Asymmetric palladium(II)-catalyzed cascade reaction giving quaternary amino succinimides by 1,4-addition and a nef-type reaction

Article abstract of DOI:10.1002/anie.201307334

Simple starting materials, high-value products: A dinuclear ferrocene-based Pd^II complex transforms mixtures of racemic N-benzoyl α-amino acids, nitroolefins, acetic anhydride, and manganese acetate into biologically interesting quaternary amin

Full text of DOI:10.1002/anie.201307334

Angewandte
Chemie
DOI: 10.1002/anie.201307334
Cascade Reactions
Asymmetric Palladium(II)-Catalyzed Cascade Reaction Giving
Quaternary Amino Succinimides by 1,4-Addition and a Nef-Type
Reaction**
Manuel Weber, Wolfgang Frey, and Renꢀ Peters*
Chiral succinimides play a vital role in pharmaceutical
sciences.[1] They are typically synthesized by 1,4-additions to
maleimides.[1] The pharmacologically important class of
quaternary a-amino succinimides—formal derivatives of a-
alkyl aspartic acid[2]—has received particular attention from
both academic and industrial laboratories for its benefit for
application in drug design (Figure 1). For instance, introduc-
Scheme 1. Retrosynthetic analysis of N-acyloxy succinimides 4.
azlactone 8, which acts as a synthetic equivalent for the
d2/a1 synthon 7.[13] We speculated that nitroolefins 6 might be
suitable synthetic equivalents for the a2/d0 synthon 5,[14] since
they can act as Michael acceptors[15] and the nitro group might
allow for a subsequent Nef-type reaction,[16] in which Ac2O
and an acetate salt would be involved.[17]
Figure 1. Examples of pharmaceutically relevant a-amino succinimides.
Spiroimide 3 is a precursor to amathaspiramides A–F.
We have recently shown that ferrocene-based pallada-
cycles are capable of catalyzing 1,4-additions of azlactones to
enones.[18] The azlactones could also be generated in situ from
a-amino acid precursors and carboxylic acid anhydrides. We
thus examined racemic N-benzoyl alanine 9a as an azlactone
source in a model reaction with 2-nitrostyrene (6a, Table 1).
tion of succinimides 1 in peptidomimetics results in a high
preference for b-turn type-II/type-II’ conformations.[3,4]
Related N-mesyloxysuccinimides 2 behave as irreversible
mechanism-based inhibitors of serine proteases.[5] Of partic-
ular value is Ranirestat (AS-3201) which is an aldose
reductase inhibitor currently in the final stage of clinical
phase III trials.[6,7] a-Amino succinimide 3 is a late-stage
precursor in the elegant recent total syntheses of all six
amathaspiramides A–F by Fukuyama et al.[8,9]
Table 1: Development of the title reaction.
Despite the value of quaternary a-aminosuccinimides, few
catalytic asymmetric methods are known for a direct catalytic
asymmetric access.[10] Driven by the need for efficient
approaches towards Ranirestat, methods have been devel-
oped for the asymmetric amination of a-carboxylated succin-
imides.[7] Here we report a new cascade reaction[11] for a rapid
divergent asymmetric access to quaternary succinimides 4
using very simple starting materials. This development is
based on the retrosynthetic analysis depicted in Scheme 1.
The quaternary stereocenter[12] should be formed by the
regio-, enantio-, and diastereoselective C4 alkylation of
No.
X
Y M(OAc)n T [8C]
10a
4a
Yield ee
Yield
[%][a]
d.r.[c] ee
[%][a] [%][b]
[%][b]
1[d]
2[d]
3
4
5
6
7
8
9
2
2
2
5
5
5
5
5
5
5
5
0.5 NaOAc 23
46
62
72
14
17
<2
12
61
70
50
5
80
83
85
n.d.
n.d.
–
n.d.
85
17
17
5
>50:1 n.d.
13:1 n.d.
9:1 n.d.
6:1 72
2 NaOAc
2 NaOAc
2 NaOAc
2 KOAc
23
23
50
50
50
50
85
80
91
75
37
29
34
95
7:1 66
3:1 63
4:1 61
4 CsOAc[e]
2 TBAOAc
2 Ca(OAc)2 50
2 Zn(OAc)2 50
2 Mn(OAc)2 50
5 Mn(OAc)2 50
>50:1 76
>50:1 69
>50:1 77
>50:1 81
[*] Dipl.-Chem. M. Weber, Dr. W. Frey, Prof. Dr. R. Peters
Institut fꢀr Organische Chemie, Universitꢁt Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
E-mail: rene.peters@oc.uni-stuttgart.de
81
81
n.d.
10
11
1
[a] Yield determined by H NMR spectroscopy using an internal
standard. [b] Enantiomeric excess determined by HPLC using a chiral
stationary phase. [c] Diastereomeric ratio determined from the 1H NMR
spectrum of the crude product. [d] The reaction was performed in the
absence of n-hexane. [e] CsOAc was generated in situ from Cs2CO3. n.d.:
not determined.
Homepage: http://www.peters.oc.uni-stuttgart.de
[**] This work was financially supported by the Deutsche Forschungs-
gemeinschaft (DFG, PE 818/4-1).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201307334.
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Table 2: Catalytic asymmetric synthesis of a-amino succinimides 4.
As a precatalyst we chose the planar–chiral ferrocene
bisimidazoline bispalladacycle [FBIP-Cl]2 (Figure 2).[19–21]
For catalytic activity this dimeric complex must be activated
by removing the otherwise inert chloro bridges. This is
achieved by reaction with silver salts (AgX) in acetonitrile to
form the monomeric complexes FBIP-X (XÀ = anionic
ligand).[19]
No.
4
R1
R2
Yield [%][a] d.r. [%][b] ee [%][c]
1
2
3
4
5
6
7
8
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Me
Me
Me
Et
nPr
nPr
nPr
nPr
nPr
nPr
nBu
Ph
95
84
92
83
91
78
85
70
86
78
85
67
89
46
59
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
82
87
78
91
93
89
85
85
94
92
94
93
96
95
94
4-Me-C6H4
4-MeO-C6H4
Ph
Ph
3-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
4-Me-C6H4
4-MeO-C6H4
Ph
9
10
11
12
13
14
15
(CH2)2CO2Me 3-MeO-C6H4
Figure 2. The dimeric precatalyst [FBIP-Cl]2 and the monomeric acti-
vated catalyst species FBIP-X.
nPr
nPr
nPr
nPr
iPr
cyclohexyl
[a] Yield of isolated product. [b] Diastereomeric ratio determined from
the 1H NMR spectrum of the crude product. [c] Enantiomeric excess
determined by HPLC using a chiral stationary phase.
Initial attempts provided the 1,4-adduct 10a as the major
product with promising enantioselectivity (Table 1, entries 1–
3).[22] Nitroolefins have already been studied in catalytic 1,4-
addition reactions with azlactones, but regioselective addition
at the C4 azlactone position was accomplished only for
phenylglycine-derived azlactones.[23] With the FBIP catalyst
only the C4 regioisomer has been detected in the present
study. At room temperature, in the absence of an additional
solvent, the Michael adduct was produced in moderate yield
with application of 0.5 equiv of NaOAc. Gratifyingly, the
imide 4a was already found as a side product (Table 1,
entry 1). An excess of NaOAc (2 equiv) provided more 1,4-
adduct, but the amount of imide 4a was not increased
(Table 1, entry 2) and the larger amount of base had a negative
impact on the diastereomeric ratio (d.r.) of 4a.
When n-hexane was used as a cosolvent the ee of 10a
could be slightly increased (Table 1, entry 3). Further exper-
imentation showed that application of higher temperatures,
increased precatalyst loadings (5 mol%), and a higher excess
of Ac2O gave imide 4a as the major product with moderate
enantio- and diastereoselectivity (Table 1, entry 4). Control
experiments showed that the diastereomeric ratio suffered
from a base-catalyzed epimerization (see the Supporting
Information). A number of alternative acetate salts were thus
examined (Table 1, entries 5–10). Acetates with strong ionic
character gave unsatisfactory stereoselectivity (Table 1,
entries 5–7). The use of less basic metal(II) acetates resulted
in diastereomerically pure imide (Table 1, entries 8–10), but
only as a side product, whereas the major product was 10a.
Suitable reactivity was achieved with a larger excess of
Mn(OAc)2 (Table 1, entry 11). Under these conditions the
cascade reaction product 4a was produced as a single
diastereomer in high yield and with good enantioselectivity.
The optimized reaction conditions are practical for differ-
ent racemic N-benzoyl a-amino acids 9 and nitroolefins 6
(Table 2). The imides 4 were always formed as single
diastereomers and isolated in useful yields. In the reaction
with b-nitrostyrene the ee values of 4 increased from R1 = Me
(Table 2, entry 1) to Et (entry 4), nPr (entry 5), and nBu
(entry 11). The substrate with a glutamic acid methyl ester
side chain R1 provided highly enantioenriched 4l (Table 2,
entry 12), which might serve as advanced intermediate toward
the (epimeric) series of amathaspiramides A–F.[8] Regarding
the nitroolefin component, electron-donating (Table 2,
entries 2, 3, 9, and 10) and -withdrawing substituents
(entries 6–8) in meta or para position on the aromatic residues
R2 were tolerated. ortho Substituents impeded the product
formation. The method is also compatible with aliphatic
nitroolefins (Table 2, entries 13–15), which give products 4m–
o as single diastereomers with high ee. When the nitroolefin
was bearing an unbranched alkyl residue (R2 = n-propyl), 4m
was furnished in high yield with 96% ee. This high efficiency
À
was unexpected due to the considerable g-C H acidity of
alkyl substituted nitroolefins, which is comparable to that of
the azlactones. The constitution and relative and absolute
configuration of 4a have been confirmed by X-ray crystal
structure analysis (see structure in Table 2).[24]
A mechanism is suggested in Scheme 2. The catalytic
action of FBIP might be explained by N-coordination of the
in situ generated azlactone 8 to a Pd center,[18c] which triggers
the enolization required for a subsequent conjugate addition
to nitroolefin 6. It seems feasible that this conjugate addition
proceeds by a bimetallic activation mode,[25] in which the
nitroolefin might be simultaneously activated as a Michael
acceptor by the other Pd center, because control experiments
with 10 mol% of related monopalladacycles[26] gave either no
product or 4a was formed with only moderate enantioselec-
tivity (see the Supporting Information).
The constitution and relative configuration of the 1,4-
adduct 10c have been confirmed by X-ray crystal structure
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Scheme 3. Confirmation of the Nef-type reactivity by formation of 15.
electrophilic a-C atom, resulting in the transformation of
a nitro group into a carboxylic acid derivative.[28]
Compounds 4 proved to be valuable synthetic building
blocks providing access to interesting new product classes
(Scheme 4). N-Hydroxyimide 16 was obtained by treatment
Scheme 2. Proposed mechanism of the title reaction and structural
proof of the 1,4-adduct intermediate 10c by X-ray analysis.
analysis (Scheme 2).[24] The assumption that 10 is an inter-
mediate en route to imide 4 has been confirmed by control
experiments, in which isolated 10a was transformed to 4a
under the reaction conditions of the tandem process. When
we applied the conditions listed in Table 1 (entry 4), diaste-
reomerically pure 10a (84% ee) provided the imide 4a in
73% yield (d.r. 6:1) with 83% ee. O-Acylation of the
nitronate derivative of 10 might give the dipolar species 11,
which could undergo a subsequent 1,2-addition of acetate to
Scheme 4. Examples of the derivatization of title compounds 4 and
the X-ray crystal structure of the bicyclic oxazoline 18.
of 4k with morpholine in CH2Cl2 at À358C. It could be further
employed to generate the 4-substituted analogue 17 of the
known suicide inhibitors 2 by O-sulfonylation using a steri-
cally demanding base. The N-OMs moiety in 17 also
permitted access to succinimide 18 with an annellated oxazo-
line featuring two adjacent quaternary stereocenters. The
constitution of this novel chiral bicyclic [3.3.0] scaffold has
been determined by X-ray crystal analysis.
In summary, we have developed a regio-, diastereo-, and
enantioselective cascade reaction to prepare biologically
interesting a-alkyl-a-aminosuccinimides from simple sub-
strates. The formal derivatives of a-alkyl aspartic acids are
generated by in situ formation of azlactones, which undergo
a C4-regioselective asymmetric conjugate addition to nitro-
olefins. Succinimide formation proceeds through a Nef-type
transformation. Crucial for high stereoselectivity is the use of
a divalent acetate salt like Mn(OAc)2 to avoid epimerization.
We have showcased the synthetic value of the products by
describing a rapid access to a suicide inhibitor analogue and
a novel bicyclic [3.3.0] scaffold featuring two adjacent
quaternary stereocenters.
=
the C N bond generating the nucleophilic nitrogen center in
12. This in turn should be suitable for a subsequent intra-
molecular azlactone ring opening giving ammonium oxide 13.
The latter is expected to undergo elimination of acetic acid to
form iminium oxide 14. A subsequent acyl transfer would
finally furnish the neutral N-acetoxysuccinimide 4 after
a cascade of several steps.
We attempted to obtain further information about the
mechanism of the reaction by continuous NMR monitoring.
Since Mn(OAc)2 is paramagnetic, NaOAc was used as the
base. In order to increase the chances of detecting and
identifying intermediates that follow the confirmed inter-
mediate 10a, the latter served as the starting material. During
the course of this reaction only 10a and product 4a (including
its epimer) were detected (e.g. after: 1 h: 54% 10a and 46%
4a; 3.5 h: 10% 10a and 90% 4a). This indicates that the
proposed nitronate acylation arguably proceeds as the slowest
step starting from 10a.[27]
Since other intermediates were not observable by
1H NMR spectroscopy, the isopropyl ester 10a’ was formed
from 10a by azlactone ring opening with iPrOH. This change
should retard the imide formation, as the ester is less
electrophilic than the azlactone carbonyl moiety. We then
examined the reaction of 10a’ with NaOAc, HOAc, and Ac2O
(Scheme 3). Formation of the iminooxazine 15 (next to
unreacted 10a’ and traces of 4a) confirms a Nef-type reaction
pathway. In this case the benzamide function has trapped an
Received: August 20, 2013
Published online: October 21, 2013
Keywords: azlactones · Nef reaction · nitroolefins ·
.
palladacycles · quaternary amino acids
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[13] Reviews on azlactones: a) R. A. Mosey, J. S. Fisk, J. J. Tepe,
Tetrahedron: Asymmetry 2008, 19, 2755; b) A.-N. R. Alba, R.
Rios, Chem. Asian J. 2011, 6, 720.
[14] D. Seebach, Angew. Chem. 1979, 91, 259; Angew. Chem. Int. Ed.
Engl. 1979, 18, 239.
[1] a) Review: P. Chauhan, J. Kaur, S. S. Chimni, Chem. Asian J.
2013, 8, 328; examples: b) R. Shintani, W.-L. Duan, T. Hayashi, J.
Am. Chem. Soc. 2006, 128, 5628; c) G. Bartoli, M. Bosco, A.
Carlone, A. Cavalli, M. Locatelli, A. Mazzanti, P. Ricci, L.
Sambri, P. Melchiorre, Angew. Chem. 2006, 118, 5088; Angew.
Chem. Int. Ed. 2006, 45, 4966.
[15] a) N. Ono, The nitro group in organic synthesis, Wiley-VCH,
New York, 2001.
[2] a) H. Vogt, S. Brꢀse, Org. Biomol. Chem. 2007, 5, 406; b) C.
Cativiela, M. D. Dꢁaz-de-Villegas, Tetrahedron: Asymmetry
2007, 18, 569.
[16] Reviews about the Nef reaction: a) R. Ballini, M. Petrini,
Tetrahedron 2004, 60, 1017; b) H. W. Pinnick, Org. React. 1990,
38, 655.
[3] D. Obrecht, C. Abrecht, M. Altorfer, U. Bohdal, A. Grieder, M.
Kleber, P. Pfyffer, K. Mꢂller, Helv. Chim. Acta 1996, 79, 1315.
[4] Aminosuccinimides also display, e.g., anticonvulsant activity and
play a crucial role in protein splicing and other posttranslational
protein modifications: a) M. Park, J. Lee, J. Choi, Bioorg. Med.
Chem. Lett. 1996, 6, 1297; b) Y. Shao, M.-Q. Xu, H. Paulus,
Biochemistry 1995, 34, 10844; c) P. E. Thompson, N. L. E.
Wijaya, F. M. Ng, M. T. W. Hearn, Bioorg. Med. Chem. Lett.
1993, 3, 1625.
[5] a) W. C. Groutas, M. J. Brubaker, M. A. Stanga, J. C. Castrisos,
J. P. Crowley, E. J. Schatz, J. Med. Chem. 1989, 32, 1607; b) A. D.
Abell, M. D. Oldham, J. Org. Chem. 1997, 62, 1509; c) A. D.
Abell, M. D. Oldham, Bioorg. Med. Chem. Lett. 1999, 9, 497.
[6] a) T. Negoro, M. Murata, S. Ueda, B. Fujitani, Y. Ono, A.
Kuromiya, M. Komiya, K. Suzuki, J.-i. Matsumoto, J. Med.
Chem. 1998, 41, 4118; b) M. Kurono, I. Fujiwara, K. Yoshida,
Biochemistry 2001, 40, 8216; c) V. Bril, R. A. Buchanan,
Diabetes Care 2004, 27, 2369; d) M. Kurono, A. Fujii, M.
Murata, B. Fujitani, T. Negoro, Biochem. Pharmacol. 2006, 71,
338.
[7] Selected approaches towards AS-3201: a) M. Mashiko, K. Hara,
D. Tanaka, Y. Fujiwara, N. Kumagai, M. Shibasaki, J. Am. Chem.
Soc. 2007, 129, 11342; b) M. Mashiko, N. Kumagai, M. Shibasaki,
Org. Lett. 2008, 10, 2725; c) M. Mashiko, N. Kumagai, M.
Shibasaki, J. Am. Chem. Soc. 2009, 131, 14990; d) B. M. Trost, M.
Osipov, G. Dong, Org. Lett. 2010, 12, 1276; e) formal total
synthesis: R. He, X. Wang, T. Hashimoto, K. Maruoka, Angew.
Chem. 2008, 120, 9608; Angew. Chem. Int. Ed. 2008, 47, 9466.
[8] K. Chiyoda, J. Shimokawa, T. Fukuyama, Angew. Chem. 2012,
124, 2555; Angew. Chem. Int. Ed. 2012, 51, 2505.
[9] Other approaches towards amathaspiramides: a) C. C. Hughes,
D. Trauner, Angew. Chem. 2002, 114, 4738; Angew. Chem. Int.
Ed. 2002, 41, 4556; b) K. Sakaguchi, M. Ayabe, Y. Watanabe, T.
Okuda, K. Kawamura, T. Shiada, Y. Ohfune, Org. Lett. 2008, 10,
5449.
[17] J. Guillaumel, P. Demerseman, J.-M. Clavel, R. Royer, N.
Platzer, C. Brevard, Tetrahedron 1980, 36, 2459.
[18] a) M. Weber, S. Jautze, W. Frey, R. Peters, J. Am. Chem. Soc.
2010, 132, 12222; b) M. Weber, W. Frey, R. Peters, Adv. Synth.
Catal. 2012, 354, 1443; c) M. Weber, S. Jautze, W. Frey, R. Peters,
Chem. Eur. J. 2012, 18, 14792; d) M. Weber, R. Peters, J. Org.
Chem. 2012, 77, 10846; e) M. Weber, W. Frey, R. Peters, Chem.
Eur. J. 2013, 19, 8342; f) M. Weber, J. E. M. N. Klein, B.
Miehlich, W. Frey, R. Peters, Organometallics 2013, DOI:
10.1021/om400360d.
[19] a) S. Jautze, P. Seiler, R. Peters, Angew. Chem. 2007, 119, 1282;
Angew. Chem. Int. Ed. 2007, 46, 1260; b) S. Jautze, P. Seiler, R.
Peters, Chem. Eur. J. 2008, 14, 1430; c) S. Jautze, S. Diethelm, W.
Frey, R. Peters, Organometallics 2009, 28, 2001; d) S. Jautze, R.
Peters, Angew. Chem. 2008, 120, 9424; Angew. Chem. Int. Ed.
2008, 47, 9284; e) S. H. Eitel, S. Jautze, W. Frey, R. Peters, Chem.
Sci. 2013, 4, 2218.
[20] a) J. Dupont, M. Pfeffer, Palladacycles, Wiley-VCH, Weinheim,
2008; b) C. J. Richards in Chiral Ferrocenes in Asymmetric
Catalysis (Eds.: L.-X. Dai, X.-L. Hou), Wiley-VCH, Weinheim,
2010, pp. 337 – 368.
[21] For recent applications of imidazolines as chiral ligands in
asymmetric catalysis, see for example, a) S. Nakamura, K.
Hyodo, Y. Nakamura, N. Shibata, T. Toru, Adv. Synth. Catal.
2008, 350, 1443; b) T. Arai, N. Yokoyama, Angew. Chem. 2008,
120, 5067; Angew. Chem. Int. Ed. 2008, 47, 4989; c) review: H.
Liu, D.-M. Du, Adv. Synth. Catal. 2009, 351, 489. Selected recent
applications of bisimidazoline ligands: d) H. Huang, R. Peters,
Angew. Chem. 2009, 121, 612; Angew. Chem. Int. Ed. 2009, 48,
604; e) H. Liu, D.-M. Du, Adv. Synth. Catal. 2010, 352, 1113;
f) M. Ohara, S. Nakamura, N. Shibata, Adv. Synth. Catal. 2011,
353, 3285; g) K. Hyodo, S. Nakamura, K. Tsuji, T. Ogawa, Y.
Funahashi, N. Shibata, Adv. Synth. Catal. 2011, 353, 3385; h) M.
Weiss, W. Frey, R. Peters, Organometallics 2012, 31, 6365.
[22] Selected reviews about asymmetric 1,4 additions: a) J. Chris-
toffers, A. Baro, Angew. Chem. 2003, 115, 1726; Angew. Chem.
Int. Ed. 2003, 42, 1688; b) A. Alexakis, J.-E. Bꢀckvall, N. Krause,
O. Pꢃmies, M. Diꢄguez, Chem. Rev. 2008, 108, 2796; c) S. R.
Harutyunyan, T. den Hartog, K. Geurts, A. J. Minnaard, B. L.
Feringa, Chem. Rev. 2008, 108, 2824; d) D. Enders, C. Wang, J. X.
Liebich, Chem. Eur. J. 2009, 15, 11058.
[10] For a direct access to racemic bicyclic products, see: Z. Xu, F.
De Moliner, A. P. Cappelli, C. Hulme, Angew. Chem. 2012, 124,
8161; Angew. Chem. Int. Ed. 2012, 51, 8037.
[11] Reviews on cascade reactions: a) L. F. Tietze, A. Modi, Med.
Res. Rev. 2000, 20(4), 304; b) L. F. Tietze, Pure Appl. Chem.
2004, 76, 1967; c) D. Enders, C. Grondal, M. R. M. Huettl,
Angew. Chem. 2007, 119, 1590; Angew. Chem. Int. Ed. 2007, 46,
1570; d) H. Clavier, H. Pellissier, Adv. Synth. Catal. 2012, 354,
3347; e) L.-Q. Lu, J.-R. Chen, W.-J. Xiao, Acc. Chem. Res. 2012,
45, 1278. Asymmetric multi-component reactions: f) C.
de Graaff, E. Ruijter, R. V. A. Orru, Chem. Soc. Rev. 2012, 41,
3969; g) “Catalytic Asymmetric Multi-Component Reactions”:
J. Seayad, B. List in Multicomponent Reactions (Eds.: J. Zhu, H.
Bienayme), Wiley-VCH, Weinheim, 2005, 277 – 299; h) E.
Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. 2011,
123, 6358; Angew. Chem. Int. Ed. 2011, 50, 6234.
[23] J. Alemꢅn, A. Milelli, S. Cabrera, E. Reyes, K. A. Jørgensen,
Chem. Eur. J. 2008, 14, 10958.
[24] CCDC 936656 (4a), 936657 (10c), and 936658 (20) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[25] Selected reviews about bimetallic catalysis: a) J. Park, S. Hong,
Chem. Soc. Rev. 2012, 41, 6931; b) M. Shibasaki, M. Kanai, S.
Matsunaga, N. Kumagai, Acc. Chem. Res. 2009, 42, 1117; c) M.
Shibasaki, S. Matsunaga, Chem. Soc. Rev. 2006, 35, 269.
[26] a) M. E. Weiss, D. F. Fischer, Z.-q. Xin, S. Jautze, W. B.
Schweizer, R. Peters, Angew. Chem. 2006, 118, 5823; Angew.
Chem. Int. Ed. 2006, 45, 5694; b) Z.-q. Xin, D. F. Fischer, R.
Peters, Synlett 2008, 1495; c) D. F. Fischer, A. Barakat, Z.-q. Xin,
M. E. Weiss, R. Peters, Chem. Eur. J. 2009, 15, 8722; d) R. Peters,
Z.-q. Xin, F. Maier, Chem. Asian J. 2010, 5, 1770; e) S. H. Eitel,
[12] a) J. Christoffers, A. Baro, Quaternary Stereocenters: Challenges
and Solutions for Organic Synthesis, Wiley-VCH, Weinheim,
2005; b) J. Christoffers, A. Baro, Adv. Synth. Catal. 2005, 347,
1473.
13226 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 13223 –13227

Angewandte
Chemie
M. Bauer, D. Schweinfurth, N. Deibel, B. Sarkar, H. Kelm, H.-J.
Krꢂger, W. Frey, R. Peters, J. Am. Chem. Soc. 2012, 134, 4683.
[27] ESI-MS investigations led to the same conclusion.
[28] B. Mendler, U. Kazmaier, V. Huch, M. Veith, Org. Lett. 2005, 7,
2643. These authors found a Nef-type reaction pathway via
nitrile oxide intermediates. In the present study nitrile oxide
intermediates might also be involved; however, trapping experi-
ments with methylacrylate gave no 1,3-dipolar cycloaddition
products.
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