Cu(I)-catalyzed highly exo-selective and enantioselective [3 + 2] cycloaddition of azomethine ylides with acrylates

Article abstract of DOI:10.1021/ol0516925

(Chemical Equation Presented) A novel Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with acrylates has been developed. Up to 98/2 exo/endo selectivity and up to 98% enantiomeric excess have been achieved.

Full text of DOI:10.1021/ol0516925

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4241-4244
Cu(I)-Catalyzed Highly Exo-selective and
Enantioselective [3 2] Cycloaddition
of Azomethine Ylides with Acrylates
+
Wenzhong Gao, Xumu Zhang,* and Malati Raghunath
104 Chemistry Building, Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
Received July 18, 2005
ABSTRACT
A novel Cu(I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with acrylates has been developed. Up to 98/2 exo/endo
selectivity and up to 98% enantiomeric excess have been achieved.
1,3-Dipolar cycloaddition is one of the most powerful
methods for the construction of highly substituted five-
membered heterocycles.1 More specifically, 1,3-dipolar cy-
cloaddition of azomethine ylides and alkenes afford substi-
tuted prolines with high stereoselectivities. It is well-known
that substituted prolines are widely used as organic catalysts
and also serve as important structural units in many biologi-
cally active molecules.2,3 Among various versions of this
reaction,4 the most practical approach is the combination of
N-metalated azomethine yildes and electron-deficient alkenes,
which has been extensively investigated in both racemic5,6
and chiral forms.7,8 To the best of our knowledge, the endo
adduct was either the major or the single product in most
cases, while highly exo- and enantioselective 1,3-dipolar
cycloaddition reaction of azomethine ylides has not yet been
well developed.9,10 Our group has explored Ag(I)-catalyzed
(5) (a) Kanemasa, S.; Tsuge, O. In AdVances in cycloaddition; Curran,
D. P., Ed.; JAI: London, 1993; Vol. 3, pp 99-159. (b) Grigg, R.; Sridharan,
V. In AdVances in cycloaddition; Curran, D. P., Ed.; JAI: London, 1993;
Vol. 3, pp 161-204.
(6) (a) Casas, J.; Grigg, R.; Najera, C.; Sansano, J. M. Eur. J. Org. Chem.
2001, 1971. (b) Tsuge, O.; Kanemasa, S.; Yoshioka, M. J. Org. Chem.
1988, 53, 1384.
(7) (a) Ruano, J. L. G.; Tito, A.; Peromingo. M. T. J. Org. Chem. 2003,
68, 10013. (b) Ruano, J. L. G.; Tito, A.; Peromingo. M. T. J. Org. Chem.
2002, 67, 981. (c) Merino, I.; Laxmi, Y. R. S.; Florez, J.; Barluenga, J.;
Ezquerra, J.; Pedregal, C. J. Org. Chem. 2002, 67, 648. (d) Cooper, D. M.;
Grigg, R.; Hargreaves, S.; Kennewell, P.; Redpath, J. Tetrahedron 1995,
51, 7791. (e) Gally, G.; Liebscher, J.; Paetzel, M. J. Org. Chem. 1995, 60,
5005. (f) Grigg, R. Tetrahedron: Asymmetry 1995, 6, 2475. (g) Grigg, R.;
Montgomery, J.; Somasunderam, A. Tetrahedron 1992, 48, 10431. (h)
Kanemasa, S.; Hayashi, T.; Tanaka, J.; Yamamoto, H.; Sakurai, T. J. Org.
Chem. 1991, 56, 4473.
(8) (a) Kno¨pfel, T. F.; Aschwanden, P.; Ichikawa, T.; Watanabe, T.;
Carreira, E. M. Angew. Chem., Int. Ed. 2004, 43, 5971. (b) Chen, C.; Li,
X.; Schreiber, S. L. J. Am. Chem. Soc. 2003, 125, 10174. (c) Longmire, J.
M.; Wang, B.; Zhang, X. J. Am. Chem. Soc. 2002, 124, 13400. (d) Gothelf,
A. S.; Gothelf, K. V.; Hazell, R. G.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2002, 41, 4236. (e) Allway, P.; Grigg, R. Tetrahedron Lett. 1991, 32,
5817.
(1) (a) Harwood: L. M.; Vickers, R. J. In The Chemistry of Heterocyclic
Compounds: Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry
Toward Heterocycles and Natural Products; Padwa, A., Pearson, W. H.,
Eds.; Wiley and Sons: New York, 2002. (b) 1,3-Dipolar Cycloaddtion
Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vols. 1 and 2.
(2) (a) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127,
3240. (b) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2003, 125, 10808.
(3) (a) Pearson, W. H. In Studies in Natural Products Chemistry; Atta-
Ur-Rahman, Ed.; Elsevier: New York, 1998; Vol. I, pp 323-358. (b) Obst,
U.; Betschmann, P.; Lerner, C.; Seiler, P.; Diederich, F. HelV. Chim. Acta
2000, 83, 855.
(4) For some reviews, see: (a) Kanemasa, S. Synlett 2002, 1371. (b)
Gothelf, K. V.; Jørgensen, K. A. Chem. ReV. 1998, 98, 863. (c) Pichon,
M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927. (d) Grigg, R. Chem.
Soc. ReV. 1987, 16, 89.
10.1021/ol0516925 CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/13/2005

highly endo- and enantioselective 1,3-dipolar cyclization
reactions.8c Herein, we present our investigation on the Cu-
(I)/P,N-ligand catalyzed [3 + 2] cycloaddition of N-metalated
azomethine ylides with acrylates (Scheme 1). The exo adduct
Table 1. Screening Reaction Conditions for the
Enantioselective Cu(I)-Catalyzed [3 + 2] Cycloaddition
Reaction of N-(4-Chlorobenzylidene)glycine Methyl Ester 1a
and tert-Butyl Acrylate 2aa
ee of
exoc
entry (5 mol %) (5.5 mol %) solvent (°C) exo endo (%)
yieldb (%)
Scheme 1. 1,3-Dipolar Cycloaddition of Azomethine Ylides
Cu(I)
ligand
T
and Alkenes
1d
2d
3d
4d
5
6
7
8
9
CuOAc (S,S,Sp)-FAP THF
CuOAc (S,S,Sp)-FAP MeOH
CuOAc (S,S,Sp)-FAP MeOH -20 46
rt 62
rt 58
15 -22
10 -75
9
-83
<2
70
76
86
89
77
72
89
91
CuOAc (S)-BINAP
CuOAc L1
CuOAc L2
CuOAc L3
CuOAc L4
CuOAc L5
CuOAc L6
CuClO4 L4
CuClO4 L4
MeOH
THF
THF
THF
THF
THF
THF
THF
THF
rt 54 <5
0
0
0
0
0
0
0
62
72
67
76
64
69
92
20
11
16
5
12
16
6
10
11
12e
-25 85
4
a 10 mol % of Et3N was applied as the base. For experimental details,
see the Supporting Information. b Isolated yields after column chromatog-
raphy. c Enantiomeric excesses were measured by chiral HPLC. d 3 mol %
of CuOAc, 3.3 mol % of ligand, and 10 mol % of (i-Pr)2NEt were applied.
e NMR spectroscopic analysis of the crude product indicated the ratio of
exo/endo was 96/4; also see entry 1, Table 2.
was obtained as the major product in all cases with high
enantioselectivity. In addition, our study is the first to use
copper(I) salt as the catalyst in the 1,3-dipolar cycloaddition
reaction of azomethine ylides.
Our initial study began with N-(4-chlorobenzylidene)-
glycine methyl ester (1a) as the 1,3-dipole and tert-butyl
acrylate (2a) as the dipolarophile, and the experimental
results are summarized in Table 1 and Figure 1. The first
%), afforded the desired product exo-3a in 62% yield and
22% ee along with 15% of endo-3a (entry 1, Table 1). The
stereochemistry was confirmed by the NOESY spectrum (see
the Supporting Information). Higher enantioselectivities could
be achieved when methanol was applied as the solvent;
however, the yields were still only moderate (entries 2 and
3, Table 1). Various chiral ligands other than FAP were next
employed in this reaction (Figure 1). We found that several
phosphino-oxazoline ligands L1-6,11 in combination with
CuOAc, could catalyze this [3 + 2] cycloaddition reaction,
providing good exo selectivity and high enantiomeric
excesses of exo adduct (entries 5-10, Table 1). Notably,
the highest exo selectivity (exo adduct 76%; endo adduct
5% based on isolated yield) and enantiomeric excess (89%
ee for exo adduct) were obtained when L4, which is derived
from (S)-tert-leucinol, was employed (entry 8, Table 1). The
yield and enantiomeric excess of the exo adduct could be
further improved by applying CuClO4 as the copper precursor
and conducting the reaction at a lower temperature (compare
entries 8 and 12, Table 1). Thus, the optimized reaction
conditions were established as 5 mol % of CuClO4, 5.5 mol
% of L4, and 10 mol % of Et3N in THF at -25 °C.12 In
contrast to the excellent enantiomeric excess of the exo
adduct, very low enantiomeric excesses (about 5%) of the
corresponding endo adduct were observed under the opti-
mized conditions.
Figure 1. Structure of ligands for 1,3-dipolar cycloaddition.
attempt, using CuOAc (3 mol %) and (S,S,Sp)-FAP (3.3 mol
(9) (a) Peddibhotla, S.; Tepe, J. J. J. Am. Chem. Soc. 2004, 126, 12776.
(b) Oderaotoshi, Y.; Cheng, W.; Fujitomi, S.; Kasano, Y.; Minakata, S.;
Komatsu, M. Org. Lett. 2003, 5, 5043. (c) Ayerbe, M.; Arrieta, A.; Cossio,
F. P. J. Org. Chem. 1998, 63, 1795. (d) Nyerges, M.; Rudas, M.; Toth, G.;
Herenyi, B.; Kadas, I.; Bitter, I.; Toke, L. Tetrahedron 1995, 51, 13321.
(e) Harwood: L. M.; Manage, A. C.; Robin, S.; Hopes, S. F. G.; Watkin,
D. J.; Walliams, C. E. Synlett 1993, 777.
To explore the scope of Cu(I)/L4 catalytic system, the
[3 + 2] cycloadditions of various imines 1a-i with several
dipolarophiles 2a-d were carried out under the optimized
(10) For asymmetric exo-selective [3 + 2] cycloaddition of nitrones,
see: Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2004, 126, 718.
(b) Sibi, M. P.; Ma, Z.; Itoh, K.; Prabagaran, N.; Jasperse, C. P. Org. Lett.
2005, 7, 2349.
(11) For Cu(I)-P,N-ligand catalyzed asymmetric mannich reactions of
glycine derivatives with immines, see: Bernardi, L.; Gothelf, A. S.; Hazell,
R. G.; Jørgensen, K. A. J. Org. Chem. 2003, 68, 2583 and references therein.
4242
Org. Lett., Vol. 7, No. 19, 2005

Table 2. Cu(I)-Catalyzed Enantioselective Cycloaddition of 1a-i with Various Dipolarophile Substrates 2a-da
entry
Ar in 1
R1,R2 in 2
base
adduct
exo/endob
yield of exoc (%)
ee of exod (%)
1
2e
3
4
5
6
7
8
9
p-ClPh (1a)
o-ClPh (1b)
m-ClPh (1c)
p-FPh (1d)
p-CNPh (1e)
Ph (1f)
p-MePh (1g)
p-OMePh (1h)
â-Naph (1i)
1a
H,t-Bu (2a)
2a
2a
2a
2a
2a
2a
2a
Et3N
Et3N
Et3N
Et3N
DBU
DBU
DBU
DBU
DBU
Et3N
Et3N
Et3N
3a
3b
3c
3d
3e
3f
3g
3h
3i
96/4
76/24
96/4
94/6
95/5
95/5
97/3
97/3
98/2
83/17
84/16
98/2
85
71
80
70
84
65
61
82
84
77
79
87
91
98
91
91
91
84
89
91
90
91
91
93
2a
10f
11g
12h
H,Me (2b)
H,Et (2c)
CO2Me,Me (2d)
3j
3k
3l
1a
1a
a All of the reactions were carried out under the optimized reaction conditions: 5 mol % of CuClO4, 5.5 mol % of L4, and 10 mol % of base in THF at
-25 °C for 20 h. b The ratio of exo/endo was determined by NMR spectroscopic analysis of the crude product; exo and endo diastereoisomers were readily
separated by flash column chromatography. c Isolated yields after column chromatography. d Enantiomeric excesses were measured by chiral HPLC. e 20%
of endo-3b (42% ee) was isolated. f 13% of endo-3j (67% ee) was isolated. g 16% of endo-3k (58% ee) was isolated. h Reaction was carried at 0 °C, and 1
mol % of CuOAc and 1.1 mol % of L4 were employed.
reaction conditions, and the results are summarized in Table
2. Very high exo selectivities and excellent enantiomeric
excesses were observed in all of the reactions. The cycload-
dition of 1b with tert-butyl acrylate 2a gave the best
enantiomeric excess (98%) of the exo adduct 3b in 71%
isolated yield, though a relatively higher percentage of the
endo adduct was observed (exo/endo ) 76/24, entry 2, Table
2). For imines bearing an electron-withdrawing substituent
on the phenyl, the reactions proceeded smoothly in the
presence of 10 mol % of triethylamine as the base (entries
1-4, Table 2), while for substrates having no substituent or
an electron-donating substituent, such as a methyl or methoxy
group, on the phenyl unit, the reactions were sluggish and
could not reach complete conversion under the same reaction
conditions (even with a prolonged reaction time). However,
we were pleased to find that the reactions of these substrates
could take place more efficiently when a stronger base, such
as 8-diazabicyclo[5.4.0]undec-7-ene (DBU), was used instead
of triethylamine, leading to the desired exo adducts in high
yields and excellent enantioselectivities (entries 5-9, Table
2). The reactions of 1a with other acrylates, such as methyl
acryate (2b) and ethyl acrylate (2c), also proceeded smoothly
at -25 °C with the same catalytic system. The corresponding
exo adducts 3j and 3k were obtained with high ee’s (91%
for both) and good yields (entries 10 and 11, Table 2).
Cu(I)/L4-catalyzed 1,3-dipolar cycloaddition between
imine 1a and dimethyl maleate 2d afforded exo adduct 3l in
excellent diastereo- and enantioselectivities (87% yield, exo/
endo ) 98/2, 93% ee), furnishing four new stereogenic
centers in one cycloaddition process (entry 12, Table 2).
Notably, this transformation reached completion within a few
hours even with catalyst loading as low as 1 mol %. The
absolute configuration of the exo adduct 3l was determined
by X-ray analysis of its corresponding tosylate derivative 4
(eq 1), and it was assigned as 2S,3S,4R,5R (see the Sup-
porting Information).13
On the basis of our results, we propose the following
reaction pathway (Scheme 2). The first step is the formation
of complex A by coordination of imine 1 to the copper(I)
catalyst. The reactive azomethine ylide-copper(I) complex
B is generated through the abstraction of a proton by the
amine base. Complex B reacts with different dipolarphiles
to give intermediate C, which releases the desired cycload-
dition product and regenerates both the active catalyst and
the base. The intermediate B is an 18-electron complex and
has a tetrahedral arrangement of the ligands around the
copper metal atom. The steric repulsion between the electron-
(12) General Procedure. The catalyst was prepared by stirring Cu(CH3-
CN)4ClO4 (8.2 mg, 0.025 mmol, 5 mol %) and ligand L4 (15.1 mg, 0.0275
mmol, 5.5 mol %) in THF (2 mL) for 1 h at room temperature. The mixture
was then cooled to -25 °C, imine substrate 1 (0.50 mmol), dipolarophile
2 (0.75 mmol, 1.5 equiv), and base (0.05 mmol, 10 mol %) were added
subsequently, and the resulting mixture was stirred at -25 °C for 20 h.
When the reaction was complete as monitored by TLC, the mixture was
passed through a short column of silica gel and the diastereometric ratio
(exo/endo) was determined by the NMR spectroscopic analysis of the crude
product. The pure adducts were then purified by column chromatography
on silica gel (hexanes/ethyl acetate/1% triethylamine).
(13) CCDC-268934 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge via www.ccdc.ca-
m.ac.uk/conts/ retrieving.html (or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ, UK.; fax: (+44)1223-336-
033; or depost@ccdc.cam.ac.uk).
Org. Lett., Vol. 7, No. 19, 2005
4243

to the good exo selectivity that is observed for this Cu(I)-
catalyzed transformation.
Scheme 2. Mechanism of Cu(I)-Catalyzed 1,3-Dipolar
Cycloaddition
In conclusion, we have developed a novel Cu(I)/P,N-ligand
catalyzed asymmetric 1,3-dipolar cycloaddition of azome-
thine ylides with acrylates, providing exo products of
polysubstituted proline derivatives in up to 98% enantiomeric
excess. To our knowledge, these results are the best to date
for metal-catalyzed 1,3-dipolar cycloaddition of N-metalated
azomethine ylides in terms of both exo selectivities and
enantioselectivities. Further investigation of the reaction
scope and detailed mechanism study are underway.
Acknowledgment. This work was supported by National
Institutes of Health grants, and we thank Dr. H. Yennawar
for solving the crystal structure.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
withdrawing group of dipolarophiles and the substituent of
the ligand inhibits the endo approach. This may contribute
OL0516925
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Org. Lett., Vol. 7, No. 19, 2005