrolidine-
2,3,5-tricarboxylate (endo-trans-4f).14 Yellowish oil; Rf 0.29 (n-
hexane/ethyl acetate 7/3); IR (neat) nmax 2984, 2953, 1727,
1658 cmꢁ1
;
1H NMR dH: 1.30 (t, J¼7.1 Hz, 3H, CO2CH2CH3),
4.2.27. Ethyl (1S*,3R*,3aS*,6aR*)-3-(dimethoxymethyl)-4,6-dioxo-5-
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
2.36e2.46 [m, 2H, CH2CH(CO2Et)], 3.19, 3.72 (2s, 3H, CO2CH3), 3.92
[deform. dd, J¼8.0, 7.6 Hz, Ph1H, CHC(CO2Me)Ph], 4.04 [deform. dd,
J¼6.5, 5.9 Hz, 1H, CH(CO2Et)NH], 4.26 (q, J¼7.1 Hz, 2H, CO2CH2CH3),
(endo-cis-
5c). Yellowish prisms, mp: 98e102 ꢀC (from hexane/CH2Cl2); IR
(neat) nmax 2995, 2939, 2310, 1718, 1700 cmꢁ1; 1H NMR dH: 1.32 (t,
J¼7.2 Hz, 3H, CO2CH2CH3), 2.55 (br s, 1H, NH), 3.39 (s, 3H, OCH3),
3.43 [deform. dd, J¼7.7, 7.2 Hz,1H, CHCH(CH(OMe)2)NH], 3.50e3.55
(m, 4H, CHCH(OMe)2NH, OCH3), 3.66 [deform. dd, J¼7.7, 7.2 Hz, 1H,
CHCH(CO2Et)NH], 3.97 [d, J¼7.7 Hz, 1H, CH(CO2Et)NH], 4.28 (q,
J¼7.2 Hz, 2H, CO2CH2CH3), 4.79 [d, J¼4.0 Hz, 1H, CH(OMe)2],
7.24e7.51 (m, 5H, ArH); 13C NMR dC: 14.2 (CO2CH2CH3), 47.1
[CHCH(CH(OMe)2)NH], 49.5 [CHCH(CO2Et)NH], 55.8, 55.9
(2ꢂOCH3), 61.8 (CO2CH2CH3), 62.9 [CH(CH(OMe)2)NH], 64.1
[CH(CO2Et)NH], 102.2 [CH(OMe)2], 126.7, 128.9, 129.3, 131.9 (ArC),
169.6 (CO2Et), 174.8, 175.0 (2ꢂCON); MS (EI-GC) m/z: 362 (Mþ,
7.24e7.37 (m, 3H, ArH), 7.49e7.53 (m, 2H, ArH), NH nd; 13C NMR dC
:
14.3 (CO2CH2CH3), 32.7 [CH2CH(CO2Et)NH], 50.6, 51.5 (2ꢂCO2CH3),
53.4 [CHC(CO2Me)Ph], 58.5 [CH(CO2Et)NH], 61.3 (CO2CH2CH3), 76.0
[C(CO2Me)Ph], 126.3, 128.3, 128.5, 137.5 (ArC), 172.6, 173.0, 173.9
(3ꢂCO2); MS (EI-GC) m/z: 335 (Mþþ1, <2%), 277 (21), 276 (100),
262 (15), 202 (38), 201 (10), 170 (25), 144 (13), 143 (11), 115 (11), 99
(17); HRMS calcd for C17H21NO6: 335.1369, found: 335.1308.
4.2.24. 5-Ethyl 2-methyl (2R*,3R*,4R*,5S*)-2-phenyl-3,4-
bis(phenylsulfonyl)pyrrolidine-2,5-dicarboxylate
(exo-trans-

8814
J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
<1%), 331 (11), 287 (29), 257 (24), 94 (21), 75 (100); HRMS calcd for
18H22N2O6þ1: 363.1556, found: 363.1550.
MS (EI-GC) m/z: 466 (Mþ, <1%), 308 (12), 307 (55), 290 (16), 289
(100), 281 (11), 215 (14), 207 (21), 187 (12), 174 (15), 119 (11), 91
(64); HRMS calcd for C26H30N2O6þ1: 467.2182, found: 467.2175.
C
4.2.28. Methyl (1S*,3R*,3aS*,6aR*)-3-(dimethoxymethyl)-1,5-
dimethyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(endo-cis-6a). Yellow solid, mp: 120e123 ꢀC (from hexane/CH2Cl2);
4.2.32. Ethyl (1S*,3R*,3aS*,6aR*)-1-benzyl-3-(dimethoxymethyl)-4,6-
dioxo-5-phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate (endo-
cis-7c). Yellowish solid, mp: 118e121 ꢀC (from hexane/CH2Cl2); IR
(neat) nmax 2992, 2945, 2315, 1718, 1689 cmꢁ1; 1H NMR dH: 1.33 (t,
J¼7.2 Hz, 3H, CO2CH2CH3), 3.01, 3.39 (2d, J¼13.7 Hz, 2H, CH2Ph),
3.34, (s, 3H, OCH3), 3.47e3.53 [m, 5H, CHCH(CH(OMe)2)NH,
CHC(CO2Et)BnNH, OCH3], 3.74 [dd, J¼7.8, 3.4 Hz, 1H, CHCH(O-
Me)2NH], 4.26 (qd, J¼7.2, 2.1 Hz, 2H, CO2CH2CH3), 4.82 [d, J¼3.8 Hz,
1H, CH(OMe)2], 7.23e7.50 (m, 10H, ArH), NH nd; 13C NMR dC: 14.0
(CO2CH2CH3), 41.3 (CH2Ph), 47.5 [CHC(CO2Et)BnNH], 54.7
[CHCH(CH(OMe)2)NH], 55.6, 56.0 (2ꢂOCH3), 62.0 [CH(CH(OMe)2)
NH], 62.2 (CO2CH2CH3), 72.8 [C(CO2Et)BnNH], 101.6 [CH(OMe)2],
126.6, 127.2, 128.3, 128.8, 129.2, 130.2, 131.8, 135.8 (ArC), 170.6
(CO2Et), 174.6, 174.9 (2ꢂCON); MS (EI-GC) m/z: 452 (Mþ, <1%), 315
(23), 299 (24), 285 (13), 269 (15), 268 (15), 267 (100), 241 (10), 91
(29), 75 (35); HRMS calcd for C25H28N2O6þ1: 453.2025, found:
453.2014.
IR (neat) nmax 2976, 1720, 1702 cmꢁ1 1H NMR dH: 1.47 [s, 3H,
;
C(CO2CH3)CH3], 2.92 (s, 3H, NCH3), 3.20 [d, J¼7.7 Hz, 1H,
CHC(CO2Me)CH3], 3.34 [deform. dd, J¼8.6, 7.7 Hz, 1H,
CHCH(CH(OMe)2)NH], 3.38 3.51 (2s, 6H, 2ꢂOCH3), 3.68 (dd, J¼8.6,
3.0 Hz, 1H, CHCH(OMe)2NH), 3.83 (s, 3H, CO2CH3), 4.76 [d, J¼3.0 Hz,
1H, CH(OMe)2], NH nd; 13C NMR dC: 24.1 [C(CO2CH3)CH3], 25.1
(NCH3), 47.6 [CHCH(CH(OMe)2)NH], 52.9 [CHC(CO2Me)CH3], 55.7,
56.0 (2ꢂOCH3), 56.7 (CO2CH3), 62.4 [CH(CH(OMe)2)NH], 68.3
[C(CO2Me)CH3], 101.9 [CH(OMe)2], 172.3 (CO2Me), 175.7, 176.1
(2ꢂCON); MS (EI-GC) m/z: 300 (Mþ, <1%), 241 (13), 225 (37), 209
(24), 165 (40), 108 (20), 75 (100); HRMS calcd for C13H20N2O6þ1:
301.1399, found: 301.1392.
4.2.29. Trimethyl (2S*,3S*,4S*,5R*)-5-(dimethoxymethyl)-2-
methylpyrrolidine-2,3,4-tricarboxylate (endo-cis-6d). Sticky pale
yellow oil; IR (neat) nmax 2987, 1715, 1713, 1692 cmꢁ1 1H NMR dH
; :
1.60 [s, 3H, C(CO2CH3)CH3], 3.25 [deform. dd, J¼10.5, 8.3 Hz, 1H,
CHCH(CH(OMe)2)NH], 3.34 [d, J¼10.5 Hz, 1H, CHC(CO2Me)CH3],
3.40 (s, 6H, 2ꢂOCH3), 3.60 (dd, J¼8.3, 6.2 Hz, 1H, CHCH(OMe)2NH),
3.68 (s, 6H, 2ꢂCO2CH3), 3.74 (s, 3H, CO2CH3), 4.33 [d, J¼6.2 Hz, 1H,
CH(OMe)2], NH nd; 13C NMR dC: 25.6 [C(CO2CH3)CH3], 49.2
[CHCH(CH(OMe)2)NH], 52.2 [CHC(CO2Me)CH3], 52.3, 52.4
(2ꢂOCH3), 54.5, 55.5, 58.0 (3ꢂCO2CH3), 62.3 [CH(CH(OMe)2)NH],
67.9 [C(CO2Me)CH3], 106.1 [CH(OMe)2], 171.0, 173.4, 174.4
(3ꢂCO2Me); MS (EI-GC) m/z: 333 (Mþ, <1%), 258 (11), 215 (15), 200
(12), 156 (31), 75 (100); HRMS calcd for C14H23NO8þ1: 334.1502,
found: 334.1525.
4.2.33. 2-Ethyl 3,4-dimethyl (2S*,3R*,4R*,5R*)-2-benzyl-5-(dime-
thoxymethyl)pyrrolidine-2,3,4-tricarboxylate
(exo-cis-7d). Sticky
pale yellow oil; IR (neat) nmax 2985, 2947, 1714, 1712, 1691 cmꢁ1; 1H
NMR dH: 1.26 (t, J¼7.1 Hz, 3H, CO2CH2CH3), 2.76, 2.95 (d, J¼13.0 Hz,
2H, CH2Ph), 3.29, 3.34 (s, 6H, 2ꢂOCH3), 3.68e3.73 [m, 6H,
CHCH(CH(OMe)2)NH, CHC(CO2Et)BnNH, CHCH(OMe)2NH, CO2CH3],
3.79 (s, 3H, CO2CH3), 4.07e4.23 [m, 3H, CH(OMe)2, CO2CH2CH3],
7.16e7.22 (m, 5H, ArH), NH nd; 13C NMR dC: 14.2 (CO2CH2CH3), 42.0
(CH2Ph), 47.9 [CHC(CO2Et)BnNH], 52.0 [CHCH(CH(OMe)2)NH], 52.4,
53.1 (2ꢂCOCH3), 54.5, 54.8 (2ꢂOCH3), 59.7 [CH(CH(OMe)2)NH],
61.7 (CO2CH2CH3), 69.9 [C(CO2Et)BnNH], 103.8 [CH(OMe)2], 126.8,
128.0, 130.6, 136.3 (ArC), 171.3, 171.6 (2ꢂCO2Me), 174.1 (CO2Et); MS
(EI-GC) m/z: 423 (Mþ, <1%), 392 (14), 350 (19), 348 (45), 332 (36),
318 (21), 317 (13), 316 (68), 301 (11), 300 (76), 288 (39), 286 (11),
268 (59), 258 (26), 256 (15), 242 (16), 240 (15), 226 (20), 224 (11),
216 (11), 210 (18), 196 (13), 194 (17), 166 (11), 91 (100), 75 (28);
HRMS calcd for C21H29NO8þ1: 424.1971, found: 424.1968.
4.2.30. Ethyl (1S*,3R*,3aS*,6aR*)-1-benzyl-3-(dimethoxymethyl)-5-
methyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(endo-cis-7a). Yellowish prisms, mp: 85e88 ꢀC (from hexane/
CH2Cl2); IR (neat) nmax 2988, 2335, 1717, 1699 cmꢁ1 1H NMR dH
; :
1.34 (t, J¼7.2 Hz, 3H, CO2CH2CH3), 2.79 (br s, 1H, NH), 2.92 (d,
J¼13.7 Hz, 1H, CHHPh), 2.93 (s, 3H, NCH3), 3.30e3.35 [m, 6H,
CHHPh, CHCH(CH(OMe)2)NH, CHC(CO2Et)BnNH, OCH3], 3.49 (s, 3H,
OCH3), 3.66 [m, 1H, CHCH(OMe)2NH], 4.26 (q, J¼7.2 Hz, 2H,
CO2CH2CH3), 4.68 [d, J¼4.1 Hz, 1H, CH(OMe)2], 7.19e7.30 (m, 5H,
ArH); 13C NMR dC: 14.2 (CO2CH2CH3), 24.2 (NCH3), 41.0 [CHC(CO2Et)
BnNH], 47.1 [CHCH(CH(OMe)2)NH], 55.0 (CH2Ph), 55.7, 55.8
(2ꢂOCH3), 61.5 (CO2CH2CH3), 61.9 [CH(CH(OMe)2)NH], 74.2
[C(CO2Et)BnNH], 102.1 [CH(OMe)2], 127.3, 128.5, 130.2, 135.8 (ArC),
170.7 (CO2Et), 175.5, 175.9 (2ꢂCON); MS (EI-GC) m/z: 390 (Mþ,
<1%), 315 (26), 299 (27), 285 (13), 269 (14), 268 (14), 267 (100), 91
(13), 75 (13); HRMS calcd for C20H26N2O6þ1: 391.1869, found:
391.1875.
4.2.34. 2-Ethyl 3,4-dimethyl (2S*,3S*,4S*,5R*)-2-benzyl-5-(dime-
thoxymethyl)pyrrolidine-2,3,4-tricarboxylate (endo-cis-7d). Sticky
pale yellow oil; IR (neat) nmax 2987, 2955, 1719, 1716, 1696 cmꢁ1; 1H
NMR dH: 1.24 (t, J¼7.1 Hz, 3H, CO2CH2CH3), 2.61 (br s, 1H, NH),
3.12e1.19 [m, 2H, CHHPh, CHCH(CH(OMe)2)NH], 3.29e3.40 [m, 9H,
CHHPh, CHC(CO2Et)BnNH, CHCH(OMe)2NH, 2ꢂOCH3], 3.69 (s, 3H,
CO2CH3), 3.77 (s, 3H, CO2CH3), 4.05e4.15 [m, 2H, CO2CH2CH3], 4.36
[d, J¼6.4 Hz, 1H, CH(OMe)2], 7.17e7.27 (m, 5H, ArH); 13C NMR dC
:
14.1 (CO2CH2CH3), 43.1 (CH2Ph), 49.0 [CHC(CO2Et)BnNH], 52.2, 52.3
(2ꢂCOCH3), 53.8 [CHCH(CH(OMe)2)NH], 55.2, 55.7 (2ꢂOCH3), 61.7
[CH(CH(OMe)2)NH], 61.9 (CO2CH2CH3), 72.0 [C(CO2Et)BnNH], 105.9
[CH(OMe)2], 127.1, 128.3, 130.7, 136.1 (ArC), 171.1, 173.1 (2ꢂCO2Me),
173.4 (CO2Et); MS (EI-GC) m/z: 423 (Mþ, <1%), 348 (11), 333 (11),
332 (65), 316 (33), 300 (45), 288 (46), 286 (11), 268 (61), 258 (33),
256 (14), 242 (14), 240 (17), 226 (21), 216 (12), 210 (17), 194 (16),
166 (10), 91 (100), 75 (27); HRMS calcd for C21H29NO8þ1: 424.1971,
found: 424.1959.
4.2.31. Ethyl (1S*,3R*,3aS*,6aR*)-1,5-dibenzyl-3-(dimethoxymethyl)-
4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(endo-cis-
7b). Yellowish prisms, mp: 92e94 ꢀC (from hexane/CH2Cl2); IR
(neat) nmax 2996, 2938, 2310, 1715, 1700 cmꢁ1; 1H NMR dH: 1.29 (t,
J¼7.2 Hz, 3H, CO2CH2CH3), 2.86 (br s,1H, NH), 2.92 (d, J¼13.8 Hz,1H,
CHHPh), 3.08, 3.41 (2s, 6H, 2ꢂOCH3), 3.28e3.35 [m, 3H, CHHPh,
CHCH(CH(OMe)2)NH, CHC(CO2Et)BnNH], 3.63 [dd, J¼7.4, 3.8 Hz,1H,
CHCH(OMe)2NH], 4.23 (q, J¼7.2 Hz, 2H, CO2CH2CH3), 4.54, 4.66 (d,
J¼14.4 Hz, 2H, NCH2Ph), 4.61 [d, J¼3.8 Hz,1H, CH(OMe)2], 7.20e7.33
(m, 10H, ArH); 13C NMR dC: 14.1 (CO2CH2CH3), 41.1, 42.7 (CH2Ph,
NCH2Ph), 47.1 [CHC(CO2Et)BnNH], 54.5 [CHCH(CH(OMe)2)NH],
55.4, 55.6 (2ꢂOCH3), 61.8 [CH(CH(OMe)2)NH], 62.0 (CO2CH2CH3),
72.5 [C(CO2Et)BnNH], 101.7 [CH(OMe)2], 127.2, 127.9, 128.4, 128.5,
128.6, 130.2, 135.6, 135.9 (ArC), 170.6 (CO2Et), 175.2, 175.5 (2ꢂCON);
4.2.35. Diethyl (3R*,3aS*,6aR*)-3-(dimethoxymethyl)-5-methyl-4,6-
dioxohexahydropyrrolo[3,4-c]pyrrole-1,1(2H)-dicarboxylate (all-cis-
8). Sticky pale yellow oil; IR (neat) nmax 2999, 1718, 1713,
1691 cmꢁ1
;
1H NMR dH: 1.29 (t, J¼7.1 Hz, 3H, CO2CH2CH3), 1.33 (t,
J¼7.1 Hz, 3H, CO2CH2CH3), 2.97 (s, 3H, NCH3), 3.32 (deform. dd,
J¼7.8, 7.5 Hz, 1H, CHCHNH), 3.42, 3.54 (2s, 6H, 2ꢂOCH3), 4.08 [d,
J¼7.5 Hz, 1H, CHC(CO2Et)2NH], 4.18e4.40 (m, 5H, CHNH,
2ꢂCO2CH2CH3), 4.56 [d, J¼6.1 Hz, 1H, CH(OMe)2], NH nd; 13C NMR

J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
8815
dC: 14.1, 14.2 (2ꢂCO2CH2CH3), 25.4 (NCH3), 45.5 (CHCHNH), 50.6
[CHC(CO2Et)2NH], 55.5, 56.2 (2ꢂOCH3), 60.9 (CHNH), 62.6, 62.9
(2ꢂCO2CH2CH3), 74.1 [C(CO2Et)2], 103.5 [CH(OMe)2], 166.9, 169.3
(2ꢂCO2Et), 175.2, 175.4 (2ꢂCON); MS (EI-GC) m/z: 372 (Mþ, <1%),
341 (14), 299 (24), 298 (10), 297 (52), 268 (10), 267 (65),166 (30), 75
(100); HRMS calcd for C16H24N2O8þ1: 373.1611, found: 373.1599.
NH), 2.87 (s, 3H, MeN), 3.36 (d, J¼7.7 Hz, 1H, CHCON), 3.91e3.81 (m
with s at 3.80, MeO and CHCON), 5.16 (d, J¼8.3 Hz, 1H, CHN), 7.53 (t,
J¼7.5 Hz, 2H, ArH), 7.68e7.61 (m, 1H, ArH), 8.05e8.00 (m, 2H, ArH);
13C-RMN dC: 25.0 (MeC), 25.4 (MeN), 51.7 (OMe), 53.2, 57.9
(2ꢂCHCON), 63.6, 69.2 (CHNC),128.4, 129.1,134.1, 136.1 (ArC), 171.6;
174.5; 175.0; 195.2 (4ꢂCO); MS (EI) m/z (%): 330 (Mþ, 1%), 269
(17%), 225 (100%), 165 (87), 108 (38), 105 (57), 80 (22), 77 (44);
HRMS calcd for (C17H18N2O5-2): 328.1216, found: 328.1215.
4.2.36. Methyl (1S*,3R*,3aS*,6aR*)-3-benzoyl-5-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
9a). Pale yellow oil; IR (neat) nmax: 2359, 1749, 1693, 1676, 1435,
1286, 1209, 1129, 701 cmꢁ1 1H-RMN dH: 2.92 (s, 3H, NMe), 3.01
(endo-cis-
4.2.41. Ethyl (1S*,3R*,3aS*,6aR*)-3-benzoyl-1-benzyl-5-methyl-4,6-
;
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(endo-cis-
(br s, 1H, NH), 3.10e2.95, 3.80e3.74 (2m, 2H, 2ꢂCHCON), 3.83 (s,
3H, OMe), 4.46 (d, J¼1.0 Hz, 1H, 2ꢂCHCON), 5.11 (d, J¼7.6 Hz, 1H,
CHCOPh), 7.55e7.49 (m, 2H, ArH), 7.67e7.60 (m, 1H, ArH),
8.02e7.97 (m, 2H, ArH); 13C-RMN dC: 25.6 (CH3N), 50.1 (CH3O), 50.7,
53.1 (2ꢂCCHON), 62.7, 64.6 (2ꢂCHN), 128.3, 129.0, 134.1, 136.1
(ArC), 172.4, 175.1, 176.6, 195.8 (4ꢂCO); MS (EI) m/z (%): 316 (Mþ,
1%), 211 (100), 151 (18), 105 (20), 94 (25), 77 (13); HRMS calcd for
(C16H16N2O5): 316.1059, found: 316.1049.
11a). Pale yellow oil; IR (neat) nmax: 1700, 1684, 1434, 1268, 1129,
1002, 699 cmꢁ1
;
1H-RMN dH: 1.37 (t, J¼7.2 Hz, 3H, CH3CH2), 2.80
(br s, 1H, NH), 2.88 (s, 3H, MeC), 3.18, 3.41 (2ꢂd, J¼13.9 Hz, 2H,
CH2Ph), 3.57 (d, J¼7.7 Hz, 1H, CHCON), 3.66 (dd, J¼8.4, 7.7 Hz, 1H,
CHCON), 4.30 (qd, J¼7.2, 2.0 Hz, 2H, CH2Me), 4.87 (d, J¼8.4 Hz, 1H,
CHN), 7.39e7.29 (m, 5H, ArH), 7.58e7.50 (m, 2H, ArH), 7.69e7.62
(m, 1H, ArH), 7.91 (dd, J¼5.3, 3.3, 2H, ArH); 13C-RMN dC: 14.0 (MeC),
25.2 (MeN), 42.9 (CH2Ph), 51.9 (CHCON), 57.1 (CHCON), 62.4 (CH2O),
63.2, 73.3 (CHNC),127.2, 128.1, 128.2, 128.9, 130.5,133.9, 135.9,136.0
(ArC), 170.1, 174.4, 174.8, 195.2 (4ꢂCO); MS (EI) m/z (%): 420 (Mþ,
1%), 347 (30), 330 (35), 315 (100), 269 (36), 241 (30), 184 (20), 156
(25), 105 (46), 91 (43), 77 (32); HRMS calcd for (C24H24N2O5-2):
418.1685, found: 418.1692.
4.2.37. Methyl (1S*,3R*,3aR*,6aS*)-3-benzoyl-5-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
9a). Pale yellow oil; IR (neat) nmax: 2356, 1701, 1441, 1382, 1265,
1125, 732, 699 cmꢁ1 1H-RMN dH 2.59 (br s, 1H, NH), 3.03 (s, 3H,
(exo-cis-
;
MeN), 3.56 (t, J¼8.0 Hz, 1H, CHCON), 3.73 (dd, J¼8.0, 1.5 Hz, 1H,
CHCON), 3.82 (s, 3H, OMe), 4.21 (d, J¼8.1 Hz, 1H, CHCO2), 5.18 (d,
J¼1.6 Hz, 1H, CHCOPh), 7.56e7.50 (m, 2H, ArH), 7.66e7.61 (m, 1H,
ArH), 8.19e8.15 (m, 2H, ArH); 13C-RMN dC: 25.7 (MeN), 48.2, 49.7
(2ꢂCHCON), 52.7 (MeO), 61.8, 65.0 (2ꢂCHN), 129.1, 129.4, 133.4,
134.3 (ArC), 170.4, 175.6, 177.5, 196.7 (4ꢂCO); MS (EI) m/z (%): 316
(Mþ 1%), 211 (100), 179 (26), 151 (40), 105 (13), 94 (36), 77 (12);
HRMS calcd for (C16H16N2O5): 316.1059, found: 316.1057.
4.2.42. Ethyl (1S*,3R*,3aS*,6aR*)-3-benzoyl-1-benzyl-4,6-dioxo-5-
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(endo-cis-
11b). Pale yellow oil; IR (neat) nmax: 1712, 1683, 1497, 1384, 1231,
1002, 699 cmꢁ1
;
1H-RMN dH: 1.31 (t, J¼7.2 Hz, 3H, CH3CH2), 2.40
(br s, 1H, NH), 3.21, 3.42 (2ꢂd, J¼13.8 Hz, 2H, CH2Ph), 3.08e3.68 (m,
2H, 2ꢂCHCON), 4.27 (dq, J¼7.2, 3.7 Hz, 2H, CH3CH2), 4.92 (d,
J¼8.1 Hz, 1H, CHN), 7.16e7.11 (m, 2H, ArH), 7.43e7.28 (m, 8H, ArH),
7.53e7.45 (m, 2H, ArH), 7.64e7.57 (m, 1H, ArH), 7.88 (dd, J¼5.2,
3.3 Hz, 2H, ArH); 13C-RMN dC: 13.9 (MeC), 43.1 (CH2Ph), 51.9, 57.2
(2ꢂCHCON), 62.5 (CH2O), 63.7, 73.9 (CHNC), 126.5, 127.2, 128.2,
128.3,128.8,128.9,129.1,130.6,131.2,133.9,135.9,136.0 (ArC),170.3,
173.6, 174.0, 195.0 (4ꢂCO); MS (EI) m/z (%): 482 (Mþ 1%), 409 (10),
392 (14), 391 (57), 378 (23), 377 (100), 331 (23), 303 (28), 184 (25),
156 (18), 105 (83), 91 (41), 77 (23); HRMS calcd for (C29H26N2O5-1):
481.1842, found: 481.1832.
4.2.38. Methyl (1S*,3R*,3aS*,6aR*)-3-benzoyl-5-benzyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
9b). Pale yellow oil; IR (neat) nmax: 1735, 1699, 1677, 1438, 1403,
1349, 1288, 1170, 701 cmꢁ1 1H-RMN dH: 2.86 (br s, 1H, NH), 3.69
(endo-cis-
;
(dd, J¼8.3, 8.1 Hz, 1H, CHCON), 3.80 (s, 3H, OMe), 3.83 (dd, J¼8.3,
8.1 Hz, 1H, CHCON), 4.25 (d, J¼8.3 Hz, 1H, CHCO2), 4.51, 4.58 (2d,
J¼14.0 Hz, 2H CH2Ph), 5.09 (d, J¼8.3 Hz,1H, CHCOPh), 7.29e7.27 (m,
5H, ArH), 7.33e7.30 (m, 1H, ArH), 7.52 (t, J¼7.6 Hz, 2H, ArH),
7.66e7.60 (m, 1H, ArH), 8.03e7.98 (m, 2H, ArH); 13C-RMN dC: 43.2
(CH2Ph), 49.8, 50.5 (2ꢂCHCON), 51.1 (MeO), 62.7, 64.8 (2ꢂCHN),
128.2, 128.4, 128.8, 128.8, 129.2, 134.3, 135.2, 135.7 (ArC), 169.0,
175.8, 176.0, 195.0 (4ꢂCO); MS (EI) m/z (%): 392 (Mþ, 1%), 288 (17),
287 (100), 227 (44), 105 (16), 94 (21), 91 (42), 77 (12); HRMS calcd
for (C22H20N2O5): 392.1372, found: 392.1374.
4.2.43. 2-Ethyl 3,4-dimethyl (1S*,3R*,3aS*,6aR*)-5-benzoyl-2-
benzylpyrrolidine-2,3,4-tricarboxylate (endo-cis-11c). Pale sticky
oil; IR (neat) nmax: 1733, 1436, 1265, 1203, 732, 700 cmꢁ1; 1H-RMN
for major endo isomer, dH: 1.31e1.17 (m, 3H, CH3CH2), 2.10 (br s, 1H,
NH), 3.22, 3.35 (2ꢂd, J¼13.5 Hz, 2H, CH2Ph), 3.43 (s, 3H, MeO),
3.62e3.58 (m, 1H, CHCO2), 3.77 (s, 3H, MeO), 3.81 (d, J¼4.8 Hz, 1H,
CHCO2), 4.19e4.03 (m, 2H, CH2O), 4.68 (d, J¼8.8 Hz, 1H, CHN),
7.23e7.14 (m, 2H, ArH), 7.33e7.24 (m, 5H, ArH), 7.40e7.35 (m, 2H,
ArH), 7.50e7.43 (m, 4H, ArH), 7.61e7.53 (m, 2H, ArH), 7.88e7.82 (m,
2H, ArH); 13C-RMN for major endo isomer dC: 14.0 (MeC), 42.9
(CH2Ph), 49.7, 52.3, 52.4, 55.3 (2ꢂMeO and 2ꢂCHCO2Me), 62.2
(CH2O), 64.1, 72.5 (CHNC), 127.2, 128.2, 128.7, 128.8, 130.9, 133.8,
135.5, 135.9 (ArC), 170.6, 172.3, 172.4, 196.8 (4ꢂCO); MS (EI) m/z (%):
453 (Mþ, 6%), 360 (15), 346 (21), 300 (20), 286 (22), 105 (100), 91
(96), 77 (46); HRMS calcd for (C25H27NO7-2): 451.1788, found:
451.1788.
4.2.39. Methyl (1S*,3R*,3aS*,6aR*)-3-benzoyl-4,6-dioxo-5-
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(endo-cis-
9c). Sticky oil; IR (neat) nmax: 1707, 1669, 1389, 1326, 1290, 1192,
1174, 697 cmꢁ1
;
1H-RMN dH: 3.68 (br s, 1H, NH), 3.81 (dd, J¼8.0,
7.9 Hz,1H, CHCON), 3.86 (s, 3H, OMe), 3.92 (t, J¼8.0 Hz,1H, CHCON),
4.31 (d, J¼8.0 Hz, 1H, CHCO2), 5.15 (d, J¼7.9 Hz, 1H, CHCOPh),
7.19e7.13 (m, 2H, ArH), 7.45e7.31 (m, 4H, ArH), 7.50 (t, J¼7.5 Hz, 2H,
ArH), 7.65e7.58 (m, 1H, ArH), 8.03e7.97 (m, 2H, ArH); 13C-RMN dC
:
50.6 (CHCON), 51.1 (MeO), 52.8 (CHCON), 63.0, 65.0 (2ꢂCHN),126.4,
128.2, 128.9, 129.2, 131.1, 134.1, 135.6, 169.4 (ArC), 173.5, 174.0, 174.5,
194.8 (4ꢂCO); MS (EI) m/z (%): 378 (Mþ, 1%), 273 (100), 241 (15), 213
(15), 126 (13), 110 (25), 94 (75), 77 (25); HRMS calcd for
(C21H18N2O5): 378.1216, found: 378.1209.
4.2.44. Diethyl (3R*,3aS*,6aR*)-3-benzoyl-5-methyl-4,6-
dioxohexahydropyrrolo[3,4-c]pyrrole-1,1(2H)-dicarboxylate (all-cis-
12a). Colourless oil; IR (neat) nmax: 1748, 1700, 1685, 1275, 1212,
1173, 1109, 998, 772, 700 cmꢁ1 1H-RMN dH: 1.42e1.29 (m, 6H,
;
4.2.40. Methyl (1S*,3R*,3aS*,6aR*)-3-benzoyl-1,5-dimethyl-4,6-
2ꢂCH3C); 2.00 (br s, 1H, NH), 2.90 (s, 3H, MeN), 3.88 (d, J¼8.1 Hz,
1H, CHCON), 4.23 (dd, J¼8.5, 8.1 Hz, 1H, CHCON), 4.52e4.30 (m, 4H,
2ꢂCH2), 4.87 (d, J¼8.5 Hz, 1H, CHN), 7.54 (t, J¼7.5 Hz, 2H, ArH),
7.69e7.61 (m, 1H, ArH), 8.02e7.96 (m, 2H, ArH); 13C-RMN dC: 14.1,
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(endo-cis-
10a). Pale yellow oil; IR (neat) nmax: 1752, 1698, 1681, 1436, 1281,
1142, 786, 699 cmꢁ1; 1H-RMN dH: 1.63 (s, 3H, MeC), 2.40 (br s, 1H,

8816
J. Mancebo-Aracil et al. / Tetrahedron 71 (2015) 8804e8816
2011, 6784e6794; (i) Adrio, J.; Carretero, J. C. Chem. Commun. 2014,
12434e12446; (j) Najera, C.; Sansano, J. M. J. Organomet. Chem. 2014, 771,
14.2 (2ꢂCH3C), 25.5 (MeN), 51.3, 53.1 (2ꢂCHCON), 63.1, 63.2
(2ꢂCH2), 63.4, 75.6 (CHNC), 128.3, 129.1, 134.2, 135.9 (ArC), 166.5,
169.1, 174.4, 174.6, 194.6 (5ꢂCO); MS (EI) m/z (%): 402 (Mþ, 1%), 329
(12), 297 (100), 223 (10), 166 (62), 138 (10), 105 (46), 77 (23); HRMS
calcd for (C20H22N2O7eCO2Et): 329.1137, found: 329.1127.
ꢀ
78e92; (k) Hashimoto, T.; Maruoka, K. Chem. Rev. 2015, 115, 5366e5412.
7. For recent applied MCRs using azomethine ylides, see: Craven, P.; Aimon, A.;
Dow, M.; Fleury-Bregeot, N.; Guilleux, R.; Morgentin, R.; Roche, D.; Kalliokoski,
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Ríos, R.; Vesely, J.; Cordova, A. Tetrahedron Lett. 2007, 48, 6252e6257; (c) Yu, J.;
Acknowledgements
He, L.; Chen, X.-H.; Song, J.; Chen, W.-J.; Gong, L.-Z. Org. Lett. 2009, 11,
4946e4949; (d) Iza, A.; Carrillo, L.; Vicario, J. L.; Badía, D.; Reyes, E.; Martínez, J.
I. Org. Biomol. Chem. 2010, 8, 2238e2244; (e) Martín-Rodríguez, M.; Najera, C.;
ꢀ
The Spanish Ministerio de Ciencia e Innovacion (MICINN)
ꢀ
(projects CTQ2010-20387, and Consolider Ingenio 2010, CSD2007-
00006), the Spanish Ministerio de Economia y Competitividad
(MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC),
FEDER, the Generalitat Valenciana (PROMETEO 2009/039 and
PROMETEOII/2014/017), and the University of Alicante.
Sansano, J. M.; Costa, P. R. R.; Crizanto de Lima, E.; Dias, A. G. Synlett 2010,
962e966; (f) Chaulagain, M. R.; Aron, Z. D. J. Org. Chem. 2010, 75, 8271e8274;
(g) Shi, F.; Luo, S.-W.; Tao, Z.-L.; Yu, J.; Tu, S.-J.; Gong, L.-Z. Org. Lett. 2011, 13,
4680e4683; (h) He, L.; Chen, X.-H.; Wang, D.-N.; Luo, S.-W.; Zhang, W.-Q.; Yu,
J.; Ren, L.; Gong, L.-Z. J. Am. Chem. Soc. 2011, 133, 13504e13518; (i) Shi, F.; Tao, Z.-
L.; Yu, J.; Tu, S.-J. Tetrahedron: Asymmetry 2011, 22, 2056e2064; (j) Shi, F.; Tao,
Z.-L.; Luo, S.-W.; Tu, S.-J.; Gong, L.-Z. Chem.dEur. J. 2012, 18, 6885e6894; (k) Shi,
F.; Tao; Guo; Chang; Song, J.; Gong, L.-Z. Org. Lett. 2013, 15, 2676e2679; (l) Shi,
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Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.09.039.
9. For multicomponent metal-catalyzed examples, see: (a) Martín-Rodríguez, M.;
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Najera, C.; Sansano, J. M.; Costa, P. R. R.; Crizanto de Lima, E.; Dias, A. G. Synlett
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2010, 962e966; (b) Mancebo-Aracil, J.; Martín-Rodríguez, M.; Najera, C.; San-
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€
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~
17. The enantioselective version of this multicomponent synthesis has been re-
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