Binap-gold(I) versus Binap-silver trifluoroacetate complexes as catalysts in 1,3-dipolar cycloadditions of azomethine ylides

Article abstract of DOI:10.1002/chem.201101606

The 1,3-dipolar cycloaddition between azomethine ylides and alkenes is efficiently catalysed by [{(S_a)-Binap-Au(tfa)}₂] (Binap=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; tfa=trifluoroacetyl). Maleimides, 1,2-bis(phenylsulfonyl)ethy

Full text of DOI:10.1002/chem.201101606

DOI: 10.1002/chem.201101606
Binap–Gold(I) versus Binap–Silver Trifluoroacetate Complexes as Catalysts
in 1,3-Dipolar Cycloadditions of Azomethine Ylides**
Marꢀa Martꢀn-Rodrꢀguez,[a] Carmen Nꢁjera,*[a] Josꢂ M. Sansano,[a] Abel de Cꢃzar,[b] and
Fernando P. Cossꢀo*[b]
Dedicated to Professor Francisco Palacios on the occasion of his 60th birthday
Abstract: The 1,3-dipolar cycloaddition
between azomethine ylides and alkenes
is efficiently catalysed by [{(Sa)-Binap-
even when using sterically hindered
1,3-dipole precursors. The results ob-
tained in these transformations im-
prove the analogous ones obtained in
the same reactions catalysed by
[Binap–AgACTHNUTRGNEUNG(tfa)]. In addition, computa-
Au
(tfa)}2]
(Binap=2,2’-bis(diphenyl-
tfa=tri-
tional studies have also been carried
out to demonstrate both the high enan-
tioselectivity exhibited by the chiral
gold(I) complex, and the non-linear
effect observed in this transformation.
phosphino)-1,1’-binaphthyl;
Keywords: asymmetric synthesis ·
azomethine · cycloaddition · gold ·
silver
fluoroacetyl). Maleimides, 1,2-bis(phe-
nylsulfonyl)ethylene, chalcone and ni-
trostyrene were suitable dipolarophiles
Introduction
addition (1,3-DC)[3] being one of them. The enantioselective
version of 1,3-DC of stabilised azomethine ylides[4] that em-
ploys substoichiometric amounts[5] of catalyst has been stud-
ied extensively since 2002.[6] Silver(I)-[7] and copper(I)-cata-
lysed[8] 1,3-dipolar cycloadditions offer excellent comple-
mentary results in terms of endo-/exo-diastereoselectivity
and are the most frequently employed metals nowadays.
This work, which is focused on the activity and efficiency of
Binap–silver(I) salt (Binap=2,2’-bis(diphenylphosphino)-
1,1’-binaphthyl) complexes, can be considered an evolution
from the first attempt at the enantioselective 1,3-DC of azo-
methine ylides with dimethyl maleate described in 2002 by
Zhang et al. by using (Sa)-Binap (3 mol%), AgOAc and
Et3N as base with very poor results.[5] Our research group
has found out that the very stable and recoverable (Sa)- or
(Ra)-Binap–AgClO4 complexes are able to catalyse the
enantioselective 1,3-DC of azomethine ylides with
maleimides.[9] When using a less coordinating anion such as
AgSbF6 instead of AgClO4, it was possible to achieve better
results for bulky substrates and even with 1,3-bis(phenylsul-
fonyl)ethylene as a dipolarophile.[6e] Toste et al. published
the first enantioselective 1,3-dipolar cycloaddition between
mesoionic azomethine ylides (mꢀnchnones) with electron-
The application of soluble gold complexes as catalysts for
organic transformations has been widely explored over the
last ten years.[1] In spite of the numerous published gold-
ACHTUNGTRENNUNG
(III)-catalysed processes,[2] the diverse range of transforma-
tions developed by gold(I) complexes have generated partic-
ular interest as catalysts. Gold(I) complexes catalyse reac-
tions under very mild conditions to give wide functional
group compatibility and high efficiency. They act as soft car-
À
bophilic Lewis acids towards C C multiple bonds. This high
carbophilicity translates to a relatively low oxophilic charac-
ter of the gold(I) cation. However, recent advances in syn-
thetic catalytic organic transformations have demonstrated
that the weak heteroatom–gold(I) interaction is sufficient
for the reaction to succeed.[1] Its size, together with the al-
ready mentioned chemoselectivity and functional-group
compatibility, are crucial features for application in complex
crowded molecular structures. There are many processes
that are sensitive to steric hindrance, the 1,3-dipolar cyclo-
[a] M. Martꢁn-Rodrꢁguez, Prof. Dr. C. Nꢂjera, Dr. J. M. Sansano
Quꢁmica Orgꢂnica e Instituto de Sꢁntesis Orgꢂnica
Universidad de Alicante, Apdo 99
03080 Alicante (Spain)
poor alkenes catalysed by [Cy–SegphosACTHNUTRGENUG(N AuCl)2] (Segphos=
4,4’-bi-1,3-benzodioxole-5,5’-diylbis(diphenylphosphane)).
The reaction afforded in all cases only the exo adduct in
high yields and very good enantioselectivities.[10] However,
the classical 1,3-dipolar cycloaddition of iminoesters and
electrophilic olefins was not described using gold complexes.
In this article, we present the general scope of this transfor-
mation using Binap–gold(I) complexes and a comparison
with the analogous reactions performed with chiral Binap–
silver(I) salts.[11,12]
Fax : (+34)965903549
E-mail: cnajera@ua.es
[b] Dr. A. d. Cꢃzar, Prof. Dr. F. P. Cossꢁo
Quꢁmica Orgꢂnica I, Institution: Facultad de Quꢁmica
Universidad del Paꢁs Vasco, P. K. 1072
20018 San Sebastiꢂn (Spain)
E-mail: fp.cossio@ehu.es
[**] Binap=2,2’-bis(diphenylphosphino)-1,1’-binaphthyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101606.
14224
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Chem. Eur. J. 2011, 17, 14224 – 14233

FULL PAPER
Table 1. Optimisation of the 1,3-dipolar cycloaddition of 3a and 4a.
Results and Discussion
Cat. [10 mol%][a]
Base [10 mol%]
Conv. [%][b]
ee [%][c]
The gold(I) cation has only two coordination sites, and its
linear geometry makes asymmetric catalysis extremely diffi-
cult. Fortunately, a key to the development of enantioselec-
tive gold(I)-catalysed transformations has been the identifi-
1
2
3
4
5
6
7
8
1-Cl
1-tfa
DIPEA
DIPEA
DIPEA
>95
>95
>95
>95
>95
>95
>95
>95
>95
>95
90
rac
rac
62
2-OAc
2-OAc
2-OBz
2-OBz
2-tfa
–
70
DIPEA
74
cation of enantiomerically pure bisACTHUNTGRNEUNG(gold)–chiral diphosphine
–
94[d]
74
À
complexes of the form [(AuX)2ACTHNUTRGNEUGN(P P)*] as catalysts for enan-
DIPEA
tioselective transformations.[1] A clear and recent example
of the isolation, identification and characterisation of two
chiral Binap–gold(I) complexes 1 and 2, which bear tri-
fluoroacetate as counteranion, have been reported by Pud-
dephatt et al.[13] These complexes were prepared by mixing
(Me2S)AuCl and the corresponding amount of the chiral
Binap ligand. The resulting gold(I) chloride complexes[14]
were treated with different silver salts for 1 h in toluene,
and the suspension was filtered through a Celite plug. The
remaining solution was evaporated to obtain 1 or 2 in 89
2-tfa
–
–
–
–
–
99
99
9
2-tfa[e]
2-tfa[f]
2-tfa[g]
6
10
11
12
ent-99
60
>95
99
[a] The generation of gold catalysts was achieved by mixing equivalent
amounts of gold(I) complex and the corresponding silver(I) salt.
1
[b] Determined by 1H NMR spectroscopy on the crude sample obtained
by using the filtered solution of the gold complex after anionic inter-
change. The observed endo/exo ratio was always >98:2 (1H NMR spec-
troscopy). [c] Determined by using analytical chiral HPLC columns
(Daicel, Chiralpak AS). [d] Notable amounts of unidentified side prod-
ucts were observed (1H NMR spectroscopy). [e] The reaction was carried
out with the chiral complex isolated by recrystallisation. [f] The reaction
was performed with (Ra)-Binap as ligand. [g] Reaction performed with
5 mol% catalyst.
vironment of the bis-gold(I) complexes of type 1 hardly par-
ticipated in the enantio-discriminating step. However, di-
meric complexes of the type 2 proved to be the appropriate
catalysts. Thus, in the case of the chiral complex 2-OAc,
product endo-5aa was obtained with high conversion and
60% ee in the presence of DIPEA (entry 3). Interestingly, in
the absence of base, a 70% ee was obtained by working with
the complex as a bifunctional catalyst (entries 3 and 4).
Better results were achieved when using complex 2-OBz in
the presence of DIPEA or in the absence of added base to
afford cycloadduct endo-5aa in 74 and 94% ee, respectively
(entries 5 and 6). Although product endo-5aa was obtained
with the higher enantioselectivity of 94% ee in the absence
of DIPEA, it was contaminated with secondary byproducts.
The same inconvenience was detected when triethylamine
was used as base in this cycloaddition reaction. When the
gold(I) trifluoroacetate complex 2-tfa was used as catalyst,
compound endo-5aa was obtained with 74% ee in the pres-
ence of DIPEA (entry 7), whereas without base, 99% ee
was obtained (entry 8). This last reaction was performed in-
troducing a previously synthesised (isolated and recrystal-
lised) complex 2-tfa[12] to obtain identical results (entry 9).
The enantiomeric form of cycloadduct endo-5aa was gener-
ated in 99% ee by the employment of the corresponding
R,R-dimeric complex 2-tfa (entry 10). Attempts to reduce
the catalyst loading to 5 mol% were not successful, as re-
vealed by the lower 60% ee obtained (entry 11). At this
point, an identical result was obtained independently of
using the chiral complex 2-tfa
and 96% yields, respectively. These cationic complexes were
immediately employed without any other purification in the
catalytic enantioselective 1,3-DC of the imino ester 3a and
N-methylmaleimide 4a (NMM) in toluene at RT (Scheme 1
and Table 1).
Scheme 1. Optimisation of the 1,3-dipolar cycloaddition of 3a and 4a.
According to our experience, the model reaction between
3a (1,3-dipole precursor) and 4a, in toluene at RT
(Scheme 1 and Table 1), was selected for the initial optimi-
sation of the gold(I) catalytic efficiency. When this cycload-
dition was performed in the presence of diisopropylethyl-
amine (DIPEA; 10 mol%) and complex 1 (X=Cl or
CF3CO2 (tfa); 10 mol%), product endo-5aa was obtained
with high conversion but in racemic form (Table 1, entries 1
and 2). These two examples demonstrated that the chiral en-
(entry 8) and the chiral complex
[(Sa)-Binap–AgACTHNUTRGNEUGN(tfa)] (6) in the
absence of base (entry 12). In
every example, the major cyclo-
adduct obtained was the endo
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C. Nꢂjera, F. P. Cossꢁo et al.
Table 2. 1,3-DC of iminoesters 3a and maleimides 4 catalysed by chiral complex 2-tfa.
(>98:2 diastereomeric ratio (d.r.)) according to the
NMR spectroscopic experiments of the crude prod-
ucts. Analogously, the absolute configuration was
confirmed by comparison of their retention times
by using analytical chiral HPLC columns and spe-
cific optical rotations with those described for enan-
tiomerically pure samples.
Comparative studies for this catalysed enantiose-
lective 1,3-DC were performed by using gold(I) and
silver(I) complexes together with different imi-
noesters and maleimides under the best reaction
conditions depicted in Table 1 (Scheme 2 and
Gold catalysis
endo-5 Yield ee
[%][a,b] [%][c] [%][a,b] [%][c,d]
Silver catalysis
Yield ee
3
Ar
R
Base
1
2
3
4
5
6
7
8
9
3a Ph
3a Ph
3a Ph
3a Ph
3a Ph
3a Ph
3b 2-naphthyl
3b 2-naphthyl
3b 2-naphthyl
Me
–
5aa
95
90
78
80
81
89
87
85
82
90
88
88
88
85
99
70
99
70
80
64
90
50
99
99
88
88
99
22
89
89
78
81
80
88
88
81
84
92
89
88
88
81
99
99
99
99
rac
rac
99
50
46
50
60
99
99
rac
Me DIPEA 5aa
Et 5ab
Et DIPEA 5ab
Ph 5ac
Ph DIPEA 5ac
Me
Et
Ph
–
–
–
–
–
–
–
–
–
–
5ba
5bb
5bc
5ca
5da
5ea
5 fa
5ga
10 3c 2-MeC6H4
Me
Me
Me
Table 2). In the first example, in the absence of 11 3d 2-ClC6H4
12 3e 4-MeC6H4
13 3 f 4-(MeO)C6H4 Me
14 3g 4-ClC6H4 Me
base (including the above-described reaction of 3aa
with 4a) and performed with N-ethylmaleimide
(NEM, 4b) and N-phenylmaleimide (NPM, 4c),
products 5ab and 5ac were isolated with higher
enantioselectivity when the reaction was catalysed
by the chiral gold complex (Table 2, entries 1, 3 and
[a] Isolated yields after flash chromatography (silica gel). [b] The observed endo/exo
ratio was >98:2 (1H NMR spectroscopy). [c] Determined by using analytical chiral
HPLC columns. [d] The reaction was performed exclusively with 6 (10 mol%).
phenylalaninate (7a) was allowed to react with 4a under the
standard reaction conditions, the reaction performed with
the gold(I) complex needed 24 h more than the correspond-
ing reaction that used the analogous silver(I) complex to
achieve almost total conversion (Scheme 3). The enantiose-
Scheme 2. [{(S)-Binap–Au
ACHTUNGTERN(NUNG tfa)}2]-catalysed 1,3-dipolar cycloaddition of
iminoesters 3 and maleimides 4.
5). However, in the presence of DIPEA (10 mol%) the
chiral silver(I)-catalysed process was more efficient except
in the reaction carried out with 4c (compare entries 1 with
2, 3 with 4, and 5 with 6). In fact, the result obtained when
4c was employed as a dipolarophile (entry 5) is particularly
noteworthy because it is the best ee value (80% ee) ach-
ieved to date with chiral Binap ligands. When 6 was used as
catalyst, racemic product 5ac was obtained. For the 1,3-DC
of other arylideneaminoesters 3b–h, and maleimides, the
conversions were identical, independent of the metal cation
employed. In the case of 2-naphthyl-derived iminoester, the
enantioselectivities were very close to each other, but NPM
chiral gold(I) catalysts 2-tfa (entries 7–9) again was much
more efficient in generating the highest enantioselectivities.
The dipole precursors 3c and 3d, which contain an ortho-
substituent in the aryl moiety, were appropriate sterically
hindered starters in the gold(I)-catalysed 1,3-DC with 4a to
afford endo compounds 5ca and 5da with 99 and 88% ee,
respectively. In both examples, the resulting enantioselectivi-
ties induced with the corresponding chiral silver(I) complex
were very poor (entries 10 and 11). The para-substituted
methyl iminoglycinates 3e, 3 f and 3g underwent the gold(I)
and the silver(I)-mediated 1,3-DC to obtain no rational re-
sults in terms of enantioselectivity (entries 12–14). The inser-
tion of a substituent at the a position of the 1,3-dipole pre-
cursor was next evaluated. Thus, when methyl benzylidene-
Scheme 3. [{(S)-Binap–Au
1,3-dipolar cycloaddition of iminoester 7a and 4a.
ACHUTGTNRNENUG(tfa)}2] versus [(S)-Binap–AgACHTUNGTRENN(UGN tfa)]-catalysed
lectivity showed by the [{(Sa)-Binap–AuACTHUNRTGNEU(GN tfa)}2] complex
(99% ee) was higher than that which used 6 (65% ee) as cat-
alyst. Product 8aa was obtained as an endo diastereoisomer
(>98:2, determined by 1H NMR spectroscopy). According
to the published results of compounds obtained from chiral
Binap–silver(I) complexes,[9] we also tested the efficiency of
the Binap–gold(I) trifluoroacetate complexes in the enantio-
selective cycloaddition of azomethine ylides and trans-1,2-
Fbis(phenylsulfonyl)ethylene (9), a synthetic equivalent of
acetylene (Scheme 4 and Table 3). The reaction, which was
Scheme 4. [{(S)-Binap–Au
1,3-dipolar cycloaddition of iminoesters 3 and disulfone 9.
ACHUTGTNRNENUG(tfa)}2] versus [(S)-Binap–AgACHTUNGTRENN(UGN tfa)]-catalysed
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Binap Complexes as Catalysts
FULL PAPER
Table 3. 1,3-DC of iminoester 3a and disulfone 9 catalysed by chiral complex 2-tfa.
performed at 25 or À208C, respectively (Scheme 5b,
and Table 4, entries 4 and 5). The lowering of the
temperature in the reactions that involved chalcone
or b-nitrostyrene afforded incomplete crude reac-
tion mixtures after 48 h and furnished a lower enan-
tioselectivity in products 15 or 16a, respectively.
When conjugated esters such as methyl or tert-butyl
acrylate, dimethyl maleate and diisopropyl fuma-
rate were used as dipolarophiles and allowed to
react with iminoester 3a under the optimised reac-
tion conditions, high yields of the corresponding
endo cycloadducts were obtained but with very low
enantioselectivities. Several analyses were carried
out to identify the structure of the catalytic species.
The 31P NMR spectroscopic analysis of complex 2
revealed a singlet at d=41.1 ppm, whereas the sin-
glet at d=23.3 ppm corresponded to the (Sa)-
Binap–AuCl complex according to the literature.
The dimeric complex is assumed to be a non-reac-
Gold catalysis
Silver catalysis
Ar, 3
Base
10
Yield
ee
Yield
ee
G
[%][a,b]
[%][c]
[%][a,b]
[%][c,d]
1
2
3
4
5
6
7
8
Ph, 3a
Ph, 3a
DIPEA
10a
10a
10b
10b
10i
81
74
91
<40
80
<40
73
73
91
67
81
80
99
90
rac
30
40
96
96
88
99
22
rac
80
81
88
<40
83
<40
70
70
90
75
80
86
96
64
rac
20
20
92
96
96
96
rac
rac
–
2-naphthyl, 3b
2-naphthyl, 3b
2-(MeO)C6H4, 3i
2-(MeO)C6H4, 3i
3-pyridyl, 3e
3-pyridyl, 3e
4-MeC6H4, 3 f
4-MeC6H4, 3 f
4-ClC6H4, 3h
4-ClC6H4, 3h
DIPEA
–
DIPEA
–
10i
DIPEA
10e
10e
10 f
10 f
10h
10h
–
9
DIPEA
10
11
12
–
DIPEA
–
<40
<40
[a] Isolated yields after flash chromatography (silica gel). [b] The observed endo/exo
ratio was always >98:2 (1H NMR spectroscopy). [c] Determined by using analytical
chiral HPLC columns. [d] Reaction performed with 6.
performed with 5 mol% of the gold(I) 2-tfa catalyst, afford-
ed cycloadducts 10 in unpredictable enantioselectivities in
the absence or in the presence of DIPEA (10 mol%) as
base. In the case of product 10a, a lower enantiomeric
excess was obtained when 6 was used as catalyst, and better
results were obtained in the absence of base (Table 3, com-
pare entries 1 and 2). Compound endo-10b was obtained in
better enantiomeric excesses in the absence of base (com-
pare entries 3 and 4). The rest of the examples gave the best
enantioselectivities in the absence of base (compare en-
tries 5 and 6; 7 and 8; 9 and 10). Again, the p-chloro-substi-
tuted iminoester gave very poor ee values (entries 11 and
12). The absolute configuration of the endo cycloadducts
was assigned according to the retention times by using ana-
lytical chiral HPLC columns, and by comparison of the
physical properties of the isolated samples with the proper-
ties published in the literature for the analogous compounds.
In our search for other appropriate dipolarophiles for this
enantioselective catalysed 1,3-DC of azomethine ylides,
chalcone and b-nitrostyrene were used. Similarly to that
which occurred in the 1,3-DC catalysed by chiral phosphor-
amidites and silver perchlorate, chalcones reacted efficiently
to afford exclusively very clean endo cycloadducts 14 after
24 h at room temperature and in the presence of Et3N
(10 mL%) as base, rather than DIPEA, independently of
the selected metal. The most important difference consisted
of the enantioselectivity achieved. Whereas chiral dimeric
gold catalyst furnished very high ee value of 15, silver com-
plex gave always lower enantio-discriminations (Scheme 5a
and Table 4, entries 1–3). The reaction between iminoester
3a and b-nitrostyrene afforded very complex mixtures of un-
identified compounds when chiral silver complexes were
employed. However, very clean crude reaction products
tive complex, but in our case, the existence of the dipole
would induce a reorganisation of 2. For this study, the
strongly coordinating thiazole-derived iminoester was select-
ed. In the ESI-MS experiments, peaks at m/z 819, 819.2 and
819.6 were observed upon elution with a mixture of acetoni-
trile and water, thereby demonstrating the existence of such
Scheme 5. [{(S)-Binap–AuACTHNUTRGNNEG(U tfa)}2] versus [(S)-Binap–AgACHTUNTGREN(NUGN tfa)]-catalysed
1,3-dipolar cycloaddition of iminoesters 3 and chalcone or b-nitrostyrene.
Table 4. 1,3-DC of iminoesters 3 with chalcone and b-nitrostyrene
Gold catalysis
Silver catalysis
Ar, 3
Product
Yield
ee
Yield
ee
[%][a,b]
[%][c]
[%][a,b]
[%][c,d]
1
2
3
4
5
Ph, 3a
2-naphthyl, 3b
4-MeC6H4, 3 f
Ph, 3a
15a
15b
15 f
16a
16a
95
90
80
60
80
70
60
80
81
80
20
50
74
–
80
78[e]
77[e]
–
[f]
[f]
Ph, 3a[g]
–
–
[a] Isolated yields after flash chromatography (silica gel). [b] The ob-
served endo/exo ratio was always >98:2 (1H NMR spectroscopy). [c] De-
termined by using analytical chiral HPLC columns. [d] Reaction per-
formed with 6. [e] The observed endo/exo ratio was 20:80 (1H NMR spec-
troscopy and using analytical chiral HPLC columns). [f] The reaction
failed. [g] Reaction performed at À208C.
were obtained when dimeric [{(S)-Binap–AuACTHNURGTNEUNG(tfa)}2] was
used. The diastereoselectivity was not as high as in previous
cycloadditions, with 20:80 endo/exo mixtures of 16a formed
despite of running the reaction at 208C. Cycloadduct exo-
16a was obtained in 70 or 60% ee whether the reaction was
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C. Nꢂjera, F. P. Cossꢁo et al.
a dimeric complex. However, apart from the already de-
scribed [M+] at m/z 819, a very intense one was observed at
m/z 1053, which possibly originated from the formation of
the cluster 17 that involved two molecules of the corre-
Figure 1. Experimental (a) and theoretical (b) NLE observed in the 1,3-
DC between the iminoester 3a and NMM catalysed by chiral complex 2.
sponding dipole. Efforts to obtain crystals from the mixture
of equimolar amounts of chiral complex and the dipole de-
rived from thiazole in dichloromethane were unfruitful. This
analysis also revealed the existence (in lower proportion) of
fragments and peaks that originated from the analogous
complex 18 coordinated with just one equivalent of the imi-
noester (m/z 966.4 [M+]).
In the case of monomeric (Sa)-Binap–Au ylide I complex
(Figure 2B), the gold atom presents a linear coordination
and it is surrounded by only one phosphorous atom of the
ligand and the nitrogen atom of the ylide. In this case, the
carboxy–gold distance is about 0.3 ꢅ larger than the car-
boxy–silver distance as one might expect from the known
low oxophilicity of the gold(I) cation. This geometry makes
the two prochiral faces approximately equivalent. Therefore,
no significant enantioselectivity should be expected in the
[3+2] reaction.
We also considered the existence of (Sa)-Binap–Au dimer-
ic units as the actual catalytic complex (Figure 2B and C).
Under these conditions, only two significant conformations
are energetically accessible. In [{(Sa)-Binap–Au}2] ylide I,
only the (2Si,5Re) face is accessible. By contrast, in [(Sa)-
Binap–Au]2 ylide Ib, the accessible face is the opposite one
(called (2Re,5Si)). However, the difference in energy of the
less stable one is enough to assume that only I is present in
solution at room temperature. Therefore, the major product
corresponds to the (S,S,S,R) cycloadducts. In previous works
that focused on catalysed 1,3-DC of azomethine ylides and
maleimides, we demonstrated the exclusive preference of
the reaction for endo cycloadducts. Therefore, only this ap-
proach will be considered in the following study.[8b]
We observed a strong positive non-linear effect (NLE;
Figure 1) when the reaction of iminoester 3a was allowed to
react with 4a by employing different enantiomeric purities
of the catalytic chiral complex 2-tfa. This behaviour can be
justified by the generation of a reservoir of unproductive
non-chiral heterodimer complex,[15] thereby increasing the
concentration of the chiral catalytic active species in solu-
tion. Next, we performed DFT calculations to shed light on
the origins of the great stereocontrol obtained in these (Sa)-
Binap–AuI-catalysed 1,3-DC reactions. In a previous work,
we demonstrated that the stereoselectivity obtained by em-
ploying chiral-ligand-metallated azomethine ylide in 1,3-DC
is a consequence of the blockage of one of the ylide stereo-
genic faces by the chiral ligand.[8f,16] We calculated the geo-
metries of the most stable (Sa)-Binap–silver(I) or –gold(I)
ylide I reactive complexes (Figure 2). As expected, in the
case of the silver complex (Figure 2A), the metallic centre
adopts a tetrahedral environment. This AgI is surrounded by
both phosphorous atoms of the ligand and by the nitrogen
and oxygen atoms of the ylide (Figure 2A). Due to this coor-
dination pattern, the distance between the chiral ligand and
the prochiral faces is short enough to induce a proper ste-
reoselectivity that allows the attack of the dipolarophile
only by the (2Si,5Re) face of the ylide. This is in good agree-
ment with the experimental evidence of the major formation
of the (S,S,S,R) cycloadducts.[8b]
The main geometric features and relative energies of the
stationary points that correspond to the 1,3-DC of (S)-
Binap–Au ylide dimers are gathered in Figure 3. As expect-
ed from the previous analysis, endo saddle points that corre-
spond to the reaction of the dipolarophile through the hin-
dered (2Re,5Si) face of ylide [{(Sa)-Binap–Au}2]-I are of
much higher energy than the obtained from suprafacial ap-
proach through (2Si,5Re) of ylide [{(Sa)-Binap–Au}2]-Ib (see
14228
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Chem. Eur. J. 2011, 17, 14224 – 14233

Binap Complexes as Catalysts
FULL PAPER
Figure 2. Geometry of the most stable (Sa)-Binap AgI or AuI complexes computed at the ONIOM(B3LYP/LanL2DZ:UFF) level of theory. The B3LYP/
LanL2DZ and UFF levels in the ONIOM calculation are depicted in ball-and-stick and tube representations, respectively. The numbers in parentheses
correspond to the relative Gibbs free energies at 298 K and are given in kcalmolÀ1. Surfaces represent the solvent-accessible surface with a probe radius
of 1.9 ꢅ. B)–D) Schematic drawing of the possible stereochemical course of the corresponding [3+2] cycloaddition is also displayed.
tween both possible reactive ylides, Curtin–Hammet kinetics
show that the product ratio should depend on the free
Gibbs activation energy difference of both corresponding
transition structures. Under this kinetic framework, our cal-
culations predict the major formation of (S,S,S,R)-II with
about 90% ee, which is in good agreement with the experi-
mental results.
The formation of the major complexed cycloadduct is
thermodynamically favoured (about 6 kcalmolÀ1, Figure 3).
The catalytic cycle is completed because the final step (3i+
(S,S,S,R)-II to release the cycloadduct 5 fa) is endothermic
(3 kcalmolÀ1) and the recovery of the reactive ylide is en-
sured (Scheme 6).
Figure 3. Gibbs activation energy and main geometrical features of the
computed reaction paths of the transition structures that correspond to
the two possible 1,3-DC of AuI ylide dimeric complexes and N-methyl
maleimide computed at the ONIOM (B3LYP/LanL2DZ:UFF) level of
theory. High- and low-level layers are represented as ball-and-stick and
wireframe models, respectively.
Scheme 6. The last step in the catalytic cycle to generate compound 5 fa.
the Supporting Information for further details). Our calcula-
tions also indicate that the reaction presents a concerted but
slightly asynchronous transition structure in which the criti-
Finally, we studied computationally the strong positive
NLE observed in the reaction of the iminoester 3a and 4a
catalysed by gold(I) complexes. We calculated the stability
of the possible azomethine ylide complexes with hetero-
Binap–gold(I) dimers. Our results indicate that there is only
one energetically feasible geometry for the [(Sa)-Binap,(Ra)-
Binap–Au2]-I reactive complex, and this complex is much
À
cal distance of the C2 CNMM bond that forms is shorter than
À
that associated with formation of the C5 C’NMM bond.
The activation Gibbs free energy barrier associated with
the formation of (S,S,S,R)-II is about 4.5 kcalmolÀ1 higher
than the one associated with the formation of the corre-
sponding enantiomer. If we assume a pre-equilibrium be-
Chem. Eur. J. 2011, 17, 14224 – 14233
ꢄ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14229

C. Nꢂjera, F. P. Cossꢁo et al.
more stable than the possible homodimeric species. Our re-
sults also indicate that all of the (Ra)-Binap present in solu-
tion would be involved in the generation of the heterodi-
meric form. Therefore the presence of [{(Ra)-Binap–Au}2]-I
complex can be neglected (Scheme 7). We also studied the
catalyst improved the analogous ones described for the reac-
tions carried out in the presence of [(Sa)-Binap–AgACTHNUTRGNEUG(N tfa)], es-
pecially when a hindered component (dipole or dipolaro-
phile) are involved. In some examples, [{(Sa)-Binap–Au-
AHCTUNGTERG(NUNN tfa)}2] catalyst, once ligated to the 1,3-dipole, acted as an
internal base and as a bifunctional complex to activate the
dipolarophile. Even non-reactive dipolarophiles under silver
catalysis, such as nitrostyrene, were appropriate under the
gold(I) catalysis. The origin of the enantioselectivity was
confirmed by DFT calculations, which revealed very inter-
esting geometric data about the transition states. Computa-
tional studies of the strong positive NLE showed important
differences between all of the possible catalytic species, thus
demonstrating the existence of very stable and non-reactive
heterodimeric complexes. Finally, with regards to the ob-
served positive NLE, calculations predicted a very close
NLE plot with respect to the experimental data. To the best
of our knowledge, this is the first work in which NLE was
analysed using computational tools.
Scheme 7. Equilibrium between all the possible reactive dimeric gold(I)
azomethine ylide complexes when non-enantiopure Binap ligand is em-
ployed.
reaction mechanism when the heterochiral gold(I) com-
plexes are involved. The calculated activation free-energy
barrier associated with the reaction of [(Sa)-Binap,(Ra)-
Binap–Au2]-I and 4a is 20.2 kcalmolÀ1, which is about 1 kcal
molÀ1 higher than the value associated with the reaction of
[{(Sa)-Binap–Au}2]-I complex (see the Supporting Informa-
tion for further geometrical details of the transition struc-
ture). The kinetic constants of the [3+2] cycloaddition pro-
cess within the framework indicated in Scheme 8 have been
Experimental Section
General: All reactions were carried out in the absence of light. Anhy-
drous solvents were freshly distilled under an argon atmosphere. Alde-
hydes were also distilled prior to use for the elaboration of the iminoest-
ers. Melting points were determined using a Reichert Thermovar hot
plate apparatus and are uncorrected. Only the structurally most impor-
tant peaks of the IR spectra (recorded using a Nicolet 510 P-FT and a
Jasco FTIR 4100) are listed. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were obtained using a Bruker AC-300 with CDCl3 as
solvent and TMS as internal standard unless otherwise stated. Optical ro-
tations were measured using a Perkin–Elmer 341 polarimeter. HPLC
analyses were performed using a JASCO 2000 series equipped with a
chiral column (detailed for each compound in the main text), and by
using mixtures of n-hexane/isopropyl alcohol as mobile phase at 258C.
Low-resolution electron impact (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. HRMS (EI) were recorded
using a Finnigan MAT 95S instrument. Microanalyses were performed
using a Perkin–Elmer 2400 and a Carlo Erba EA1108. Analytical TLC
was performed using Schleicher & Schuell F1400/LS silica gel plates, and
the spots were visualised under UV light (l=254 nm). For flash chroma-
tography, we employed Merck silica gel 60 (0.040–0.063 mm). Complexes
1 and 2 were prepared according to the reported procedure.[12] Silver
complex was ready prepared simply by mixing equimolar amounts of the
Scheme 8. Reaction framework for the reaction of the 1,3-DC between
iminoester 3a and 4a, catalysed by chiral complex 2, when non-enantio-
pure Binap ligand is employed.
calculated by employing the Eyring equations and using the
previously computed activation free-energy barriers. We
have analysed the kinetic system by employing numerical in-
tegration and assuming the total recovery of the catalyst and
the irreversibility of the process. Within this framework, the
expected stereochemical outcome of the reaction that em-
ploys different non-enantiopure catalyst mixtures shown in
Figure 1 (vide supra) was surveyed. Our calculations show
that the generation of the heterodimer produces less reac-
tive complexes, which avoids the formation of the undesired
homodimer [{(Ra)-Binap–Au}2]-I. Therefore, an increase in
the ee value of the cycloadduct is observed. Our results are
in qualitative agreement with the experimental evidence
(Figure 1).
BIANP chiral ligand and AgACTHNUTRGNE(NUG tfa). All of the transformations performed
with this catalyst were performed in the absence of light.
Hybrid quantum mechanical/molecular modelling (QM/MM) calculations
for optimisations of saddle points were performed in terms of the
ONIOMc[17] method implemented in Gaussian 09 suite of programs.[18]
The ball-and-stick model in Figure 2 shows atoms included in the high-
level layer, and a wire model is used to represent atoms included in the
low-level layer. In the high-level layer, the electron correlation was par-
tially taken into account by using the hybrid functional B3LYP[19] com-
bined with Hay–Wadt small-core effective potential (ECP)[20] basis set.
Universal force field (UFF)[21] molecular mechanics were employed in
the low-level layer. This combination has offered excellent results in
studies of organocatalytic mechanisms.[22] Thermal corrections of Gibbs
free energies were computed at the same level of theory and were not
scaled. All stationary points were characterised by harmonic analysis. Re-
actant intermediates and cycloadducts have positive definite Hessian ma-
trices. Transition structures show only one negative eigenvalue in their di-
agonalised force constant matrices, and their associated eigenvectors
Conclusion
The enantioselective 1,3-DC of azomethine ylides and elec-
trophilic alkenes has been successfully catalysed by [{(Sa)-
Binap–Au
ACHTUNGTRENNUNG
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Chem. Eur. J. 2011, 17, 14224 – 14233

Binap Complexes as Catalysts
FULL PAPER
were confirmed to correspond to the motion along the reaction coordi-
nate under consideration.
ArH), 7.81–7.77 ppm (m, 2H; ArH); 13C NMR: d=38.5 (OCH3), 48.6
(CHCO), 49.1, 52.7 (2ꢆCHS), 55.9 (ArCH), 109.3, 109.4, 111.2, 111.3,
112.0, 112.3, 112.4, 112.5, 113.0, 113.3, 113.4, 113.5, 113.8, 114.0, 114.2,
114.3, 119.3, 119.2, (ArC), 152.5 ppm (CO2); IR (neat): n˜ =3340,
1,3-Dipolar cycloaddition of iminoesters 3 or 7 and dipolarophiles—Gen-
eral procedure: A solution of the iminoester (0.5 mmol) and dipolaro-
phile (0.5 mmol) in toluene (2 mL) was added at room temperature to a
solution of the in situ prepared chiral gold complex or chiral silver com-
plex (0.05 mmol) in toluene (2 mL). In some cases, DIPEA or triethyl-
amine (0.05 mmol) was added (see Tables 1–4), and the mixture was
stirred at room temperature for 16–48 h (see Tables 1–4). The reaction
was filtered off through a Celite pad, the organic filtrate was directly
evaporated, and the residue was purified by recrystallisation or by flash
chromatography to yield pure endo cycloadducts 5, 8, 10, 15 or 16.
1741.45 cmÀ1
; , n-hexane/iPrOH
HPLC (Chiralpak AD): 1 mLminÀ1
75:25, l=227 nm, tmaj =57.01 min, tmin =51.97 min; MS (EI): m/z (%): 535
[M+] (<1), 394 (26), 392 (11), 391 (35), 359 (28), 268 (21), 267 (19), 266
(17), 253 (19), 252 (100), 251 (31), 250 (13), 220 (31), 219 (31), 194 (35),
193 (62), 192 (22), 191 (31), 190 (41), 167 (15), 166 (11), 165 (47), 164
(13), 163 (15), 155 (11), 153 (11), 152 (22), 142 (11), 127 (17), 125 (14), 78
(20), 77 (46), 51 (15); HRMS: m/z calcd for C28H25NO6S2: 535.6312;
found: 535.6315.
Methyl (2R,3R,4R,5S)-3,4-bis(phenylsulfonyl)-5-(pyrid-3-yl)pirrolidine-2-
carboxylate (10e): Pale yellow oil; [a]2D0 =À63.98 (c=1.2 in CH2Cl2,
Data for methyl (1S,3R,3aS,6aR)-5-methyl-3-phenyl-4,6-dioxooctahydro-
pyrrolo
ethyl-3-phenyl-4,6-dioxooctahydropyrrolo
(5ab),[21,22] methyl (1S,3R,3aS,6aR)-3,5-diphenyl-4,6-dioxooctahydro-
pyrrolo
[3,4-c]pyrrole-1-carboxylate (5ac),[21,22] methyl (1S,3R,3aS,6aR)-5-
methyl-3-(2-naphthyl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carbox-
ylate (5ba),[8] methyl (1S,3R,3aS,6aR)-3-(2-naphthyl)-5-phenyl-4,6-
dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate methyl
(5bc),[7f]
(1S,3R,3aS,6aR)-5-methyl-4,6-dioxo-3-o-tolyloctahydropyrrolo[3,4-c]pyr-
role-1-carboxylate (5ca),[8] methyl (1S,3R,3aS,6aR)-3-(2-chlorophenyl)-5-
methyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate
(5da),[8]
methyl (1S,3R,3aS,6aR)-5-methyl-3-(4-methylphenyl)-4,6-dioxooctahydro-
pyrrolo
[3,4-c]pyrrole-1-carboxylate (5ea),[8] methyl (1S,3R,3aS,6aR)-3-(4-
methoxyphenyl)-5-methyl-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-car-
boxylate (5 fa),[8] methyl (1S,3R,3aS,6aR)-3-(4-chlorophenyl)-5-methyl-
4,6-dioxooctahydropyrrolo
[3,4-c]pyrrole-1-carboxylate (5ga),[8] methyl
(1S,3R,3aS,6aR)-1-benzyl-5-methyl-4,6-dioxo-3-phenyloctahydropyrrolo-
ACHTUNGTRENNUNG
[3,4-c]pyrrole-1-carboxylate (5aa),[23, 24] methyl (1S,3R,3aS,6aR)-5-
1
92% ee by HPLC); H NMR: d=1.90 (brs, 1H; NH), 3.68 (s, 3H; CH3);
AHCTUNGTRENGN[UN 3,4-c]pyrrole-1-carboxylate
4.33 (dd, J=2.3 Hz, 6.4 Hz, 1H; CHS), 4.35 (m, 1H; NCHCO), 4.43 (dd,
J=2.3 Hz, 5.9 Hz, 1H; CHS), 4.66 (d, J=6.2 Hz, 1H; ArCHN), 7.46 (t,
J=7.7 Hz, 8.0 Hz, 2H; ArH), 7.53 (t, J=7.4 Hz, 8.2 Hz, 2H; ArH), 7.61–
7.65 (m, 2H; ArH), 7.70 (t, J=7.3 Hz, 7.9 Hz, 6H; ArH), 8.36 (s, 1H;
ArH), 8.52 ppm (s, 1H; ArH); 13C NMR: d=34.6 (OCH3), 45.8 (CHCO),
48.9, 52.4, (2ꢆCHS), 55.7 (ArCH), 108.7 113.3, 113.4, 114.3, 114.6, 119.3,
119.5, 119.6, 119.8, 121.5, 122.5, 134.0, 134.7 (ArC), 152.3 ppm (CO2Me);
IR (neat): n˜ =3310, 1753 cmÀ1; HPLC (Chiralpak AD): 1 mLminÀ1, n-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
hexane/iPrOH 50:50, l=222 nm,
tmaj =15.05 min, tmin =7.91 min; MS
(EI): m/z (%): 486 [M+] (<1), 285 (10), 204 (14), 203 (100), 171 (10), 145
(19), 144 (30), 77 (18); HRMS: m/z calcd for C28H25NO6S2: 486.5606;
found: 486.5601.
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Methyl (2R,3R,4R,5S)-5-(4-methylphenyl)-3,4-bis(phenylsulfonyl)pyrroli-
dine-2-carboxylate (10 f): Colourless viscous oil; [a]2D0 = +2.38 (c=1.0 in
CH2Cl2, 88% ee by HPLC); 1H NMR: d=2.30 (s, 3H; ArCH3); 2.95 (brs,
1H; NH), 3.66 (s, 3H; OCH3), 4.31–4.27 (m, 1H; CHCO), 4.35 (dd, J=
2.4 Hz, 6.4 Hz, 1H; CHS), 4.41 (dd, J=2.4 Hz, 6.0 Hz, 1H; CHS), 4.61–
4.57 (brs, 1H; ArCHN), 7.06 (d, J=8.1 Hz, 1H; ArH), 7.20 (d, J=
8.1 Hz, 1H; ArH), 7.54–7.40 (m, 6H; ArH), 7.64–7.57 (m, 2H; ArH),
7.70–7.66 ppm (m, 4H; ArH); 13C NMR: d=21.2 (CH3Ph) 53.6 (OCH3),
63.5 (CHCO), 64.2 67.9 (2ꢆCHS), 71.2 (ArCHN), 127.3 128.5, 128.6,
129.1, 129.2, 129.3, 129.4, 129.5, 134.3, 135.0, 138.1, 138.2 (ArC),
167.6 ppm (CO); IR (neat): n˜ =3341, 1747 cmÀ1; HPLC (Chiralpak AD):
ACHTUNGTRENNUNG
[3,4-c]pyrrole-1-carboxylate (8aa),[8] methyl (2S,3R,4S,5R)-4-benzoyl-3,5-
diphenylpyrrolidine-2-carboxylate (15a)[6b] and 2-methyl (2S,3R,4R,5S)-4-
nitro-3,5-diphenyl-2-pyrrolidinocarboxylate 16a[7f] can be found in the lit-
erature.
Methyl (1S,3R,3aS,6aR)-5-ethyl-3-(2-naphthyl)-4,6-dioxooctahydro-
pyrroloACHTUNGTRENNUNG[3,4-c]pyrrole-1-carboxylate (5bb): Colourless solid; m.p. 196–
1978C (n-hexane/ethyl acetate); [a]2D0 =7.0 (c=0.5 in CH2Cl2, 50% ee by
HPLC); 1H NMR: d=1.05 (t, J=7.2 Hz, 1H; CH2CH3), 2.45 (s, 1H;
NH), 3.39 (m, 2H; CH2), 3.47 (dd, J=7.6, 8.0 Hz, 1H; CHCCO2), 3.55
(dd, J=7.0, 8.0 Hz, 1H; CHCCAr), 3.91 (s, 3H; OCH3), 4.08 (dd, J=7.0,
5.2 Hz, 1H; CHCO2), 4.63 (dd, J=7.6, 5.2 Hz, 1H; CHAr), 7.46 (dd, J=
6.2, 3.3 Hz, 3H; ArH), 7.95–7.65 ppm (m, 4H; ArH); 13C NMR: d=13.1
(CH3CH2), 33.9 (CH3), 48.1, 49.1, 52.3 (2ꢆCHCON and CO2CH3), 61.6,
63.9 (CHCO2Me), 67.9 (ArCHN), 125.3, 125.4, 125.9, 126.1, 126.2, 127.8,
127.9, 133.2, 134.2, 134.2 (ArC), 170.15, 174.33, 175.70 ppm (3ꢆCO); IR
(neat): n˜ =3330, 2946, 1748 cmÀ1; HPLC (Chiralpak AS): 1 mL n-hexane/
iPrOH 20:80, l=225 nm, tmaj =7.4 min, tmin =20 min; MS (EI): m/z (%):
352 (20), 293 (45), 127 (34), 91 (100); HRMS: m/z calcd for C20H20N2O4:
352.3838; found: 352.3830.
1 mLminÀ1
, n-hexane/iPrOH 75:25, l=220 nm, tmaj =50.08 min, tmin =
26.11 min; MS (EI): m/z (%): 499 [M+] (<1), 358 (24), 217 (15), 216
(100), 184 (22), 158 (22), 157 (48), 156 (14), 77 (15); HRMS: m/z calcd
for C25H25NO6S2: 499.5991; found: 499.6000.
Methyl (2R,3R,4R,5S)-5-(4-chlorophenyl)-3,4-bis(phenylsulfonyl)pyrroli-
dine-2-carboxylate (10h): Colourless viscous oil; [a]2D0 =+91.68 (c=1.0 in
1
CH2Cl2, 45% ee by HPLC); H NMR: d=2.90 (deform. t, 1H; NH), 3.67
(s, 3H; CH3), 4.30 (dd, J=2.3 Hz, 6.3 Hz, 1H; CHS), 4.34 (brs, 1H;
CHCO), 4.38 (dd, J=2.3 Hz, 5.9 Hz, 1H; CHS), 4.66–4.61 (m, 1H;
ArCHN), 7.30–7.21 (m, 3H; ArH), 7.53–7.43 (m, 4H; ArH), 7.71–
7.59 ppm (m, 7H; ArH); 13C NMR: d=37.5 (OCH3), 45.2 (CHCO), 48.9,
52.6 (2ꢆCHS), 55.9 (ArCH), 113.2, 113.7, 113.8, 114.0, 114.1, 114.3,
114.5, 114.8, 119.4, 119.5, 121.7, 123.0 (ArC), 152.3 ppm (CO); IR (neat):
Methyl (2R,3R,4R,5S)-5-phenyl-3,4-bis(phenylsulfonyl)pyrrolidine-2-car-
boxylate (10a): Colourless viscous oil; [a]2D0 = +1.28 (c=1.0 in CH2Cl2,
90% ee by HPLC); 1H NMR: d=3.00 (brs, 1H; NH) 3.68 (s, 3H; CH3);
4,33 (brs, 1H; NCHCO), 4.41, 4.47 (2ꢆdd, J=2.4 and 6.3 Hz, 2H; 2ꢆ
CHS), 4.64 (m, 1H; PhCHN), 7.28–7.26 (m, 2H; ArH), 7.34–7.32 (m,
2H; ArH), 7.46–7.42 (m, 2H; ArH), 7.61–7.52 (m, 3H; ArH), 7.72–
7.65 ppm (m, 5H; ArH), 13C NMR: d=37.4 (OCH3), 48.6 (CHCO), 49.1,
52.7 (2ꢆCHS), 56.0 (CHPh), 112.3, 112.9, 113.2, 113.4, 113.7, 113.9, 114.1,
114.2, 119.2, 121.9, 122.8, 123.1 (Ar), 152.4 ppm (CO2); IR (neat): n˜ =
n˜ =3341, 1750 cmÀ1
; , n-hexane/
HPLC (Chiralpak AD): 1 mLminÀ1
iPrOH 70:30, l=220 nm), tmaj =41.08 min, tmin =34.69 min; MS (EI): m/z
(%): 519 [M+] (<1), 238 (32), 237 (17), 236 (100), 235 (12), 204 (19), 203
(15), 179 (17), 178 (19), 177 (48), 143 (21), 140 (14), 125 (16), 115 (13), 77
(29), 152 (13); HRMS: m/z calcd for C24H22ClNO6S2: 520.0176; found:
520.0170.
3311, and 1753 cmÀ1 HPLC (Chiralpak IA): 1 mLminÀ1
; , n-hexane/
Methyl (2R,3R,4R,5S)-5-(4-chlorophenyl)-3,4-bis(phenylsulfonyl)pyrroli-
dine-2-carboxylate (10i): Pale yellow oil; [a]2D0 =À38 (c=0.5 in CH2Cl2,
40% ee); 1H NMR: d=2.98 (brt, 1H; NH). 3.66 (s, 3H; CO2CH3), 3.78
(s, 3H; ArOCH3), 3.83 (t, J=6.5 Hz, 1H CHCO2), 4.33 (dd, J=7.0,
2.5 Hz, 1H; CHS), 4.42 (dd, J=6.5, 2.5 Hz, 1H; CHS), 4.59 (dd, J=10.0,
7.0 Hz, 1H; ArCHN), 6.79–6.75 (m, 2H; ArH), 7.43 (t, J=7.7 Hz, 2H;
ArH), 7.53 (td, J=13.5, 6.6 Hz, 5H; ArH), 7.67 ppm (dt, J=10.5, 4.1 Hz,
5H; ArH); 13C NMR: d=52.5, 55.2 (2ꢆOCH3), 63.2, 64.1, 67.8 (2ꢆCHS,
and CHCO2), 71.1 (ArCHN), 114.1, 128.4, 128.5, 128.6, 129.3, 129.4,
130.1, 134.3, 134.5, 136.9, 138.1, 159.5 (ArC), 167.55 ppm (CO); IR
iPrOH 80:20, l=224 nm, tmaj =50.23 min, tmin =30.92 min; MS (EI): m/z
(%): 485 [M+] (<1), 284 (11), 203 (15), 202 (100), 170 (18), 144 (27), 143
(60), 115 (14), 77 (14); HRMS: m/z calcd for C24H23NO6S2: 485.5725;
found: 485.5717.
Methyl (2R,3R,4R,5S)-5-(naphth-2-yl)-3,4-bis(phenylsulfonyl)pirrolidine-
2-carboxylate (10b): Colourless viscous oil; [a]2D0 = +17.18 (c=0.5 in
CH2Cl2, 92% ee by HPLC); 1H NMR: d=3.15 (brs, 1H; NH), 3.69 (s,
3H; CH3); 4.38 (brs, 1H; NCHCO), 4.45 (dd, J=2.4 Hz, 6.4 Hz, 1H;
CHS), 4.49 (dd, J=2.4 Hz, 6.0 Hz, 1H; CHS), 4.79 (brs, 1H; PhCHN),
7.39–7.35 (m, 2H; ArH), 7.56–7.45 (m, 6H; ArH), 7.72–7.60 (m, 7H;
(neat): n˜ =2957, 1747, 1308, 1249 cmÀ1
; HPLC (Chiralpak AD):
Chem. Eur. J. 2011, 17, 14224 – 14233
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14231

C. Nꢂjera, F. P. Cossꢁo et al.
1 mLminÀ1
,
n-hexane/iPrOH 70:30,
t
maj =31.3 min,
t
min =36.4 min; MS
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J. M. Sansano, P. R. R. Costa, E. C. de Lima, A. G. Dias, Synlett
2010, 962–967; f) R. Robles-Machꢁn, I. Alonso, J. Adrio, J. C. Carre-
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(EI): m/z (%): 515 (0.03), 277 (23), 141 (56), 91 (22), 77 (100); HRMS:
m/z calcd for C25H25NO7S2; 515.5985; found: 5155991.
Methyl
(2S,3R,4S,5R)-4-benzoyl-5-(naphth-2-yl)-3-phenylpyrrolidine-2-
carboxylate (15b): Colourless solid; m.p. 128–1298C (n-hexane/ethyl ace-
tate); [a]2D0 =À37 (c=0.8 in CH2Cl2, 60% ee by HPLC); 1H NMR: d=
3.35 (brs, NH), 3.76 (s, 3H; CH3). 4.19 (deform. t, J=7.5 Hz, 1H;
CHCHCO2) 4.25 (d, J=8.0 Hz, 1H; CHCO2), 4.62 (dd, J=15.0, 7.5 Hz,
1H; CHCOPh), 5.17 (d, J=8.5 Hz, 1H; ArCHN), 7.83–7.10 ppm (m,
17H; ArH); 13C NMR: d=52.3, 52.7 (CH3, CPh), 60.5 (CHCO2), 66.7,
67.8 (2ꢆCHN), 125.0, 125.1, 125.8, 125.9, 126.3, 126.4, 127.1, 127.6, 127.7,
127.8, 127.9, 128.1, 128.5, 128.8, 132.8, 136.4, 137.4, 140.7 (ArC), 173.3
(CO2), 198.8 ppm (COPh); IR (neat): n˜ =3345, 1736, 1677 cmÀ1; HPLC
(Chiralcel OD-H): 1 mLminÀ1, n-hexane/iPrOH 99:1, tmaj =17.3 min, tmin
25.8 min; MS (EI): m/z (%): 435 (10) [M+]; HRMS (ESI): m/z calcd for
C29H25NO3: 435.5135; found: 435.5137.
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Acknowledgements
This work has been supported by the DGES of the Spanish Ministerio de
Ciencia e Innovaciꢃn (MICINN) (Consolider Ingenio 2010 CSD2007-
00006, FEDER-CTQ2007-62771/BQU, CTQ2007/67528, CTQ2010-20387
and by the Hispano-Brazilian project PHB2008-0037-PC), Generalitat
Valenciana (PROMETEO/2009/039), the Basque government (grant IT-
324-07) and by the University of Alicante. M.M.-R. also thanks DGES
for a grant. The authors also thank the SGI/IZO-SGIker of UPV/EHU
for allocation of computational resources.
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Published online: November 8, 2011
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