Enantioselective synthesis of polysubstituted prolines by Binap-silver-catalyzed 1,3-dipolar cycloadditions

Article abstract of DOI:10.1016/j.tetasy.2008.12.021

The enantioselective 1,3-dipolar cycloaddition reaction of stabilized azomethine ylides, generated from iminoesters, with maleimides was efficiently achieved by intermediacy of an equimolar mixture of chiral (R)- or (S)-Binap and AgClO₄. The high stability of the titled catalytic metal-complex to light exposure and its insolubility in toluene made possible its recovery and reutilization in other new process. In order to get a better understanding of the behavior of these chiral catalysts, we have carried out DFT1 calculations demonstrating the experimentally observed high enantio- and endo-selectivity through a very asynchronous transition state.

Full text of DOI:10.1016/j.tetasy.2008.12.021

Tetrahedron: Asymmetry 19 (2008) 2913–2923
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective synthesis of polysubstituted prolines by
Binap-silver-catalyzed 1,3-dipolar cycloadditions
a
a,
b
c,
Carmen Nájera a, , M. de Gracia Retamosa , José M. Sansano , Abel de Cózar , Fernando P. Cossío
*
*
a Departamento de Química Orgánica e Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080 Alicante, Spain
b Area de Química Orgánica, Universidad de Castilla-La Mancha, E-13071 Ciudad Real, Spain
c Departamento de Química Orgánica I, Facultad de Química, Universidad del País Vasco—Euskal Herriko Unibertsitatea, P. K. 1072, E-20018 San Sebastián-Donostia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective 1,3-dipolar cycloaddition reaction of stabilized azomethine ylides, generated from
iminoesters, with maleimides was efficiently achieved by intermediacy of an equimolar mixture of chiral
(R)- or (S)-Binap and AgClO4. The high stability of the titled catalytic metal-complex to light exposure and
its insolubility in toluene made possible its recovery and reutilization in other new process. In order to
get a better understanding of the behavior of these chiral catalysts, we have carried out DFT1 calculations
demonstrating the experimentally observed high enantio- and endo-selectivity through a very asynchro-
nous transition state.
Received 24 October 2008
Accepted 10 December 2008
Available online 21 January 2009
Dedicated to Professor José M. Saá on the
occasion of his 60th birthday
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
against the hepatitis C virus,4 kainoids 2 possess neuro-excitatory
activity and can be also used as insecticides,5 and (ꢀ)-dysibetaine
Proline is singular among the genetically encoded
a
-amino
3 is a known neuroexcitotoxin.6 Hydroxyprolines 4 and 5 are cru-
cial in collagen catabolism, and for the stabilization of protocolla-
gens and glycoproteins in plants and animals,7 respectively (Fig. 1).
acids ( -AA) due to the rigidity conferred by its pyrrolidine ring,
a
which leads to a steric hindrance that is useful in the design of bio-
logically active peptides,1 including the proline rich amphipathic
cell-penetrating peptides.2 Substitution on the pyrrolidine hetero-
cycle opens new perspectives on these areas, especially in struc-
ture–activity relationships studies of the newly generated
peptides.1 Restriction of the conformational space concerns not
only proline or its derivative, but also the preceding residue. The
CF3
O
CO2H
HO2C
N
substituent attached at the 2-position of the heterocycle (a-meth-
S
ylation) is widely used to stabilize the helical conformation of pep-
tides, as well as some type I b-trans arrangements. However,
substitution at the 3-position has not been much studied, and
the results are not so predictable. Substituted prolines at the 4-po-
sition can be considered as a constrained analogues of homocyste-
ine glutamate, homoarginine, and homoserine depending on the
nature of the functional group used as a substituent. These 4-
substituted surrogates, together with prolines incorporating a sub-
stituent at the 5-position, are used to stabilize type VI b-turns con-
formations and favor the preference of the CV-exo-puckering in the
peptide.1
CO2H
N
H
CO2H
1
2
H
+
N
NMe3
O
_
CO2
HO
(_)-dysibetaine
3
The proline-derived structures themselves have been employed
as organocatalyst3 in many useful transformations and also as po-
tent drugs. For example, antiviral agents 1 are active products
H
H
N
N
CO2H
CO2H
OH
HO
4
* Corresponding authors. Fax: +34 96 5903549 (C.N.).
5
E-mail addresses: cnajera@ua.es (C. Nájera), jmsansano@ua.es (J.M. Sansano).
For correspondence on computational studies:fp.cossio@ehu.es.
Figure 1. Some biologically active proline derivatives.
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.12.021

2914
C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
The synthesis of enantioenriched-substituted prolines8 can be
achieved by several routes, as for example, starting from prolines
or proline derivatives, and through C–N or C–C bond-forming cycli-
zations. These routes operate under a diastereoselective key step
included in a lengthy synthetic sequence. Since 2002, several fasci-
nating enantioselective syntheses of substituted prolines through
1,3-dipolar cycloaddition9 (1,3-DC) of azomethine ylides and elec-
tron poor alkenes have been developed by several groups.10 The
simultaneous formation of the three or four new stereocenters of
the resulting pyrrolidine can be achieved using chiral complexes
of silver,11 copper,12 zinc,13 nickel,14 calcium,15 or chiral organocat-
alysts,16 the metal-catalyzed reaction being the most efficient and
reliable route. Particularly, the most elevated endo/exo diastereose-
lectivities and enantioselectivities were obtained with mono- or
bidentate chiral ligands AgI or CuI complexes.
The combination of (S)-Binap–AgOAc showed low ee in 1,3-DC
when dipoles derived from iminoesters and dimethyl maleate
(up to 13% ee),11a or phenyl vinyl sulfone (up to 26% ee),12e,i were
used as dipolarophiles. In our group, we have used the Binap li-
gand17 and AgClO4 to generate active catalysts in the 1,3-DC using
N-methylmaleimide (NMM) and iminoesters.11h In this work, we
will describe the scope of this reaction, the study of another
diphosphines as well as the origin of the elevated enantioselectiv-
ity and endo-diastereoselectivity.
PPh2
PPh2
P(p-Tol)2
P(p-Tol)2
(S)-p-tolylBinap
(S)-9
(S)-Binap
8
(S)-
O
O
O
PPh2
PPh2
PPh2
PPh2
O
(S)-H8-Binap
(S)-10
(S)-SynPhos
(S)-11
N
O
O
N
i
O
O
Ph
N
CO2Me
6aa
Ph
CO2Me
N
H
7 (NMM)
endo-12aa
Scheme 1. Reagents and conditions: (i) (S)-Diphosphine (5 mol %), AgI salt
(5 mol %), Et3N (5 mol %), toluene, rt, 16 h.
2. Results and discussion
of a very clear crude 12aa product with excellent enantioselectiv-
ities (>99% ee), high endo-diastereoselectivity (>98/2), and 90%
yield were achieved with AgClO4 (Table 1, entry 7). Just 3 mol %
of the catalytic complex also gave good enantioselectivities, but
the reaction time was too long (1.5 d, Table 1, entry 8). This AgClO4
was used rather than the corresponding monohydrate because the
last compound was more difficult to weight (Table 1, entry 9).
Next, different ratios of Binap/AgClO4 were tested. Thus, when a
2:1 mixture of Binap/AgClO4 was added (Table 1, entry 10), the
percentage of the exo-cycloadduct was increased. When a 1:2 mix-
ture was prepared in situ, the product 12aa was obtained with a
very low enantioselectivity (Table 1, entry 11). In summary, the
equimolar Binap/AgClO4 was definitively the most efficient com-
plex for this process (compare entries 7, 10, and 11).
2.1. Optimization of the reaction conditions
The selected model reaction between methyl benzylideneimi-
noglycinate 6aa and NMM 7 was carried out in toluene at room
temperature using 5 mol % of (S)-Binap 8 and 5 mol % of AgI salt
as catalyst precursor (Scheme 1, Table 1).
The reaction run with an equimolar amount of both Binap 8 and
silver(I) salts such as AgBF4, AgNO3, and Ag2O (5 mol %) gave poor
results in terms of enantioselectivity and conversion (Table 1, en-
tries 1–3). When AgOAc was used, excellent results of the com-
pound 6aa were obtained (Table 1, entry 4), but the crude
reaction product was not as clean as in the case of AgClO4 does.
AgOTf and AgF were also tested giving irreproducible results in
both cases (Table 1, entries 5 and 6). However, reproducible results
Table 1
Optimization of the reaction of iminoesters 6a with NMM
Entry
Iminoester 6
Ligand
AgI salt
Product 12a
No.
Yield (%)b
endo/exoc
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
6aa
8
8
8
8
8
8
8
8
8
8
8
9
10
11
AgBF4
AgNO3
Ag2O
AgOAc
AgOTf
AgF
12aa
12aa
12aa
12aa
12aa
12aa
12aa
12aa
12aa
12aa
12aa
12aa
12aa
12aa
77
65
65
89
88
81
90
90
89
89
91
91
90
90
89:11
85:11
90:10
>98:2
90:10
90:10
>98:2
>98:2
>98:2
90:10
90:10
>98:2
>98:2
>98:2
72
67
18
99
99
98
AgClO4
AgClO4
>99
>99
99
e
AgClO4ꢁH2O
f
AgClO4
98
g
AgClO4
<50
>99
>99
98
AgClO4
AgClO4
AgClO4
a
The conversions were higher than 95% (determined by 1H NMR spectroscopy).
Isolated yield after recrystallization.
b
c
d
e
f
Determined by 1H NMR spectroscopy of the crude product.
Determined by chiral HPLC (Daicel Chiralpak AS) of the recrystallized product.
Reaction performed with a 3 mol % of the catalyst taking more than 1.5 d to complete.
Reaction performed with 2 equiv of 8 and 1 equiv of AgClO4.
Reaction performed with 1 equiv of 8 and 2 equiv of AgClO4.
g

C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
2915
The effect of solvent was also important because almost race-
mic mixtures were obtained with diethyl ether, whilst dichloro-
methane and THF gave moderate enantioselectivities (<60% ee) of
product 12aa.
Three additional diphosphines (9–11) were evaluated in this
particular model reaction (Scheme 1). It is very well known that
improvements of the enantioselectivity promoted by diphosphines
were associated with changes in the corresponding dihedral and
bite angles of the resulting chiral metal complex.18 Thus, equimolar
mixtures of silver perchlorate and ligands 9, 10, and 11 (5 mol%
each) afforded cycloadduct endo-12aa with very high conversions
and excellent enatioselectivities (>99% ee) except in the example
of the reaction product generated by the intermediacy of the chiral
ligand 11, which was isolated with 98% ee (Table 1, entries 12–14).
According to these data, the AgI complex formed with (R)- and
(S)-Binap 8 exhibited almost identical enantiodiscrimination other
than the complexes generated from more expensive chiral ligands
9–11. In addition, the resulting equimolar Binap–AgClO4 can be
recovered more easily than the analogous complexes generated
from diphosphines 9, 10, and 11.
Graphic 1. ESI experiments of complex (S)-16.
The absolute configuration of the four stereocenters of known
product endo-14aa (2Sꢁ3Rꢁ4Rꢁ5R) was confirmed by NOESY experi-
ments and by comparison of the obtained data with the previous
ones published in the literature.19
2.2. Characterization and properties of the complexes formed
by (S)-Binap 8 and AgClO4
Complexes formed from silver triflate and (R) or (S)-Binap 8
were isolated at different temperatures and further characterized
by X-ray diffraction analysis by Yamamoto’s group.20 These studies
revealed that mixture of structures 13–15 is in equilibrium and at
room temperature, the 1:1 complex 14 being the most abundant
system (Fig. 2).
TfO-
P
P
P
Ag+
*
P
P
P
P
AgOTf
P
PPh2
PPh2
=
13
*
*
Graphic 2. ESI experiments of complex (S)-17.
P
-
AgOTf
O
O
Ag+
S
15
in situ formed Binap complexes 16 and 17 could not be differenti-
ated by 31P NMR spectroscopy. Unfortunately, we could not obtain
appropriate crystals for their comprehensive and definitive charac-
terization by X-ray diffraction analysis (See Fig. 3).
*
(R)-Binap
(R)-8
O
CF3
P
14
Figure 2. [(R)-Binap]AgOTf complexes.
Ph
Ph
Ph
Ph
In spite of equimolar [(S)-Binap]–AgClO4 and [(S)-Binap]–AgOAc
complexes gave identical chemical yields of product endo-12aa
and very high enantioselectivity (>99 and 99% ee, respectively, Ta-
ble 1, entries 4, and 7) the presumed major complex 16 was much
more insoluble in toluene than the analogous formed by AgOAc.
This property allowed the separation of the complex 16 from the
reaction mixture by simple filtration (see Section 4). Surprisingly,
complexes (R)- and (S)-16 exhibited a high stability and any appar-
ent decomposition occurred upon the light exposure. Both com-
plexes 16 and 17 were prepared and isolated by reaction with 1
and 2 equiv of (R)- or (S)-Binap together to 1 equiv of AgClO4,
respectively. The mixture was stirred for 1 h at room temperature,
and the complexes were obtained in quantitative yield. Complex
(S)-16 was further characterized by ESI–MS experiments showing
an M++1 signal at 731 and a tiny one at 1353 (Graphic 1). In the
case of complex (S)-17 (Graphic 2), the same experiment revealed
a peak at 1353 and a very small one at 731. However, these two
P
P
Ag+ ClO4
Ag+ ClO4
-
-
P
P
Ph
Ph
Ph
Ph
16
16
(R)-
(S)-
[α]D = +174.5 (c 1, CHCl3)
[α]D
=
_174.5 (c 1, CHCl3)
Ph
Ph
Ph
Ph
P
P
Ag+
-
ClO4
P
P
Ph
Ph
Ph
Ph
(S)-17
Figure 3. Structures of complexes (R)-16, (S)-16, and (S)-17.

2916
^exo
C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
Graphic 4. NLE study of the model reaction catalyzed by the presumed major
complex 16.
Lab: SSTTI
STARe SW 8.10
Graphic 3. TG-DTA plot of complex (S)-16.
N
O
O
i
Due to the perchlorates being very hygroscopic materials and
also classified as low order explosives, thermogravimetric (TG)
and differential thermal analysis (DTA) of the stable species 16
were studied (Graphic 3). The integrated TG–DTA plot revealed
that the loss of water of the sample occurred from 50 to 180 °C
without any variation of the heat of the system. The melting point
of this complex 16 is placed in Graphic 3 in the range of 209–
211 °C. The three most important exothermic decomposition pro-
cesses occurred approximately at 300, 550, and 860 °C.
+ 7
CO2Me
Ar
N
6
Ar
CO2Me
N
H
end o-12
Scheme 2. Reagents and conditions: (i) (S)-Binap 8 (5 mol %), AgClO4 (5 mol %),
base (5 mol %), toluene, rt, 16 h.
was surveyed. Several ester and aryl groups were appropriate sub-
stituents in iminoglycinates 6 to perform the 1,3-DC efficiently
with NMM 11 (Scheme 2 and Table 3).
As was described before, the easy separation of the most active
major complex (S)-16 was a very important feature to apply in a lar-
ger-scale process. So, a series of cycles were run employing the same
catalytic mixture (1:1 8-AgClO4), which was recovered and reused
without any additional purification (Scheme 1 and Table 2). The
reaction shown in Scheme 1 was performed on a 1 mmol scale on
6aa with a 10 mol % of catalyst to facilitate its manipulation and suc-
cessive reutilization. In the cycles 1–4, the enantioselectivity was
higher than 99% ee keeping identical chemical yields (81–91%) (Ta-
ble2, entries1–4). Thefifthcyclealsoaffordedthetitleproductendo-
12aa in high yield but with a slightly lower ee (98%) (Table 2, entry 5)
due to the effect of the possible impurities contained in the catalyst.
In all of the five cycles tested, the endo/exo diastereoselectivity was
higher than 98:2 according to 1H NMR experiments.
The existence of NLE was discarded when the reaction shown in
Scheme 1 was performed using different enantiomeric purities of
the in situ-generated major complex (S)-16 (Graphic 4). In this
case, an almost linear behavior was observed and, in consequence,
it was reasonable to assume that monomeric complexes can be the
catalytically active species.
Non-substituted methyl aryliminoglycinates 6, derived from
benzaldehyde and 2-naphthalenecarbaldehyde, were the best sub-
strates affording >99% ee (Table 3, entries 1, 2, and 6). In the exam-
ple performed with catalytic complex (R)-16, the corresponding
enantiomer (2S.3R.4R.5R)-endo-12aa was obtained (Table 3, entry
2). It was also demonstrated for these phenyl and 2-naphthyl
derivatives that ethyl, isopropyl, and tert-butyl iminoglycinates
were not suitable groups for obtaining the highest enantioselectiv-
ities (Table 3, entries 3, 4, 5, and 7). In these examples, it was also
observed that larger amounts of the exo-diastereoisomer 12 were
formed according to 1H NMR spectroscopy and chiral HPLC. More
sterically hindered iminoglycinates derived from ortho-substituted
aromatic aldehydes gave lower enantioselectivity (Table 3, entries
8 and 9), even working at 0 or ꢀ20 °C and with bases other than
Et3N, such as DBU or DIEA. Using Et3N as base, the imines derived
from electron-donating or electron-withdrawing para-substituted
aromatic aldehydes show a very similar tendency (Table 3, com-
pare entries 11, 13, 14, and 16). In a few compounds, the ee was
increased after recrystallization of the previously purified sample
endo-12fa (Table 3, entry 13), but in other situations the employ-
ment of DBU as a base at 0 °C was crucial in order to achieve excel-
lent enantioselectivity of endo-12ea and endo-12ga (Table 3,
2.3. Scope of the 1,3-DC catalyzed by complexes (R)- and (S)-16
The scope of the reaction employing different aryl- and ester
groups at the iminoester structure with assorted dipolarophiles
Table 2
Recycling experiments of the 1:1 [(S)-Binap 8]/AgClO4 complex
Cycle
Reaction (mmol)
(S)-6aa (mmol)a
Recovered catalyst (%)
Yield (%)b
eeendo (%)c
1
2
3
4
5
1
1
1
1
1
0.100
0.095d
0.088d
0.081d
0.073d
95
93
92
90
90
91
89
91
90
88
>99
>99
>99
99
98
a
Recovered after filtration of the crude reaction suspension and washed several times with toluene.
Isolated yield of compound endo-12aa after recrystallization. The conversions were >99%, and the endo/exo ratio were >98:2 in all of the assayed cycles.
Determined by chiral HPLC (Daicel Chiralpak AS).
b
c
d
Amount recovered from the previous cycle.

C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
2917
Table 3
1.3-DC of iminoglycinates 6 and NMM 7
Entry
No
Ar
R
Base
Product endo-12
endo/exob
No.
Yield. (%)a
eeendo (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
6aa
6aa
6ab
6ac
6ad
6ba
6bd
6ca
6da
6da
6ea
6ea
6fa
Ph
Ph
Ph
Ph
Me
Me
Et
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
Et3N
Et3N
Et3N
Et3N
DBU
Et3N
Et3N
Et3N
12aa
12aae
12ab
12ac
12ad
12ba
12bd
12ca
12da
12da
12ea
12ea
12fa
12fa
12fd
12ga
12ga
12gd
12ha
12ha
90
90
78
80
81
>98:2
>98:2
90:10
90:10
75:25
>98:2
95:5
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
95:5
>99 (>99)d
>99 (>99)d
90 (91)
70 (72)
92 (92)
99 (>99)d
92 (94)
70 (75)
82 (85)
82 (85)
86 (88)d
99 (>99)d
80 (99)
80 (99)
90 (91)
64 (65)
98 (99)
80 (80)
90 (92)h
90 (92)h
Pri
Ph
But
Me
But
Me
Me
Me
Me
Me
Me
Me
But
Me
Me
But
Me
Me
2-Naphthyl
2-Naphthyl
2-CH3C6H4
2-ClC6H4
2-ClC6H4
4-CH3C6H4
4-CH3C6H4
4-(CH3O)C6H4
4-(CH3O)C6H4
4-(CH3O)C6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
2-Thienyl
2-Thienyl
89
87
85f
82f
82f,g
88
88
85
6fa
85g
84
6fd
6ga
6ga
6gd
6ha
6ha
87
>98:2
>98:2
>98:2
>98:2
>98:2
87g
83
87
87g
a
Isolated yield after recrystallization.
Determined by 1H MNR.
Determined by chiral HPLC (Chiralcel OD-H), the results of the recrystallized product are given in parentheses.
Determined by chiral HPLC (Chiralpak AS).
Molecule (2R.3S.4S.5S) endo-12aa obtained employing (R)-16.
Purification by flash chromatography.
Reaction performed with the recycled catalytic mixture.
Determined by chiral HPLC (Chiralpak AD).
b
c
d
e
f
g
h
entries 12 and 17). Unlike the results described from phenyl and
naphthyl derivatives the tert-butyl esters were more effective than
the corresponding methyl esters in those examples containing a
para-substituted aromatic residue imino group (compare entries
13 and 15, 16 and 18 of Table 3). Heteroaromatic iminoglycinate
bearing a 2-thienyl group furnished endo-cycloadduct 12ha with
92% ee after recrystallization (Table 3, entry 19). The recovery of
the complex (S)-16 was successfully attempted in the examples re-
corded in entries 10, 14, and 20 of Table 3 in 88–93% yield by sim-
ple filtration.
Next, sterically hindered
a-substituted benzaldimino esters
were tested as substrates in the 1,3-DC with NMM. Methyl benzy-
lidenealaninate 18, methyl phenyliminophenylalaninate 19, and
methyl 2-thienyliminoleucinate 20 reacted with NMM under the
same reaction conditions at room temperature for 48 h (Scheme
3). Cycloadducts endo-21–23 were obtained diastereoselectively
(>98:2 endo/exo ratio) and with good enantioselectivities (72–
76% ee). However, compound endo-22 was obtained after recrystal-
lization in 98% ee, and in 58% yield (Scheme 3). The absolute con-
figuration of the heterocycle (2Rꢁ3Sꢁ4Sꢁ5S) endo-21 was determined
by X-ray diffraction analysis (Fig. 4). 2-Thienyl derivatives endo-
12ha and endo-23 can be considered as structurally related precur-
sors of active inhibitors of the virus that is responsible for hepatitis
C 1 (Fig. 1).11i,21
N
O
O
i
+
NMM
Ph
N
CO2Me
80%
Ph
CO2Me
N
18
7
H
endo-21
72% ee
Several maleimides were essayed employing the model reaction
described in Scheme 1, which means benzyliminoglycinate 6aa,
Ph
N
O
O
i
+
NMM
Ph
N
CO2Me
Ph
CO2Me
83%
Ph
N
19
7
H
endo-22
64% ee
Af ter recryst. 56%, 98% ee
N
O
O
i
+ NMM
N
CO2Me
81%
CO2Me
S
N
H
20
7
S
endo-23
74% ee
Scheme 3. Reagents and conditions: (i) (S)-Binap 8 (5 mol %), AgClO4 (5 mol %),
Et3N (5 mol %), toluene, rt, 48 h.
Figure 4. ORTEP of cycloadduct endo-21.

2918
C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
4). Acrylates 29, fumarates 30, maleate 31, and acrylonitrile 32
Ph
N
gave very high reaction conversions, but the enantioselectivities
never exceeded of the 36% ee (Table 4) maintaining the high
endo/exo diastereoselection. Maleic anhydride, nitrostyrene, acryl-
amide, and N-isopropylacrylamide did not react at all in spite of
using DBU (10 mol %) as base or even other chiral ligands 9–11.
N
N
O
O
O
O
O
O
Ph
CO2Me Ph
12aa
CO2Me Ph
24
CO2Me
N
H
N
H
N
H
25
endo-
endo-
endo-
2.4. Computational studies
91%, >99% ee
endo:exo >98:2
86%, 62% ee
endo:exo 90:10
90%, >99% ee
endo:exo >98:2
In order to get a better understanding of the behavior of these
chiral catalysts, we have carried out DFT23 calculations on the
model reaction depicted in Scheme 1 and entry 7 of Table 1, using
the DFT functional usually denoted as B3LYP.24 Silver atoms were
treated using the Hay and Wadt effective core potential and basis
set25 (denoted as LANL2DZ), whereas the remaining elements were
described using the standard 6-31G* split-valence basis set.26 All
the calculations were carried out using the GAUSSIAN 03 suite of pro-
grams.27 The graphics shown in Figures 6 and 7 were built up using
the Maestro interface.28 In the model systems A–C, we have in-
cluded the cationic part of the presumed active complex (S)-16
as well as a model azomethine ylide and maleimide B.
The chief geometric features of complex (S)-A are gathered in
Figure 6. The azomethine ylide part of (S)-A shows different dis-
tances for the two C–N bonds. These distances are compatible with
an iminium-enolate structure as shown in Scheme 6, thus antic-
ipating quite asynchronous transition structures in the reaction
with the dipolarophile. It is also observed that the metallic center
is coordinated to the two phosphorus atoms of the catalysts and to
the oxygen and nitrogen atoms of the azomethine ylide. This coor-
dination pattern leads to the blockage of the Re face of (S)-A by one
of the phenyl groups of the phosphine unit (Fig. 6). This steric hin-
drance is also generated by the (S)-Binap moiety, in which the two
Figure 5. Products obtained from different N-substituted maleimides.
room temperature, (S)-8 (5 mol %), AgClO4 (5 mol %) and Et3N
(5 mol %) in toluene. N-Ethylmaleimide afforded similar results of
endo-24 to those analogous obtained with NMM 7 after 8 h of reac-
tion (Fig. 5). Nevertheless, the bulkier N-phenylmaleimide (NPM)
furnished a lower ee (62%) of endo-25 and a lower diastereoselec-
tivity (90:10 endo/exo ratio) (Fig. 5).
a
-Monomethylated and a,b-dimethylated N-ethylmaleimides
26 and 29, respectively, were prepared22 and used as dipolaro-
philes. Non-symmetric maleimide 26 was an attractive reagent
for studying the regioselectivity of this process. When the reaction
was completed, cycloadducts 27 and 28 were obtained in a 44:56
ratio, respectively. This ratio remained unaltered when the reac-
tion was run at 0 or at ꢀ20 °C, both in the presence of Et3N or
DBU. In general, better enantioselectivity was achieved with DBU
(84 and 89% ee) (Scheme 4). However, no reaction was observed
when 3,4-dimethyl-N-ethylmaleimide 29 was allowed to react
with imino ester 6aa.
Ph
N
CO2Me
a-naphthyl subunits form a dihedral angle of ca. 75°.
6aa
In previous work on chiral Ag-based catalysts we have observed
O
a clear preference for the endo-cycloadducts because of the electro-
static interaction between the nitrogen atom of maleimide and the
silver atom.12e Therefore, we considered the formation of the dia-
stereomeric endo-cycloadducts C and D via transition structures
TS1 and TS2, respectively. The main geometric features and the rel-
ative energies of these transition structures are reported in Figure
7. It is found that the Gibbs activation energies are larger than the
total activation energies because of the unfavorable entropic bal-
ance on going from the reactants to the saddle points, thus result-
ing in larger reaction times. As expected both TS1 and TS2 are quite
asynchronous, TS1 being ca. 2 kcal/mol more stable than TS2. In
the latter transition structure, there is an appreciable steric clash
between one of the phenyl groups of the phosphine moiety of
(S)-16 and the dipolarophile B. This results in a larger distortion
of the (S)-16 moiety in TS2 with respect to (S)-A. As a result, exclu-
sive formation of endo-(S,S,S,R)-C is predicted, in full agreement
with the experimentally observed formation of cycloadducts endo
described in the text. The same trend is found for the cycloadducts
endo-(S,S,S,R)-C and endo-(S,R,R,S)-D, the latter being ca. 1.3 kcal/
mol less stable than the former. Moreover, the slightly positive val-
ues of the Gibbs reaction energies associated with the formation of
these catalyst-bound cycloadducts are compatible with the cata-
lyst turnover since there is no inhibition of the catalyst by the
product of the cycloaddition step. These calculations support that
NMM is the best dipolarophile due to the coordination of the nitro-
gen atom to the metal center. On the other hand, the presence of a
bulkier substituent in this nitrogen atom blocks the endo-approach
reducing the enantioselectivity, such as that occurred with NPM. In
summary, our calculations are in full agreement with the experi-
mental findings and provide a rationale for the excellent asymmet-
ric induction and catalytic efficiency of species similar to (S)-16.
i
N
Et
26
O
Et
N
Et
N
O
O
O
O
+
Ph
Ph
CO2Me
:
CO2Me
N
H
27
N
H
28
44
56
(Et3N)
(DBU)
77% ee
84% ee
86% ee
89% ee
Scheme 4. Reagents and conditions: (i) (S)-Binap 8 (5 mol %), AgClO4 (5 mol %),
Et3N (5 mol %), toluene, rt, 16 h.
Dipolarophiles other than maleimides were not appropriate for
the particular requirements of this enantioselective 1,3-DC cata-
lyzed by the in situ-generated complex (S)-16 (Scheme 5 and Table
Y
R
Ph
N
CO2Me
i
6aa
Ph
CO2Me
endo-33-36
N
+
H
Dipolarophile
29-32
Scheme 5. (S)-Binap 8 (5 mol %), AgClO4 (5 mol %), Et3N (5 mol %), toluene, rt, 16 h.

C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
2919
Table 4
1,3-DC of iminoester 6aa with several dipolarophiles different to maleimides
Entry
Dipolarophile
No.
29a
29d
30a
30c
30e
31a
32
Structure
Product
endo:exob
No.
Yielda (%)
99
eeendo (%)c
MeO2C
Ph
CO2Me
1
2
3
4
5
6
33a
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
90:10
30
CO2Me
CO2Me
N
H
ButO2C
Ph
CO2But
33d
34a
34c
34e
35a
36
99
99
99
99
99
95
36
28
30
36
16
5
N
H
MeO2C
Ph
CO2Me
CO2Me
CO2Pri
CO2Me
CO2Pri
CO2Bui
MeO2C
PriO2C
N
H
PriO2C
Ph
CO2Me
N
H
BuiO2C
Ph
CO2Bui
CO2Me
CO2Me
CO2Me
BuiO2C
MeO2C
N
H
MeO2C
Ph
CO2Me
N
H
NC
CN
7
Ph
N
CO2Me
H
a
Isolated crude yields.
b
c
Determined by 1H MNR.
Determined by chiral HPLC (see Section 4).
(75 MHz) spectra were obtained on a Bruker AC-300 using CDCl3
as solvent and TMS as internal standard, unless otherwise stated.
Optical rotations were measured on a Perkin Elmer 341 polarime-
3. Conclusions
By evaluating all the data described in the main text, we found
that the employment of the complex generated by the 1:1 mixture
of chiral Binap and AgClO4 is very stable and can be manipulated
without any special care. It was efficient in the catalyzed 1,3-DC
using maleimides and aryliminoesters; however, other dipolaro-
philes did not work satisfactorily. The whole catalytic mixture
can be recovered from the reaction mixture and reused without
any loss of efficiency. The TS responsible for the enantiodiscrimina-
tion is, as expected, quite asynchronous, an appreciable steric clash
between one of the phenyl groups of the phosphine moiety of (S)-
16 and the dipolarophile being the crucial interaction.
ter. HPLC analyses were performed on
a JASCO 2000-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).
4. Experimental
4.1. General
4.2. 1,3-Dipolar cycloaddition of iminoesters 6 and
dipolarophiles. General procedure
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-
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 AgClO4 (0.05 mmol,
10 mg) in toluene (5 mL). To the resulting suspension, triethyl-
noesters. 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
amine (0.05 mmol, 7 lL) was added, and the mixture stirred at
room temperature and in the absence of the light for 16–48 h
(see main text). The precipitate was filtered, and the complex

2920
C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
Figure 7. Fully optimized structure (B3LYP/LANL2DZ&6-31G* level) of TS1 and TS2
leading to endo-(S,S,R)-C and endo-(S,R,R,S)-D, respectively. The hydrogen atoms
have been omitted for clarity. Bond distances and dihedrals are given in Å and °,
respectively. Numbers in parentheses and in square brackets are the relative total
and Gibbs free energies respectively, computed at the B3LYP/LANL2DZ&6-
31G*+
DZPVE level.
Figure 6. (I) Fully optimized structure (B3LYP/LANL2DZ&6-31G* level) of (S)-A. The
hydrogen atoms have been omitted for clarity. The carbon atoms of the azomethine
was recovered. The organic filtrate was directly evaporated, and
the residue was purified by recrystallization or by flash chromatog-
raphy yielding pure endo-cycloadducts.
The solid was washed with warm toluene twice, and then dis-
solved in DCM in order to transfer the catalytic complex into the
ylide moiety have been highlighted with asterisks. Bond distances and dihedrals are
0
given in ÅA and deg., respectively. The molecular surface (Probe radius: 1.4 Å) is also
included. (II) View over the Si face of (S)-A along the axis determined by the Ag and
P2 atoms.
H
H
Ph
P
Ph
H
N
H
H
N
O
Ag
O
O
+
P
Ph
Ph
(S)-A
B
ΔEa=5.6 kcal/mol
ΔEa=7.8 kcal/mol
TS1
TS2
ΔGa298=19.9 kcal/mol
ΔGa298=21.9 kcal/mol
O
H
O
H
H
H
N
S
N
R
H
H
Ph
P
Ph
P
Ph
Ph
R
S
N
N
O
O
O
S
R
Ag
Ag
H
H
H
H
O
P
P
Ph
Ph
Ph
Ph
endo-(S,S,S,R)-C
endo-(S,R,R,S)-D
Δ
Δ
ΔErxn=-10.1 kcal/mol
ΔGrxn298=+4.0 kcal/mol
Erxn=-8.8 kcal/mol
Grxn298=+5.3 kcal/mol
Scheme 6. Model reaction used in the computational studies. The hydrogen atoms highlighted in blue, green and red correspond to a phenyl, a methoxy and a methyl group
respectively in the reaction depicted in Scheme 1.

C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
2921
flask. After evaporation of DCM, the resulting solid was ready to
ethyl acetate: 1/5); IR (KBr) m ;
: 1715, 1689, 1678, 3341 cmꢀ1 1H
catalyze a new batch.
NMR dH: 1.32 [s, 9H, CO2C(CH3)3], 2.29 (br s, 1H, NH), 3.05 (s, 3H,
NCH3), 3.56 (m, 1H, CHCHAr), 3.86 (m, 1H, CHCHCO2CH3), 4.00
(d, J = 4.2 Hz, 1H, CHCO2CH3), 4.65 (d, J = 4.9 Hz, 1 H, CHAr), 7.40-
7.49 (m, 3H, ArH), 7.80-7.86 (m, 4H, ArH); 13C NMR dC: 25.2
(NCH3), 27.7 [CO2C(CH3)3].48.2, 49.1, 52.0 (2CHCON and CO2CH3),
63.3 (CHCO2But), 65.3 (2-Napht–CH), 82.6 [CO2C(CH3)3], 124.8,
125.2, 126.2, 126.4, 127.6, 128.0, 128.7 (ArCH), 133.0, 133.3
137.9 (ArC), 170.4, 176.9, 177.1 (CO2 But and CON); MS (EI) m/z
(%): 380 (M+, 1.78%), 280 (18), 279 (100), 194 (22), 167 (13); HRMS
calcd for C22H24N2O4: 380.1736, found: 380.1725; Microanalysis
calcd for C22H24N2O4: C, 69.5; H, 6.4; N, 7.4. found: C, 69.5; H,
6.3; N, 7.1. HPLC (Chiralcel OD-H, 1 mL/min, n-hexane/i-PrOH:
70/30, k 225 nm), tRmaj = 13.5 min, tRmin = 22.0 min.
4.2.1. Methyl (1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-dioxoocta-
hydropyrrolo[3,4-c]pyrrole-1-carboxylate 12aa12a,19
4.2.2. Ethyl (1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-dioxooc-
tahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12ab
Colorless prisms, mp, 195–197 °C (CH2Cl2/hex); ½a D20
¼ þ74 (c 1,
ꢂ
CHCl3, 90% ee from HPLC); Rf: 0.36 (n-hexane/ethyl acetate: 1/5); IR
(KBr) m
: 1752, 1702, 3325 cmꢀ1; 1H NMR dH: 1.38 (t, J = 7.1 Hz, 3H,
CO2CH2CH3), 2.41 (br s, 1H, NH), 2.85 (s, 3H, NCH3), 3.41 (dd,
J = 8.2, 8.0 Hz, 1H, CHCHAr), 3.55(dd, J = 7.3, 7.1 Hz, 1H, CHCHCO2Et),
4.01 (d, J = 5.7 Hz, 1H, CHCO2CH3), 4.32 (m, 2H, CO2CH2CH3), 4.47 (d,
J = 8.1 Hz, 1H, CHPh), 7.28–7.36 (m, 5H, ArH); 13C NMR dC: 14.1
(CO2CH2CH3), 24.9 (NCH3), 48.1, 49.5 (2CHCON), 61.3 (CO2CH2CH3),
61.7 (CHCO2Et), 63.9 (Ph–CH), 126.9, 128.2, 128.3 (ArCH), 136.7
(ArC), 169.6, 174.7, 175.8 (CO2Me and CON); MS (EI) m/z (%): 302
(M+, 3.90%), 230 (16), 229 (100), 191 (37), 144 (37), 117 (43); HRMS
calcd for C16H18N2O4: 302.1267, found: 302.1292; Microanalysis
calcd for C16H18N2O4: C, 63.5; H, 6.0; N, 9.2. Found: C, 63.5; H, 5.7;
N, 9.1. HPLC (Chiralcel OD-H, 1 mL/min, n-hexane/i-PrOH: 80/20, k
215 nm), tRmaj = 24.1 min, tRmin = 25.8 min.
4.2.7. Methyl (1S,3R,3aS,6aR)-5-methyl-4,6-dioxo-3-o-
tolyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12ca
Colorless prisms, mp, 151 °C (CH2Cl2/hex); ½a D20
¼ 50:8 (c 0.6,
ꢂ
CHCl3, 75% ee from HPLC); Rf: 0.25 (n-hexane/ethyl acetate: 1/5); IR
(KBr) m
: 1768, 1734, 1698, 2954 cmꢀ1; 1H NMR dH: 2.35 (s, 3H, ArCH3),
2.75 (s, 3H, NCH3), 3.46 (m, 1H, CHCHAr), 3.67 (m, 1H, CHCHCO2CH3),
3.82 (s, 3H, CO2CH3), 3.99 (d, J = 6.2 Hz, 1H, CHCO2CH3), 4.54 (d,
J = 8.1 Hz, 1H, CHAr), 7.08-7.15 (m, 3H, ArH), 7.36-7.39 (m, 1H,
ArH);13CNMRdC:19.4(ArCH3),24.9(NCH3),46.9, 48.0,52.3(2CHCON
and CO2CH3), 61.2 (CHCO2Me), 67.9 (2-MePh–CH), 125.1, 126.1,
127.8, 130.1 (ArCH), 135.2, 135.5 (ArC), 170.2, 174.4, 176.1 (CO2Me
and CON); MS (EI) m/z (%): 302 (M+, 15.36%), 243 (67), 244 (10), 193
(10), 192 (85), 191 (78), 160 (28), 159 (11), 158 (38), 132 (38), 131
(100), 130 (36), 118 (15), 115 (14), 105 (20), 104 (11), 103 (13), 91
(15), 77 (11); HRMS calcd for C16H18N2O4: 302.1267, found:
302.1247; Microanalysis calcd for C16H18N2O4: C, 63.6; H, 6.0; N,
9.3. found: C, 63.6; H, 6.3; N, 9.0. HPLC (Chiralcel OD-H, 1 mL/min,
n-hexane/i-PrOH:70/30,k225 nm),tRmin = 24.7 min, tRmaj = 28.1 min.
4.2.3. Isopropyl (1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12ac
Colorless prisms, mp, 202 °C (CH2Cl2/hex); ½a D20
¼ þ63 (c 0.7,
ꢂ
CHCl3, 99% ee from HPLC); Rf: 0.50 (n-hexane/ethyl acetate: 1/5);
IR (KBr) m ;
: 1735, 1703, 3328 cmꢀ1 1H NMR dH: 1.33 [d, J = 6.2 Hz,
3H, CO2CH(CH3)2], 1.41 [d, J = 6.3 Hz, 3H, CO2CH(CH3)2], 2.42 (br s,
1H, NH), 2.87 (s, 3H, NCH3), 3.43 (dd, J = 8.3, 8.0 Hz, 1H, CHCHPh),
3.56 (dd, J = 7.2, 7.1 Hz, 1H, CHCHCO2Pri), 4.00 (dd, J = 6.7, 5.7 Hz,
1H, CHCO2Pri), 4.49 (dd, J = 8.4, 5.8 Hz, 1H, CHPh), 5.22 [m, 1H,
CO2CH(CH3)2], 7.29–7.40 (m, 5H, ArH); 13C NMR dC: 21.6, 21.9
[CO2CH(CH3)2], 24.9 (NCH3), 48.2, 49.7 (2CHCON), 62.0
[CO2CH(CH3)2], 64.0 (CHCO2 Pri), 69.3 (Ph–CH), 126.6, 128.3, 128.4
(ArCH), 136.6 (ArC), 169.1, 174.8, 175.8 (CO2Me and CON); MS (EI)
m/z (%): 316 (M+, 2.23%), 230 (15), 229 (100), 205 (14), 144 (29),
117 (19); HRMS calcd for C17H20N2O4: 316.1423, found: 316.1426;
Microanalysis calcd for C17H20N2O4: C, 64.5; H, 6.3; N, 8.8. Found:
C, 64.5; H, 6.3; N, 8.5. HPLC (Chiralcel OD-H, 1 mL/min, n-hexane/i-
PrOH: 80/20, k 215 nm), tRmaj = 21.5 min, tRmin = 33.4 min.
4.2.8. Methyl (1S,3R,3aS,6aR)-3-(2-chlorophenyl)-5-methyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12da11h
4.2.9. Methyl (1S,3R,3aS,6aR)-5-methyl-3-(4-methylphenyl)-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12ea11h
4.2.10. Methyl (1S,3R,3aS,6aR)-3-(4-methoxyphenyl)-5-methyl-
4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12fa11h
4.2.11.tert-Butyl (1S,3R,3aS,6aR)-3-(4-methoxyphenyl)-5-meth-
yl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12fd
4.2.4. tert-Butyl (1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-
Colorless prisms, mp, 179 °C (CH2Cl2/hex); ½a D20
¼ þ93 (c 0.5,
ꢂ
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12ad
CHCl3, 84% ee from HPLC); Rf: 0.29 (n-hexane/ethyl acetate: 1/5);
Colorless prisms, mp, 210 °C (subl.) (CH2Cl2/hex); ½a D20
¼ þ33:9
ꢂ
IR (KBr)
m ;
: 1702, 1733, 2977 cmꢀ1 1H NMR dH: 1.58 [s, 9H,
(c 0.8, CHCl3, 92% ee from HPLC); Rf: 0.39 (n-hexane/ethyl acetate:
CO2C(CH3)3], 1.86 (br s, 1H, NH), 2.88 (s, 3H, NCH3), 3.38 (dd,
J = 8.2, 8.0 Hz, 1H, CHCHAr), 3.53 (dd, J = 7.1, 7.0 Hz, 1H, CHCHCO2-
But), 3.80 (s, 3H, OCH3), 3.92 (d, J = 6.7 Hz, 1H, CHCO2But), 4.43 (d,
J = 8.6 Hz, 1H, CHAr), 6.87 (d, J = 8.7 Hz, 2H, ArH), 7.24 (d, J = 8.7 Hz,
2H, ArH); 13C NMR dC: 24.9 (NCH3), 28.1 [CO2C(CH3)3], 48.2, 49.7
(2CHCON), 55.1 (OCH3), 62.3 (CHCO2But), 63.4 (4-MeOPh–CH),
82.5 [CO2C(CH3)3], 113.7, 128.1 (ArCH), 159.3, 168.6 (ArC), 175.1,
175.9 (CON); MS (EI) m/z (%): 360 (M+, 4.15%), 260 (15), 259
(100), 249 (12), 193 (45), 174 (24), 147 (29); HRMS calcd for
C19H24N2O5: 360.1685, found: 360.1674; Microanalysis calcd for
C19H24N2O5: C, 63.3; H, 6.7; N, 7.7. found: C, 63.5; H, 6.6; N, 7.4.
1/5); IR (KBr) m ;
: 1734, 1705, 3328 cmꢀ1 1H NMR dH: 1.58 [s, 9H,
CO2C(CH3)3], 2.40 (br s, 1H, NH), 2.86 (s, 3H, NCH3), 3.42 (dd,
J = 8.2, 8.1 Hz, 1H, CHCHPh), 3.54 (dd, J = 7.2, 7.1 Hz, 1H, CHCHCO2-
But), 3.94 (m, 1H, CHCO2But), 4.49 (dd, J = 8.5, 6.1 Hz, 1H, CHPh),
7.26–7.36 (m, 5H, ArH); 13C NMR dC: 24.9 (NCH3), 28.1
[CO2C(CH3)3].48.2, 49.8 (2CHCON), 62.4 (CHCO2But), 63.8 (Ph–
CH), 82.5 [CO2C(CH3)3], 126.6, 128.2, 128.4 (ArCH), 136.7 (ArC),
174.8, 175.8 (CON); MS (EI) m/z (%): 330 (M+, 0.01%), 230 (18),
229 (100), 144 (25)117 (18); HRMS calcd forC18H22N2O4:
330.1580, found: 229.0986; Microanalysis calcd for C18H22N2O4:
C, 65.4; H, 6.7; N, 8.5. found: C, 65.4; H, 6.6; N, 8.3. HPLC (Chiralcel
OD-H, 1 mL/min, n-hexane/i-PrOH: 70/30, k 215 nm), tRmaj = 12.1 -
min, tRmin = 17.3 min.
HPLC (Chiralpak AS, 1 mL/min, n-hexane/i-PrOH: 90/10,
205 nm), tRmin = 25.2 min, tRmaj = 43.7 min.
k
4.2.12. Methyl (1S,3R,3aS,6aR)-3-(4-chlorophenyl)-5-methyl-
4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12ga11h
4.2.5. Methyl (1S,3R,3aS,6aR)-5-methyl-3-(2-naphthyl)-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12ba11h
4.2.6. tert-Butyl (1S,3R,3aS,6aR)-5-methyl-3-(2-naphthyl)-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12bd
4.2.13. tert-Butyl (1S,3R,3aS,6aR)-3-(4-chlorophenyl)-5-methyl-
4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12gd
Colorless prisms, mp, 129-131 °C (CH2Cl2/hex); ½a D20
¼ þ16 (c
ꢂ
Colorless prisms, mp, 150-152 °C (CH2Cl2/hex); ½a D20
¼ þ39:8 (c
ꢂ
0.5, CHCl3, 82% ee from HPLC); Rf: 0.36 (n-hexane/ethyl acetate:
1, CHCl3, 92% ee from HPLC, 75:25 endo/exo); Rf: 0.46 (n-hexane/

2922
C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
1/5); IR (KBr)
m
: 1729, 1708, 3328 cmꢀ1
;
1H NMR dH: 1.57 [s, 9H,
52.4 (CHCO2Pri), 53.8 (CO2CH3), 63.4 [CHCO2Me], 65.2 (Ph-CH),
CO2C(CH3)3], 2.39 (br s, 1H, NH), 2.84 (s, 3H, NCH3), 3.41 (dd,
J = 8.2, 8.1 Hz, 1H, CHCHAr), 3.54 (dd, J = 7.6, 6.9 Hz, 1H, CHCHCO2-
But), 3.95 (dd, J = 6.4, 5.7 Hz, 1H, CHCO2But), 4.45 (dd, J = 8.6,
5.8 Hz, 1H, CHAr), 7.24-7.31 (m, 5 H, ArH); 13C NMR dC: 24.9
(NCH3), 28.0 [CO2C(CH3)3], 47.8, 49.4 (2CHCON), 62.2 (CHCO2But),
63.0 (p-Cl–CH), 82.6 [CO2C(CH3)3], 128.3, 128.6 (ArCH), 133.9,
135.3 (ArC), 174.6, 175.6 (CON); MS (EI) m/z (%): 364 (M+, 0.21%),
265 (32), 264 (15), 263 (100), 178 (21), 151 (10), 143 (11), 57
(12); HRMS calcd for C18H21ClN2O4: 364.1190, found: 364.1207;
Microanalysis calcd for C18H21ClN2O4: C, 59.3; H, 5.8; N, 7.7. found:
C, 59.1; H, 5.8; N, 7.4. HPLC (Chiralcel OD-H, 1 mL/min, n-hexane/i-
PrOH: 80/20, k 215 nm), tRmaj = 14.5 min, tRmin = 26.5 min.
68.2, 68.8 [CH(CH3)2], 127.0, 127.7, 128.2 (ArCH), 138.4 (ArC),
170.5, 171.5, 171.6 (CO2Me, CO2Pri); MS (EI) m/z (%): 377 (M+,
13.84%), 318 (33), 317 (23), 316 (23), 290 (20), 276 (17), 274
(12), 258 (38), 248 (15), 230 (43), 228 (17), 216 (10), 205 (25),
202 (50), 188 (47), 187 (23), 177 (67), 170 (34), 149 (12), 146
(29), 145 (46), 144 (100), 143 (29), 119 (22), 118 (19), 117 (96),
116 (14), 115 (28), 106 (11), 104 (10), 91 (12), 90 (10); HRMS calcd
for C20H27NO6: 377.1838, found: 377.1863; HPLC (Chiralcel OD-H,
1 mL/min, n-hexane/i-PrOH: 80:20, k 220 nm), tRmaj = 6.6 min,
tRmin = 13.5 min.
4.2.26. 3,4-Diisobutyl 2-methyl (2S,3S,4S,5R)-5-phenylpyrroli-
dine-2,3,4-tricarboxylate 35e
4.2.14. Methyl (1S,3R,3aS,6aR)-5-methyl-4,6-dioxo-3-(2-thienyl)
octahydropyrrolo[3,4-c]pyrrole-1-carboxylate 12ha11h
Sticky oil; ½a 2D0
ꢂ
¼ þ47:1 (c 0.5, CHCl3.82% ee from HPLC); Rf: (n-
hexane/ethyl acetate: 1/5); IR (liq.)
m
: 1737, 1730, 2958 cmꢀ1 1H
;
4.2.15. Methyl (1S,3R,3aS,6aR)-1,5-dimethyl-4,6-dioxo-3-pheny-
NMR dH: 0.66 [d, J = 6.7 Hz, 3H, CH(CH3)2], 0.68 [d, J = 6.6 Hz, 3H,
CH(CH3)2], 0.95 [d, J = 6.7 Hz, 6H, CH(CH3)2], 1.51 [d, J = 6.7 Hz,
1H, CH(CH3)2], 1.63 (br s, 1H, NH), 1.97 [d, J = 6.7 Hz, 1H, CH(CH3)2],
3.25 [dd, J = 10.5, 6.6 Hz, 1H, CH2CH(CH3)2], 3.50 [dd, J = 10.6,
6.6 Hz, 1H, CH2CH(CH3)2], 3.63 (m, 2H, 2 ꢃ CHCO2Bui), 3.83 (s,
3H, CO2CH3), 3.96 [m, 2H, CH2CH(CH3)2], 4.19 (d, J = 7.3 Hz, 1H,
CHCO2Me), 4.66 (d, J = 7.5 Hz, 1H, CH-Ph), 7.25-7.32 (m, 5H,
ArH); 13C NMR dC: 18.8, 18.9, 19.0 [CH(CH3)2], 27.2, 27.7
[CH(CH3)2], 51.3 (CHCO2Bui), 52.5 (CO2CH3), 54.0 (CHCO2Bui),
63.4 [CHCO2Me], 65.5 (Ph–CH), 71.1, 71.5 (CH2), 126.9, 127.8,
128.3 (ArCH), 138.1 (ArC), 171.4, 172.1, 172.2 (CO2Me, CO2Bui);
MS (EI) m/z (%): 405 (M+, 10.61%), 346 (11), 345 (22), 332 (20),
304 (20), 272 (36), 245 (11), 244 (54), 219 (11), 202 (38), 188
(38), 178 (11), 177 (90), 170 (26), 164 (46), 155 (12).149 (14),
146 (54), 145 (46), 144 (82), 143 (24), 119 (12), 118 (19), 117
(100), 116 (13), 115 (21), 106 (11), 105 (11), 90 (11), 57 (46), 56
(21), 55 (12); HRMS calcd for C22H31NO6: 405.2151, found:
405.2171; HPLC (Chiralcel OD-H, 1 mL/min, n-hexane/i-PrOH:
80:20, k 220 nm), tRmaj = 8.5 min, tRmin = 16.7 min.
loctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 2111h
4.2.16. Methyl (1S,3R,3aS,6aR)-1-benzyl-5-methyl-4,6-dioxo-3-
phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 2211h
4.2.17. Methyl (1S,3R,3aS,6aR)-1-isobutyl-5-methyl-4,6-dioxo-3-
(2-thienyl)octahydropyrrolo[3,4-c]pyrrole-1-carboxylate 2311h
4.2.18. Methyl (1S,3R,3aS,6aR)-5-ethyl-3-phenyl-4,6-dioxoocta-
hydropyrrolo[3,4-c]pyrrole-1-carboxylate 2412a,19
4.2.19. Methyl (1S,3R,3aS,6aR)-3,5-diphenyl-4,6-dioxooctahy-
dropyrrolo[3,4-c]pyrrole-1-carboxylate 2512a,19
4.2.20. Methyl (1S,3R,3aS,6aR)-5-ethyl-3a-methyl-3-phenyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 27
(Isolated together isomer 28): 1H NMR dH:1.09 (t, J = 7.2 Hz, 3H,
NCH2CH3), 1.49 (s, 3H, CCH3), 2.39 (br s, 1H, NH), 3.12 (d, J = 6.4 Hz,
1H, CHCHCO2CH3), 3.43 (m, 2H, NCH2CH3), 3.87 (s, 3H, CO2CH3),
4.00 (br s, 1H, CHPh), 4.07 (d, J = 4.4, Hz, 1H, CHCO2CH3), 7.32-
7.34 (m, 4H, ArH); 13C NMR dC: 13.1 (CH2CH3), 20.0 (CCH3), 33.9
(CH2CH), 52.2 (CO2CH3), 54.5 (CHCON), 54.6 (CCH3), 60.4
(CHCO2Me), 71.9 (Ph–CH), 126.9, 128.2, 128.5 (ArCH), 136.6,
136.9 (ArC), 170.2, 173.9, 175.1 (CO2Me and CON).
4.2.27. Trimethyl (2S,3R,4S,5R)-5-phenylpyrrolidine-2,3,4-tri-
carboxylate 35a12a,19
4.2.21. Methyl (1S,3R,3aS,6aR)-5-ethyl-6a-methyl-3-phenyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate 28
4.2.28. Methyl (2S,4S,5R)-4-cyano-5-phenylpyrrolidine-2-car-
(Isolated together isomer 27). 1H NMR dH:1.09 (t, J = 7.2 Hz, 3H,
NCH2CH3), 1.60 (s, 3H, CCH3), 2.39 (br s, 1H, NH), 2.98 (d, J = 8.4 Hz,
1H, CHCHPh), 3.43 (m, 2H, NCH2CH3), 3.71 (d, J = 3.4 Hz, 1H,
CHCO2CH3), 3.87 (s, 3H, CO2CH3), 4.53 (dd, J = 8.2, 4.1 Hz, 1H,
CHAr), 7.32-7.34 (m, 4H, ArH); 13C NMR dC: 13.1 (CH2CH3), 20.0
(CCH3), 33.9 (CH2CH), 52.2 (CO2CH3), 54.6 (CCH3), 56.9 (CHCON),
63.0 (Ph–CH), 68.2 (CHCO2Me), 126.9, 128.2, 128.5 (ArCH), 136.6,
136.9 (ArC), 170.2, 177.3, 178.7(CO2Me and CON).
boxylate 3629
Acknowledgments
This work This work has been supported by the DGES of the Span-
ish Ministerio de Educación y Ciencia (MEC) (Consolider INGENIO
2010 CSD2007-00006, CTQ2007-62771/BQU, and CTQ2004-00808/
BQU), Generalitat Valenciana (CTIOIB/2002/320, GRUPOS03/134
and GV05/144), and by the University of Alicante. M.G. Retamosa
thanks the University of Alicante for a predoctoral fellowship. The
authors also thank the SGI/IZO-SGIker UPV/EHU for generous alloca-
tion of computational resources and Prof. V. Ratovelomanana-Vidal
for her generous gift of (S)-SynPhos (S)-11.
4.2.22. Dimethyl (2S,4S,5R)-5-phenylpyrrolidine-2,4-dicarboxyl-
ate 33a11b
4.2.23. 4-tert-Butyl 2-methyl (2S,4S,5R)-5-phenylpyrrolidine-
2,4-dicarboxylate 33b11b
4.2.24. Trimethyl (2S,3S,4S,5R)-5-phenylpyrrolidine-2,3,4-tri-
carboxylate 34a12a,19
References
4.2.25. 3,4-Diisopropyl (2S,3S,4S,5R)-2-methyl-5-phenylpyrroli-
1. Karoyan, P.; Sagan, S.; Lequin, O.; Cluancard, J.; Lavielle, S.; Chassaing, G. Targets
Heterocycl. Syst. 2004, 8, 216–273.
2. Pujals, S.; Giralt, E. Adv. Drug Delivery Rev. 2008, 60, 473–484.
dine-2,3,4-tricarboxylate 34c
Sticky oil; ½a 2D0
ꢂ
¼ þ32:1 (c 0.5, CHCl3.82% ee from HPLC); Rf:
3. (a) Gruttadauria, M.; Giacalone, F.; Noto, R. Chem. Soc. Rev. 2008, 37, 1666; (b)
Almasi, D.; Alonso, D.; Nájera, C. Tetrahedron: Asymmetry 2007, 18, 299–365; (c)
Guillena, G.; Nájera, C.; Ramón, D. J. Tetrahedron: Asymmetry 2007, 18, 2249; (d)
Pellissier, H. Tetrahedron 2007, 63, 9267; (e) Guillena, G.; Ramón, D. J.
Tetrahedron: Asymmetry 2006, 17, 1465; (f) Asymmetric Organocatalysis: from
Biomimetic Concepts to Applications in Asymmetric Synthesis; Berkessel, A.,
Gröger, H., Eds.; Wiley-VCH: Weinheim, 2005; (g) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138; (h) Special organocatalysis issue: . Chem. Rev.
2007, 107, 5413–5883; (i) Special organocatalysis issue: Tetrahedron 2006, 62,
243–502. Enantioselective Organocatalysis: Reactions and Experimental
Procedures, ed. Dalko, P. I. Wiley-VCH, Weinheim, 2007.
0.37 (n-hexane/ethyl acetate: 3/2); IR (liq.)
m:
1741, 1731,
2982 cmꢀ1 1H NMR dH: 0.65 [d, J = 6.2 Hz, 3H, CH(CH3)2], 0.94 [d,
;
J = 6.2 Hz, 3H, CH(CH3)2], 1.27 [d, J = 6.2 Hz, 3H, CH(CH3)2], 1, 28
[d, J = 6.2 Hz, 3H, CH(CH3)2], 2.86 (br s, 1H, NH), 3.55 (m, 2H,
2 ꢃ HCO2Pri), 3.83 (s, 3H, CO2CH3), 4.14 (d, J = 7.3 Hz, 1H,
CHCO2Me), 4.56 [sept, J = 6.2 Hz, 1H, CH(CH3)2], 4.65 (d,
J = 7.3 Hz, 1H, CH-Ph), 5.08 [sept, J = 6.2 Hz, 1H, CH(CH3)2], 7.22-
7.34 (m, 5H, ArH); 13C NMR dC: 20.8, 21.4, 21.6 [CH(CH3)2], 51.4,

C. Nájera et al. / Tetrahedron: Asymmetry 19 (2008) 2913–2923
2923
4. (a) Burton, G.; Ku, T. W.; Carr, T. J.; Kiesow, T.; Sarisky, R. T.; Lin-Goerke, J.;
15. Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364–5365.
Baker, A.; Earnshaw, D. L.; Hofmann, G. A.; Keenan, R. M.; Dhanak, D. Bioorg.
16. The employment of organocatalysts as well as chiral bases has been reported:
(a) Alemparte, C.; Blay, G.; Jørgensen, K. A. Org. Lett. 2005, 7, 4569–4572; (b)
Arai, S.; Takahashi, F.; Tsuji, R.; Nishida, A. Heterocycles 2006, 67, 495–501; (c)
Ibrahem, I.; Ríos, R.; Vesely, J.; Córdova, A. Tetrahedron Lett. 2007, 48, 6252–
6257; (d) Vicario, J. L.; Reboredo, S.; Badía, D.; Carrillo, L. Angew. Chem. Int. Ed.
2007, 46, 5168–5170; (e) Xue, M.-X.; Zhang, X.-M.; Gong, L.-Z. Synlett 2008,
691–694.
Med. Chem. Lett. 2005, 15, 1553;
b Dhanak, D.; Carr, T. J. Patent WO
2001085720, 2001; Chem. Abstr. 2001, 135, 371990.
5. (a) Parsons, A. F. Tetrahedron 1996, 52, 4149; (b) Baldwin, J. E.; Fryer, A. M.;
Pritchard, G. J.; Spyvee, M. R.; Whitehead, R. C.; Wood, M. E. Tetrahedron 1998,
54, 7465.
6. Wardrop, D. J.; Burge, M. S. Chem. Commun. 2004, 1230–1231.
7. Remuzon, P. Tetrahedron 1996, 52, 13803.
17. For reviews of binap chemistry, see: Noyori, R. Adv. Synth. Catal. 2003, 345, 15–
78.
8. Nájera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4273–4303.
9. For recent reviews of 1,3-dipolar cycloaddition reactions of azomethine ylides,
see: (a) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887–2902; (b) Álvarez-
Corral, M.; Muñoz-Dorado, M.; Rodríguez-García, I. Chem. Rev. 2008, 108, 3174–
3198; (c) Naodovic, M.; Yamamoto, H. Chem. Rev. 2008, 108, 3132–3148; (d)
Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247–12275; (e) Pellisier, H.
Tetrahedron 2007, 63, 3235–3285; (f) Pandey, G.; Banerjee, P.; Gadre, S. R. Chem.
Rev. 2006, 106, 4484–4517; (g) Pinho e Melo, T. M. V. D. Eur. J. Org. Chem. 2006,
2873–2888; (h) Bonin, M.; Chauveau, A.; Micouin, L. Synlett 2006, 2349–2363;
(i) Nájera, C.; Sansano, J. M. Angew. Chem. 2005, 117, 6428–6432; (j) Husinec, S.;
Savic, V. Tetrahedron: Asymmetry 2005, 16, 2047–2061; (k) Coldham, I.; Hufton,
R. Chem. Rev. 2005, 105, 2765–2809.
18. Jeulin, S.; DupratdePaule, S.; Ratovelomanana-Vidal, V.; Gênet, J.-P.; Champion,
N.; Dellis, P. Proc. Natl. Acad. Sci. 2004, 101, 5799–5804.
19. Dogan, O.; Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W. J.; Panzner, M. Org.
Lett. 2006, 8, 4687.
20. Momiyama, N.; Yamamoto, H. J. Am. Chem. Soc. 2004, 126, 5360–5361.
21. (a) Burton, G.; Ku, T. W.; Carr, T. J.; Kiesow, T.; Sarisky, R. T.; Lin-Goerke, J.;
Baker, A.; Earnshaw, D. L.; Hofmann, G. A.; Keenan, R. M.; Dhanak, D. Bioorg.
Med. Chem. Lett. 2005, 15, 1553;
b Dhanak, D.; Carr, T. J. Patent WO
2001085720, 2001; Chem. Abstr. 2001, 135, 371990.; For the first asymmetric
synthesis of these inhibitors of the RNA-polymerase of the hepatitis C virus,
using a diastereoselective 1,3-DC involving chiral lactate derived acrylates, see:
(c) Nájera, C.; Retamosa, M. G.; Sansano, J. M.; de Cózar, A.; Cossío, F. P. Eur. J.
Org. Chem. 2007, 30, 5038–5049.
10. Najera, C.; Sansano J. M. in Topics Heterocyclic Chem. Ed. Hassner, A, 2008, 12,
117–145.
11. (a) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400–
13401; (b) Chen, C.; Li, X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174–
10175; (c) Knöpfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.; Carreira,
E. M. Angew. Chem. 2004, 116, 6097–6099; (d) Zheng, W.; Zhou, Y.-G. Org. Lett.
2005, 7, 5055–5058; (e) Stohler, R.; Wahl, F.; Pfaltz, A. Synthesis 2005, 1431–
1436; (f) Zheng, W.; Zhou, Y.-G. Tetrahedron Lett. 2007, 48, 4619–4622; (g)
Zheng, W.; Chen, G.-Y.; Zhou, Y. G.; Li, Y.-X. J. Am. Chem. Soc. 2007, 129, 750–
751; (h) Nájera, C.; Retamosa, M. G.; Sansano, J. M. Org. Lett. 2007, 9, 4025–
4028; (i) Nájera, C.; Retamosa, M. G.; Sansano, J. M. Angew. Chem., Int. Ed. 2008,
47, 6055–6058.
12. (a) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata, S.; Komatsu,
M. Org. Lett. 2003, 5, 5043–5046; (b) Cabrera, S.; Gómez-Arrayás, R.; Carretero,
J. C. J. Am. Chem. Soc. 2005, 127, 16394–16395; (c) Gao, W.; Zhang, X.;
Raghunath, M. Org. Lett. 2005, 7, 4241–4244; (d) Yan, X.-X.; Peng, Q.; Zhang, Y.;
Zhang, K.; Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem. Int. Ed. 2006, 45, 1979–
1983; (e) Cabrera, S.; Gómez-Arrayás, R.; Martín-Matute, B.; Cossío, F. P.;
Carretero, J. C. Tetrahedron 2007, 63, 6587–6602; (f) Llamas, T.; Gómez-Arrayás,
R.; Carretero, J. C. Org. Lett. 2006, 8, 1795–1798; (g) Martín-Matute, B.; Pereira,
S. I.; Peña-Cabrera, E.; Adrio, J.; Silva, A. M. S.; Carretero, J. C. Adv. Synth. Catal.
2007, 349, 1714–1724; (h) Shi, J.-W.; Shi, J. W. Tetrahedron: Asymmetry 2007,
18, 645–650; (i) Llamas, T.; Gómez-Arrayás, R.; Carretero, J. C. Synthesis 2007,
950–957.
22. Zoutendam, P. M. G. H.; Kissinger, P. T. J. Org. Chem. 1979, 44, 758.
23. Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and Molecules; Oxford:
New York, NY, 1989.
24. (a) Kohn, W.; Becke, A. D.; Parr, R. G. J. Phys. Chem. 1996, 100, 12974; (b) Becke,
A. D. J. Chem. Soc. 1993, 98, 5648; (c) Becke, A. D. Phys. Rev. A 1988, 38, 3098.
25. Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.
26. Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab initio Molecular Orbital
Theory; Wiley: New York, NY, 1986, and references therein.
27. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao,
O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken,
V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A.
J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G.
A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.;
Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.;
Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.;
Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe,
M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A.
GAUSSIAN 03, Revision C.02; Gaussian: Wallingford, CT, 2004.
13. (a) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem. Int.
Ed. 2002, 41, 4236–4238; (b) Panzner, M. J. Org. Lett. 2006, 8, 4687–4690.
14. Shi, J.-W.; Zhao, M.-X.; Lei, Z.-Y.; Shi, M. J. Org. Chem. 2008, 73, 305–308.
28. Maestro, version 8.5, Schrödinger, LLC, New York, NY, 2008.
29. Tsuge, O.; Kanemasa, S.; Yoshioka, M. J. Org. Chem. 1988, 53, 1384–1391.