Catalytic asymmetric 1,3-dipolar cycloaddition reactions of azomethine ylides - A simple approach to optically active highly functionalized proline derivatives

Article abstract of DOI:10.1002/1521-3773(20021115)41:22<4236::AID-ANIE4236>3.0.CO;2-W

Highly substituted pyrrolidines 4 are formed in a highly diastereo- and enantioselective 1,3-dipolar cycloaddition reaction of azomethine ylides with electron-deficient alkenes 2. The azomethine ylides are generated from glycinates 1 catalyzed by a chiral zinc(II) bisoxazoline catalyst 3.

Full text of DOI:10.1002/1521-3773(20021115)41:22<4236::AID-ANIE4236>3.0.CO;2-W

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have been the focus of attention[2,3] as a result of the
importance of the formed isoxazolidines as building blocks
for more complex molecules.
[7] Copies of the NMR spectra recorded in CDCl3 and [D6]DMSO, all
binding data from NMR titration and isothermal calorimetry experi-
ments, and Job plots are provided in the Supporting Information.
[8] The binding constants were calculated by fitting the data using
NMRTit HG software, kindly provided by Prof. C. A. Hunter,
University of Sheffield. See: A. P. Bisson, C. A. Hunter, J. C. Morales,
K. Young, Chem. Eur. J. 1998, 4, 845.
Azomethine ylides can react in a 1,3-dipolar cycloaddition
reaction with alkenes to form pyrrolidines, and several
examples of the formation of optically active pyrrolidines
based on diastereoselective reactions are known.[4,5] However,
investigations on the metal-catalyzed enantioselective version
of the 1,3-dipolar cycloaddition of azomethine ylides with
alkenes are very limited. Grigg and co-workers[6] were the first
to demonstrate that applying a stoichiometric amount of
chiral cobalt or manganese complexes with ephedrine deriv-
atives as the chiral ligand could give the cycloaddition product
of azomethine ylides derived from imines of glycine alkyl
esters with up to 96% ee. It has also been mentioned that
silver(i) salts in combination with chiral phosphane ligands
can catalyze the 1,3-dipolar cycloaddition reaction of azome-
thine ylides.[6b,7]
[9] A. Cooper, Curr. Opin. Chem. Biol. 1999, 3, 557, and references
therein.
[10] For the specific application of isothermal calorimetry to dicarboxylate
recognition, see a) B. R. Linton, M. S. Goodman, E. Fan, S. A.
van Arman, A. D. Hamilton, J. Org. Chem. 2001, 66, 7313. See also,
for example, b) F. P. Schmidtchen, Org. Lett. 2002, 4, 431; c) B. Linton,
A. D. Hamilton, Tetrahedron 1999, 55, 6027.
[11] The data give binding constants at the upper limit of detectability by
NMR titrations (104 105 mꢀ1) and it can be concluded that Ka > 104 mꢀ1
,
but more precise values cannot be reliably obtained from the NMR
titration data: a) L. Fielding, Tetrahedron 2000, 56, 6151; b) C. S.
Wilcox, Frontiers in Supramolecular Organic Chemistry and Photo-
chemistry (Eds.: H.-J. Schneider, H. D¸rr), VCH, Weinheim, 1991,
p. 123; c) G. Weber, S. R. Anderson, Biochemistry 1965, 4, 1942. See
also the Supporting Information.
[12] K. A. Connors, Binding Constants, Wiley, New York, 1987.
[13] The ITC data was obtained with a MicroCal VP-ITC isothermal
calorimeter. Data was analyzed by nonlinear least-squares fitting
using the Origin software supplied by MicroCal: T Wiseman, S.
Williston, J. F. Brandts, L.-N. Lin, Anal. Biochem. 1989, 179, 131. Data
was modeled using the 1:1 binding site model, or the model with two
independent binding sites in cases where the data could not be fitted
with the 1:1 binding site model (see ref. [10c])
[14] T. R. Kelly, M. H. Kim, J. Am. Chem. Soc. 1994, 116, 7072.
[15] a) P. G¸ntert, C. Mumenthaler, K. W¸thrich, J. Mol. Biol. 1997, 273,
283; L. Brennan, D. L. Turner, A. C. Messias, M. L. Teodoro, J.
LeGall, H. Santos, A. V. Xavier, J. Mol. Biol. 2000, 298, 61. Full details
of experimental methods are provided in the Supporting Information.
We present herein a new highly diastereo- and enantiose-
lective 1,3-dipolar cycloaddition reaction of azomethine ylides
with alkenes catalyzed by readily available chiral Lewis acids.
Although there are few stable azomethine ylides,[8] most are
unstable. Azomethine ylides 2 can be generated from, for
example, imines of glycine alkyl esters 1 by reaction with a
base in the presence of a Lewis acid complex. The metal-
stabilized azomethine ylide 2 reacts with an alkene 3 to give
highly functionalized pyrrolidines 4 (Scheme 1).
M
O
O
R
N
R
N
OR
OR
R
MX
R
H
H
H
H
1
EWG
Catalytic Asymmetric 1,3-Dipolar
Cycloaddition Reactions of Azomethine
Ylides–A Simple Approach to Optically
Active Highly Functionalized Proline
Derivatives**
EWG
R
M
O
3
R
N
R3N
CO2R
N
H
OR
2
4
Scheme 1. Formation of highly functionalized pyrrolidines 4 from azome-
thine ylides 2 and alkenes 3. EWG ¼ electron-withdrawing group.
Aase Sejr Gothelf, Kurt V. Gothelf, Rita G. Hazell,
and Karl Anker J˘rgensen*
The reactions of N-benzylidene- and N-(2-naphthylmethy-
lidene) glycinates 1a and 1b, respectively, with methyl
acrylate (3a) and Et3N as the base in the presence of chiral
ligands such as the bisoxazolines (BOX) 5a,b[9] and dibenzo-
furanyl-2,2’-bisoxazoline (DBFOX) 5c[10] and Lewis acids
were used in the screening process (Scheme 2). Some
representative results are listed in Table 1.
The 1,3-dipolar cycloaddition reaction constitutes one of
the most fundamental reactions for the stereoselective con-
struction of five-membered heterocyclic compounds.[1] In
recent years, the development of catalytic asymmetric reac-
tions has been one of the challenging areas within the field of
1,3-dipolar cycloaddition reactions, and especially nitrones
The use of copper(ii) salts in combination with the chiral
bisoxazoline ligands 5a,b as catalysts for the reaction of N-
benzylidene glycinate 1a with methyl acrylate (3a) gave high
conversion only when using the (S)-tBu-BOX (5a) ligand, but
unfortunately product 4a was formed as a racemate (Table 1,
entries 1 and 2). When zinc(ii)[9e] was used as the Lewis acid
instead, the reaction proceeded smoothly and 4a was formed
with 76% ee using 5a as the chiral ligand and THF as the
solvent at room temperature (Table 1, entry 3). Furthermore,
the reaction is also highly diastereoselective as only one
[*] Prof. Dr. K. A. J˘rgensen, A. S. Gothelf, Dr. K. V. Gothelf,
Dr. R. G. Hazell
Danish National Research Foundation: Center for Catalysis
Department of Chemistry, Aarhus University
8000 Aarhus C (Denmark)
Fax : (þ 45)8619 6199
E-mail: kaj@chem.au.dk
[**] We wish to expressed our gratitude to The Danish National Research
Foundation for financial support.
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
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R2O2C
Ar
R1
CO2Me
was independent of the amount of base used, as ee values of
78 80% were found for all the reactions studied.
O
CO2R2
base
+
Ar
N
M(II)–
ligand
The potential of this new catalytic enantioselective 1,3-
dipolar cycloaddition reaction of azomethine ylides with
alkenes is demonstrated in the reactions of a series of imines
of glycine methyl ester 1a-d with different electron-deficient
alkenes 3a d catalyzed by ZnII-tBu-BOX (Scheme 2). The
results are presented in Table 2.
OMe
N
H
R1
1
3
4
a: R1 = H, R2 = Me
b:R1 = H, R2 = Et
a: Ar = Ph
b: Ar = 2-Np
a: Ar = Ph, R1 = H, R2 = Me
b: Ar = 2-Np, R1 = H, R2 = Me
c: Ar = 2-Np, R1 = H, R2 = Et
c: R1 = H, R2 = tBu
d:R1 = CO2Me, R2 = Me
c: Ar = p-BrC6H4
d: Ar = 2-Np, R1 = H, R2 = tBu
e: Ar = p-BrC6H4, R1 = H, R2 = Me
f: Ar = Ph, R1 = CO2Me, R2 = Me
g: Ar = 2-Np, R1 = CO2Me, R2 = Me
h: Ar = p-BrC6H4, R1 = CO2Me, R2 = Me
Table 2. Catalytic enantioselective 1,3-dipolar cycloaddition reaction of
1a d with various alkenes 3a d in the presence of ZnII-tBu-BOX
(10 mol%) as catalyst in THF.[a]
Entry
Azomethine ylide
Dienophile
Yield[b] (%)
ee[c] [%]
O
O
O
N
O
O
1
2[e]
3
4[e]
5[e,f]
6
7
8
9[e]
10[e]
11
12
1a
1a
1b
1b
1b
1b
1b
1c
1c
1a
1b
1c
3a
3a
3a
3a
3a
3b
3c
3a
3a
3d
3d
3d
4a (> 95[d]
4a (80)
4b (93)
4b (84)
4b (86)
4c (76)
4d (12)
4e (89)
4e (89)
4 f (78)
4g (84)
4h (87)
)
78
88
78
91
87
68
O
N
N
N
O
N
N
tBu
tBu
Ph
Ph
Ph
Ph
5a: (S)-t-Bu-BOX
5b: (R)-Ph-BOX
5c: (R,R)-Ph-DBFOX
< 5
Scheme 2. Chiral ligands 5a c used in the preparation of optically active
pyrrolidines 4.
61
94
76
90
68
Table 1. Representative results for the screening of reaction conditions for
the catalytic enantioselective 1,3-dipolar cycloaddition reaction of N-
benzylidene and N-(2-naphthylmethylidene) glycinate 1a,b with methyl
acrylate 3a.[a]
[a] Zn(OTf)2-tBu-BOX and Et3N (10 mol% each) were used. For exper-
imental details, see Supporting Information. [b] Yield of isolated product.
[c] Determined by chiral HPLC. [d] Conversion based on 1H NMR
spectroscopy. [e] Reaction temperature ꢀ208C. [f] Reaction in the absence
of solvent.
Entry Lewis acid Ligand Solvent
1
Conversion[b] (%) ee[c] [%]
1
2
Cu(OTf)2
Cu(OTf)2
5a
5b
5a
5a
5b
5a
5a
5b
5c
THF
THF
THF
neat
THF
THF
neat
neat
neat
a
a
a
a
a
b
b
b
b
4a (> 95)
4a (< 10)
4a (> 95)
4a (> 95)
4a (< 50)
4b (> 95)
4b (> 95)
4b (> 95)
4b (> 95)
rac
n.d.[d]
78
79
n.d.[d]
78
76
17
7
3Zn(OTf)
2
4
5
6
7
8
9
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
The reaction of N-benzylidene glycinate 1a with methyl
acrylate (3a) proceeds in high yield and only one diaster-
eomer of 4a is formed at room temperature with 78% ee
(Table 2, entry 1). Performing the reaction at ꢀ208C leads to
an improvement in the enantioselectivity of 4a to 88% ee
(Table 2, entry 2). N-(2-Naphthylmethylidene) glycinate 1b
was treated with the different acrylates 3a-c under various
reaction conditions. At room temperature, the 1,3-dipolar
cycloaddition adduct 4b was obtained in high yield and as a
diastereomerically pure product with 78% ee and an improve-
ment in the enantioselectivity to 91% ee was observed at
ꢀ208C (Table 2, entries 3,4). The enantiomeric excess of the
1,3-dipolar cycloadducts formed is dependent on the ester
substituent of the acrylate used. Ethyl acrylate (3b) reacted
with 1b to give the pyrrolidine 4c in the same high yield and
diastereoselectivity as did the methyl acrylate; however, the
enantiomeric excess of 4c dropped to 68% ee (Table 2,
entry 6). For tert-butyl acrylate (3c), pyrrolidine 4d was
obtained in only 12% yield with < 5% ee (Table 2, entry 7).
The p-bromo-N-benzylidene glycinate 1c reacted smoothly
with 3a in a highly diastereo- and enantioselective reaction
with up to 94% ee (Table 2, entries 8 and 9). Dimethyl
fumarate (3d) reacted in a highly diastereo- and enantiose-
lective 1,3-dipolar cycloaddition reaction with the different
azomethine ylides 1a c. The reaction of 1a with 3d gives four
new stereogenic centers in the addition step, and in this
reaction pyrrolidine 4 f was obtained in high yield and as one
diastereomer with 76% ee (Table 2, entry 10). The 1,3-dipolar
cycloaddition reaction of 1b with 3d at ꢀ208C provided 4g
[a] Lewis acid, ligand, and Et3N (10 mol% each) were used. For exper-
imental details, see Supporting Information. [b] Conversion determined by
crude 1H NMR spectroscopy. [c] Enantiomeric excesses were measured by
chiral HPLC. [d] Not detected.
1
diastereomer of 4a was observed by H NMR spectroscopy.
The same trends are found for N-(2-naphthylmethylidene)
glycinate 1b in the presence of ZnII-tBu-BOX (Table 1,
entries 6 and 7), whereas the use of the ZnII-Ph-BOX and
ZnII-Ph-DBFOX catalysts in the absence of solvent gave 4b
with low enantiomeric excess (Table 1, entries 8 and 9).
The reaction of N-(2-naphthylmethylidene) glycinate 1b
with methyl acrylate (3a) and Et3N as the base catalyzed by
ZnII-tBu-BOX was studied in different solvents. In less polar
solvents such as Et2O and toluene in which 1b has a low
solubility, the enantiomeric excess of 4b was decreased to 23
and 25% ee, respectively, although complete conversion and
diastereoselectivity was observed. In solvents such as CH2Cl2
and MeCN, the enantiomeric excess of 4b was only slightly
lower (65 and 62% ee) than in reactions performed in THF.
The influence of the amount of base on the enantiomeric
excess of the reaction of 1b with 3a catalyzed by ZnII-tBu-
BOX (10 mol%) in THF at room temperature was inves-
tigated. The addition of Et3N (5 20 mol% relative to the
azomethine ylide) showed that the enantioselectivity of 4b
Angew. Chem. Int. Ed. 2002, 41, No. 22
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(Table 2, entry 11) in high yield and with excellent enantio-
selectivity (90% ee), whereas the reaction of 1c gives a
slightly lower enantiomeric excess, but the same high yield
and diastereoselectivity (Table 2, entry 12).
not undergo reaction with metal-stabilized azomethine ylides,
whereas the acrylates 3a c do.
In conclusion, we have developed a new catalytic asym-
metric 1,3-dipolar cycloaddition reaction of azomethine ylides
with alkenes. The reactions are catalyzed by zinc(ii) bisoxazo-
lines and proceed in high yield, thus giving diastereomerically
pure products with up to 94% ee. This reaction provides an
easy entry to optically active highly substituted pyrrolidines.
To determine the absolute configuration of the product of
the asymmetric ZnII-tBu-BOX-catalyzed 1,3-dipolar cyclo-
addition, compound 4g was converted into 6 by tosylation
[Eq. (1)]. An X-ray analysis of crystals of 6 revealed a
2S,3S,4S,5R configuration for 6 and therefore also for 4g (see
Supporting Information. CCDC 188992 contains the supple-
mentary crystallographic data for this paper. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB21EZ, UK;
fax: (þ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).).
Received: July 5, 2002 [Z19669]
[1] a) Synthetic Applications of Dipolar Cycloaddition Chemistry towards
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[2] For reviews, see: a) K. V. Gothelf, K. A. J˘rgensen, Chem. Rev. 1998,
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MeO2C
2-Np
CO2Me
CO2Me
MeO2C
2-Np
CO2Me
CO2Me
TsCl, Et3N
CH2Cl2, reflux
(1)
N
Ts
N
H
(2S,3S,4S,5R)-6
(95% ee)
4g
(90% ee)
Based on the absolute configuration of 6, we propose a
model for the intermediate in the ZnII-tBu-BOX-catalyzed
1,3-dipolar cycloaddition reactions. This intermediate 7 (Fig-
ure 1), which consists of the azomethine ylide coordinating to
the ZnII-tBu-BOX catalyst is an 18-electron complex and
should, from an electronic point of view, give a tetrahedral
arrangement of the ligands around the zinc center.[9d] The
tetrahedral conformation would, however, lead to the oppo-
site enantiomer as observed in the reaction. To account for the
stereochemical outcome of the reaction, we propose a
bipyramidal intermediate 8, which also involves coordination
of the a,b-unsaturated ester carbonyl group to the metal
center (Figure 1). This additional coordination activates the
a,b-unsaturated ester for reaction with the azomethine ylide,
thus leading to the experimentally observed diastereomer and
enantiomer of the product. Experimentally, the additional
coordination is supported by the fact that acrylonitrile does
[6] a) P. Allway, R. Grigg, Tetrahedron Lett. 1991, 32, 5817; b) R. Grigg,
Tetrahedron: Asymmetry 1995, 6, 2475.
[7] Patent application: X. Zhang, 2002, WO 01/58588 A1.
[8] G. Kill, J.-P. Fleury, Bull. Soc. Chim. Fr. 1968, 4636.
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Figure 1. Coordination complex 7 (unspecified geometry) consisting of the
ZnII-tBu-BOX catalyst and the azomethine ylide, and the proposed
bipyramidal intermediate 8, involving coordination of the a,b-unsaturated
ester carbonyl group to the metal center.
4238
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Angew. Chem. Int. Ed. 2002, 41, No. 22