A highly enantio- and diastereoselective Cu-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes

Article abstract of DOI:10.1002/anie.200503672

(Chemical Equation Presented) Electronic properties of the ligands switch the diastereoselectivity in the Cu-catalyzed 1,3-dipolar cycloaddition of azomethine ylides to nitroalkenes: exo- or endopyrrolidines were obtained with high diastereo- and enantios

Full text of DOI:10.1002/anie.200503672

Angewandte
Chemie
Cycloadditions
DOI: 10.1002/anie.200503672
A Highly Enantio- and Diastereoselective
Cu-Catalyzed 1,3-Dipolar Cycloaddition of
Azomethine Ylides with Nitroalkenes**
Xiao-Xia Yan, Qian Peng, Yan Zhang, Kai Zhang,
Wei Hong, Xue-Long Hou,* and Yun-Dong Wu
Dedicated to Professor Wei-Yuan Huang
on the occasion of his 85th birthday
The 1,3-dipolar cycloaddition of azomethine ylides to elec-
tron-deficient alkenes is one of the most powerful methods
for the construction of highly substituted pyrrolidine rings.[1]
Following early research on the preparation of optically active
pyrrolidines in the presence of either a stoichiometric amount
of a chiral metal complex[2] or a chiral auxiliary,[3] an
asymmetric catalytic version of this reaction has been
developed recently.[4–8] The groups of Jørgensen,[4a]
Zhang,[5a] Schreiber,[6] Zhou,[8a] and Carretero[8b] have
reported that the reaction of glycine derivatives with elec-
tron-deficient alkenes is highly enantio- and endo-selective in
the presence of chiral ZnII–bisoxazolines, AgI–phosphanes,
AgI–quinap, Ag–P,N ligands, and Cu–fesulphos, while the
groups of Komatsu and Zhang have reported exo selectivity
with a Cu–diphosphane complex and P,N ligands as cata-
lyst.[5b,7] Each of these reactions involves derivatives of
unsaturated carboxylates as the dipolarophiles and the
diastereoselectivity is not switchable.[9a] Herein, we report a
CuI–P,N-ferrocene-catalyzed 1,3-dipolar cycloaddition of
nitroalkenes to an imino ester derived from glycine and our
observation of a dramatic switch in exo/endo selectivity due to
[*] Dr. X.-X. Yan, Y. Zhang, Prof. Dr. X.-L. Hou
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Road, Shanghai 200032 (China)
Fax: (+86)21-5492-5100
E-mail: xlhou@mail.sioc.ac.cn
Q. Peng, K. Zhang, W. Hong, Prof. Dr. X.-L. Hou, Prof. Dr. Y.-D. Wu
Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032 (China)
Prof. Dr. Y.-D. Wu
Department of Chemistry
Hong Kong University of Science and Technology
Hong Kong (China)
[**] This research was supported financially by the Major Basic Research
Development Program (grant G 200077506), the National Natural
Science Foundation of China, the Chinese Academy of Sciences, the
Shanghai Committee of Science, and the Technology and Croucher
Foundation of Hong Kong. We thank Professors L.-X. Dai, H. N. C.
Wong, and T.-L. Ho for their helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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1979

Communications
the electronic properties of the chiral ligand. A qualitative
model is also proposed to rationalize the observed stereo-
chemistry.
in THF for the reaction, an 87:13 ratio of exo and endo isom-
ers (91% and 62% ee, respectively) was obtained in an
overall yield of 67%.
Initially, the reaction of imino ester 1a with nitroalkene
2a was examined in the presence of CuClO4 and ligands 3a[9b]
and 3 f–h [Eq. (1)].[10d,11] The results are compiled in Table 1.
Although the reaction provides the pyrrolidine deriva-
tives with high ee, the yields are only moderate because
Michael addition occurs as a side reaction.[12] This supports
the stepwise mechanism proposed by Cossío and co-work-
ers.[12,14] As shown in Scheme 1, a zwitterionic species 5 should
Scheme 1. Proposed mechanism of the reaction of 1 with 2.
Table 1: Reaction of 1a with 2a in the presence of different ligands.[a]
Entry
Ligand
Yield [%][b]
exo/endo[c]
ee [%] (exo/endo)[d]
be formed as an intermediate, from which the cycloaddition
product 4 is formed. However, 5 can also be protonated by
Et3NH+, the conjugate acid of Et3N, to form the Michael
adduct. In this case the yield of pyrrolidine 4 could be
improved by using a stronger base (weaker conjugate acid) to
slow down the protonation. Indeed, when tBuOK was used as
the base in the reaction of 1a and 2a with 3a as ligand, the
yield of exo-4a increased from 58% to 87%, albeit with a
slight decrease in ee (from 97% to 95%).
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3 f
58
67
65
49
62
37
75
60
only exo
73:27
only exo
only exo
18:82
49:51
only endo
18:82
97 (n.d.)
95 (84)
98 (n.d.)
98 (n.d.)
88 (97)
92 (15)
n.d. (17)
n.d. (3)
3g
3h
[a] Molar ratio of 1a to 2a=1.2:1. [b] Yield of isolated product.
[c] Determined by 1H NMR spectroscopy. [d] Determined by chiral
HPLC. n.d.=not determined.
The 1,3-cycloaddition of different imino esters 1 and
nitroalkenes 2 in the presence of ligands 3a and 3e was
studied under these optimized conditions (Table 2).[15] All
reactions in the presence of 3a provided exo-4 either
exclusively (Table 2, entries 1–7) or as the major isomer in a
ratio between 88:12 and 92:8 (Table 2, entries 8–11). The
yields were always high and the ee values for exo-4 ranged
from 92% to 98%, except for product 4k (Table 2, entry 11).
An aliphatic nitroalkene was also found to be a suitable
dipolarophile; it gave exo-4g as the sole diastereomer with
98% ee (Table 2, entry 7). When ligand 3e was used, the
endo-4 diastereomers were obtained in high yields. The ratio
of endo-4 to exo-4 ranged from 70:30 to 94:6 (Table 2,
entries 12–19), with ee values between 92% and 98%
(Table 2, entries 12–16 and 18), with the exception of products
4i and 4k, for which the ee values were 84 and 88%,
respectively (Table 2, entries 17 and 19). After one recrystal-
lization from dichloromethane/petroleum ether, exo-4k and
endo-4k were obtained with over 99% and 96% ee,
respectively.
The reaction with ligand 3a yielded exo-4a[12] as the sole
product in 58% yield with 97% ee (Table 1, entry 1), while
the endo isomer was obtained with 17% ee with ligand 3g
(Table 1, entry 7). A sharp decrease in diastereo- and/or
enantioselectivities was observed with ligands 3 f and 3h
(Table 1, entries 6 and 8, respectively).
Encouraged by the result with ligand 3a, we synthesized a
series of P,N-ferrocenyl ligands 3b–e bearing different aryl
groups on the P atom[11,13] and used them in the reaction. As
shown in Table 1, a dramatic variation in diastereoselectivity
was observed. Ligands 3c and 3d, which have electron-
donating substituents on the phenyl rings, gave exclusively the
exo product with excellent enantioselectivity (entries 3 and 4,
Table 1), whereas ligand 3b, which has one electron-with-
drawing CF3 group on each phenyl ring, gave a mixture of exo
and endo isomers in a ratio of 73:27 with 95% and 84% ee,
respectively. Ligand 3e with two CF3 substituents on each
phenyl ring, gave the endo isomer as the major product with
97% ee (entry 5, Table 1). THF proved to be a better solvent
than CH2Cl2, toluene, Et2O, or CH3CN in terms of yields and
diastereoselectivities. When AgOAc and ligand 3a were used
The absolute configurations of exo-4k and endo-4k were
assigned as (2S,3S,4R,5R) and (2S,3R,4S,5R), respectively, by
X-ray diffraction analysis (Figure 1). The same (2S,5R)
configuration for the two products indicates that the addition
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Table 2: Enantioselective CuI-catalyzed 1,3-dipolar cycloaddition of azomethine ylides 1 to nitroalkenes
2.
of the nitroalkene occurs at the
Si face of the Cu-bound imino ester
anion with both 3a and 3e.
Varying the electronic proper-
ties of ligands to fine-tune the
stereoselectivity in asymmetric cat-
alysis has been conceptually attrac-
tive.[16] Pioneered by Jacobsen[16a]
and others, there have since been
many reports of improved stereo-
selectivity by utilizing this elec-
tronic effect.[11,16] However, there
has been only limited success in
Entry R1
R2
Ligand exo/endo[a] Product Yield [%][b] ee [%][c]
1
2
3
4
5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3e
3e
3e
3e
3e
3e
3e
3e
only exo
only exo
only exo
only exo
only exo
only exo
only exo
89:11
88:12
92:8
86:14
14:86
30:70
11:89
6:94
18:82
17:83
19:81
18:82
4a
4b
4c
4d
4e
4 f
4g
4h
4i
87
70
77
73
64
74
75
96
97
92
77
85
79
82
88[e]
79
98
98
71
95
96
96
96
92
95
98
97
p-NO2-C6H4
p-MeO-C6H4
p-Me-C6H4
p-Cl-C6H4
m-Cl-C6H4
iPr
6
7
switching
the
stereoselectivi-
ty.[16d,h,j–l] Our current finding of a
dramatic switch in diastereoselec-
tivity while still keeping high enan-
tioselectivity represents an excep-
tional example. Our results also
indicate that the effect is not due to
a p–p interaction (see entries 7 and
15 in Table 2).
8
p-MeO-C6H4 Ph
9
m-Cl-C6H4
2-naphthyl
p-Br-C6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
92
92
10
11
12
13
14
15
16
17
18
19
4j
4k
4a
4c
4 f
4g
4h
4i
83 (99)[d]
98
p-MeO-C6H4
m-Cl-C6H4
iPr
95
92
97
96
Ph
p-MeO-C6H4 Ph
m-Cl-C6H4
2-naphthyl
p-Br-C6H4
Ph
Ph
Ph
84
A computational study of the
complex formed by Cu–3a and the
anion of the imino ester 1a was
also performed. The two structures
were fully optimized with the den-
sity functional theory method at
the B3LYP/6-31G*(lanldz) level.[17]
When these structures assume a
4j
4k
97
88 (96)[d]
[a] Determined by 1H NMR spectroscopy. [b] Yield of isolated product. [c] Major product determined by
HPLC. [d] The ee value obtained after one recrystallization is given in parentheses. [e] Yield of isolated
endo products.
distorted tetrahedral geometry with a more or less coplanar
Cu-P-N-N array (Figure 2), structure A is calculated to be
about 4.3 kcalmolÀ1 more stable than B.[18] The latter is
significantly destabilized by the steric interactions between
the phenyl group of the imino ester and one of the phenyl
groups of the ligand and the ferrocene. Therefore, the
stereoselectivity can be discussed on the basis of the addition
of nitroalkene to structure A.[19]
The Re face of structure A is apparently shielded by the
À
isopropyl group, as indicated by the short C1 H1 distance
(3.14 Š). On the other hand, the two phenyl groups on the
P atom are oriented in such a way that they do not shield the
Si face. Therefore, it is reasonable to assume that the attack of
nitroalkene occurs at the Si face of the Cu-bound imino ester
anion, in agreement with the experimental observations
(Figure 1). As shown by the Newman projections, there are
three transition structures with staggered conformations for
the exo and endo diastereomers. Upon nucleophilic addition
at C2 of the nitroalkene there should be an accumulation of
negative charge at C3. Therefore, we argue that 7c and 8b are
more favorable transition structures for the exo and endo
products, respectively, because the developing negative
charge at C3 can be stabilized by electrostatic interaction
with the Cu center. In structure 7c, the nitro group, which
carries partial negative charge, lies away from the valley
formed by the two aryl groups of the P ligand, whereas the
nitro group in 8b lies in the valley. Therefore, when the aryl
groups are electron-rich, structure 7c is expected to be more
stable than 8b, which leads to the favorable formation of the
Figure 1. ORTEP diagrams of the X-ray crystal structures of exo-4k and
endo-4k.
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1981

Communications
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Figure 2. Calculated structures (A and B) of complexation modes of
CuI–3a with the anion of imino ester 1a and staggered transition-
structure models of nitrostyrene on the Si face of the Cu-bound imino
ester anion. Fe brown, Cu black, C green, O red, N blue, H violet.
exo product. When the aryl groups are electron-deficient,
however, structure 8b is stabilized by electrostatic interac-
tion, which leads to formation of the endo product.
The present report reveals for the first time the CuI-
catalyzed asymmetric 1,3-dipolar cycloaddition of azome-
thine ylides to nitroalkenes.[20] A high yield of either exo or
endo adducts can be achieved, with excellent enantioselec-
tivity, by using electron-rich or electron-deficient aryl groups
on the P atom of chiral P,N-ferrocene ligands, respectively. A
qualitative model has been proposed to rationalize the
observed stereoselectivity. These results point to a new
possibility to switch the stereoselectivity of the reaction by
varying the electronic properties of the ligands. Furthermore,
useful hints for ligand design are revealed. The application of
this reaction and the use of other electron-deficient alkenes as
dipolarophiles is currently being studied further.
[12] M. Ayerbe, A. Arrieta, F. P. Cossío, J. Org. Chem. 1998, 63,
1795 – 1805.
[13] See Supporting Information of ref. [5].
[14] S. Vivanco, B. Lecea, A. Arrieta, P. Prieto, I. Morao, A. Linden,
F. P. Cossío, J. Am. Chem. Soc. 2000, 122, 6078 – 6092.
[15] Other Cu and Ag salts, including Cu(OTf)2, CuOTf, CuBF4,
AgOTf, AgClO4, and AgBF4, were tested in the reaction of 1a
with 2a in the presence of ligands 3a or 3e under these
optimized reaction conditions. All Cu salts gave similar enantio-
and diastereoselectivities with comparable yields to the reaction
using CuClO4, while Ag salts gave somewhat higher yields of the
endo product but lower enantioselectivity.
Received: October 17, 2005
Revised: December 30, 2005
Published online: February 21, 2006
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Keywords: asymmetric catalysis · azomethine ylides · copper ·
cycloaddition · diastereoselectivity
.
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Angewandte
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[19] The stereochemical course of the reaction can be determined in
two reaction steps: the formation of 5 or the formation of 4
(Scheme 1). We assume that formation of 5 is the crucial to
stereochemistry because it would be difficult to understand the
stereoseclectivity based on the models shown in Figure 2 (that is,
7a and 8c) if formation of 4 was the rate-determining step.
[20] Whilst this paper was under review, Carretero and co-workers
published a paper that includes one example of the use of a
nitroalkene in Cu-catalyzed asymmetric dipolar cycloaddition.
See ref. [8b].
[17] The calculations were performed with the Gaussian03 program
(Gaussian03, Revision B.03, M. J. Frisch et al.). See Supporting
Information for details.
Angew. Chem. Int. Ed. 2006, 45, 1979 –1983
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1983