Binap-gold(I) trifluoroacetate as a bifunctional catalyst for the synthesis of chiral prolines through 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1016/j.tetasy.2010.06.011

Highly enantioselective 1,3-dipolar cycloadditions of amino acid-derived azomethine ylides with alkenes have been performed, for the first time, under gold-catalysis using (S_a)-or (R_a)-Binap-gold(I) trifluoroacetate complexes, with t

Full text of DOI:10.1016/j.tetasy.2010.06.011

Tetrahedron: Asymmetry 21 (2010) 1184–1186
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Binap-gold(I) trifluoroacetate as a bifunctional catalyst for the synthesis of
chiral prolines through 1,3-dipolar cycloaddition of azomethine ylides
*
*
María Martín-Rodríguez, Carmen Nájera , José M. Sansano , Feng-Liu Wu
Departamento de Química Orgánica and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, E-03080-Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly enantioselective 1,3-dipolar cycloadditions of amino acid-derived azomethine ylides with alkenes
have been performed, for the first time, under gold-catalysis using (Sa)- or (Ra)-Binap-gold(I) trifluoroace-
tate complexes, with the cationic Binap-gold acting as a Lewis acid and the counteranion as a base. Malei-
mides and trans-1,2-bis(phenylsulfonyl)ethylene were reacted with imino esters at room temperature in
the absence of a base to afford, in very good yields, the corresponding polysubstituted prolines with total
endo-diastereoselection and higher enantioselectivities than the Binap-silver trifluoroacetate complex.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 4 March 2010
Accepted 8 June 2010
Available online 30 June 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
1. Introduction
of (Sa)-Binap and AgOAc and Et3N as base with very poor results.6
Our research group found that (Sa)- or (Ra)-Binap-AgClO4
Coinage metals attract particular interest from synthetic organ-
ic chemists, because those metals become useful catalysts for syn-
thesizing the core of many important drugs containing heterocyclic
structures.1 The main features of these metal complexes are good
chemoselectivity, good functional group compatibility, and stabil-
ity, traits that are crucial for application in complex molecular
environments. One of the most representative examples concerns
the synthesis of enantiomerically enriched prolines2 through the
catalytic enantioselective 1,3-dipolar cycloaddition3 (1,3-DC) be-
tween azomethine ylide and alkenes. In fact, silver- and copper-
catalyzed 1,3-DC are very well known and constitute as the most
reliable and inexpensive enantioselective methodology to build
up to four stereogenic centers of the resulting proline derivatives,
in only one reaction step. In addition, they exhibit more versatility
and a wider scope than the analogous enantioselective organocat-
alyzed 1,3-dipolar cycloadditions.3a
complexes were excellent recoverable catalysts for the 1,3-DC of
azomethine ylides and maleimides furnishing excellent enantios-
elections7 Recently, we also reported an improvement of this reac-
tion using AgSbF6 instead of silver perchlorate.8 In general, these
last two mediated (Sa)-Binap-Ag(I) cycloadditions are very sensi-
tive to the presence of a bulky substituent in the dipole and in
the maleimide and to the organic base used as a co-catalyst. In or-
der to overcome it, we envisaged that the existence of a larger cat-
ionic center such as gold(I) in the presence of a basic counteranion
would be interesting to test in this catalytic enantioselective 1,3-
DC. Herein, we survey the efficiency of (Ra)- and (Sa)-Binap-gold(I)
trifluoroacetate in the intermolecular 1,3-DC employing iminoest-
ers and electrophilic alkenes.
2. Results and discussion
Chiral gold complexes have been employed in the enantioselec-
tive activation of allenes, and in the nucleophilic additions onto
alkynes and alkenes.4 Toste et al. reported a very efficient enantio-
selective cycloaddition of münchnones and electron-deficient al-
kenes employing (Sa)-Cy-SEGPHOS(AuOBz)2 as a catalyst. This
transformation, followed by an ester/amide formation, furnished
pyrrolines in very high enantioselectivity.5 However, chiral gold
complexes have not been employed as catalysts for the 1,3-DC of
amino acids-derived iminoesters.
Chiral (Ra)- and (Sa)-Binap-AuCl complexes were prepared by
mixing (Me2S)AuCl and the corresponding amount of the chiral
diphosphane ligand. These complexes were treated with different
silver salts derived from carboxylic acids for 1 h in toluene. The
resulting suspension was filtered through a celite plug and the solu-
tion was evaporated to yield the title complexes. These cationic
complexes were immediately employed in the catalytic enantiose-
lective 1,3-DC of imino ester 1a and N-methylmaleimide (NMM) in
toluene at rt (Scheme 1 and Table 1). When this cycloaddition was
performed in the presence of 10 mol % of diisopropylethylamine
(DIPEA) and 10 mol % of complex (Sa)-Binap-AuCl, product
endo-2aa was obtained with high conversion but in racemic form
(Table 1, entry 1). In the case of the gold(I) acetate complex, product
endo-2aa was obtained with high conversion and 60% ee in the
presence of DIPEA and in 70% ee in the absence of base (Table 1,
entries 2 and 3). Better results were achieved when using the
The first attempt for the enantioselective 1,3-DC of azomethine
ylides with dimethyl maleate was described in 2002 using 3 mol %
* Corresponding authors. Tel.: +34 96 590 3728; fax: +34 96 590 3549 (C.N.).
E-mail addresses: cnajera@ua.es (C. Nájera), jmsansano@ua.es (J.M. Sansano).
PhD student from School of Chemistry and Molecular Biosciences, University of
Queensland, Brisbane, Qld 4072, Australia.
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.011

M. Martín-Rodríguez et al. / Tetrahedron: Asymmetry 21 (2010) 1184–1186
1185
R1
N
R1
N
N
O
O
O
O
O
O
N
O
O
(Sa)-Binap-AuTFA (10 mol%)
Au complex (10 mol%)
(NMM)
toluene, rt
Ar
CO2Me
PhMe, base or not
rt, 16 h
N
H
Ph
CO2Me
Ar
N
CO2Me
N
H
Ph
N
CO2Me
1
endo-2
1a
endo-2aa
R1 = Me (NMM), Et (NEM), Ph (NPM)
Scheme 1.
Scheme 2.
Table 1
Table 2
Gold-catalyzed 1,3-DC between iminoglycinates 1 and maleimides
Catalyst studies for 1,3-DC between iminoester 1a and NMM
Entry Gold(I) catalyst (10 mol %)
Base (10 mol %) Conv.a,b (%) eec (%)
Entry
1
Ar
R1
Base
Time
(h)
2
Yielda,b
(%)
eec
(%)
1
2
3
4
5
6
7
8
9
(Sa)-Binap-AuCl
DIPEA
DIPEA
—
DIPEA
—
>95
>95
>95
>95
>95
>95
90
rac.
(Sa)-Binap-AuCl/AgOAc
(Sa)-Binap-AuCl/AgOAc
(Sa)-Binap-AuCl/AgOBz
(Sa)-Binap-AuCl/AgOBz
(Sa)-Binap-AuCl/AgTFA
(Sa)-Binap-AuCl/AgTFA
(Ra)-Binap-AuCl/AgTFA
(Sa)-Binap-AgTFA
62
70
74
1
2
3
4
5
6
7
1a Ph
1a Ph
1a Ph
1a Ph
1b 2-MeC6H4
1c 2-ClC6H4
1d 4-
Et
Et
DIPEA 16
48
DIPEA 16
2ab Quant.
2ab Quant.
2ac 90
2ac 92
2ba 86
70
99
64
80
88
—
Ph
Ph
Me
Me
Me
94d
74
—
—
—
—
48
48
48
48
DIPEA
—
99
2ca 88
2da 95
99
>99
—
—
—
—
>95
>95
>95
90
ent-99
99
rac.
60
(MeO)C6H4
10
11
(Sa)-Binap-(AuCl)2/(AgTFA)2
8
1e 2-Naphthyl Me
—
48
2ea 94
91
(Sa)-Binap-AuCl/AgTFAe
a
b
c
Isolated yields after flash chromatography (silica gel).
The observed endo:exo ratio was >98:2 (1H NMR).
Determined by chiral HPLC analysis.
a
b
c
Determined by 1H NMR of the crude sample.
The observed endo:exo ratio was always >98:2 (1H NMR).
Determined by chiral HPLC analysis (Daicel, Chiralpak AS).
d
e
Notable amounts of unidentified side products were observed (1H NMR).
The reaction was performed with 5 mol % of catalyst.
total conversions (Scheme 3). The enantioselection showed by (Sa)-
Binap-AuTFA complex (99% ee) was higher than in the case of using
(Sa)-BinapAgTFA (65% ee) as a catalyst.
benzoate anion to afford endo-2aa in 74% and 94% ees (Table 1, en-
tries 4 and 5). Although product endo-2aa was obtained in higher
94% ee in the absence of DIPEA, it was contaminated with secondary
by-products (Table 1, entry 5). When gold(I) trifluoroacetate com-
plexes were used as catalysts, 74% ee was obtained in the presence
of DIPEA (Table 1, entry 6), whereas without base, 99% ee was ob-
tained (Table 1, entries 7 and 8). A similar result was obtained when
the reaction was performed with the chiral complex (Sa)-Binap-
AgTFA in the absence of base (Table 1, entry 9). On the other hand,
the (Sa)-Binap-(AuCl)2/(AgTFA)2 complex proved to be ineffective
catalysts because endo-2aa was obtained as a racemate (Table 1, en-
try 10). Attempts to decrease the (Sa)-Binap-AuTFA loading to
5 mol % gave lower enantioslectivity (Table 1, entry 11).
N
O
O
N
O
O
(Sa)-Binap-AuTFA (10 mol%)
or (Sa)-Binap-AgTFA (10 mol%)
CO2Me
Ph
+
Ph
toluene, rt
Ph
N
H
endo-4
Ph
N
3
CO2Me
AuI complex (3 d) 78%, 99% ee
AgI complex (2 d) 95%, 65% ee
Scheme 3.
The scope of this enantioselective 1,3-DC was studied using dif-
ferent iminoesters and maleimides under the best reaction condi-
tions (Scheme 2 and Table 2). Products 2 were obtained as endo-
diastereomers (>98:2, determined by 1H NMR spectroscopy). In
the first examples performed with N-ethyl and N-phenylmaleimide
the absence of base gave products 2ab and 2ac with higher enanti-
oselectivity (Table 2, compare entries 1 with 2 and 3 with 4). The
result obtained when NPM was employed as a dipolarophile is par-
ticularly noteoworthy. When (Sa)-Binap-AgTFA was used as catalyst
racemic product 2ac was obtained. For the 1,3-DC of other arylide-
neaminoesters 1b, c, d, and e with NMM, products 2ba, 2ca, 2da,
and 2ea were obtained in high yields and enantioselectivities
(Table 2, entries 5–8). When the catalyst loading employed was re-
duced to 5 mol % these 1,3-DC needed longer periods to complete,
yielding endo-cycloadducts 2 with lower enantioselection.
According to our experience with the results obtained from the
application of chiral Binap-silver(I) complexes in the enantioselec-
tive 1,3-DC of azomethine ylide and electrophilic alkenes,7,8 we
also tested the efficiency of the Binap-gold(I) trifluoroacetate com-
plexes in the enantioselective cycloaddition of azomethine ylides
and trans-1,2-bis(phenylsulfonyl)ethylene, a synthetic equivalent
of acetylene (Scheme 4 and Table 3). The reaction performed with
10 mol % of the gold(I) catalyst afforded cycloadducts 5 in similar
or higher enantioselectivities in the absence of DIPEA. In the case
of product 5a, a lower enantiomeric excess was obtained when
(Sa)-Binap-AgTFA was used as catalyst (Table 3, compare entries
1 and 3). Compounds endo-5f and 5g were obtained in better enan-
tiomeric excesses in the absence of base (Table 3, entries 4–7).
The absolute configuration of the endo-cycloadducts was as-
signed according to the chiral HPLC retention times and by com-
parison of the physical properties of the isolated samples with
the properties published in the literature for the analogous
compounds.
The insertion of a substituent at the a-position of the 1,3-dipole
precursor was next evaluated. Thus, when methyl benzylidenei-
minophenylalaninate 3 was allowed to react with NMM under
the standard reaction conditions, the reaction performed with
the gold(I) complex needed 24 h more than the corresponding
reaction using the analogous silver(I) complex for achieving almost
The full characterization of the dimeric species [(rac)-Binap-
AuTFA]2 was published by Puddephatt et al.9 when they mixed
equimolar amounts of the ligand and gold(I) salt. In our case, all

1186
M. Martín-Rodríguez et al. / Tetrahedron: Asymmetry 21 (2010) 1184–1186
SO2Ph
CO2Me
bis(phenylsulfonyl)ethylene, and a-substituted iminoesters, than
PhO2S
PhO2S
Ar
SO2Ph
the (Sa)-Binap-silver(I) trifluoroacetate complex.11
(Sa)-Binap-AuTFA (10 mol%)
toluene, rt, 48 h
CO2Me
N
H
Ar
N
Acknowledgments
1
endo-5
This work has been supported by the DGES of the Spanish
Ministerio de Educación y Ciencia (MEC) (Consolider INGENIO
2010 CSD2007-00006, and CTQ2007-62771/BQU), by the General-
itat Valenciana (PROMETEO/2009/039), and by the University of
Alicante. M.M.-R. thanks MEC for a predoctoral fellowship and
F.-L. W. thanks the UQ Graduate School for a Research Travel Grant.
Scheme 4.
Table 3
Gold-catalyzed
1,3-DC
between
iminoglycinates
1
and
trans-1,2-
bis(phenylsulfonyl)ethylene
Yielda,b (%)
eec (%)
References
Entry
1
Ar
Base (10 mol %)
5
1
1a
1a
1a
1f
1f
1g
1g
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
3-Pyridyl
3-Pyridyl
DIPEA
—
—
DIPEA
—
DIPEA
—
5a
5a
5a
5f
5f
5g
5g
80
74
76
81
67
73
73
86
99
96
88
99
96
96
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3. For recent reviews, see: (a) Nájera, C.; Sansano, J. M.; Yus, M. J. Braz. Chem. Soc.
2010, 21, 377–412; (b) Nájera, C.; Sansano, J. M. Topics Heterocyclic Chem., Ed.
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2
3d
4
5
6
7
a
b
c
Isolated yields after flash chromatography (silica gel).
The observed endo:exo ratio was always >98:2 (1H NMR).
Determined by chiral HPLC analysis.
d
Reaction performed with (Sa)-Binap-AgTFA.
the data obtained were in accordance with those published. Thus,
the 31P NMR analysis of [(Sa)-Binap-AuTFA]2 in CDCl3 showed a
singlet at 41.1 ppm, whereas the (Sa)-Binap-AuCl complex gave a
singlet at 23.3 ppm; in the case of ESI-MS experiments, peaks at
819, 819.2 and 819.6 were observed on elution with a mixture of
acetonitrile and water, demonstrating the existence of such a
dimeric complex. Further experimental and theoretical studies on
the structure of the dimeric 1:1 Binap-gold complexes and the
1,3-dipole are currently underway.
9. (a) Wheaton, C. A.; Jennings, M. C.; Puddephatt, R. J. J. Am. Chem. Soc. 2006, 128,
15370–15371; (b) Wheaton, C. A.; Jennings, M. C.; Puddephatt, R. J. Z.
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Ichikawa, E.; Shibasaki, M. Pure Appl. Chem. 2005, 77, 2047–2052; (c) Kanai, M.;
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11. General procedure for the catalytic enantioselective 1,3-DC using (Ra)- or (Sa)-
BinapAuTFA complexes: To a solution of the in situ prepared chiral gold
complex (0.05 mmol, 46 mg) in toluene (2 mL) was added at room temperature
3. Conclusion
In conclusion, it has been demonstrated that cationic gold com-
plexes efficiently catalyze 1,3-DC of azomethine ylides and dipol-
arophiles. Chiral (Ra)- and (Sa)-Binap-AuTFA complexes work as
bifunctional catalysts.10 The trifluoroacetate acts as Brønsted base
forming the imino ester enolate, which is coordinated with the Le-
wis acid, the Binap-gold cation. In general, the (Sa)-Binap-gold(I)
trifluoroacetate complex induces higher enantioselections, even
with sterically hindered substrates such as, NPM, trans-1,2-
a
solution of the iminoester (0.5 mmol) and dipolarophile (0.5 mmol) in
toluene (2 mL). In some cases DIPEA (0.05 mmol, 14 L) was added (see Tables)
l
and the mixture was stirred at room temperature for 16–48 h (see Tables) The
reaction was filtered off and the organic filtrate was directly evaporated and
the residue was purified by recrystallization or by flash chromatography
yielding pure endo-cycloadducts 2, 4, or 5.