Highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides catalyzed by AgOAc/TF-BiphamPhos

Article abstract of DOI:10.1039/b902556a

A novel and highly efficient AgOAc/TF-BiphamPhos catalytic system shows excellent reactivity, diastereo-/enantioselectivity and structural scope in asymmetric 1,3-dipolar cycloaddition of azomethine ylides, especially derived from various α-substituted α-amino acids, with N-substituted maleimides and other electron-deficient alkenes.

Full text of DOI:10.1039/b902556a

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Highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides
catalyzed by AgOAc/TF-BiphamPhosw
Chun-Jiang Wang,* Zhi-Yong Xue, Gang Liang and Zhou Lu
Received (in College Park, MD, USA) 6th February 2009, Accepted 23rd March 2009
First published as an Advance Article on the web 24th April 2009
DOI: 10.1039/b902556a
A novel and highly efficient AgOAc/TF-BiphamPhos catalytic
system shows excellent reactivity, diastereo-/enantioselectivity
and structural scope in asymmetric 1,3-dipolar cycloaddition of
azomethine ylides, especially derived from various a-substituted
a-amino acids, with N-substituted maleimides and other
electron-deficient alkenes.
chiral metal complexes for the cycloaddition of less sterically
hindered azomethine ylides.5–10,13 In this communication,
we describe the development of a AgOAc/TF-BiphamPhos
system for the highly enantio/diastereoselective 1,3-dipolar
cycloaddition of various azomethine ylides, especially
derived from a-substituted a-amino acids, with N-substituted
maleimides and other dipolarophiles.
The catalytic asymmetric 1,3-dipolar cycloaddition1 of
azomethine ylides to electron-deficient alkenes has become
one of the most powerful and diversity-oriented synthesis
(DOS)2 for the construction of highly substituted pyrrolidines
with up to four stereogenic centers. It is well known
that substituted pyrrolidines are prevalent in many natural
alkaloids, compounds of pharmaceutical significance, organo-
catalysts, and building blocks in organic synthesis.3 Since the
pioneering work of Grigg4 employing stoichiometric amounts
of chiral metal complex, and the first catalytic asymmetric
version reported by Zhang5 using the AgI/xylyl-FAP system,
much attention has been paid to developing enantioselective
catalytic protocols for the reaction over the past decade.
Asymmetric 1,3-dipolar cycloadditions have been reported
Initially, we selected the asymmetric 1,3-dipolar cycloaddition
of N-phenyl maleimide with imino ester 3c as the model
reaction in the presence of chiral TF-BiphamPhos and various
metal salts to establish the optimal reaction conditions and
results are given in Table 1. Except for the low activity of
Ni(ClO4)2ꢀ6H2O and Zn(OTf)2 as metal precursors (Table 1,
entries 3 and 4), CuI/II salts combined with the chiral ligand 1a
showed high reactivities albeit unsatisfactory diastereo/
enantioselectivities (Table 1, entries 1 and 2). To our delight,
combinations of silver(I) salts with 1a gave the endo-product
exclusively in good yields with much higher enantioselectivities
(Table 1, entries 5, 6 and 8). Among the examined silver
precursors, AgOAc gave the best results in terms of the yield
and diastereo/enantioselectivity (Table 1, entry 9). Another
attractive advantage of AgOAc over other silver(I) salts is that
no extra base was required in the reaction, which is similar to
the cases reported by Zhou6f and Fukuzawa.8a Subsequently,
other TF-BiphamPhos were also examined (Table 1, entries
9–13). The asymmetric induction of ligand 1a was superior to
that of 1b or 1c with substituent groups on the N atom and 1d
with a bulky cyclohexyl group on the P atom. Ligand 1e
bearing two bromines at the 3,30-position of TF-BIPHAM
backbone emerged as the most effective chiral ligand in this
reaction and provided endo-4c as the sole product in high yield
and excellent enantioselectivity of 96% ee. The solvent effect
using chiral metal complexes of AgI,5,6 ZnII,7 CuI/II 8 NiII,9
,
CaII,10 and organocatalysts,11 to afford moderate to high
enantio/diastereoselectivities. Although various methods are
developed for this transformation, most of them rely on the
use of less sterically hindered azomethine ylides derived from
glycinate. In contrast, successful examples of the catalytic
asymmetric 1,3-dipolar cycloaddition of azomethine ylides
derived from amino esters other than glycinate are very
limited.6j,12 Recently, we reported a novel and highly efficient
CuI/TF-BiphamPhos catalytic system that exhibited excellent
results (97–99% ee and 498/o2 dr) in asymmetric 1,3-dipolar
cycloaddition of various azomethine ylides, especially derived
from a-substituted a-amino acids, with several dipolarophiles
such as dimethyl maleate, methyl and tert-butyl acrylate.13
However, when N-methyl and phenyl maleimide were used as
the dipolarophiles, only 66 and 39% ee were achieved for the
1,3-dipolar cycloaddition of alanine derived azomethine
ylides, although the corresponding diastereoselectivities still
remained high (Scheme 1).14 To further broaden the substrate
scope and improve the enantioselectivity for the cycloaddition
of N-substituted maleimide, the screening of various metal
precursors would be desirable and practicable considering the
good to excellent results achieved by the above-mentioned
College of Chemistry and Molecular Sciences, Wuhan University,
430072, China. E-mail: cjwang@whu.edu.cn; Fax: 86-27-68754067;
Tel: 86-27-65241880
w Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b902556a
Scheme 1 The results for CuI/TF-BiphamPhos catalyzed asymmetric
1,3-dipolar cycloaddition of azomethine ylides derived from alanine
with N-substituted maleimide.
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Table 1 Screening studies of the asymmetric 1,3-dipolar cyclo-
addition of azomethine ylide 3c with N-phenyl maleimide 2aa
Table 2 Asymmetric 1,3-dipolar cycloaddition of azomethine ylides 3
derived from glycinate with maleimide 2 catalyzed by AgOAc/1ea
Yieldb
(%)
Yieldb
Solvent t/h (%)
Entry
R
3
R1
4
Eecd (%)
Entry
L
[M]
Endo/Exoc Eede (%)
1
2
3
4
5
6
7
8
9
Ph
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
88
85
95
94
98
81
99
90
93
99
45
95 (99)e
93
1f
2f
1a CuClO4
DCM
0.2 78
0.2 88
75
73
0.2 87
0.2 90
498/o2
80/20
60/40
54
37
0
g
4-MeC6H4
4-ClC6H4
2-ClC6H4
4-FC6H4
4-CNC6H4
Ph
2-MeC6H4
4-MeOC6H4 3h
4-ClC6H4
t-Bu
96 (99)e
94
95
1a Cu(OTf)2 DCM
1a Ni(ClO4)2 DCM
1a Zn(OTf)2 DCM
3f
3
3
4f
73/27
0
5f
1a AgClO4
1a AgSbF6
1a AgSbF6
1a AgOAc
1a AgOAc
1b AgOAc
1c AgOAc
1d AgOAc
1e AgOAc
1e AgOAc
1e AgOAc
1e AgOAc
1e AgOAc
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
PhMe
498/o2
498/o2
498/o2
498/o2
498/o2
498/o2
498/o2
498/o2
498/o2
498/o2
498/o2
498/o2
498/o2
82
87
81
84
90
35
19
19
96
83
88
80
77
96
95
96
94
97
92
6f
3a
3g
7
3
36
0.2 97
8f
9
3
8
8
8
3
3
85
90
88
95
94
90
97
89
76
10
11
3c
3i
4j
4k
10
11
12
13
14
15
16h
17i
a
All reactions were carried out with 0.23 mmol of 2 and 0.45 mmol of
b
in 2 mL DCM. Isolated yield. Enantiomeric excesses were
c
3
determined by chiral HPLC analysis. The absolute configurations were
d
e
determined by comparing the optical rotation with reported data. Data
in parentheses refer to enantiomeric excesses after recrystallization.
MeOH 15
DCM
DCM
6
15
a
All reactions were carried out with 0.23 mmol of 2a and 0.45 mmol
b
of 3c in 2 mL of solvent at r.t. unless specified. Isolated yield.
derived imino ester and various aromatic aldehydes have
proved to be excellent substrates affording the corresponding
endo-adducts with high yields and excellent enantioselectivities,
regardless of the position and electronic property of the
substituents on the aromatic ring (Table 3, entries 1–9).
Noticeably, up to 96% ee and almost quantitative yield was
c
d
Determined from crude 1H NMR spectra. Enantiomeric excesses
e
were determined by chiral HPLC analysis. The absolute configura-
tion of 4c was determined by comparing the optical rotation with the
=
f
reported data. 15 mol% Et3N was added as the base. CuClO4
g
h
i
Cu(CH3CN)4ClO4. T = 0 1C. T = ꢂ20 1C.
Table 3 Asymmetric 1,3-dipolar cycloaddition of azomethine ylides
derived from a-substituted-a-amino acids (3j–3v) catalyzed by
AgOAc/1ea
was then studied, and DCM was revealed to be the best
solvent of choice (Table 1, entries 13–15). Reducing the
temperature from room temperature to 0 1C or ꢂ20 1C had
detrimental effect on the reactivity and enantioselectivity
(Table 1, entries 16 and 17).
Having established the optimal reaction conditions, we then
investigated a series of representative imino esters 3 derived
from glycinate. As shown in Table 2, a wide array of imino
esters derived from aromatic aldehyde reacted smoothly with
N-phenyl or methyl maleimide to afford the corresponding
endo-adducts exclusively in high yields and excellent enantio-
selectivities (Table 2, entries 1–10). It appears that the position
and the electronic property of the substituents on the aromatic
rings have a very limited effect on the enantioselectivities.
Azomethine ylides from aliphatic aldehydes has been seldom
studied in the asymmetric 1,3-dipolar cycloaddition reaction
probably due to their lower reactivity. Remarkably, the
relatively challenging azomethine ylide 3i from tert-butyl
aldehyde also works well in this transformation producing
the endo-4k with high enantioselectivity (92% ee) albeit with
moderate yield (45%) (Table 2, entry 11).
Yieldb
(%)
Entry R1
R2
3
R3
5
Eecd (%)
1
2
Ph Me
4-MeOC6H4 Me
3j Me
3k Me
3l Me
3m Me
3n Me
3o Me
3p Me
3q Me
3r Me
3s Me
3p Ph
3t Me
3u Me
3v Me
5a 95
5b 92
5c 83
5d 99
5e 87
5f 99
5g 99
5h 97
5i 90
5j 99
5k 92
5l 90
5m 96
5n 93
98
95
97
97
97
96
95
97
98
96
96
94
91
96f
3
4
5
6
7
8
9
10
11
12
13
14
4-MeC6H4
2-MeC6H4
4-ClC6H4
2-ClC6H4
3-ClC6H4
4-BrC6H4
4-FC6H4
2-Furyl
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ee
3-ClC6H4
Ph
Ph
Bn
Ph
4-BrC6H4
a
Encouraged by the results for less sterically hindered
azomethine ylides from glycinate, we then investigated
1,3-dipolar cycloaddition of azomethine ylides derived from
a-substituted amino acids in which a quaternary stereogenic
center15 was generated among the four contiguous stereocenters
in the corresponding highly substituted pyrrolidines. The
results are summarized in Table 3. Gratifyingly, alanine
All reactions were carried out with 0.23 mmol of 2 and 0.45 mmol of
c
3 in 2 mL DCM. b Isolated yield. Enantiomeric excesses were determined
d
by chiral HPLC analysis. The absolute configuration of the known
compounds 5a and 5m were determined by optical rotation comparisons
e
with reported data. E = 3-indolymethyl, 24 h. f AgSbF6/1e (3 mol%)
and Et3N (15 mol%) was used as the catalyst and the base, 0.5 h; 90% ee
was achieved when AgOAc/1e (3 mol%) was used.
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Fig. 1 The results of 1,3-dipolar cycloaddition of other dipolarons/
dipolarophiles catalyzed by AgOAc/1e.
still obtained even for heteroaromatic 2-furyl imino ester
(Table 3, entry 10). High yield and excellent diastereo/
enantioselectivity was also observed when N-phenyl maleimide
was used as the dipolarophile (Table 3, entry 11). Furthermore,
under the optimized reaction conditions, the azomethine ylides
derived from tryptophan, phenylalanine and 2-phenylglycine,
successfully reacted with N-methyl maleimide leading to high
endo-selectivities (498/o2) and excellent enantioselectivities
(91–96% ee) (Table 3, entries 12–14). Fortunately, all the
products are solid, and enantiopure compounds can be easily
obtained by direct crystallization of the crude products.
Finally, in order to probe more deeply the scope and
generality of this AgOAc/TF-BiphamPhos catalytic system,
other dipolarophiles were also examined under the optimized
reaction conditions. As shown in Fig. 1, tert-butyl acrylate
and dimethyl maleate proved to be excellent dipolarophiles
affording high yields and excellent diastereo/enantioselectivities
for this transformation. Moreover, the commercially available
glycine ethyl ester benzophenone Schiff base was an equally
acceptable dipolar partner.
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73, 305.
In conclusion, we have developed a novel and highly efficient
AgOAc/TF-BiphamPhos catalytic system, which exhibited
excellent reactivity, diastereo/enantioselectivity, and structural
scope in asymmetric 1,3-dipolar cycloaddition of azomethine
ylides derived from various a-substituted a-amino acids with
N-substituted maleimides and other electron-deficient alkenes.
This methodology presented herein nicely complements the
highly efficient Cu(I)/TF-BiphamPhos catalytic system.13 Future
applications of TF-BiphamPhos in asymmetric catalysis are
ongoing in our laboratory and will be reported in due course.
This work is supported by the National Natural Science
Foundation of China, the National Science Foundation for
Fostering Talents in Basic Research of the National Natural
Science Foundation of China (J0730426), and the startup fund
from Wuhan University.
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12 64–92% ee were achieved for transition-metal-catalyzed cyclo-
additions of azomethine ylides derived from imino esters other
than glycinate with tert-butyl acrylate or N-phenyl/methyl maleimide,
see ref. 6a, 6i, 8e and 10. Exceptionally, 97% ee was achieved for
the cycloaddition of the in situ azomethine ylide derived from
a-phenylglycine methyl ester and dimethyl maleate with 20 mol%
organocatalyst at 50 1C in 60 h, see ref. 11c; 98% ee for the
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and tert-butyl acrylate catalyzed by 5 mol% Ag(I)/phosphoramidite
in 48 h, see ref. 6j.
Notes and references
1 For recent reviews about 1,3-dipolar cycloaddition reactions of
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13 C.-J. Wang, G. Liang, Z.-Y. Xue and F. Gao, J. Am. Chem. Soc.,
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14 88 and 86% ee were achieved when N-phenyl and N-methyl
maleimide were used as dipolarophiles and glycine derived
azomethine ylide as dipolaron, and the corresponding endo/exo
ratios were 498/o2, see ref. 13.
15 (a) Quaternary Stereocenters: Challenges and Solution for Organic
Synthesis, ed. J. Christoffers, A. Baro, Wiley-VCH, Weinheim,
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2 S. L. Schreiber, Science, 2000, 287, 1964.
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This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 2905–2907 | 2907