Highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides catalyzed by copper(l)/TF-BiphamPhos complexes

Full text of DOI:10.1021/ja807669q

Published on Web 11/26/2008
Highly Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Ylides
Catalyzed by Copper(I)/TF-BiphamPhos Complexes
Chun-Jiang Wang,* Gang Liang, Zhi-Yong Xue, and Feng Gao
College of Chemistry and Molecular Sciences, Wuhan UniVersity, P.R. China 430072
Received September 28, 2008; E-mail: cjwang@whu.edu.cn
Table 1. Screening Studies of the Asymmetric CuI-Catalyzed
Five-membered nitrogen heterocycles, especially the highly
1,3-Dipolar Cycloaddition of Azomethine Ylied 3a with Dimethyl
substituted pyrrolidines are very important pharmaceuticals, natural
Maleate 2aa
alkaloids, and building blocks in organic synthesis.1 The catalytic
asymmetric 1,3-dipolar cycloaddition of azomethine ylides to
electron-deficient alkenes is one of the most powerful and diversity-
oriented synthesis (DOS)2 for the construction of this type of
structures.3 Since the first catalytic asymmetric 1,3-dipolar cy-
cloaddition reported by Zhang employing the AgOAc/xylyl-FAP
system,4 much attention has been paid to developing enantiose-
lective protocols for the reaction over the past decade. Asymmetric
1,3-dipolar cycloadditions have been reported using chiral metal
complexes such as AgI,4,5 ZnII,6 CuI/II,7 NiII,8 CaII,9 and organo-
catalysts10 to afford moderate to high enantio-/diastereoslectivities.
Most recently, Carretero and co-workers reported an efficient CuI/
Fesulphos catalyzed 1,3-dipolar cycloadditions of azomethine ylides
derived from glycinate, and excellent enantio-/diastereoslectivities
were obtained especially when N-phenyl or methylmaleimide was
used as a dipolarophile.7e For azomethine ylides derived from amino
esters other than glycinate,11 however, such high efficiency and
excellent enantio-/ diastereoslectivity have not been achieved so
far. Therefore, there is substantial room for improvement in terms
of efficiency and substrate scopes for 1,3-dipolar cycloadditions.
Recently, we reported the first resolution of the axially chiral
TF-BIPHAM, and the effectiveness of the diamine was demon-
strated by highly enantioselective hydrogenation.12 Extending the
application of TF-BIPHAM in asymmetric catalysis, herein we
report that CuI/TF-BiphamPhos exhibits high enantio-/diastereo-
selectivity and broad scope in the asymmetric 1,3-dipolar cycload-
dition of various azomethine ylides.
entry
ligand
Cu/L (mol%)
time (min)
T (°C)
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1e
1e
1e
3
3
3
3
3
3
0.5
0.1
10
720
720
1440
10
10
10
60
room temp
room temp
room temp
room temp
room temp
0
97
76
77
64
98
97
96
85
88
57
8
28
97
>99
>99
97
0
0
a All of the reaction was carried out with 0.33 mmol of 2a and 0.40
mmol of 3a in 2 mL of solvent. CuBF4 ) Cu(CH3CN)4BF4. b Isolated
yield. c Determined by HPLC analysis.
the temperature to 0 °C led to a completed reaction with 99% ee in
less than 10 min (Table 1, entry 6). High yield, selectivity, and fast
reaction rate remained even when the reaction was performed as low
as 0.1-0.5 mol % of catalyst loading (Table 1, entries 7 and 8).
Our initial investigation began with N-(4-chlorobenzylidene)-glycine
methyl ester 3a and dimethyl maleate 2a with 3 mol % CuI/ligand
complex, and the representative results are summarized in Table 1.
To our delight, the reaction was finished in less than 10 min at room
temperature in DCM with newly designed ligand 1a, and endo-4a was
achieved as the sole product with 97% yield and 88% ee (Table 1,
entry 1),13 which was different from the exo preference achieved by
CuII/BINAP7f or CuI/ferrocenyl-P,N-ligand7g complexes. Encouraged
by this result, we synthesized a series of P,N-ligands 1b-d and applied
them in the model reaction. The catalytic ability of N-ethyl substituted
ligand 1b was inferior to that of N-unsubstituted ligand 1a (Table 1,
entry 2). Ligands 1c or 1d containing more sterically hindered NMe2
or cyclohexyl groups on the phosphorus atom, displayed a similar trend
on the enantioselectivity and reactivity (Table 1, entries 3 and 4).
Considering the significant role that ortho-subsitituted binaphthyl
skeleton played in the tremendous asymmetric catalysis,14 we envi-
sioned that the enantioselectivity could be further improved through
the introduction of substituents into the corresponding 3,3′-position
of the TF-BIPHAM backbone. Thus, TF-BiphamPhos 1e was syn-
thesized through highly efficient bromination and then phosphorylation
protocol. Both perfect endo selectivity and enantioselectivity (97.3%)
were observed with 1e as the chiral ligand (Table 1, entry 5). Reducing
The 1,3-cycloaddition of various imino ester 3 and dimethyl
maleate 2a in the presence of ligand 1e was investigated under the
optimized experimental condition. As shown in Table 2, a variety
of azomethine ylides from aromatic aldehydes, which bear electron-
rich, electron-neutral, or electron-deficient groups on the phenyl
ring, reacted with dimethyl maleate to afford the corresponding
endo-4 exclusively in high yields (85-99%) and excellent ee’s
(>99%) within 10 min (Table 2, entries 1-11);13 98% ee was still
obtained for the heteroaromatic 3-pyridyl imino ester 3k (Table 2,
entry 12). Noticeably, the challenging and less reactive azomethine
ylide 3l from aliphatic aldehyde also works well in this transforma-
tion producing the endo-4l with remarkably high ee (97%), albeit
moderate yield (41%), in 24 h (Table 2, entry 13). The best literature
report for 3l is only 81% ee using AgI/P,N-ligand complex.4
The scope and generality of this catalytic system with regard to
iminoesters and dipolarophiles were also investigated. The present
catalytic system is remarkably tolerant and remains high in reactivity
for azomethine ylides derived from amino esters other than glycinate
(Table 3). Although the generated pyrrolidines containing a
9
17250 J. AM. CHEM. SOC. 2008, 130, 17250–17251
10.1021/ja807669q CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective CuI/1e Catalyzed 1,3-Dipolar
Cycloaddition of Various Azomethine Ylied 3 with Dimethyl
Maleate 2aa
reaction. Excellent reactivity, selectivity, and structural scope were
uniformly observed for various azomethine ylides, especially derived
from amino esters other than glycinate. In addition, the azomethine
ylide from aliphatic cyclohexanecarbaldehyde has been successfully
employed in the cycloaddition leading to the corresponding adduct in
remarkably high enantioselectivity. The mechanistic origin of the high
enantiocontrol and efficiency and future application of TF-BiphamPhos
in asymmetric catalysis are ongoing.
entry
R
4
time (min)
yield (%)b
ee (%)c
1
2
3
4
p-Cl-Ph (3a)
p-Me-Ph (3b)
o-Me-Ph (3c)
p-MeO-Ph (3d)
Ph (3e)
4a
4b
4c
4d
4e
4e
4f
4g
4h
4i
10
10
10
10
10
10
10
10
10
10
10
60
1440
97
97
98
98
93
90
98
97
96
98
98
85
41
>99
>99
>99
>99
>99
99
>99
>99
>99
>99
>99
98
Acknowledgment. This work was supported by National Natural
Science Foundation of China (Grant 20702039) and Wuhan University.
We thank Prof. Liu-Zhu Gong in USTC for his helpful discussion.
5
6e
7
Ph (3e)
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
o-Cl-Ph (3f)
p-F-Ph (3g)
p-CN-Ph (3h)
1-naphthyl (3i)
2-naphthyl (3j)
3-pyridyl(3k)
cyclohexyl (3l)
8
9
10
11
12
13
4j
4k
4l
References
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97
a All of the reaction was carried out with 0.33 mmol of 2a and 0.40
mmol of 3a in 2 mL of solvent. CuBF4 ) Cu(CH3CN)4BF4. b Isolated
yield. c Determined by HPLC analysis. e Run using 0.5 mol% catalyst.
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Table 3. Asymmetric 1,3-Dipolar Cycloaddition of Azomethine
Ylids 3 Derived from R-Amino Acids Catalyzed by CuI/ 1ea
entry
R1
R2
R3
R4
R5
4
yield (%)b ee (%)c
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(11) Exceptionally, 97% ee was achieved for the cycloaddition of the in situ
azomethine ylide derived from leucine and dimethyl maleate with 20 mol %
organocatalyst at 50 °C in 60 h, see ref 10c. The ee was 98% for the
cycloaddition of azomethine ylide derived from phenylalanine and tert-butyl
acrylate catalyzed by 5 mol % Ag(I)/phosphoramidite in 48 h, see ref 5j.
(12) Wang, C.-J.; Gao, F.; Liang, G. Org. Lett. 2008, 10, 4711.
(13) The absolute configurations of the known products 4a-l and 4p were
assigned by HPLC and optical rotation comparisons with the reported data
(see ref 4, 5f, 10c and Supporting Information), and those of other adducts
were deduced on the basis of these results.
1
2
3
4d
5
6
7
8
9
Ph
H
H
H
H
H
H
H
H
Ph
H
H
Me
Me
Me
Me
Ph
Me
Me
Me
Me
Me
Me
CO2Me 4m
CO2Me 4n
CO2Me 4o
CO2Me 4o
CO2Me 4p
CO2Me 4q
CO2Me 4r
CO2Me 4s
CO2Me 4t
95
72
92
83
87
90
89
80
75
90
94
>99
>99
>99
98
p-MeO-Ph
p-Cl-Ph
p-Cl-Ph
p-Br-Ph
Ph
>99e
99
Bn
Ph
Ph
Ph
i-Bu Me
98
Ef
H
H
H
Me
Me
Me
t-Bu
97
97g
97h
97i
10 Ph
11 Ph
H
H
4u
4v
a All of the reaction was carried out with 0.33 mmol of 2a and 0.40
mmol of 3a in 2 mL of solvent. CuBF4 ) Cu(CH3CN)4BF4. b Isolated
yield. c Determined by HPLC analysis. d Run using 1 mol% catalyst.
e Run in 12 h. f E ) 3-indolymethyl, 24 h. g Glycine ethyl ester benzophe-
none Schiff base was used. h Run at -40 °C, 1 h. i Run at -25 °C, 1 h.
quaternary stereocenter15 at the 2-position are of great importance
and synthetic potential, only limited successful protocols have been
reported in achieving moderate to high levels of enantioselectivity.11
Under the optimized reaction conditions, the azomethine ylides
derived from alanine, leucine, phenylalanine, and tryptophan,
successfully reacted with dimethyl maleate leading to perfect endo-
selectivities (>98 to <2) and excellent enantioselectivities (97 to
>99% ee) (Table 3, entries 1-8). Furthermore, glycine ethyl ester
benzophenone Schiff base works well affording the corresponding
endo-product 4t in good yield and excellent ee (Table 3, entry 9).
Methyl and tert-butyl acrylate (2b and 2c) also proved to be
excellent dipolarophiles in this transformation (Table 3, entries 10
and 11).16 This methodology presented herein is the best result for
asymmetric 1,3-dipolar cycloaddition of azomethine ylides, espe-
cially derived from amino esters other than glycinate in terms of
reactivity and enantioselectivity.
(14) Brunel, J. M. Chem. ReV. 2005, 105, 857; 2007, 107, PR1.
(15) Quaternary Stereocenters: Challenges and Solution for Organic Synthesis;
Christoffers, J., Baro A., Eds.; Wiley-VCH: Weinheim, Germany, 2005.
(16) Yields of 90%, 88%, and 86% ee were achieved when dimethyl fumarate,
N-phenyl maleimide and N-methyl maleimide were used as dipolarophiles,
and the corresponding endo/exo ratios were 86 to 14, >98 to <2, and >98
to <2, respectively (also see Supporting Information).
In conclusion, CuI/TF-BiphamPhos complex served as a novel and
highly efficient catalyst for the asymmetric 1,3-dipolar cycloaddition
JA807669Q
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J. AM. CHEM. SOC. VOL. 130, NO. 51, 2008 17251