Catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with α,β-unsaturated ketones

Article abstract of DOI:10.1021/ol802664m

(Chemical Equation Presented) αβ-Unsaturated ketones are no longer the missing dipolarophiles in catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. In the presence of Cu¹-Fesulphos complexes as catalysts (5 mol %), these subst

Full text of DOI:10.1021/ol802664m

ORGANIC
LETTERS
2009
Vol. 11, No. 2
393-396
Catalytic Asymmetric 1,3-Dipolar
Cycloaddition of Azomethine Ylides with
r,ꢀ-Unsaturated Ketones
Jorge Herna´ndez-Toribio, Ramo´n Go´mez Arraya´s, Bele´n Mart´ın-Matute,†
and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de
Madrid, Cantoblanco, 28049 Madrid, Spain
juancarlos.carretero@uam.es
Received November 18, 2008
ABSTRACT
r,ꢀ-Unsaturated ketones are no longer the missing dipolarophiles in catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. In
the presence of CuI-Fesulphos complexes as catalysts (5 mol %), these substrates combine high reactivity, wide substitution tolerance,
moderate to good endo/exo selectivities, and high enantiocontrol. The endo/exo-diastereoselectivity of the reaction is strongly dependent on
the cis or trans nature of the enone moiety.
Owing to the wide-range significance of the pyrrolidine ring
structural unit in pharmacy, organocatalysis, and as a
synthetic building block, the catalytic asymmetric 1,3-dipolar
cycloaddition of azomethine ylides to alkenes has been a
subject of intense research1-7 since the first report in 2002.2,3
As a result, a number of efficient protocols relying on the
combination of Lewis acidic metal salts, especially copper4
and silver salts,5,6 with appropriate chiral ligands has been
developed. Since 2007, several organocatalytic asymmetric
versions of this reaction have also appeared.7 With regard
to dipolarophile scope, unsaturated acid derivatives such as
acrylates, maleates, fumarates, maleimides, and fumaronitrile,
as well as nitroalkenes and alkenyl sulfones, have been
successfully employed in this reaction. However, despite this
impressive progress, a review of the literature reveals that
R,ꢀ-unsaturated ketones, which hold great interest because
of their synthetic potential,8 have not yet been incorporated
to the arsenal of suitable dipolarophiles for the catalytic
asymmetric 1,3-dipolar cycloaddition of azomethine ylides.
To the best of our knowledge, the moderately enantioselec-
tive (70% ee) and noncatalytic reaction of 2-naphtylidene-
alanine methyl ester with methyl vinyl ketone in the presence
of a stoichiometric amount of a diphosphine-AgI complex
constitutes the only isolated example on the use of a chiral
Lewis acid complex.3
† Current address: Department of Organic Chemistry, Arrhenius Labora-
tory, Stockholm University, 106 91 Stockholm, Sweden.
(1) Reviews on catalytic asymmetric 1,3-dipolar cycloaddition: (a)
Pellissier, H Tetrahedron 2007, 63, 3235. (b) Stanley, L. M.; Sibi, M. P.
Chem. ReV. 2008, 108, 2887. Reviews on cycloaddition with azomethine
ylides: (c) Na´jera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44,
6272. (d) Husinec, S.; Savic, V Tetrahedron: Asymmetry 2005, 16, 2047
(2) (a) Longmire, J. M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002,
124, 13400. (b) Gothelf, A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen,
.
Herein, we wish to fill this literature gap by reporting a
highly enantioselective catalytic azomethine ylide dipolar
cycloaddition procedure with R,ꢀ-unsaturated ketones.
K. A. Angew. Chem., Int. Ed. 2002, 41, 4236
(3) For the early development using a stoichiometric amount of chiral
catalyst, see: Grigg, R Tetrahedron: Asymmetry 1995, 6, 2475
.
.
10.1021/ol802664m CCC: $40.75
Published on Web 12/18/2008
2009 American Chemical Society

Table 1. Optimization Experiments in the Cycloaddition of 2 with Cyclopentenone Catalyzed by Fesulphos Complexes
entry
[M]
AgOAc
ligand
x
base
endo/exoa
yieldb (%)
eec (%)
1
1a
1a
1a
1a
1a
1a
1a
1a
1b
10
10
10
5
3
5
5
5
5
Et3N
Et3N
Et3N
Et3N
Et3N
DIPEA
Et3N
Et3N
Et3N
80:20
87:13
90:10
90:10
88:12
88:12
85:15
90:10
70:30
72
69
71
70
52e
66
62
58e
60
63
78
93
94
94
89
91
95
90
2d
3
AgOAc
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
4
5
6
7
8d
9
a Determined by NMR from the crude reaction mixture. b Of pure endo-3 after chromatographic purification. c ee of endo-3 determined by chiral HPLC
(Chiralcel IB). d Reaction performed at 0 °C. e The reaction did not reach complete conversion.
On the basis of the good performance of copper(I) and
silver(I) complexes of Fesulphos ligands9 (1) as catalysts in
the azomethine imine cycloaddition with several acid
derivatives4b,f (maleimides and R,ꢀ-unsaturated esters) and
bis-sulfonylethylenes,4i an extension of this catalyst system
to R,ꢀ-unsaturated ketones was particularly attractive. There-
fore, the reaction of N-benzylideneglycine methyl ester (2)
with 2-cyclopentenone catalyzed by AgI- and
CuI-Fesulphos complexes was initially investigated. Opti-
mization experiments listed in Table 1 led us to identify the
superiority of cationic copper(I) complexes10 of 1a (entries
3-8) over the corresponding silver catalyst (entries 1 and
mol % of metal/ligand catalyst to reach complete conversion
at room temperature (compare entries 4 and 5). Under such
conditions, the bicyclic pyrrolidine 3 was obtained with high
endo-selectivity (endo/exo ) 90:10), enantioselectivity (94%
ee endo-3), and chemical yield (70% in endo-3 after standard
silica gel chromatographic purification). Lowering the reac-
tion temperature (0 °C) had a detrimental effect on the
reactivity (58% isolated yield) without a significant impact
on the stereocontrol (endo/exo ) 90:10, 95% ee, entry 8).
The bulkier Fesulphos ligand 1b (R ) 1-Naph) also proved
to be suitable, yet slightly less effective, providing endo-3
in 60% yield and 90% ee (entry 9).
To evaluate the scope of this cycloaddition protocol, a
representative set of aryl imines of glycine methyl ester was
surveyed under the optimized conditions (5 mol % of chiral
catalyst, 18 mol % of Et3N, CH2Cl2 at rt, Table 2). The
corresponding endo-adduct was isolated in good yields
(61-70%) and high levels of endo-selectivity (90:10-98:
2) and enantiocontrol (91-95% ee), except for the electron-
11
2), as well as Et3N and CH2Cl2 as the optimal base and
solvent, respectively. The reaction was found to require 5
(4) For recent examples on Cu catalysts, see: (a) Oderaotoshi, Y.; Cheng,
W.; Fujitomi, S.; Kasano, Y.; Minakata, S.; Komatsu, M. Org. Lett. 2003,
5, 5043. (b) Cabrera, S.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am. Chem.
Soc. 2005, 127, 16394. (c) Yan, X.-X.; Peng, Q.; Zhang, Y.; Zhang, K.;
Hong, W.; Hou, X.-L.; Wu, Y.-D. Angew. Chem., Int. Ed. 2006, 45, 1979.
(d) Llamas, T.; Go´mez Arraya´s, R.; Carretero, J. C. Org. Lett. 2006, 8,
1795. (e) Mart´ın-Matute, B.; Pereira, S. I.; Pen˜a-Cabrera, E.; Adrio, J.; S.
Silva, A. M.; Carretero, J. C AdV. Synth. Catal. 2007, 349, 1714. (f) Cabrera,
S.; Go´mez Arraya´s, R.; Mart´ın-Matute, B.; Cossío, F. P.; Carretero, J. C.
Tetrahedron 2007, 63, 6587. (g) Shi, M.; Shi, J.-W. Tetrahedron: Asymmetry
2007, 18, 645. (h) Fukuzawa, S.-i.; Oki, H. Org. Lett. 2008, 10, 1747. (i)
Lo´pez-Pe´rez, A.; Adrio, J.; Carretero, J. C. J. Am. Chem. Soc. 2008, 130,
10084.
(8) For the use of R,ꢀ-unsaturated ketones in diastereoselective azome-
thine ylide 1,3-dipolar cycloadditions, see: (a) Garc´ıa Ruano, J. L.; Tito,
A.; Peromingo, M. T J. Org. Chem. 2003, 68, 10013. (b) Bashiardes, G.;
Cano, C.; Mauze, B. Synlett 2005, 587. (c) Agbodjan, A. A.; Cooley, B. E.;
Copley, R. C. B.; Corfield, J. A.; Flanagan, R. C.; Glover, B. N.; Guidetti,
R.; Haigh, D.; Howes, P. D.; Jackson, M. M.; Matsuoka, R. T.; Medhurst,
K. J.; Millar, A.; Sharp, M. J.; Slater, M. J.; Toczko, J. F.; Xie, S. J. Org.
Chem. 2008, 73, 3094.
(5) AgI-catalysts: (a) Na´jera, C.; de Gracia Retamosa, M.; Sansano, J. M.
Org. Lett. 2007, 9, 4025. (b) Zeng, W.; Zhou, Y.-G. Tetrahedron Lett. 2007,
48, 4619. (c) Zeng, W.; Chen, G.-Y.; Zhou, Y.-G.; Li, Y.-X. J. Am. Chem.
Soc. 2007, 129, 750. (d) Na´jera, C.; de Gracia Retamosa, M.; Sansano,
(9) For recent applications of Fesulphos ligands, see: (a) Garc´ıa
Manchen˜o, O.; Go´mez Arraya´s, R.; Carretero, J. C J. Am. Chem. Soc. 2004,
126, 456. (b) Cabrera, S.; Go´mez Arraya´s, R.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2004, 43, 3944. (c) Cabrera, S.; Go´mez Arraya´s, R.; Alonso, I.;
Carretero, J. C. J. Am. Chem. Soc. 2005, 127, 17938. (e) Salvador Gonza´lez,
A.; Go´mez Arraya´s, R.; Carretero, J. C. Org. Lett. 2006, 8, 2977. (d)
Salvador Gonza´lez, A.; Go´mez Arraya´s, R.; Rodr´ıguez Rivero, M.;
Carretero, J. C. Org. Lett. 2008, 10, 4335, and ref 4b, 4e, 4f, 4i.
(10) Other cationic CuI complexes provided similar results. For instance,
the model reaction of 2 with 2-cyclopentenone in the presence of
Cu(CH3CN)4PF6 (5 mol %), 1a (5 mol %), and Et3N (18 mol %) afforded
endo-3 in 52% isolated yield (endo/exo ) 87:13) and 93% ee.
(11) The model reaction catalyzed by Cu(CH3CN)4PF6/1a (5 mol %) in
THF led to a much lower conversion (30% isolated yield of endo-3). Very
low conversion was observed in acetonitrile.
J. M. Angew. Chem., Int. Ed. 2008, 47, 6055.
II
¨
(6) Zn -catalysts: (a) Dogan, O.; Koyuncu, H.; Garner, P.; Bulut, A.;
Youngs, W. J.; Panzner, M. Org. Lett. 2006, 8, 4687. For NiII-catalysts:
(b) Shi, J.-W.; Zhao, M.-X.; Lei, Z.-Y.; Shi, M. J. Org. Chem. 2008, 73,
305. For CaII-catalysts: (c) Saito, S.; Tsubogo, T.; Kobayashi, S. J. Am.
Chem. Soc. 2007, 129, 5364. (d) Tsubogo, T.; Saito, S.; Seki, K.; Yamashita,
Y.; Kobayashi, S. J. Am. Chem. Soc. 2008, 130, 13321.
(7) (a) Vicario, J. L.; Reboredo, S.; Bad´ıa, D.; Carrillo, L. Angew. Chem.,
Int. Ed. 2007, 46, 5168. (b) Ibrahem, I.; Rios, R.; Vesely, J.; Co´rdova, A.
Tetrahedron Lett. 2007, 48, 6252. (c) Chen, X.-H.; Zhang, W.-Q.; Gong,
L.-Z. J. Am. Chem. Soc. 2008, 130, 5652. (d) Guo, C.; Xue, M.-X.; Zhu,
M.-K.; Gong, L.-Z. Angew. Chem., Int. Ed. 2008, 47, 3414. (e) Xue, M.-
X.; Zhang, X.-M.; Gong, L.-Z. Synlett 2008, 691.
394
Org. Lett., Vol. 11, No. 2, 2009

the reaction with cyclopentenone, the cycloadditions of the
trans-substituted enones15 took place with moderate to high
exo-selectivity (endo/exo from 30:70 to 2:98, entries 1-26),
while maintaining an excellent enantiocontrol (81-96% ee
for the major exo isomer). The exo+endo adduct mixtures
were readily separated by silica gel chromatography (45-85%
isolated yield for the exo adduct). In contrast, the simplest
enone, methyl vinyl ketone (entry 27), provided an opposite
endoselectivity (endo/exo ) 80:20) and low asymmetric
induction (35% ee for the major endo-38),16 showing that
the presence of a substitutent at ꢀ-position is critical for
achieving both high exo-selectivity and enantioselectivity.
The absolute and relative configuration of the exo adducts
was unequivocally assigned by single X-ray diffraction
analysis of the 4-chlorophenyl-substituted adduct exo-20
(Figure 1).12,17
Table 2. Scope of the Reaction with Regard to the R-Iminoester
yieldb eec
entry
R (imine)
Ph
imine product endo/exoa
(%)
(%)
1
2
3
4
5
6
7
2
4
5
6
7
8
9
3
8
9
10
11
NRe
NRe
90:10d
98:2d
98:2d
98:2d
75:25
70
61
67
68
52
94
91
94
95
85
2-Naph
4-ClC6H4
4-BrC6H4
4-MeOC6H4
Cy
PhCH)CH
This procedure displays wide structural scope and high
enantiocontrol, especially in the case of acyclic enones,
tolerating the presence of aryl, alkenyl, and alkyl substituents
at both the carbonylic carbon (R2) and the ꢀ-position (R3).
This reaction is also compatible with the presence of an
additional functional group at the ꢀ-position, such as silyl
ether (entry 24), thioether (entry 22), or carbonyl group
(entries 25 and 26). The dicarbonyl dipolarophiles are so
reactive that the reactions were completed in 15 min at -78
°C. In some reactions, the sterically more demanding
FesulphosNaph ligand 1b provided appreciably higher dias-
tereoselectivity and asymmetric induction than that obtained
from the parent ligand 1a (entries 5, 13, 15, 23, and 25;
values in parentheses), while in other cases the performance
of 1a and 1b proved to be very similar (entries 10 and 17).
a Determined by NMR from the crude reaction mixture. b Of pure adduct
endo after chromatographic purification. c ee of endo-adduct; determined
by chiral HPLC (Chiralcel IB and IA). d A minor amount (5-10%) of the
ring-opened Michael addition product was also detected in the crude reaction
mixture. e No reaction.
rich imine 7, derived from p-methoxybenzaldehyde, which
showed a lower reactivity and stereochemical control (52%
yield, 85% ee, entry 5). The relative and absolute stereo-
chemistry of the major cycloadduct was established by single
X-ray diffraction analysis of the bromine-containing adduct
endo-10 (Figure 1, left).12,13
The high enantioselectivity observed in the reaction with
both cyclic (cyclopentenones) and acyclic enones in favor
of the pyrrolidine with (2S,5R) configuration can be explained
assumingtheparticipationofthepresumedFesulphos-Cu-azomethine
complex intermediate I (Figure 2). According to our previous
computational studies,4f the tetracoordinated complex I,
showing a highly distorted tetrahedral structure around the
copper atom, was found to be the most stable geometry in
the coordination of the metal atom with the P,S-ligand
Fesulphos and the azomethine species. In this complex, the
high steric congestion imposed by the tert-butyl group at
the sulfur atom in close proximity to the copper center
hinders the approach of the dipolarophile from the Si CdN
face of the azomethine. The reaction from the more acces-
sible Re CdN face of the dipole accounts for the high
selectivity attained in the formation of the pyrrolidines with
(2S,5R) configuration. Although we do not yet have a
conclusive explanation for the opposite endo/exo selectivity
showed by cyclopentenone and acyclic trans-configured
Figure 1. Crystal X-ray structures of endo-10 (left) and exo-20
(right).
Unfortunately, iminoesters derived from an aliphatic
aldehyde (8, R ) Cy) or an R,ꢀ-unsaturated aldehyde (9, R
) cinnamyl) proved to be unreactive under identical condi-
tions, resulting in the recovery of the starting material (entries
6 and 7). Similarly, a very low conversion was observed in
the reaction with a six-membered cyclic enone such as
2-cyclohexenone.14
Acyclic enones proved to be excellent dipolarophiles under
the optimized reaction conditions, leading to complete
conversions at room or lower temperatures (Table 3). Unlike
(15) The reaction of cis-configured chalcone with 2 under optimized
conditions led to much lower reactivity (50% conversion after 24 h at rt)
and poor diastereocontrol (exo/endo ) 60:40).
(12) See the Supporting Information for details
.
(13) CCDC 704924 [unit cell parameters: a 8.8746(2) Å, b 8.9732(2)
Å, c 17.6982(5) Å, space group P212121] contains the supplementary
crystallographic data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre (CCDC) via www.ccd-
(16) Racemic endo-38 and exo-38 were already reported: Tsuge, O.;
Kanemasa, S.; Yoshioka, M. J. Org. Chem. 1988, 53, 1384.
(17) CCDC 704925 [unit cell parameters: a 22.8459(15) Å, b 5.6625(3)
Å, c 16.0875(8) Å, ꢀ 98.411(3)°, space group C2] contains the supplemen-
tary crystallographic data for this paper. These data can be obtained free of
charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.
c.cam.ac.uk/data_request/cif
(14) <10% conversion was observed in the reaction of 2 with 2-cyclo-
hexenone under the optimized conditions after 48 h at rt.
.
Org. Lett., Vol. 11, No. 2, 2009
395

Table 3. Acyclic R,ꢀ-Unsaturated Ketones as Dipolarophiles in the 1,3-Dipolar Cycloaddition of Azomethine Ylides
entry
R1
R2
R3
conditions
product
endo/exoa, b
yieldc, b (%) eed, b (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
Ph
Ph
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
-10 °C, 12 h
rt, 5 h
rt, 5 h
rt, 5 h
rt, 5 h
rt, 5 h
rt, 5 h
-10 °C, 6 h
rt, 5 h
rt, 5 h
rt, 5 h
rt, 5 h
-40 °C, 3 h
rt, 5 h
rt, 5 h
rt, 5 h
rt, 5 h
rt, 5 h
-10 °C, 6 h
rt, 5 h
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
20:80
18:82
2:98
12:88
30:70 (15:85)
2:98
20:80
10:90
4:96
32:68 (30:70)
3:97
25:75
40:60 (30:70)
18:82
30:70 (3:97)
15:85
12:88 (10:90)
12:88
15:85
15:85
5:95
45
60
69
65
52 (67)
68
55
52
75
49 (55)
76
57
55 (64)
70
58 (65)
62
75 (73)
70
74
69
75
85
87
96
95
82 (86)
96
94
91
95
89 (89)
98
87
93 (96)
94
85 (94)
93
81 (82)
93
89
95
92
4-BrC6H4
4-OMeC6H4
2-Naph
Ph
(E)-PhCH)CH Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClC6H4
4-OMeC6H4
2-Naph
CF3
(E)-PhCH)CH Ph
Ph
Ph
Ph
Ph
Ph
4-FC6H4
4-OMeC6H4
2-Naph
2-Furyl
2-Thienyl
(E)-PhCH)CH
2-MeC6H4
4-BrC6H4
MeS-(CH2)2-
n-Bu
Ph
4-NO2C6H4
2-BrC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
Me
rt, 5 h
-20 °C, 12 h
-20 °C, 12 h
25:75
23:77 (20:80)
12:88
25:75 (10:90)
20:80
80:20
60
63 (62)
69
87
69 (81)
84
TBDMSO-(CH2)3- -20 °C, 12 h
MeCO
PhCO
H
-78 °C, 15 min
-78 °C, 15 min
-10 °C, 12 h
79 (85)
74 (82)
98
Ph
Me
75e
51f
35f
a Determined by NMR from the crude reaction mixture. b In parenthesis, values obtained using ligand 1b. c Of pure isolated exo adduct. d For the
exo-cycloadduct; determined by chiral HPLC (Chiralcel IB and IA). e Yield of the endo/exo mixture. f For the major isomer endo-38.
In summary, R,ꢀ-unsaturated ketones were demonstrated
to be efficient dipolarophiles in catalytic asymmetric 1,3-
dipolar cycloaddition of azomethine ylides. The efficiency
of this protocol strongly relies on the use of CuI-Fesulphos
catalysts, leading to highly functionalized acyl-substituted
pyrrolidine derivatives in good yields, moderate to high endo/
exo-selectivities and high enantiocontrol (81-96% ee).
Acknowledgment. This work was supported by the
Ministerio de Ciencia e Innovacio´n (MICINN, CTQ2006-
01121) and UAM-Consejer´ıa de Educacio´n de la Comunidad
de Madrid (project CCG07-UAM/PPQ-1799). J.H. and B.M.-
M. thank the MICINN for a predoctoral fellowship and a
Juan de la Cierva contract, respectively.
Figure 2. Stereochemical model.
enones with this Cu-Fesulphos catalyst system, their ster-
eochemical behavior parallels nicely to that previously found
with other cyclic and trans-acyclic dipolarophiles such as
maleimides4a,e (endo-selectivity), fumaronitrile4b,f (exo-
selectivity), trans-R,ꢀ-unsaturated nitro compounds4b,f (exo-
selectivity), or trans-bissulfonyl ethylenes4i (exo-selectivity).
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds; copies
of NMR spectra and HPLC data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL802664M
396
Org. Lett., Vol. 11, No. 2, 2009