Catalytic enantioselective 1,3-dipolar cycloaddition reactions of azomethine ylides and alkenes by using phosphoramidite-silver(I) complexes

Article abstract of DOI:10.1002/anie.200801690

(Chemical Presented) Silver catalysts: A novel chiral phosphoramidite -silver perchlorate complex has been used for the synthesis of highly substituted pyrolidine rings. This method is valuable for the synthesis of biologically active α-substituted prolines by using hindered dipoles generated from α-substituted α amino acids (see scheme; DABCO=1,4-diazabicyclo[2.2.2]octane).

Full text of DOI:10.1002/anie.200801690

Angewandte
Chemie
DOI: 10.1002/anie.200801690
Asymmetric Catalysis
Catalytic Enantioselective 1,3-Dipolar Cycloaddition Reactions of
Azomethine Ylides and Alkenes by UsingPhosphoramidite–Silver(I)
Complexes**
Carmen Nµjera,* M. de Gracia Retamosa, and JosØ M. Sansano*
Dedicated to Professor Miguel Yus on the occasion of his 60th birthday
Proline derivatives are very important molecules in many
scientific areas. The demand of these particular structures
with a determined absolute configuration motivates the
development of new asymmetric synthetic routes to obtain
them with high optical purities.[1] The best approach to
generate enantiomerically enriched polysubstituted prolines
or pyrrolidine derivatives is the 1,3-dipolar cycloaddition
(1,3-DC) between electrophilic alkenes and stabilized or
nonstabilized dipoles, respectively. This strategy allows the
creation of up to four stereogenic centers in only one step[2]
with high regioselectivity and endo/exo-diastereoselectivi-
ties.[1] The first enantioselective 1,3-DC of stabilized azome-
thine ylides, pioneered by Allway and Grigg,[3] derived from
iminoglycinates were shown to be highly efficient in 2002 by
using a substoichiometric amount of a chiral AgI complex as
the catalyst.[4] Since then, many chiral metal complexes that
are able to generate metallodipoles have shown efficient
catalytic activity for the reaction,[5–9] and recently, organo-
catalysts have been used.[10] These metal complexes constitute
of a bidentate chiral ligand coordinated to metal cations, for
example, chiral bisphosphanes with AgI [4,5a] or CuII,[7] chiral
nitrogenated phosphanes with AgI [5b,d,e,f,g,6g] or CuI,[6b,e] and
sulfur-containing phosphanes with AgI [5c] or CuI.[6a,c,d,f,h] Bis-
imines with ZnII [8b] and NiII [9] salts, as well as chiral amino
alcohols complexes with ZnII[8a] have demonstrated a less
extensive reaction scope compared to the above-mentioned
catalysts. The double coordination of the chiral ligand to the
metal generates rigid and compact chiral environments, thus
allowing high enantioselectivity, especially with less sterically
hindered 1,3-dipoles derived from iminoglycinates. However,
very poor results have been obtained with iminoesters
obtained from a-substituted a amino acids.
Recently, substituted prolines derived from leucine imi-
noesters have become important molecules because of their
extraordinary activity against the hepatitis C virus.[5a,11] We
envisaged that a monodentate chiral ligand, such as phos-
phoramidite, coordinated to a silver cation would be less
sterically demanding than the bidentate chiral ligand com-
plexes, allowing more successful enantioselectivity of the
a-branched 1,3-dipoles in the 1,3-DC reaction. Phosphora-
midites 1 and 2[12] have been extensively used in asymmetric
hydrogenations,[1,13] as well as other metal-mediated trans-
formations, such as allylations, Michael-type additions, and
carbonyl addition reactions.[13b] However, to the best of our
knowledge, coordination between a phosphoramidite ligand
and a silver cation has not been reported. Herein we report a
complex of either chiral phosphoramidite 1 or 2 and AgI salts
that efficiently catalyze the enantioselective 1,3-DC of
azomethine ylides derived from glycine with a-substituted
amino acids having electron-deficient alkenes.
[*] Prof. Dr. C. Nµjera, M. d. G. Retamosa, Dr. J. M. Sansano
Departamento de Química Orgµnica
Facultad de Ciencias, Universidad de Alicante
Apartado 99, 03080 Alicante (Spain)
Fax: (+34)96-590-3549
Initially, a 5 mol% of a 1:1 mixture of monophos 1 or
phosphoramidite 2 and different AgI salts with Et3N as the
base (5 mol%), were used in the 1,3-DC of methyl benzyli-
deneiminoglycinate (5aa) and tert-butyl acrylate at room
temperature in toluene (Table 1). Monophos 1 and AgClO4
furnished exclusively endo-6aa with an e.r. value of 76:24,
whereas ligand 2 and AgClO4 gave the best e.r. value and
purity of the cycloadduct (Table 1, entries 1 and 2). When a
2:1 mixture of 2:AgClO4 was used as the catalyst, a lower
e.r. value was obtained (Table 1, entry 3). The use of AgOAc
or AgOTf in a 1:1 ratio relative to ligand 2, gave e.r. values
similar to those with AgClO4, but the triflate did not afford
reproducible results and the reaction run with the acetate
furnished a complex mixture of crude proline derivatives
E-mail: cnajera@ua.es
jmsansano@ua.es
[**] This work has been supported by the DGES of the Spanish
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.R. thanks the
University of Alicante for a predoctoral fellowship. We also thank Dr.
T. Soler for X-ray crystallographic diffraction analyses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801690.
Angew. Chem. Int. Ed. 2008, 47, 6055 –6058
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6055

Communications
Table 1: Enantioselective 1,3-DC of iminoglycinate 5 and tert-butyl
acrylate by using several chiral phosphoramidites/AgI salts.
1,4-diazabicyclo[2.2.2]octane (DABCO) compared to using
Et3N (Table 2, entries 1 and 2). However, other bases, such as
pyridine, imidazole, Hünigꢀs base, 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU), or KOH afforded lower conversions
and enantioselectivities. Isopropyl ester derivative 5ba gave
higher enantioselectivity than the analogous methyl ester in
the presence of either base (Table 2, entries 3 and 4).
Enantiomerically pure endo-6ba was obtained in good yield
with excellent an e.r. value by employing the corresponding
chiral (Ra,S,S)-2 (Table 2, entry 5). Nevertheless, the reaction
performed with the mismatched silver complex, (Ra,R,R)-2,
furnished a lower enantioselectivity than that obtained with
the (Sa,R,R)-2 ligand (Table 2, entry 6). By using a lower
catalyst loading (3 mol%), a lower conversion and slightly
lower enantioselectivity was detected (Table 2, entry 7).
The scope of this 1,3-DC reaction with different a amino
acid derived iminoesters (5–9) and dipolarophiles is shown in
Table 3. The results obtained from using modified aryl
moieties suggested that new stereoelectronic effects
appeared, which could be tuned by carefully selecting the
ester group (R1 = Me, iPr) and the amine (DABCO or Et3N).
Thus, o-substituted aryl imines preferentially reacted with
methyl ester 5ab or 5ac (R1 = Me) and DABCO as the base
(Table 3, entries 1 and 2). In contrast, p-substituted iminogly-
cinate 5bd reacted preferentially with isopropyl esters and
Et3N as the base. (Table 3, entry 4). Other dipolarophiles such
as N-methylmaleimide (NMM) and isopropyl or isobutyl
fumarates afforded products 10 and 11, respectively, with
good yields and e.r. values when methyl benzylideneimino-
glycinate (5aa) was employed as 1,3-dipole precursor
(Table 3, entries 5–7). The behavior of NMM as a dipolar-
ophile was different to other assayed electrophilic alkenes.
The reaction was stopped after 6 hours at room temperature,
leading to endo-10 with excellent enantioselectivity (Table 3,
entry 5).
Entry
AgI salt
Ligand
Conv. [%]
e.r.[a}
1
2
3
4
5
6
7
8
AgClO4
AgClO4
AgClO4
AgOAc
AgOTf
AgF
1
2
98
98
95
98
98
90
95
98
76:24
85:15
74:26
80:20
84:16
76:24
60:40
90:10
2[b]
2
2
2
AgBF4
AgClO4
2
2[c]
[a] Determined by chiral HPLC analysis (Daicel, Chiralpak AS), more than
98:2 endo/exo ratio (1H NMR). [b] 10 mol% of the ligand was added.
[c] Reaction performed at À208C.
(Table 1, entries 4 and 5). In the case of the AgF and AgBF4
salts, there was no improvement over those achieved by using
AgClO4 (Table 1, entries 6 and 7). Other solvents, such as
THF, dichloromethane, diethyl ether, acetonitrile, and meth-
anol gave both lower conversions and e.r. values. The
influence of the temperature was analyzed within the range
from 0 to À608C, and the best enantioselectivity was obtained
at À208C (Table 1, entry 8).
Next, other crucial reaction parameters, such as the ester
substituent, the amine (base), the matched and mismatched
ligands, and the catalyst loading, were analyzed (Table 2). The
1,3-DC of methyl benzylideneiminoglycinate (5aa) with tert-
butyl acrylate by using 5 mol% of a 1:1 mixture of phosphor-
amidite 2:AgClO4 gave endo-6aa with a higher e.r. value with
As predicted, alanine, leucine, and phenylalanine derived
iminoesters 7–9 gave products 12–15 in good yields with very
high e.r. values. The reactions with alanine metallodipoles
were run for 17 hours at À208C by using 1.1 equivalents of the
dipolarophile (Table 3, entries 8 and 9). However, the more
substituted imines derived from leucine (8) and phenylalanine
(9) required 3 equivalents of tert-butyl acrylate, providing
endo-14[14] and endo-15 in 80 and 77% yields, respectively,
after 2–3 days at À208C (Table 3, entries 10 and 11). In all
examples shown in Table 3, the endo adduct was obtained as
the major stereoisomer with a d.r. value of more than 98:2
(1H NMR). All of the e.r. values were determined by chiral
HPLC analysis, and the absolute configuration was deter-
mined by comparison of the optical rotations between the
newly generated products and the reported values for the
known compounds.[4,5a,6d]
The new 1:1 and 2:1 complexes, 3 and 4, respectively, were
characterized by X-ray crystallographic diffraction analysis of
monocrystals to obtain very interesting data on the solid state
of the complexes. Complex 3 formed cross-linked sheets,[15]
the formation of these polymeric assemblies being typical of
Ag complexes, independent of the mono- or bidentate
character of the corresponding ligand.[16] The structure of
the active catalytic species can be attributed to complex 4.[17]
Table 2: Optimized enantioselective 1,3-DC of iminoglycinates 5 and
tert-butyl acrylate by using 2 and AgClO4.
endo-6[a]
Entry
5
Base
e.r.[b]
Product
Yield [%][c]
e.r.[d]
90:10
94:6
>99:1
>99:1
<1:99
28:72
98:2
1
2
3
4
5
6
7
5aa
5aa
5ba
5ba
5ba
5ba
5ba
Et3N
DABCO
Et3N
DABCO
Et3N[e]
Et3N[f]
Et3N[g]
90:10
94:6
6aa
6aa
6ba
6ba
ent-6ba
ent-6ba
6ba
80
80
83
81
81
80
67
>99:1
>99:1
<1:99
28:72
98:2
[a] Reaction run overnight at À208C with conversions of greater than
1
98% as determined by H NMRspectroscopy. [b] The e.r. values of the
crude material were determined by chiral HPLC analysis (Daicel,
Chiralpak AS), >98:2 endo/exo ratio (1H NMR). [c] Yield of product
isolated after recrystallization or flash chromatography. [d] The e.r. values
were determined after purification. [e] Reaction carried out with the
(Ra,S,S)-2. [f] Reaction carried out with (Ra,R,R)-2. [g] Reaction per-
formed with a 3 mol% of catalyst (Sa,R,R)-2.
6056 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 6055 –6058

Angewandte
Chemie
Table 3: Scope of the enantioselective 1,3-DC of iminoglycinates 5–9 with dipolarophiles catalyzed by 2 and AgClO4.
endo Cycloadduct
Entry
R1, Ar
Base
Dipolarophile
T [8C]
e.r.[a]
99:1
>99:1
>99:1
99:1
Structure
Product
Yield [%][b]
e.r.[c]
99:1
>99:1
>99:1
99:1
1
2
3
4
Me, 2-MeC6H4 (5ab)
Me, 2-ClC6H4 (5ac)
iPr, Ph (5ba)
DABCO
DABCO
DABCO
Et3N
tert-butyl acrylate
tert-butyl acrylate
tert-butyl acrylate
tert-butyl acrylate
À20
À20
0
À20
6ab
6ac
6ba
6bd
83
90
81
79
iPr, 4-MeOC6H4 (5bd)
5
Me, Ph (5aa)
DABCO
NMM[d]
25
>99:1
10
80
>99:1
6
7
Me, Ph (5aa)
Me, Ph (5aa)
Et3N
DABCO
diisopropyl fumarate
diisobutyl fumarate
À20
91:9
91:9
11a
11b
81
79
91:9
91:9
0
8
9
Me, Ph (7aa)
Et3N
Et3N
tert-butyl acrylate
tert-butyl acrylate
À20
À20
96:4
96:4
12
13
78
77
97:3
96:4
Me, 2-thienyl (7ae)
10
11
Me, 2-thienyl (8ae)
Me, Ph (9aa)
Et3N
Et3N
tert-butyl acrylate[e]
tert-Butyl acrylate[e]
À20
À20
92:8
99:1
14
15
70
77
91:9
99:1
[a] The e.r. values of the crude material were determined by chiral HPLC analysis (Daicel, Chiralpak AS), >98:2 endo/exo ratio. [b] Yield of isolated
product after recrystallization or flash chromatography. All new compounds gave satisfactory spectroscopic and spectrometric data. [c] The e.r. values
determined after purification. [d] 6 h reaction time. [e] 3 equiv were added and the reaction took 2 days to go to completion.
(5 mol%) were added sequentially. After the reaction was judged to
be complete, the solvent was evaporated and the crude reaction
mixture was filtered and analyzed by chiral HPLC analysis. The pure
cycloadduct was obtained after recrystallization or by flash chroma-
tography.
The X-ray crystallographic diffraction analysis obtained for
this solid aggregate support this hypothesis. The second
equivalent of phosphoramidite 2 is interrupted the Ag–p
interactions as a consequence of the strong phosphorous
affinity exhibited by the silver cation (see the Supporting
Information).
Received: April 10, 2008
In the light of the results described, it can be concluded
that novel monodentate phosphoramidite–silver complex 3 is
a very efficient chiral catalyst for a wide range of 1,3-dipolar
cycloaddition reactions between azomethine ylides and
dipolarophiles. This type of monodentate complex provides
new opportunities in this and other reactions because of the
ability to run cycloadditions involving sterically hindered
components, the fine-tuning of which can be achieved by
modification of the temperature, base, and ester substituent.
Keywords: azomethine ylides · chirality · cycloaddition ·
phosphoramidites · silver
.
[1] a) C. Nµjera, J. M. Sansano, Chem. Rev. 2007, 107, 4273 – 4303;
b) P. Karoyan, S. Sagan, O. Lequin, J. Quancard, S. Lavielle, G.
Chassaing, Targets Heterocycl. Syst. 2004, 8, 216 – 273.
[2] For recent reviews of 1,3-dipolar cycloaddition reactions of
azomethine ylides, see: a) V. Nair, T. D. Suja, Tetrahedron 2007,
63, 12247 – 12275; b) H. Pellissier, Tetrahedron 2007, 63, 3235 –
3285; c) G. Pandey, P. Banerjee, S. R. Gadre, Chem. Rev. 2006,
106, 4484 – 4517; d) T. M. V. D. Pinho e Melo, Eur. J. Org. Chem.
2006, 2873 – 2888; e) M. Bonin, A. Chauveau, L. Micouin, Synlett
2006, 2349 – 2363; f) C. Nµjera, J. M. Sansano, Angew. Chem.
2005, 117, 6428 – 6432; Angew. Chem. Int. Ed. 2005, 44, 6272 –
6276; g) S. Husinec, V. Savic, Tetrahedron: Asymmetry 2005, 16,
Experimental Section
A solution of AgClO4 (10.4 mg, 0.05 mmol) and chiral ligand 2
(27 mg, 0.05 mmol) in toluene (1 mL) was stirred at RT for 1 h. The
reaction mixture was then cooled to the corresponding temperature
and the iminoester (1 mmol), dipolarophile (1 mmol), and the base
Angew. Chem. Int. Ed. 2008, 47, 6055 –6058
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 6057

Communications
2047 – 2061; h) I. Coldham, R. Hufton, Chem. Rev. 2005, 105,
2765 – 2809, and references therein.
[3] P. Allway, R. Grigg, Tetrahedron Lett. 1991, 32, 5817 – 5820.
[4] J. M. Longmire, B. Wang, X. Zhang, J. Am. Chem. Soc. 2002, 124,
13400 – 13401.
[5] a) C. Nµjera, M. G. Retamosa, J. M. Sansano, Org. Lett. 2007, 9,
4025 – 4028; b) W. Zeng, G.-Y Chen, Y. G. Zhou, Y.-X. Li, J. Am.
Chem. Soc. 2007, 129, 750 – 751; c) W. Zeng, Y.-G. Zhou,
Tetrahedron Lett. 2007, 48, 4619 – 4622; d) R. Stohler, F. Wahl,
A. Pfaltz, Synthesis 2005, 1431 – 1436; e) W. Zeng, Y.-G. Zhou,
Org. Lett. 2005, 7, 5055 – 5058; f) T. F. Knöpfel, P. Aschwanden,
T. Ichikawa, T. Watanabe, E. M. Carreira, Angew. Chem. 2004,
116, 6097 – 6099; Angew. Chem. Int. Ed. 2004, 43, 5971 – 5973;
g) C. Chen, X. Li, S. L. Schreiber, J. Am. Chem. Soc. 2003, 125,
10174 – 10175.
Córdova, Tetrahedron Lett. 2007, 48, 6252 – 6257; d) S. Arai, F.
Takahashi, R. Tsuji, A. Nishida, Heterocycles 2006, 67, 495 – 501;
e) C. Alemparte, G. Blay, K. A. Jørgensen, Org. Lett. 2005, 7,
4569 – 4572.
[11] For the first asymmetric synthesis of inhibitors of the RNA-
polymerase of the hepatitis C virus, by using a diastereoselective
1,3-DC involving chiral lactate derived acrylates, see: C. Nµjera,
M. G. Retamosa, J. M. Sansano, A. de Cózar, F. P. Cossío, Eur. J.
Org. Chem. 2007, 5038 – 5049.
[12] D. Polet, A. Alexakis, K. Tissot-Croset, C. Corminboeuf, K.
Ditrich, Chem. Eur. J. 2006, 12, 3596 – 3609.
[13] a) A. J. Minnaard, B. L. Feringa, L. Lefort, J. D. de Vries, Acc.
Chem. Res. 2007, 40, 1267 – 1277; b) Comprehensive Asymmetric
Catalysis, Vol. 1–3, Suppl. 1–2 (Eds.: E. N. Jacobsen, A. Pfaltz, H.
Yamamoto), Springer, Heidelberg, 2004.
[6] a) T. Llamas, R. Gómez-Arrayµs, J. C. Carretero, Synthesis 2007,
950 – 957; b) J.-W. Shi, J. W. Shi, Tetrahedron: Asymmetry 2007,
18, 645 – 650; c) B. Martín-Matute, S. I. Pereira, E. Peæa-
Cabrera, J. Adrio, A. M. S. Silva, J. C. Carretero, Adv. Synth.
Catal. 2007, 349, 1714 – 1724; d) S. Cabrera, R. Gómez-Arrayµs,
B. Martín-Matute, F. P. Cossío, J. C. Carretero, Tetrahedron 2007,
63, 6587 – 6602; e) X.-X. Yan, Q. Peng, Y. Zhang, K. Zhang, W.
Hong, X.-L. Hou, Y.-D. Wu, Angew. Chem. 2006, 118, 2013 –
2017; Angew. Chem. Int. Ed. 2006, 45, 1979 – 1983; f) T. Llamas,
R. Gómez-Arrayµs, J. C. Carretero, Org. Lett. 2006, 8, 1795 –
1798; g) W. Gao, X. Zhang, M. Raghunath, Org. Lett. 2005, 7,
4241 – 4244; h) S. Cabrera, R. Gómez-Arrayµs, J. C. Carretero, J.
Am. Chem. Soc. 2005, 127, 16394 – 16395.
[14] This compound belongs to a family of inhibitors of the
replication of hepatitis C virus (see reference [5a]). The results
concerning the synthesis of this kind of molecules with this
important activity are currently evaluated for a patent applica-
tion.
[15] CCDC 681931 [unit cell parameters: a 10.806(4) b 15.391(6) c
11.566(4) beta 102.882(8), space group P21)] and 681932 [a
10.806(4) b 15.391(6) c 11.566(4) beta 102.882(8), space group
P21] contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.
uk/data_request/cif.
[16] a) D. L. Reger, R. F. Semeniuc, J. D. Elgin, V. Rassolov, M. D.
[7] Y. Oderaotoshi, W. Cheng, S. Fujitomi, Y. Kasano, S. Minakata,
M. Komatsu, Org. Lett. 2003, 5, 5043 – 5046.
Smith, Cryst. GrowthDes.
2006, 6, 2758 – 2768; b) M.-C.
Brandys, R. J. Puddephatt, J. Am. Chem. Soc. 2002, 124, 3946 –
3950; c) M. Munakata, M. Wen, Y. Suenaga, T. Kuroda-Sowa, M.
Maekawa, M. Anahata, Polyhedron 2001, 20, 2037 – 2043; d) O.
Mamula, A. von Zelewsky, T. Bark, G. Bernardinelli, Angew.
Chem. 1999, 111, 3129 – 3133; Angew. Chem. Int. Ed. 1999, 38,
2945 – 2948.
[8] a) O. Dogan, H. Koyuncu, P. Garner, A. Bulut, W. J. Youngs, M.
Panzner, Org. Lett. 2006, 8, 4687 – 4690; b) A. S. Gothelf, K. V.
Gothelf, R. G. Hazell, K. A. Jørgensen, Angew. Chem. 2002, 114,
4410 – 4412; Angew. Chem. Int. Ed. 2002, 41, 4236 – 4238.
[9] J.-W. Shi, M.-X. Zhao, Z.-Y. Lei, M. Shi, J. Org. Chem. 2008, 73,
305 – 308.
[10] The use of organocatalysts as well as chiral bases has been
reported: a) M.-X. Xue, X.-M. Zhang, L.-Z. Gong, Synlett 2008,
691 – 694; b) J. L. Vicario, S. Reboredo, D. Badía, L. Carrillo,
Angew. Chem. 2007, 119, 5260 – 5262; Angew. Chem. Int. Ed.
2007, 46, 5168 – 5170; c) I. Ibrahem, R. Ríos, J. Vesely, A.
[17] CCDC 681933 [unit cell parameters: a 10.3809(2) c 56.6864(16),
space group P41212] contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
6058 www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 6055 –6058