The phenylsulfonyl group as a temporal regiochemical controller in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1002/anie.200805063

(Chemical Equation Presented) Controlling the regioselectivity: The phenylsulfonyl group controlled the regioselectivity in the title reaction to afford pyrrolidine-2,3-dicarboxylates with good regioselectivity and high exo selectivity and enantioselectivity (see scheme). The products are precursors to substituted pyrrolidines and pyrrolines that are not attainable by direct 1,3-dipolar cycloadditions with typical acrylates.

Full text of DOI:10.1002/anie.200805063

Communications
DOI: 10.1002/anie.200805063
Synthetic Methods
The Phenylsulfonyl Group as a Temporal Regiochemical Controller in
the Catalytic Asymmetric 1,3-Dipolar Cycloaddition of Azomethine
Ylides**
Ana Lꢀpez-Pꢁrez, Javier Adrio, and Juan C. Carretero*
Pyrrolidine derivatives are a significant group of heterocycles
which are present in an array of natural and synthetic
biologically active products.[1] Furthermore, proline ana-
logues have applications as chiral ligands and as organo-
catalysts in asymmetric synthesis.[2] This synthetic and bio-
logical relevance has encouraged the development of efficient
routes for the stereoselective and enantioselective prepara-
tion of substituted pyrrolidines.[3] In this context, the metal-
catalyzed asymmetric [3+2] cycloaddition of stabilized azo-
methine ylides with electron-deficient alkenes has emerged as
one of the most convergent and atom-economical tools for the
enantioselective synthesis of pyrrolidine and proline-type
derivatives.[4,5]
We have recently reported that unsubstituted vinyl
sulfones[10] and bis(sulfonyl)ethylenes[11] are excellent dipo-
larophiles in the catalytic asymmetric 1,3-dipolar cycloaddi-
tion of azomethine ylides. Bearing in mind the excellent
properties of the sulfonyl group both as a powerful electron-
withdrawing group and as an easily removed substituent,[12]
we envisaged that the regioselectivity of the catalytic
asymmetric reaction of sulfonyl acrylates with azomethine
ylides derived from iminoesters could be controlled by the
sulfonyl moiety rather than the ester group,[13] and lead to the
regioselective and stereoselective formation of 2,3-dicarbox-
ylic acid substituted pyrrolidines (Scheme 1). Herein, we
The regioselectivity in the cycloaddition of stabilized N-
metalated azomethine ylides (usually derived from glycine
esters) with unsymmetrically substituted electron-deficient
olefins is controlled by electronic effects, leading to pyrroli-
dine rings, which are substituted at the 2- and 4-positions, as
the sole product.[6] However, this excellent regiocontrol
hampers the preparation of the regioisomeric pyrrolidine
rings with electron-withdrawing substituents at the 2- and 3-
positions. This type of structural unit is frequently found in
natural, and biologically active compounds. For instance, 2,3-
dicarboxylic acid substituted pyrrolidine units are potent and
selective inhibitors of glutamate receptors and glutamate
transporters,[7] and they have been used in the design of new
peptides and constrained peptidomimetics.[8] Taking into
account that most methods currently used in the preparation
of pyrrolidines with 2,3-dicarboxylic acid substitution are
based on multistep approaches from a-amino acid precur-
sors,[9] the development of more convergent synthetic strat-
egies is highly desirable.
Scheme 1. Strategy for the enantioselective synthesis of 2,3-dicarboxylic
ester substituted pyrrolidines.
describe the scope of this strategy and its application to the
enantioselective synthesis of a variety of 2,3-dicarboxylic
ester substituted pyrrolidines and derivatives.
First, we carried out the reaction of methyl (E)-3-phenyl-
sulfonylpropenoate and N-benzylideneglycine methyl ester
(1a) under the optimal reaction conditions previously
reported by us for the copper-catalyzed 1,3-dipolar cyclo-
addition of azomethine ylides and bis(sulfonyl)ethylenes.[11]
However, under these reaction conditions [[Cu(CH3CN)4]PF6
(10 mol%), fesulphos ligand (3; 10 mol%), and Et3N
(18 mol%) in CH2Cl2 at room temperature] we observed
the formation of a complex mixture of isomers.[14] In an
attempt to improve the selectivity of the cycloaddition we
next turned to using the diastereoisomeric dipolarophile,
methyl (Z)-3-phenylsulfonylpropenoate (2).[15]
Gratifyingly, under the same reaction conditions this
dipolarophile cleanly afforded a mixture of two isomers in an
86:14 ratio (Scheme 2). After chromatographic separation of
the isomers the regiochemical and stereochemical assignment
of each of the products was first determined by NMR
[*] A. Lꢀpez-Pꢁrez, Dr. J. Adrio, Prof. Dr. J. C. Carretero
Departamento de Quꢂmica Orgꢃnica, Facultad de Ciencias
Universidad Autꢀnoma de Madrid
Cantoblanco, 28049 Madrid (Spain)
Fax: (+34)91-497-3966
E-mail: juancarlos.carretero@uam.es
[**] This work was supported by the Ministerio de Ciencia e Innovaciꢀn
(MICINN, project CTQ2006-01121) and Consejerꢂa de Educaciꢀn de
la Comunidad de Madrid, Universidad Autꢀnoma de Madrid (UAM/
CAM project CCG07-UAM/PPQ-1670). A.L.P. thanks the CAM for a
predoctoral fellowship. J.A. thanks the MICINN for a Ramꢀn y Cajal
contract. We thank Solvias AG (Dr. H.-U. Blaser, Solvias ligand kit)
and Takasago (Dr. H. Shimizu and Dr. Wataru Kuriyama, segphos
and DTBM-segphos) for generous loans of chiral ligands.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200805063.
340
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Angew. Chem. Int. Ed. 2009, 48, 340 –343

Angewandte
Chemie
Table 1: Ligand survey.
Entry[a]
Ligand
4a/5a[b]
Yield 4a [%][c]
ee 4a [%][d]
1
2
3
4
5
6
7
8
7
8
9
84:16
85:15
83:17
87:13
87:13
84:16
86:14
73:27
86:14
86:14
82:18
78
24
40
43
60
58
63
61
81
80
70
20 (À)
13 (À)
14 (+)
5 (+)
13 (+)
20 (+)
40 (+)
35 (À)
96 (+)
96 (+)
91 (+)
Scheme 2. Copper/fesulphos-catalyzed asymmetric cycloaddition of
azomethine ylide 1a with sulfonylacrylate 2.
10
11
12
13
14
15
15
15
spectroscopy and later confirmed by X-ray diffraction anal-
ysis of an enantiomerically pure sample of (+)-4a[16] and by
chemical correlation of the minor isomer (5a) to the known
pyrrolidine 2,4-dicarboxylic ester 6[5k] (obtained by reductive
elimination of the sulfonyl group).
9
10[e]
11[f]
Two main conclusions can be drawn from this reaction:
a) The structure of the major isomer, 4a, with 2,3-dicarboxylic
ester substitution, shows that the regioselectivity of the 1,3-
dipolar cycloaddition is mainly controlled by the sulfonyl
group. b) For both regioisomers there is perfect control of the
endo/exo stereoselectivity, such that there is exclusive for-
mation of the exo isomer. However, concerning the enantio-
selectivity of the process, the optical purity of the main
product 4a was very low (20% ee).[17] Therefore, to identify a
more efficient chiral catalyst system we next screened a
structurally varied set of commercially available chiral ligands
(Table 1).
Interestingly, the regioselectivity in favor of (+)-4a was
similar with all the ligands tested (7–15), indicating that the
regiocontrol exerted by the sulfonyl group is hardly depen-
dent on the nature of the chiral ligand. In contrast, as
expected, this set of ligands provided very different enantio-
selectivities. Ferrocene ligands, such as josiphos (7) and
taniaphos (8) (Table 1, entries 1 and 2), or the P,P-bidentate
ligands chiraphos (9), norphos (10), and phanephos (11)
(Table 1, entries 3–5) provided low enantioselectivities. The
most interesting results were obtained with the P,P axially
chiral ligands 12–15. The low enantioselectivity achieved with
(R)-binap (Table 1, entry 6) was improved to 35% ee with
(R)-segphos (Table 1, entry 8), and to 40% ee with (R)-tol-
binap (Table 1, entry 7). To our delight, the ligand DTBM-
segphos (15), which has a bulky substituted phosphine and a
minor dihedral angle,[18] produced a dramatic enhancement in
the asymmetric induction, leading to (+)-4a in 96% ee (80%
yield). The catalyst loading could be decreased from 10 to
5 mol% with similar reactivity and enantioselectivity
(Table 1, entry 10). However, an additional reduction in the
catalyst loading to 3 mol% resulted in a somewhat lower
diastereoselectivity and enantioselectivity (Table 1, entry 11).
The stereochemical and configurational assignment of (+)-
[a] Reaction conditions: Ligand (10 mol%), [Cu(CH3CN)4]ClO4
(10 mol%), Et3N (18 mol%), CH2Cl2, RT. [b] Determined by 1H NMR
analysis of the crude reaction mixtures. [c] Adduct (+)-4a after
purification by using column chromatography. [d] Determined by HPLC
methods, see the Supporting Information for details. [e] 5 mol% of
[Cu(CH3CN)4]PF6 was used. [f] 3 mol% of [Cu(CH3CN)4]PF6 was used.
(2R,3R,4S,5R)-4a was unequivocally established by X-ray
diffraction analysis of a recrystallized sample of greater than
99% ee.[16]
With these optimal reaction conditions in hand, we next
examined the scope of the 1,3-dipolar cycloaddition with
regard to the a-iminoester (Table 2). A rather homogeneous
regioselectivity (from 78:22 to 90:10) and high enantioselec-
tivity (80–99% ee) was observed regardless of the ortho, meta,
or para substituents on the aromatic ring, as well as the
electron-withdrawing or electron-donating nature of the
substituents (Table 2, entries 1–8). In all cases the major
regioisomer 4 was isolated in good yield (65–80% yield) after
silica gel chromatographic purification of the crude reaction
mixture. Similar results were also obtained for heteroaro-
matic a-iminoesters (Table 2, entries 9 and 10). a,b-Unsatu-
rated azomethine ylides are also suitable substrates for this
reaction, providing the major regioisomer 4k with excellent
enantioselectivity (Table 2, entry 11). Unfortunately, no
cycloaddition was observed when an alkyl iminoester was
tested under the same reaction conditions (Table 2, entry 12).
From a practical point of view it is interesting to note that
similar chemical yields and enantioselectivities were obtained
in reactions performed on a 0.3 to 3.0 mmol scale, and that the
enantiopurity of the major product 4 can be enhanced to more
than 99% ee by simple recrystallization from isopropanol
(Table 2, entries 1, 8, and 10).
To highlight the versatility of sulfonylpyrrolidines 4 in the
preparation pyrrolidine-2,3-dicarboxylate derivatives, we
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341

Communications
Table 2: Copper/DTBM-segphos catalyzed 1,3-dipolar cycloaddition of
iminoesters 1a–l.
elimination of the sulfonyl group occurred without epimeri-
zation at the C2-position.[19]
In conclusion, a general procedure for the catalytic
asymmetric 1,3-dipolar cycloaddition of (Z)-sulfonyl acryl-
ates with azomethine ylides has been developed. Interest-
ingly, the regioselectivity of the cycloaddition is mainly
controlled by the sulfonyl group, providing 2,3-dicarboxylic
ester substituted pyrrolidines with very high exo selectivity
and enantioselectivity (80–99% ee) using CuI/DTBM-seg-
phos as the catalyst system. The desulfonylation of the
adducts highlights the versatility of this protocol in the
enantioselective synthesis of substituted pyrrolidines (and
pyrrolines) with opposite regioselectivity to that obtained
using typical acrylate dipolarophiles.
Entry
R
4/5[a]
86:14
87:13
78:22
82:16
Product Yield 4 [%][b] ee 4 [%][c]
1
2
3
4
5
6
7
8
Ph
4a
4b
4c
4d
4e
4 f
4g
4h
4i
80
73
75
71
75
65
70
70
78
62
67
–
96 (99)[d]
96
99
88
(p-OMe)C6H4
(m-F)C6H4
(p-Br)C6H4
(p-N(Boc)2)C6H4 >98:2
88
99
99
(p-COMe)C6H4
(o-Me)C6H4
2-naphthyl
2-thiophenyl
2-pyrryl
80:20
90:10
86:14
85:15
>98:2
86:14
–
80 (99)[d]
9
88
10
11
12
4j
84 (99)[d]
=
Experimental Section
CH CH-Ph
Cy
4k
4l
99
–
Typical procedure for asymmetric 1,3-dipolar cycloaddition of
azomethine ylides: A solution of methyl (E)-N-benzylideneglycinate
1a (468 mg, 2.60 mmol) in CH2Cl2 (5.0 mL), Et3N (83 mL, 0.59 mmol),
and a solution of methyl (Z)-3-(phenylsulfonyl)acrylate 2 (500 mg,
2.20 mmol) in CH2Cl2 (5.0 mL) were successively added to a solution
of DTBM-segphos 15 (130.0 mg, 0.11 mmol) and [Cu(CH3CN)4]PF6
(41 mg, 0.11 mmol) in CH2Cl2 (5.0 mL) under nitrogen atmosphere.
After stirring at room temperature for 5 h, the mixture was filtered
through a plug of Celite with the aid of CH2Cl2 (5.0 mL), and then the
solvent was removed under reduced pressure. The residue was
purified by silica gel flash chromathography (hexanes/EtOAc 2:1) to
afford the adduct (+)-4a (712 mg, 80%, white solid, m.p. = 156–
1578C) in 96% ee. The enantiopurity of (+)-4a was enhanced to more
than 99% ee by recrystallization from isopropanol.
[a] Determined by 1H NMR analysis of the crude reaction mixtures.
[b] Product after purification by using column chromatography. [c] Deter-
mined by HPLC methods, see the Supporting Information for details.
[d] The ee value after recrystallization.
explored some desulfonylation reactions (Scheme 3). The
reductive cleavage of the sulfonyl group was performed by
straightforward treatment with Na(Hg), leading to the
Received: October 16, 2008
Published online: December 9, 2008
Keywords: asymmetric catalysis · azomethine ylides ·
.
cycloaddition · enantioselectivity · heterocycles
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corresponding
2,3-dicarboxylic
ester
pyrrolidines
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yield) depending on the base used (LiOH or DBU, respec-
=
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=
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342
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