Cu-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with β-phenylsulfonyl enones. Ligand controlled diastereoselectivity reversal

Article abstract of DOI:10.1021/jo902103z

(Chemical Equation Presented) A catalytic asymmetric procedure for the 1,3-dipolar cycloaddition of (E)-β-phenylsulfonyl enones with azomethine ylides to provide highly functionalized pyrrolidine derivatives is described. In the presence of chiral Cu^I-Segphos catalysts the aducts were obtained with high regio-, diastereo-, and enantioselectivity. Interestingly, a switch from endo to exo selectivity was observed when Segphos or DTBM-Segphos ligand was used.

Full text of DOI:10.1021/jo902103z

pubs.acs.org/joc
of more concise procedures enabling the synthesis of enan-
Cu-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition
of Azomethine Ylides with β-Phenylsulfonyl Enones.
Ligand Controlled Diastereoselectivity Reversal
tiopure highly functionalized examples is a topic of growing
interest. In this context, the catalytic asymmetric 1,3-dipolar
cycloaddition of azomethine ylides to activated alkenes has
emerged as an essential tool, which provides a direct access to
proline derivatives with good control of the diastereoselec-
tivity and enantioselectivity.4 Since the pioneering reports in
2002, by Zhang and Jørgersen,5 several methods based on the
use of diverse metal sources and chiral ligands have been
developed.6 Several organocatalytic versions of this reaction
have also recently emerged.7 Practically all of these protocols
involve the reaction between azomethine ylides derived from
iminoesters and monoactivated (such as acrylates, enones,
nitroalkenes, and vinyl sulfones) or symmetrically double
activated (such as maleates, fumarates, malemides, and
fumaronitriles) dipolarophiles. However, the use of unsym-
metrically substituted 1,2-diactivated dipolarophiles, which
could lead to the formation of regioisomers, has been seldom
explored.8 In this topic, we have recently developed a general
procedure for the catalytic asymmetric 1,3-dipolar cycload-
dition of Ζ-sulfonyl acrylates with azomethine ylides where
the regioselectivity of the cycloaddition is mainly controlled
ꢀ
Rocıo Robles-Machın, Marıa Gonzalez-Esguevillas,
Javier Adrio,* and Juan C. Carretero*
´
ꢀ
Departamento de Quımica Organica, Facultad de Ciencias,
ꢀ
Universidad Autonoma de Madrid, Cantoblanco,
28049 Madrid, Spain
juancarlos.carretero@uam.es; javier.adrio@uam.es
Received September 30, 2009
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2008, 108, 2887. (b) Pellisier, H. Tetrahedron 2007, 63, 3235–3285. (c) Pandey,
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A catalytic asymmetric procedure for the 1,3-dipolar
cycloaddition of (Ε)-β-phenylsulfonyl enones with azo-
methine ylides to provide highly functionalized pyrroli-
dine derivatives is described. In the presence of chiral CuI-
Segphos catalysts the aducts were obtained with high
regio-, diastereo-, and enantioselectivity. Interestingly, a
switch from endo to exo selectivity was observed when
Segphos or DTBM-Segphos ligand was used.
ꢀ
ꢀ
N. Nature Chem. 2009, 1, 578–582. (c) Hernandez-Toribio, J.; Gomez Arrayas,
R.; Martın-Matute, B.; Carretero, J. C. Org. Lett. 2009, 11, 393–396.
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lysts.2 Although numerous methods have been reported for
the preparation of pyrrolidine derivatives,3 the development
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(b) Pyne, S. G.; Davis, A. S.; Gates, N. J.; Lindsay, K. B.; Machan, T.; Tang,
M. Synlett 2004, 2670–2680. (c) Cheng, Y.; Huang, Z.-T.; Wang, M.-X. Curr.
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Y.-G.; Kumano, T.; Kano, T.; Maruoka, K. Org. Lett. 2009, 9, 2027–2029.
(b) Blike, J. L.; Moore, S. P.; O0Brian, P.; Gilday, J. Org. Lett. 2009, 9, 1935–
1938. (c) Jackson, S. K.; Karadeolian, A.; Driega, A. B.; Kerr, M. A. J. Am.
Chem. Soc. 2008, 130, 4196–4201. (d) Unthank, M. G.; Tavassoli, B.;
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Bhattachriee, S.; Yan, J.; Borhan, B. J. Am. Chem. Soc. 2007, 129, 1996–
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(r) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem. Soc. 2007, 129,
750–751. (s) Stohler, R.; Wahl. F.; Pfaltz, A. Synthesis 2005, 1431-1435. Zn
catalysts: (t) Dogan, O.; Koyuncu, H.; Garner, P.; Bulut, A.; Youngs, W. J.;
Panzner, M. Org. Lett. 2006, 8, 4687–4690. (u) Zeng, W.; Zhou, Y.-G. Org. Lett.
2005, 7, 5055-5058. Ni catalysts: (v) Shi, J.-W.; Zhao, M.-X.; Lei, Z.-Y.; Shi, M.
J. Org. Chem. 2008, 73, 305-308. Ca catalysts: (w) Saito, S.; Tsubogo, T.;
Kobayashi, S. J. Am. Chem. Soc. 2007, 129, 5364. (x) Tsubogo, T.; Saito, S.;
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2008, 14, 9873–9877. (b) Chen, X.-H.; Zhang, W.-Q.; Gong, L.-Z. J. Am.
Chem. Soc. 2008, 130, 5652–5653. (c) Guo, C.; Xue, M.-X.; Zhu, M.-K.;
Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47, 3414–3417. (d) Xue, M.-X.;
Zhang, X.-M.; Gong, L.-Z. Synlett 2008, 691. (e) Vicario, J. L.; Reboredo, S.;
Badıa, D.; Carrillo, L. Angew. Chem., Int. Ed. 2007, 46, 5168. (f) Ibrahem, I.;
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(8) For an asymmetric example with a chiral azomethine ylide, see:
Sebahar, P. R.; Williams, R. M. J. Am. Chem. Soc. 2000, 122, 5666–5667.
DOI: 10.1021/jo902103z
r
Published on Web 12/03/2009
J. Org. Chem. 2010, 75, 233–236 233
2009 American Chemical Society

Robles-Machın et al.
JOCNote
TABLE 1. Optimization Experiments for the Model Reaction
entry
R
ligand
solvent
X
t (min)
T (°C)
1H NMR ratioaexo:endo:Rb
yield (%)c
yield (%) (major)d
ee (%) (major)e
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
iPr
6
7
6
7
6
7
6
7
THF
THF
THF
Et2O
THF
Et2O
THF
Et2O
10
10
10
10
3
3
3
3
10
10
240
10
240
10
240
240
rt
rt
-78
rt
-78
rt
19:71:10
61:21:18
8:88:4
81:10:9
5:92:3
83:7:10
3:97:0
98:1:1
95
93
87
93
85
72
99
85
66 (endo-4a)
54 (exo-4a)f
70 (endo-4a)
57 (exo-4a)f
76 (endo-4a)
65 (exo-4a)f
95 (endo-5a)
84 (exo-5a)
88
g99g
97
g99g
94
g99g
g99
g99
-78
rt
iPr
aBy 1H NMR from the crude reaction mixtures. bR = 3-ketosubstituted regioisomer. cCombined yield in pyrrolidine products after column
chromatography. dYield in pure isolated major isomer after column chromatography. eDeterminated by HPLC, see the Supporting Information for
details. fPurified by further recrystallization. gee of exo-4a before recrystallization.
by the sulfonyl group,9 providing 2,3-dicarboxylate ester
pyrrolidines with very high exo selectivity and enantioselec-
tivity (80-99% ee). With the aim of expanding the range of
1,2-diactivated dipolarophiles suitable for this reaction,
herein we report a highly enantioselective catalytic azo-
methine ylide dipolar cycloaddition procedure with β-phe-
nylsulfonylenones.
To evaluate the viability of the process, we selected the
reaction between N-benzylidenglycine methyl ester 1a and
(E)-4-(phenylsulfonyl)but-3-en-2-one10 (2) as the model sys-
tem. As a starting point, we carried out the reaction under
previously reported Cu-catalyzed conditions for asymmetric
dipolar cycloaddition of azomethine ylides with several
dipolarophiles6h [Cu(CH3CN)4PF6 (10 mol %), chiral ligand
ligand (10 mol %), and Et3N (20 mol %) in THF at room
temperature]. After screening a variety of chiral ligands,11
we observed a significant enhancement in the regio- and
diastereoselectivity with P,P axially chiral Segphos-type
ligands.12 Under these conditions the regioselectivity of
the cycloaddition is mainly controlled by the carbonyl
group, leading to the 4-acetyl-substituted pyrrolydines 4a
as the major regioisomer (less than 20% of the minor 3-acetyl
regiosomer was observed in all examples studied).13 More-
over, a remarkable inversion in the exo/endo diastereo-
selectivity was observed.14 Segphos ligand (6) afforded the
endo pyrrolidine 4a as the major product with 88% ee
(Table 1, entry 1), whereas DTBM-Segphos ligand (7),
with very bulky and electron-donating substituents in the
aryl group on the phosphorus atom, gave mainly exo-4a
with g99% ee (Table 1, entry 2). Further optimization of
the reaction conditions with Segphos-type ligands was
then accomplished. The best results with Segphos 6/Cu-
(CH3CN)4PF6 as the catalyst system were achieved in THF
at -78 °C, the aduct endo-4a being obtained with high
yield and 97% ee (entry 3). exo-Pyrrolidine 4a was ob-
tained as the major product with g99% ee with DTBM-
Segphos 7 as the ligand in Et2O at room temperature
(entry 4). In both cases the catalyst loading could be reduced
from 10 to 3 mol % with very similar diastereoselectivity
and enantioselectivity (Table 1, entries 5 and 6). When
the more sterically demanding isopropyl ketone 3 was used
as the dipolarophile, the cycloaddition occurred with a
nearly complete control of the regioselectivity and dias-
tereoselectivity, while maintaining an excellent enantiocon-
trol and opposite exo/endo selectivities with ligands 6 and
7 (97% endo and 93% exo, respectively; entries 7 and 8,
Table 1).
ꢀ
ꢀ
(9) Lopez-Perez, A.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed.
2009, 48, 340–343.
(10) β-Phenylsulfonyl enones were prepared according to the reported
methods: (a) Domınguez, E.; Carretero, J. C. Tetrahedron 1990, 46, 7197–
7206. (b) Leon, F. M.; Carretero, J. C. Tetrahedron Lett. 1991, 32, 5405–
5408. No reaction was observed when the (Z)-isomer was used in the
cycloaddition.
(11) Fesulphos, Taniaphos, Josiphos, Mandyphos, Solphos, and Phane-
phos were tested as chiral ligands in this cycloaddition. However, a poor
endo/exo selectivity and regioselectivity was observed with all of them (see
Scheme below). In addition, all the cycloadditions occurred with low or
moderate enantioselectivity, excepting the case of the reaction with Fesul-
phos (99% ee for exo-4a).
(13) From the starting mixture of adducts, formed by the exo þ endo
adducts 4a and the minor 3-acetyl regioisomer, the adduct endo-4a was
isolated pure after standard column chromatography. Although due to their
very similar Rf values it was not possible to separate completely exo-4a and
the 3-acetyl regioisomer by column chromatography, pure exo-4a was
obtained after final recrystallization in isopropanol.
(14) For a previous example of a switch in the diastereoselectivity of the
1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes varying the
electronic properties of the ligands, see ref 6i.
(12) For a review on biaryl-type biphosphine ligands, see: Shimizu, H.;
Nagasaki, I.; Saito, T. Tetrahedron 2005, 61, 5405–5432.
234 J. Org. Chem. Vol. 75, No. 1, 2010

Robles-Machın et al.
JOCNote
SCHEME 1. Regiochemistry Determination: Conversion to
Pyrroles
TABLE 2. Scope of the CuI/Segphos-Catalyzed 1,3-Dipolar Cycload-
dition with β-Phenylsulfonyl Enones
entry
R1
R2 R3 L* product exo:endoc yieldd (%) ee (%)e
1
2
3
4
5
6
7
8
9
m-MeC6H4
m-MeC6H4
m-MeC6H4
p-ClC6H4
p-ClC6H4
p-BrC6H4
p-BrC6H4
thienyl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me 6a endo-4b
Me 7b exo-4b
iPr 7b exo-5b
Me 6a endo-4c
Me 7b exo-4c
iPr 6a endo-5c
iPr 7b exo-5c
Me 7b exo-4d
iPr 7b exo-5d
Me 6a endo-4e
Me 7b exo-4e
iPr 7b exo-5e
Me 6a endo-4f
iPr 7b exo-5f
3:97
74:26
99:1
8:92
89:11
2:98
99:1
78:22
93:7
1:99
86:14
99:1
8:92:
98:2
2:98
98:2
49
59f
41
64
52g
54
59
63f
47
68
46
71
79
71
45
61f
g99
g99
g99
g99
g99
94
99
95
g99
g99
92
g99
g99
96
87
93
The stereochemical and configurational assignment
of (þ)-exo-4a was unequivocally established by X-ray
diffraction of a recrystallized sample of g99% ee.15 On
the other hand, the regiochemistry of aducts 4a and the
minor regioisomer 8 was confirmed by its aromatization to
the corresponding pyrroles via basic elimination of the
sulfonyl group16 (Scheme 1). Thus, the treatment of a
mixture of endo and exo 4a with DBU in toluene afforded
exclusively the 2,4,5-trisubstituted pyrrole 9, whereas the
aromatization of the regioisomer 8 led to the 2,3,5-trisu-
btituted pyrrole 10. Futhermore, the NOESY spectra of
endo-4a and 8 corroborated these assignments. Hence, im-
portant NOESY correlations were observed between the
methyl unit of the acetyl group and the ortho protons
of the phenyl group in endo-4a, while the regioisomer 8
showed a significant cross-peak between the acetyl group
and the methyl esther unit.
thienyl
10 o-MeOC6H4
11 o-MeOC6H4
12 p-MeOC6H4
13 naphtyl
14 naphtyl
15 Ph
Me Me 6a endo-4g
Me iPr 7b exo-5g
16 Ph
aTHF, -78 °C. bEt2O, rt, see the Supporting Information for reaction
times. cBy 1H NMR from the crude reaction mixtures. In pure major
d
e
isomer after column chromatography. Determined by HPLC (major
isomer), see the Supporting Information for details. fContaining 5-15%
of the 3-ketosubstituted regioisomer. gPurified by further recrystalliza-
tion
In conclusion, (E)-phenylsulfonylenones have been stu-
died as novel dipolarophiles in catalytic asymmetric 1,3-
dipolar cycloaddition of azomethine ylides. In the presence
of CuI-Segphos catalysts a high reactivity, selectivity and
structural scope were observed, the regioselectivity being
controlled by the carbonyl group at the dipolarophile. Re-
markably, either the endo or the exo pyrrolidine aduct can be
selectively obtained with Segphos 6 or DTBM-Segphos 7,
respectively.
We next studied the scope of the Cu-catalyzed 1,3-dipolar
cycloaddition of β-phenylsulfonyl enones with regard to the
substitution at the azomethine precursor, in the presence of
Segphos ligands 6 or 7 under the previously optimized
reaction conditions. Similarly to the behavior of the model
phenylimine glycinate, in all cases the regioselectivity of the
process was mainly controlled by the carbonyl group of the
dipolarophile (3-18% of the regioisomer 3-carbonyl-sub-
stituted pyrrolidine was detected in the reaction mixtures).
As shown in Table 2 a homogeneous stereochemical
behavior was observed. The reaction of aryl- and heteroar-
yl-substituted glycine derivatives in the presence of ligand 6
afforded the endo pyrrolidine as the major stereoisomer
with acceptable yields and exceptional enantioselectivities
(Table 2, entries 1, 4, 6, 10, and 13), while with DTBM-
Segphos ligand 7 the diastereomer exo-4 was selectively ob-
tained also with nearly complete enantioselectivity (Table 2,
entries 2, 3, 5, 7, 8, 9, 11, 12, and 14).
Experimental Section
Typical Procedure for the Preparation of exo-Pyrrolidines:
(2S,3S,4S,5S)-Methyl 4-Acetyl-5-phenyl-3-(phenylsulfonyl)py-
rrolidine-2-carboxylate (exo-4a). To a solution of (R)-DTBM-
Segphos (7) (3.7 mg, 3.14 ꢀ 10-3 mmol) and Cu(CH3CN)4PF6
(1.1 mg, 2.86 ꢀ 10-3 mmol) in Et2O (0.3 mL), under nitrogen
atmosphere, at room temperature, were successively added a
solution of (E)-methyl 2-(benzylideneamino)acetate (1a) (20 mg,
0.11 mmol) in Et2O (0.8 mL) and Et3N (2.6 μL, 0.019 mmol).
The resulting solution was added to a suspension of (E)-
4-(phenylsulfonyl)but-3-en-2-one (2) (20 mg, 0.09 mmol) in
Et2O (0.5 mL). The mixture was stirred for 10 min and filtered
through a plug of Celite with the aid of CH2Cl2 (5.0 mL), then
the solvent was removed under reduced pressure. After silica gel
flash chromatography purification (hexane-EtOAc 3:1) a 90:10
mixture of cycloadduct exo-4a and the 3-ketosubstituted regioi-
somer (30 mg) was obtained (g99% ee for exo-4a). Recrystalli-
zation in i-PrOH afforded pure exo-4a (24 mg, 65%, white
solid). Mp: 125-126 °C. [R]D20: þ41.3 (c 0.9, CH2Cl2), >99%
ee. HPLC: Daicel Chiralpak, i-PrOH-hexane 40-60, flow rate
0.7 mL/min (λ = 210 nm). tR: 18.56 min (2S,3S,4S,5S)-exo-4a
and 46.57 min (2R,3R,4R,5R)-exo-4a. 1H NMR (300 MHz,
Interestingly, this protocol also can be applied to alanine-
based dipoles, which lead to pyrrolidines with a quater-
nary stereocenter in position 2 (R2=Me, entries 15 and 16,
Table 2), albeit with a slightly lower enantioselectivity.
(15) Exo refers to the pyrrolidine with trans stereochemistry at C4-C5.
See the Supporting Information for details on the X-ray structure of
enantiopure exo-4a. For the configuration of the endo isomer, it has been
assumed that the endo/exo cycloaddition occurs with the same π-facial
selectivity on the dipole-Cu complex (pyrrolidine adducts with 2S,5S
configuration).
(16) For a previous example of aromatization of sulfonylpyrrolidines,
ꢀ
see: Lopez, A.; Robles-Machın, R.; Adrio, J.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2007, 46, 9261–9264.
J. Org. Chem. Vol. 75, No. 1, 2010 235

Robles-Machın et al.
JOCNote
CDCl3): δ 7.91-7.88 (m, 2H), 7.69-7.64 (m, 1H), 7.60-7.55 (m,
2H), 7.52-7.49 (m, 2H), 7.45-7.34 (m, 3H), 4.60 (dd, J = 7.34,
5.27 Hz, 1H), 4.15-3.90 (m, 2H), 3.88 (dd, J = 8.10, 5.27 Hz,
1H), 3.63 (s, 3H), 2.95 (br s, 1H), 1.79 (s, 3H). 13C NMR (75
MHz, CDCl3): δ 204.7, 168.6, 138.8, 134.1, 129.4, 129.3, 128.9,
128.8, 128.4, 127.4, 68.7, 67.4, 63.1, 61.8, 52.5, 30.2. MS
(FABþ): 388.1 ([M þ H], 100). HRMS (FABþ): calcd for
C20H22NO5S 388.1219, found 388.1215.
5R)-endo-4a. 1H NMR (300 MHz, CDCl3): δ 7.96-7.92 (m,
2H), 7.72-7.66 (m, 1H), 7.62-7.51 (m, 2H), 7.37-7.25 (m, 5H),
4.80 (d, J = 7.56 Hz, 1H), 4.35 (dd, J = 6.05, 3.21 Hz, 1H), 4.25
(d, J = 6.05 Hz, 1H), 4.03 (dd, J = 7.56. 3.02 Hz, 1H), 3.52 (s,
3H), 2.61 (br s, 1H), 1.46 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
206.3, 170.2, 137.7, 136.0, 134.2, 129.3, 128.9, 128.8, 128.5,
126.8, 69.2, 66.4, 56.9, 61.5, 52.7, 31.3. MS (FABþ): 388.1
([M þ H], 100). HRMS (FABþ): calcd for C20H22NO5S
388.1219; found 388.1224.
Typical Procedure for the Preparation of endo-Pyrrolidines:
(2S,3R,4R,5S)-Methyl 4-Acetyl-5-phenyl-3-(phenylsulfonyl)py-
rrolidine-2-carboxylate (endo-4a). To a solution of (R)-Segphos
(6) (2.87 mg, 4.7 ꢀ 10-3 mmol) and Cu(CH3CN)4PF6 (1.60 mg,
4.3 ꢀ 10-3 mmol) in THF (0.5 mL), under nitrogen atmosphere,
at -78 °C, were successively added a solution of (E)-methyl
2-(benzylideneamino)acetate (1a) (30 mg, 0.171 mmol) in THF
(0.5 mL) and Et3N (3.9 μL, 0.029 mmol). The resulting solution
was added to a suspension of (E)-1-(phenylsulfonyl)but-1-en-
3-one (2) (30 mg, 0.143 mmol) in THF (0.5 mL). The mix-
ture was stirred for 4 h and filtered through a plug of Celite
with the aid of CH2Cl2 (5.0 mL), then the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography (hexane-AcOEt 3:1) to afford the cycload-
duct endo-4a (43 mg, 76%, white solid). Mp: 125.5-126.8 °C.
[R]D20: -62.6 (c 1.5, CH2Cl2), 94% ee. HPLC: Daicel Chiralpak
AD, i-PrOH-hexane 40/60, flow rate 0.7 mL/min (λ = 210 nm).
tR: 17.05 min (2S,3R,4R,5S)-endo-4a and 23.24 min (2R,3S,4S,
Acknowledgment. Financial support of this work by the
ꢀ
Ministerio de Ciencia e Innovacion (MICINN, grant
CTQ2006-01121) and Consejerıa de Educacion de la Comu-
ꢀ
ꢀ
nidad de Madrid, Universidad Autonoma de Madrid
(UAM/CAM CCG08-UAM/PPQ-4454) is gratefully ac-
knowledged. R.R.-M. thanks the MICINN for a predoctoral
fellowship. We thank the Takasago company (Dr. H. Shimizu
and Dr. Wataru Kuriyama) for generous loans of Segphos and
DTBM-Segphos chiral ligands.
Supporting Information Available: Experimental proce-
dures, characterization data, copies of 1H and 13C NMR spectra
for all new compounds, and X-ray crystallographic data of
compound exo-4a in CIF format. This material is available free
of charge via the Internet at http://pubs.acs.org.
236 J. Org. Chem. Vol. 75, No. 1, 2010