Highly enantioselective copper(I)-fesulphos-catalyzed 1,3-dipolar cycloaddition of azomethine ylides

Article abstract of DOI:10.1021/ja0552186

The catalyst system formed by Cu(CH₃CN)₄ClO₄ and the planar chiral P,S-ligand Fesulphos behaves as a very efficient chiral Lewis acid in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This catalys

Full text of DOI:10.1021/ja0552186

Published on Web 11/03/2005
Highly Enantioselective Copper(I)-Fesulphos-Catalyzed 1,3-Dipolar
Cycloaddition of Azomethine Ylides
Silvia Cabrera, Ramo´n Go´mez Arraya´s, and Juan C. Carretero*
Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
Received August 1, 2005; E-mail: juancarlos.carretero@uam.es
Table 1. Cu(I)-Catalyzed Reaction of N-Benzylideneglycine
Methyl Ester 2a with N-Phenylmaleimide in the Presence of
Ligand (R)-1
The catalytic asymmetric 1,3-dipolar cycloaddition reaction is
conceptually an extremely powerful and efficient strategy for the
enantioselective construction of five-membered heterocycles.1 Of
particular interest is the reaction between azomethine ylides and
activated alkenes to form functionalized pyrrolidines,2 which are
key units in medicinal chemistry and highly valuable synthetic
building blocks.2b In addition, proline derivatives have found
outstanding applications as organic catalysts in many asymmetric
transformations.3 Despite its great synthetic potential, only a few
protocols for the catalytic enantioselective 1,3-dipolar reaction of
azomethine ylides have been developed to date.4 In particular,
the catalytic systems Zn(II)/t-BuBOX,4h Ag(I)/xylyl-FAP,4g and
Ag(I)/P,N-ligands4a,f afford high endo-selectivities and asymmetric
inductions in the intermolecular 1,3-dipolar cycloaddition of aryli-
dene imines of R-aminoesters with some typical electron-deficient
alkenes. On the other hand, Cu(II)/BINAP4e and, quite recently,
Cu(I)/P,N-ligands4b have been reported as efficient catatytic systems
for some exo-selective cycloadditions. However, compared to other
catalytic enantioselective 1,3-dipolar cycloadditions, especially those
involving nitrones,5 the reaction of azomethine ylides is in its
infancy and the development of novel catalysts showing high
reactivity and enantioselectivity with regard to a broad variety of
dipolarophiles and azomethine ylides remains a great challenge.6
We recently described a novel family of readily available planar
chiral P,S-ligands, Fesulphos ligands7 (1), whose copper(I) com-
plexes showed excellent performance in catalytic enantioselective
formal aza-Diels-Alder reactions of N-sulfonyl imines.8 Extending
the interest of these ligands in asymmetric catalysis, herein we report
that the combination of copper(I) salts and ligand 19 results in a
highly reactive catalyst system displaying exceptional enantiose-
lectivity and broad scope in the asymmetric 1,3-dipolar cycload-
dition of azomethine ylides.
x
time
endo:
exoa
yield
(%)b
ee
entry
CuX
(mol %)
(min)
(%)c
1
2
3
CuCl
10
10
10
0.5
3
1440
15
15
60
30
94:6
96:4
98:2
97:3
>98:<2
51
74
78
86
81
30
>99
>99
>99
>99
Cu(MeCN)4PF6
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
Cu(MeCN)4ClO4
4
5d
a Determined from the crude 1H NMR spectra. b Isolated yield of endo-
3a after column chromatography. c Determined by HPLC (Chiralpak AS
column). d Reaction performed at -10 °C.
Table 2. Structural Variations at the Aryl Imine and Maleimide
time
endo:
exoa
yield
(%)b
ee
(%)c
entry
Ar
R
(min)
product
1
2
3
2-Naph
(p-F)C6H4
(p-OMe)C6H4 Ph
o-Tol
Ph
Ph
60
60
60
30
15
97:3
3b
3c
3d
3e
4a
81
82
81
85
97
>99
>99
>99
>99
>99
>98:<2
>98:<2
>98:<2
>98:<2
4
Ph
Me
5d
Ph
The cycloaddition of N-benzylideneglycine methyl ester (2a) with
N-phenylmaleimide in the presence of catalytic amounts of Et3N
(18 mol %) and ligand (R)-1 (10 mol %) was selected as a model
reaction for the screening of several copper(I) salts10 (10 mol %).
For this transformation it was reported that the use of Cu(II)/chiral
diphosphine complexes resulted in the formation of adduct 3a with
high exo-selectivity and enantioselectivity, while endo-3a was
isolated as a minor product with very low enantiomeric excess.4e
In our case, adduct endo-3a was obtained in all cases with very
high endo-selectivity (Table 1). However, while CuCl displayed
low reactivity and very poor enantioselectivity (entry 1), more
electrophilic copper sources such as Cu(MeCN)4PF6 (entry 2) or
Cu(MeCN)4ClO4 (entry 3) led to endo-3a in good yields and with
complete enantiocontrol (>99% ee) within 15 min at room
temperature. The outstanding reactivity of the combination of
CuClO4-Fesulphos allowed a sharp reduction of the catalyst
loading. For instance, using 0.5 mol % of the catalyst system, the
reaction was complete in 1 h, preserving the high yield (86%) and
a Determined from crude 1H NMR spectra. b Isolated yield. c Determined
by HPLC (Chiralpak AS and Chiralcel OD columns). d Reaction performed
at room temperature.
the virtually complete enantioselectivity (entry 4). To the best of
our knowledge, these levels of reactivity and enantiocontrol are
the highest reported so far for catalytic asymmetric [3+2] cycload-
dition of azomethine ylides. Interestingly, upon lowering the
reaction temperature to -10 °C, both perfect endo-selectivity
(>98% endo) and enantioselectivity (>99% ee) were observed
within 30 min of reaction (3 mol % of catalyst; entry 5).
To evaluate the scope of this cycloaddition protocol, a repre-
sentative set of aryl imines of glycine methyl ester was surveyed
under the optimal experimental conditions (3 mol % of catalyst at
-10 °C in CH2Cl2). As shown in Table 2, the reactions occurred
with high yield (81-97%) and exceptional levels of endo-selectivity
and enantioselectivity (ee > 99%), regardless of the aryl substitution
at the imine and at the maleimide (R2 ) Ph or Me).
9
16394
J. AM. CHEM. SOC. 2005, 127, 16394-16395
10.1021/ja0552186 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Enantioselective Synthesis of Pyrrolidines Having a
Quaternary Center at C-2 or C-5
Interestingly, complete regioselectivity and high reactivity were also
observed with a variety of monoactivated alkenes, such as methyl
acrylate, â-nitrostyrene,13 and methacrolein, providing the corre-
sponding pyrrolidines in 95%, 94%, and 69% ee, respectively. The
reaction with methacrolein, which allows the creation of a
quaternary stereocenter at C-4 (product endo-11), deserves particular
attention.
In conclusion, the Cu(I)-Fesulphos catalyst system shows
excellent performance in enantioselective 1,3-dipolar cycloadditions
of azomethine ylides. High to very high levels of reactivity, endo/
exo selectivity, and enantioselectivity are achieved with a wide
variety of azomethine ylides and dipolarophiles with 0.5-3 mol
% of catalyst loading. Mechanistic studies, as well as the extension
of this protocol to other dipoles and dipolarophiles, are under current
investigation in our laboratory.
time
(h)
endo:
exoa
yield
(%)b
ee
entry
R1
R2
R3
product
(%)c
1
Ph
H
H
Ph
Me
Me 48 >98:<2
5a
5b
5c
5d
5e
50
78
92
78
80
80
92
93
94
>99
2
2-Naph
Ph
Me
H
H
1
1
1
1
>98:<2
>98:<2
>98:<2
>98:<2
3d
4
Ph
5
(p-Cl)C6H4 Me
H
a Determined by 1H NMR from the crude reaction mixture. b Isolated
yield. c Determined by HPLC (Chiralpak AS and Chiralcel OD columns).
d E ) CO2Et
Acknowledgment. Financial support by the MEC (project
BQU2003-0508) and Consejer´ıa de Educacio´n de la CAM (MAT/
0016/2004) is gratefully acknowledged. S.C. thanks the UAM for
a Predoctoral Fellowship. R.G.A. thanks the MEC for a Ramo´n y
Cajal Contract. We thank the reviewers for helpful suggestions.
Supporting Information Available: Experimental procedures,
characterization data of new compounds, and NMR spectra. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
(1) For recent reviews, see: (a) Gothelf, K. V. In Cycloaddition Reactions in
Organic Synthesis; Kobayashi, S., Jørgensen, K. A., Eds.; Wiley-VCH:
Weinheim, 2002; p 211. (b) Gothelf, K. V.; Jørgensen, K. A. In Synthetic
Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products; Padwa, A., Pearson, W., Eds.; Wiley & Sons: New
York, 2002; Chapter 12, p 817. (c) Kanemasa, S. Synlett 2002, 1371.
(2) Recent reviews: (a) Husinec, S.; Savic, V. Tetrahedron: Asymmetry 2005,
16, 2047. (b) Harwood, L. M.; Vickers, R. J. In Synthetic Applications of
1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural
Products; Padwa, A., Pearson, W., Eds.; Wiley & Sons: New York, 2002;
Chapter 3.
Figure 1. 1,3-Dipolar cycloaddition with other dipolarophiles. aIn THF.
bIn CH2Cl2. cReaction at room temperature. dReaction at -10 °C. eReaction
at -30 °C.
Next, we studied the effect of incorporating an R-substituent at
the azomethine on the reactivity and enantioselectivity of the
process. Although such dipoles are of great interest because they
generate pyrrolidines with a quaternary stereocenter at C-2, only
the AgOAc-QUINAP catalyst system had been studied with this
type of dipoles.4f As depicted in Table 3, the reaction of iminoesters
4a and 4b with N-phenylmaleimide at -10 °C using 3 mol % of
catalyst led to 5a and 5b with complete endo-selectivity and good
enantiocontrol (80-92% ee, entries 1 and 2).11 We also tested the
commercially available glycine ethyl ester benzophenone Schiff
base 4c.12 Pleasingly, its reaction with N-phenylmaleimide was
complete in 1 h under identical reaction conditions, affording endo-
5c in 92% yield and 93% ee (entry 3). Encouraged by this result,
we extended this study to azomethine ylide precursors having two
different groups at the ketimine moiety, a kind of azomethine ylides
not yet explored even in non-enantioselective 1,3-dipolar cycload-
ditions. Remarkably, the 1,3-dipoles derived from the ketimines
of acetophenone and p-chloroacetophenone (entries 4 and 5,
respectively) reacted mildly under the standard reaction conditions,
providing with virtually complete diastereoselectivity the pyrro-
lidines 5d and 5e, with a stereogenic quaternary center at C-5, in
94% ee and >99% ee, respectively.
(3) For a recent review, see: Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L.
Angew. Chem., Int. Ed. 2005, 44, 1758.
(4) (a) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055. (b) Gao, W.; Zhang,
X.; Raghunath, M. Org. Lett. 2005, 7, 4241. (c) Stohler, R.; Wahl, F.;
Pfaltz, A. Synthesis 2005, 1431. (d) Kno¨pfel, T. F.; Aschwanden, P.;
Ichikawa, T.; Watanabe, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2004,
43, 5971. (e) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.;
Minakata, S.; Komatsu, M. Org. Lett. 2003, 5, 5043. (f) Chen, C.; Li, X.;
Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174. (g) Longmire, J.
M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (h) Gothelf,
A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2002, 41, 4236.
(5) For some very recent reports, see: (a) Palomo, C.; Oiarbide, M.; Arceo,
E.; Garc´ıa, J. M.; Lo´pez, R.; Gonza´lez, A.; Linden, A. Angew. Chem.,
Int. Ed. 2005, 44, 6187. (b) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am.
Chem. Soc. 2005, 127, 5764. (c) Suga, H.; Nakajima, T.; Itoh, K.; Kakehi,
A. Org. Lett. 2005, 7, 1431. (d) Sibi, M. P.; Ma, Z.; Itoh, K.; Prabagaran,
N.; Jasperse, C. P. Org. Lett. 2005, 7, 2349.
(6) Na´jera, C.; Sansano, J. M. Angew. Chem., Int. Ed. 2005, 44, 6272.
(7) (a) Cabrera, S.; Go´mez Arraya´s, R.; Carretero, J. C. Angew. Chem., Int.
Ed. 2004, 43, 3944. (b) Garc´ıa Manchen˜o, O.; Priego, J.; Cabrera, S.;
Go´mez Arraya´s, R.; Llamas, T.; Carretero, J. C. J. Org. Chem. 2003, 68,
3679. (c) Priego, J.; Garc´ıa Manchen˜o, O.; Cabrera, S.; Go´mez Arraya´s,
R.; Llamas, T.; Carretero, J. C. Chem. Commun. 2002, 2512.
(8) Manchen˜o, O. G.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am. Chem. Soc.
2004, 126, 456.
(9) Gram quantities of ligand (R)-1 are readily obtained in three steps from
ferrocene (see ref 7b).
(10) Copper(II) salts led to oxidation of the Fesulphos ligand to the corre-
sponding phosphine oxide.
(11) The stereochemical assignment of the endo/exo adducts has been
established by comparison with bibliographic data for known compounds,
as well as NMR studies (for details see Supporting Information). In the
case of the trans disubstituted dipolarophiles, endo refers to the pyrrolidine
with cis stereochemistry at C4-C5.
(12) Vivanco, S.; Lecea, B.; Arrieta, A.; Prieto, P.; Morao, I.; Linden, A.;
Coss´ıo, F. P. J. Am. Chem. Soc. 2000, 122, 6078.
Finally, to explore more deeply the scope and generality of this
novel [2+3] cycloaddition protocol, other dipolarophiles of varied
nature were also examined with a 3 mol % of catalyst loading. As
shown in Figure 1, both cis and trans diactivated acyclic alkenes
(dimethyl maleate, dimethyl fumarate, and fumarodinitrile13) proved
to be excellent substrates for this reaction, providing high asym-
metric inductions (76 f 99% ee), although the endo/exo selectiv-
ity11 was poorer than in the case of the maleimide dipolarophiles.
(13) For exo-selective 1,3-dipolar cycloadditions of fumarodinitrile and trans-
â-nitrostyrene, see ref 4e and Ayerbe, M.; Arrieta, A.; Coss´ıo, F. P. J.
Org. Chem. 1998, 63, 1795.
JA0552186
9
J. AM. CHEM. SOC. VOL. 127, NO. 47, 2005 16395