Enantioselective synthesis of 4-aminopyrrolidine-2,4-dicarboxylate derivatives via Ag-catalyzed cycloaddition of azomethine ylides with alkylidene azlactones

Article abstract of DOI:10.1039/c3cc41663a

A catalytic highly enantioselective silver-DTBM-segphos catalyzed cycloaddition of α-iminoesters with alkylidene azlactones is reported. This procedure provides an effective access to 4-aminopyrrolidine-2,4- dicarboxylate derivatives with high diastereo- and enantioselectivity. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41663a

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Enantioselective synthesis of 4-aminopyrrolidine-
2,4-dicarboxylate derivatives via Ag-catalyzed
cycloaddition of azomethine ylides with alkylidene
azlactones†
Cite this: Chem. Commun., 2013,
49, 4649
Received 5th March 2013,
Accepted 26th March 2013
DOI: 10.1039/c3cc41663a
´
Mar´ıa Gonzalez-Esguevillas, Javier Adrio* and Juan C. Carretero*
www.rsc.org/chemcomm
A catalytic highly enantioselective silver–DTBM-segphos catalyzed
The existing synthetic methods for the enantioselective
cycloaddition of a-iminoesters with alkylidene azlactones is preparation of 4-amino 4-carboxylate proline derivatives usually
reported. This procedure provides an effective access to 4-amino- consist of multistep sequences starting from enantiopure starting
pyrrolidine-2,4-dicarboxylate derivatives with high diastereo- and materials.6 Therefore, the development of more convergent
enantioselectivity.
synthetic strategies, which facilitate the preparation of this
kind of cyclic amino acids, is desirable.
The pyrrolidine ring is considered to be a privileged structure in
Among the procedures reported for the enantioselective
medicinal chemistry since its derivatives are valuable scaffolds preparation of highly substituted pyrrolidines, the metal cata-
for the discovery of new therapeutic agents.1 In particular, lyzed 1,3-dipolar cycloaddition of azomethine ylides with activated
proline derivatives having a quaternary stereocenter have been olefins has emerged as one of the most powerful methodologies.7
broadly studied in peptidomimetic chemistry since their intro- In recent years an extensive effort in this area has led to the
duction into peptides restricts the conformational flexibility of development of a plethora of catalytic systems which have effi-
the peptidic chain, and may increase its selectivity and metabolic ciently extended the scope of the reaction with regard to both the
stability.2 Furthermore, proline analogues have been widely used dipole and dipolarophile partners.8 Very recently a few examples
as chiral synthons and catalysts in organic synthesis.3
In this context, 4-aminopyrrolidine-2,4-dicarboxylate derivatives spirocyclic pyrrolidines have been reported.9
of the application of this methodology to the construction of
4 (Scheme 1) are valuable multipurpose products. For instance,
We envisioned that proline analogues with amino acid
examples of these compounds have been identified as potent, substitution at C-4 could be rapidly assembled in a modular
highly selective agonists for metabotropic glutamate receptors, and highly selective manner via 1,3-dipolar cycloaddition
which are involved in the pathologies of several neurodegenerative between a-iminoesters and the appropriate olefinic azlactones
diseases.4 In addition, 4-aminopyrrolidine-2,4-dicarboxylate as dipolarophiles (Scheme 1). Nevertheless, this kind of alkene
has been used as a monomer for the preparation of non-natural has been scarcely applied in 1,3-dipolar cycloadditions,10 and
oligomers with well-defined three-dimensional structures.5
to the best of our knowledge, there are no precedents of their
use as dipolarophiles in catalytic asymmetric 1,3-dipolar cyclo-
additions of azomethine ylides.
In order to evaluate the viability of the process, we chose the
cycloaddition of the iminoester 1a with benzylidene azlactone
2a as a model reaction. After screening a variety of metal salts
and chiral ligands,11 using THF as solvent and Et3N as base, we
observed a significant improvement in the reactivity and selec-
tivity when a combination of a silver salt and the DTBM-
segphos ligand12 was used as a catalyst system. Under these
conditions a mixture of three pyrrolidines was observed by
1H-NMR analysis of the crude mixtures. The isolation of the
resulting spirocyclic intermediate 3 was not feasible because of
its instability during the purification process. Thus, it was
quantitatively transformed into the corresponding dimethyl-
4-benzamidopyrrolidine-2,4-dicarboxylates by treatment of the
Scheme 1
´
´
´
Departamento de Quımica Organica, Facultad de Ciencias, Universidad Autonoma
de Madrid, Cantoblanco, 28049 Madrid, Spain. E-mail: javier.adrio@uam.es,
juancarlos.carretero@uam.es; Fax: +34 914973966
† Electronic supplementary information (ESI) available: Experimental procedures,
spectroscopic data and NMR spectra. CCDC 924149 and 924150. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc41663a reaction mixture with a solution of HCl in MeOH. Under these
c
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Table 1 Optimization of the reaction conditions
1H-NMR ratioa
Yield 4 + 5b
eec (%)
Entry
X
Solvent
Base
T (1C)
t (h)
4 : 5 : 6
(%)
4a
5a
1
2
3
4
5
6
7
8
10
10
10
10
10
5
THF
Et3N
Et3N
Et3N
—
—
—
rt
rt
rt
rt
À10
À10
À10
À10
16
16
16
16
16
16
48
168
54 : 23 : 23
49 : 29 : 22
65 : 20 : 15
80 : 20 : 0
97 : 3 : 0
98 : 2 : 0
95 : 5 : 0
—
44
53
42
62
74
66
63
—
79
94
96
95
99
99
99
—
86 (45)d
84
99
76
82
—
—
—
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
3
1
—
—
a
1
b
c
Using H-NMR from the crude reaction mixtures. Yield of the 4 + 5 mixture after column chromatography. Using HPLC, see ESI for details.
ee of 6a.
d
Table 2 Scope of the reaction: substitution at the azomethine ylide precursor
starting reaction conditions isomer 4a was obtained in 79% ee,
isomer 5a in 86% ee and isomer 6a13 in 45% ee (Table 1, entry 1).
Next, we endeavour to optimize the reaction conditions to
improve both the diastereo- and enantioselectivity of the pro-
cess. We observed an important improvement in the enantio-
selectivity using CH2Cl2 as solvent (94% ee for 4a, entry 2) and
even higher in toluene (96% ee for 4a, entry 3).
Interestingly, it was found that in the absence of an added
base the reaction takes place with a similar yield and enantio-
selectivity but higher diastereoselectivity (entry 4). When the
reaction was carried out at À10 1C an additional enhancement
in the diastereo- and enantioselectivity was observed to provide
4a with very high diastereoselectivity (97 : 3 ratio) and excellent
enantioselectivity (entry 5). The catalyst loading could be
reduced to 5 mol% with similar reactivity and selectivity (entry 6).
However, a much longer reaction time was needed using a 3 mol%
of catalyst (entry 7) and no reaction was observed with 1 mol%
(entry 8).
With these optimal reaction conditions in hand, the scope of
the 1,3-dipolar cycloaddition with regard to the substitution in
the azomethine ylide was investigated. As shown in Table 2 the
cycloaddition tolerates a broad substitution at the aromatic
ring regardless of the steric and electronic properties of the
substituent. In all cases the corresponding pyrrolidines 4 were
isolated with moderate to good yields, almost complete diastereo-
selectivity and excellent enantioselectivity (cycloadducts 4b–4i in
up to 90% yield, dr from 78 : 22 to >98 : 2, and ee from 95 to
>99%). The procedure was also applied to heteroaryl substituted
glycine derivatives 1j and 1k with excellent enantiocontrol, albeit
a
b
c
Isolated yields of major diastereomer 4 after column chromatography.
Isolated yields of the 4 + 5 mixture after column chromatography.
Diastereomeric 4 : 5 ratio using 1H-NMR from the crude reaction
d
mixtures. ee determined using chiral HPLC, see ESI for details.
with lower diastereocontrol. In contrast, no reaction was observed of aryl substituted azlactones were tested as dipolarophiles.
when an alkyliminoester 1l was tested under the same reaction Both electron donating and withdrawing substituents were well
conditions. The stereochemical and configurational assignments tolerated in the cycloaddition that proceeded with high diastereo-
of isomers 4c and 6c were unequivocally established by X-ray selectivities providing the pure adducts 4m–4u in 45–91% yields
diffraction analysis.14
and excellent enantioselectivities (93 - >99% ee). The reactions
To further study the scope of this transformation, the effect also efficiently transformed azlactones with heteroaromatic sub-
of the substitution at the alkylidene azlactone partner on the stituents into the corresponding pyrrolidines (4v and 4w). Only in
reactivity and selectivity was investigated (Table 3). First, a variety the case of ortho arylsubstituted azlactones the reactivity and
c
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Table 3 Scope of the reaction: substitution at the alkylidene azlactone
Financial support for this work from the Ministerio de
´
Ciencia e Innovacion of Spain (MICINN, CTQ2009-07791), the
Ministerio de Economia y Competitividad (MINECO, CTQ2012-
35790) and CAM (project AVANCAT; S2009/PPQ-1634) is grate-
fully acknowledged. M.G.-E. thanks the MICINN for a predoctoral
fellowship. We thank the Takasago Company (Dr Taichiro Touge)
for generous loans of segphos chiral ligands.
Notes and references
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HPLC, see ESI.
Scheme 2
selectivity dropped significantly (cycloadduct 4x). Alkenyl azlactones
were also suitable substrates for this reaction, providing the major
isomer 4y with excellent enantioselectivity (97% ee).
The selective hydrolysis of the ester groups of the pyrrol-
idines 4a and 4c was readily achieved in the presence of NaOH
in EtOH, providing the pyrrolidine dicarboxylic acids 7a and 7c
in 85% and 80% yield respectively, without any detectable
epimerization15 (Scheme 2).
11 A variety of metal salts and structurally diverse chiral ligands were
tested in this cycloaddition, see ESI† for details.
12 For the use of segphos ligands in catalytic asymmetric 1,3-dipolar
cycloadditions of azomethine ylides, see: (a) Y. Yamashita, T. Imaizumi
and S. Kobayashi, Angew. Chem., Int. Ed., 2011, 50, 4893;
´
(b) J. Hernandez-Toribio, S. Padilla, J. Adrio and J. C. Carretero,
´
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J. Adrio and J. C. Carretero, Chem. Commun., 2012, 48, 2149;
(d) Y. Oderaotoshi, W. Cheng, S. Fujitomi, Y. Kasano, S. Minakata
and M. Komatsu, Org. Lett., 2003, 5, 5043.
In summary, we have developed an efficient methodology for 13 The absolute and relative configuration of isomers 4, 5 and 6 was
determined by X-ray diffraction analysis and NMR studies, see
ref. 14 and ESI†.
14 CCDC 924149 (4c) and 924150 (6c).† Compound 6c was obtained using
the preparation of 4-amidopyrrolidine-2,4-dicarboxylates via
catalytic asymmetric [3+2] cycloaddition of azomethine ylides
with alkylidene azlactones. The use of AgI–DTBM-segphos
as catalyst leads to the formation of the corresponding
cycloadducts with excellent levels of diastereoselectivity and
enantiocontrol (up to Z99% ee). Hydrolysis of the ester groups
under standard conditions afforded the 4-amidopyrrolidine
2,4-dicarboxylic acids which encompass potential pharmacological
applications.
different reaction conditions ((R)-Tol-Binap as a ligand), see ESI† for
details. For previous examples of azomethine ylide dipolar cyclo-
additions where 2,5-trans pyrrolidine derivatives were obtained, see:
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15 F. Clerici, M. L. Gelmi, A. Gambini and D. Nava, Tetrahedron, 2001,
57, 6429.
c
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Chem. Commun., 2013, 49, 4649--4651 4651