Catalytic asymmetric synthesis of α-quaternary proline derivatives by 1,3-dipolar cycloaddition of α-silylimines

Article abstract of DOI:10.1002/anie.201203828

Going pro: The title reaction between α-silylimines and activated olefins proceeds in the presence of a Cu^I/DTBM-Segphos catalyst system with excellent diastereoselectivity and enantioselectivity. This process provides straightforward access to highly enantioenriched 5-unsubstituted α-quaternary proline derivatives. TMS=trimethylsilyl, DTBM-Segphos=5,5'- bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole. Copyright

Full text of DOI:10.1002/anie.201203828

Angewandte
Chemie
DOI: 10.1002/anie.201203828
Asymmetric Catalysis
Catalytic Asymmetric Synthesis of a-Quaternary Proline Derivatives
by 1,3-Dipolar Cycloaddition of a-Silylimines**
Jorge Hernꢀndez-Toribio, Silvia Padilla, Javier Adrio,* and Juan C. Carretero*
In memory of Christian G. Claessens
Pyrrolidines and derivatives are privileged scaffolds in
synthetic and medicinal chemistry, and are present in
a myriad of natural products and biologically active com-
pounds.[1] In particular, modified proline derivatives have
been extensively used as conformationally rigid cores in
peptidomimetics.[2] In this area, a-quaternary amino acids
have received great attention since this type of unit improves
the lipophilicity and restricts the conformational flexibility of
the peptidic chain, and therefore has a great impact in the
biological activity.[3] Furthermore, a-quaternary prolines have
found wide application as chiral synthons and organocatalysts
in organic synthesis.[4] As a consequence, a variety of
strategies for their enantioselective preparation, mainly
based on the funtionalization of l-proline, have been
reported.[5] Despite this progress, the development of efficient
asymmetric methodologies to access densely substituted a-
quaternary prolines are still in high demand.
unsubstituted pyrrolidines,[12] a substitution pattern not acces-
sible by the typical process from Schiff bases of amino acid
esters (Scheme 1a). However, despite this structural interest,
as far as we are aware, their use in catalytic asymmetric
processes remains undocumented.
The catalytic asymmetric 1,3-dipolar cycloaddition of
azomethine ylides with activated olefins is one of the most
reliable and straightforward approaches to the preparation of
optically active highly substituted 2-carboxylate pyrrolidine
derivatives. Since the seminal contributions of Zhang and co-
workers[6] and Jørgensen and co-workers[7] in the metal-
catalyzed enantioselective preparation of 2,5-disubstituted
pyrrolidine derivatives using Schiff bases of amino acid esters
as azomethine precursors, outstanding progress has been
achieved in this research area.[8,9] In this context, and because
of its high reactivity, glycinate imines are the most frequently
employed azomethine ylide precursors in this reaction.[10,11]
a-Silylimines constitute a different and much less studied
type of azomethine ylide precursor, which leads to 5-
Scheme 1. 1,3-Dipolar cycloaddition of a-silylimines.
The great efficiency of Schiff bases of amino acid esters as
azomethine ylide precursors relies on the formation of a rigid
five-membered N,O-bidentate metalated azomethine (Sche-
me 1b). Thus, we reasoned that the presence of a coordinating
group in the a-silylimine, such as an ester moiety, could
enhance the reactivity and stereoselectivity of the process by
means of the formation of a presumed five-membered
metalated intermediate, which would approach the chiral
ligand to the reactive center (Scheme 1c). With the aim of
expanding the scope of the pyrrolidine adducts accessible by
catalytic asymmetric 1,3-dipolar cycloaddition, we report
herein the first enantioselective procedure involving a-
silylimines as azomethine precursors to provide 5-unsubsti-
tuted quaternary proline derivatives.
To evaluate the viability of the process, we chose as
a model reaction the cycloaddition of ethyl-(trimethylsilyl)-
methyliminopropanoate (1a) with N-phenylmaleimide (2;
Table 1). We began our investigation by examining the silver-
catalyzed reaction in the presence of a variety of chiral ligands
in toluene as the solvent. Although good yields and high
diastereoselectivities were obtained with the chiral ligands 4–
[*] J. Hernꢀndez-Toribio, S. Padilla, Dr. J. Adrio, Prof. Dr. J. C. Carretero
Departamento de Quꢁmica Orgꢀnica, Facultad de Ciencias,
Universidad Autꢂnoma de Madrid, Cantoblanco 28049 Madrid
(Spain)
E-mail: javier.adrio@uam.es
juancarlos.carretero@uam.es
[**] Financial support of this work from the Ministerio de Economꢁa
y Competitividad (MINECO, CTQ2009-07791), the Consejerꢁa de
Educaciꢂn de la Comunidad de Madrid (project AVANCAT; S2009/
PPQ-1634), and Consejerꢁa de Educaciꢂn de la Comunidad de
Madrid, Universidad Autꢂnoma de Madrid (UAM/CAM project
CCG-10-UAM/PPQ-5853) is gratefully acknowledged. S.P. thanks
the MINECO for a predoctoral contract. We thank the Takasago
Company (Dr. Taichiro Touge) for a generous loan of Segphos chiral
ligands.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203828.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Optimization studies for the model reaction.
Table 2: Scope of the 1,3-dipolar cycloaddition of a-silylimines with N-
phenylmaleimide (2).
Entry
R
T [8C] t [h] Product Yield [%][a,b]
ee
[%][c]
1
2
3
4
5
6
7
8
iBu
RT
RT
RT
RT
60
60
60
60
RT
60
60
60
60
RT
3
3
12
3
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3p
58
78
80
61
64
60
45
65
79
64
78
92
98
96
93
94
93
92
92
96
95
94
Ph(CH2)2
CH2 =CH(CH2)2
Ph
4-MeC6H4
4-ClC6H4
4-FC6H4
4-CNC6H4
4-MeOC6H4
3-MeC6H4
2-napht
2-ClC6H4
mesityl
12
12
12
12
12
12
12
12
12
3
Entry
Metal source [M]
L*
Yield [%][a]
trans/cis[b]
ee [%][c]
1
2
3
4
5
6
7
8
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Cu(OAc)2
CuOAc
CuBr
4
5
6
7
8
8
8
8
8
8
8
57
68
75
72
73
–
66
56
71
40
45
10:90
10:90
10:90
10:90
>95:5
–
>95:5
>95:5
>95:5
>95:5
>95:5
0
0
0
0
81
–
88
92
92
92
82
9
10
11
12
13
14
[d]
–
–
[d]
H
50
81
[d]
9
CuPF6
CuPF6
[a] Yield of isolated product. [b] Only the trans isomer was detected by
1H NMR spectroscopy. [c] Determined by HPLC. [d] No cycloaddition
product was detected. RT=room temperature.
10[e]
11[f]
[d]
[d]
CuPF6
[a] Yield of isolated product. [b] Determined by 1H NMR spectroscopy.
[c] Determined by HPLC. [d] CuPF6 =[Cu(CH3CN)4]PF6. [e] Reaction
carried out with 1.5 equiv of 1a. [f] 5 mol% of catalysts. TMS=trime-
thylsilyl.
and configurational assignment of 3g was unequivocally
established by X-ray diffraction analysis.[15] In contrast, no
cycloaddition product was isolated from the sterically more
demanding ortho-substituted aromatic silylimines 1m and 1n
(entries 12 and 13). Finally, the unsubstituted silylimine 1p,
derived from ethyl glyoxalate, was also a suitable substrate,
albeit proceeding with a lower enantioselectivity (entry 14).
Interestingly, the cycloaddition also proceeded with the
nonsymmetrical and more sterically demanding N-phenyl-3-
methylmaleimide (9). The reaction with silylimine 1c
afforded a 2:1 mixture of regioisomers of the corresponding
pyrrolidines bearing two quaternary stererocenters
[Scheme 2, Eq. (1)]. The major regioisomer, 10a, was isolated
in 42% yield and excellent enantioselectivity (95% ee),
whereas the isomer 10b having two adjacent quaternary
7, disappointingly, the pyrrolidine adduct 3a was obtained in
racemic form (entries 1–4). Interestingly, a complete inver-
sion in the cis/trans diastereoselectivity and a remarkable
81% ee was observed in the presence of the bulkier and more
electron-rich DTBM-Segphos ligand 8 (entry 5). Further
optimization of the reaction conditions with this ligand was
then undertaken. We observed a substantial enhancement in
the enantioselectivity upon employing CuI salts as catalysts
(entries 7–9), and in particular [Cu(CH3CN)4]PF6 provided
the best result (entry 9). The use of other solvents[13] or the
presence of an external base was less effective. We also
confirmed that the presence of 3 equivalents of the silylimine
was necessary to obtain good yields (a moderate 40% yield
was obtained using 1.5 equivalents of the silylimine; entry 10).
The cycloaddition can be also performed with a lower catalyst
loading (5 mol%), albeit with significant erosion in the
reactivity and the enantioselectivity (entry 11).[14]
With these optimized reaction conditions, we next studied
this cycloaddition with a variety of substituted silylimines. As
summarized in Table 2, the reaction worked well for alkyl-
substituted a-silylimines, thus affording the trans isomers with
nearly complete diastereoselectivity (only the trans isomer
1
was detected by H NMR spectroscopy) and excellent enan-
tioselectivity (entries 1–3). Similarly, the catalytic system was
effective with a variety of para-substituted aromatic silyli-
mines having both electron-donating and electron-withdraw-
ing substituents (entries 4–9), as well as meta-substituted
aromatic substrates (entries 10 and 11). The stereochemical
Scheme 2.
2
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
stereocenters was obtained in 21% yield and 45% ee. In view
of the good reactivity profile of this catalyst system, we next
turned our attention to the challenging cyclic silylimines.
Pleasingly, the reaction with the a-silylimine 1q proceeded
smoothly, thus leading to the pyrrolidine spirolactone[16] 11
with excellent yield and complete diastereo- and enantiose-
lectivity [Scheme 2, Eq. (2)].
Scheme 3.
Finally, to further explore the scope of this asymmetric
[3+2] cycloaddition of a-silylimines we extended the study to
acyclic dipolarophiles. Given the excellent properties of the
sulfonyl group both as an electron-withdrawing group and as
an easily removed substituent,[17] we tested a variety of a,b-
unsaturated sulfones as olefin partners (Table 3). The reac-
tion of the silylimines 1a and 1c with phenylvinylsulfone (12)
Table 3: 1,3-Dipolar cycloaddition of a-silylimines with vinylsulfones.
Scheme 4. Desulfonylation reactions. DMAP=4-dimethylaminopyri-
dine
Entry R1
R2 R3
R4
Product Yield [%][a] ee [%][b]
1[c]
2
3
Me
Me
Et
Et
H
H
H
H
H
H
H
H
SO2Ph
SO2Ph
H
H
H
15a
15a
15c
16a
16a
17a
17c
17r
48
75
72
70
78
80
78
89
55
83
94
73
79
97
97
99
lidines 19 and 20 were obtained by reductive cleavage of the
sulfonyl group without any detectable epimerization by
treatment with Na(Hg). It is interesting to note that the 2,3-
dicarboxylate ester pyrrolidine 20 displays the opposite
regioselectivity to that obtained using typical acrylate dipolar-
ophiles.[20] In contrast, the basic elimination of the sulfonyl
group of 17r provided the pyrroline 21 selectively.
Ph(CH2)2 Et
4
Me
Me
Me
Et
Et
5[d]
6
Et CO2Me
7
8
Ph(CH2)2 Et CO2Me
Me Me CO2Me
[a] Yield of isolated product. [b] Determined by HPLC. [c] Reaction
To gain some insight into the reaction mechanism of this
cycloaddition, some experiments were conducted. First, the
reaction of the silylimine 1a with N-phenylmaleimide (2)
catalyzed by [Cu(CH3CN)4]PF6/DTBM-Segphos was moni-
tored by ESI-MS (Scheme 5; R = Me). After 10 minutes we
were able to detect the presumed ions corresponding to the
Cu/DTBM-Segphos complex 22 (m/z 1241.6), Cu/DTBM-
Segphos/desilylated azomethine complex 23 (m/z 1370.7), and
performed in toluene. [d] (R)-MeO-biphep was used as the ligand; see
the Supporting Information for the ligand structure.
under the optimized reaction conditions (but using THF as
the solvent), afforded the corresponding sulfonyl pyrrolidines
15a and 15c with excellent diastereoselectivity (only the trans
diastereomers were detected by 1H NMR spectroscopy), and
83% and 94% ee, respectively (entries 2 and 3). The reaction
of 1a with 1,1-(bissulfonyl)ethylene (13) also proceeded
efficiently, thus leading to the adduct 16a in 73% ee
(entry 4). In this case, the asymmetric induction was enhanced
to 79% ee when the MeO-biphep ligand was used (entry 5).
Encouraged by these results we also tested the unsymmetri-
cally disubstituted Z-sulfonyl acrylate 14.[18] The [3+2] cyclo-
additions with the silylimines 1a, 1c, and 1r, catalyzed by CuI/
DTBM-segphos, took place with nearly complete regioselec-
tivity, diastereoselectivity, and enantioselectivity (entries 6–
8). According to the previous results from our research group
in other 1,3-dipolar cycloadditions of Z-sulfonyl acrylates, the
regioselectivity was controlled by the sulfonyl group.[19] We
also tested the cycloaddition of the cyclic a-silylimine 1q with
dipolarophile 14, thereby providing the pyrrolidine spirolac-
tone 17q as a single isomer in 81% ee (Scheme 3).
The usefulness of sulfonylpyrrolidines to provide a-
quaternary proline derivatives was next demonstrated by
the desulfonylation reactions shown in Scheme 4. The pyrro-
Scheme 5. Proposed mechanism.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
2006, 2873; g) M. Bonin, A. Chauveau, L. Micouin, Synlett 2006,
2349; h) S. Husinec, V. Savic, Tetrahedron: Asymmetry 2005, 16,
2047; i) I. Coldham, R. Hufton, Chem. Rev. 2005, 105, 2765; j) C.
Nꢁjera, J. M. Sansano, Angew. Chem. 2005, 117, 6428; Angew.
Chem. Int. Ed. 2005, 44, 6272.
Cu/DTBM-Segphos/cycloaddition product 24 (m/z 1543.7;
see the Supporting Information for details). These data
suggest that the desilylation step, presumably promoted by
the excess of imine substrate, takes place before the cyclo-
addition reaction. Accordingly, when silyl scavengers such as
pyridine, 2,6-lutidine or CsF were used as additives the
amount of the starting sylilimine 1 could be reduced from 3 to
1.5 equivalents to achieve full conversion.[21] On the basis of
these data, a simplified plausible mechanism is shown in
Scheme 5. Coordination of the silylimine 1 to the chiral
DTBM-Segphos/CuI catalyst 22 and desilylation (promoted
by the excess of starting imine 1 or an external base such as
pyridine, 2,6-lutidine, or CsF) would lead to the key metal-
bound azomethine ylide dipole 23, whose subsequent cyclo-
addition with 2 would provide the pyrrolidine product and the
recovery of the catalyst 22.
In summary, an efficient catalytic asymmetric protocol for
the CuI-catalyzed 1,3-dipolar cycloaddition of a-silylimines
and activated olefins has been described. A variety of a-
quaternary proline derivatives were obtained with good yields
and excellent levels of diastereoselectivity and enantiocontrol
with a variety of dipolarophiles, such as maleimides (up to
99% ee) and a,b-unsaturated sulfones (up to 99% ee). The
use of the bulky DTBM-Segphos ligand proved to be crucial
for attaining this high enantioselectivity.
[9] For selected recent references, see: copper catalysts: a) M.
Potowski, M. Schꢂrmann, H. Preut, A. P. Antonchick, H.
Waldmann, Nat. Chem. Biol. 2012, 8, 428; b) E. Conde, D.
Bello, A. de Cꢃzar, M. Sꢁnchez, M. A. Vꢁzquez, F. P. Cossꢄo,
Chem. Sci. 2012, 3, 1486; c) M. Gonzꢁlez-Esguevillas, J. Adrio,
J. C. Carretero, Chem. Commun. 2012, 48, 2149; silver catalysts:
d) M.-C. Tong, J. Li, H.-Y. Tao, Y.-X. Li, C.-J. Wang, Chem. Eur.
J. 2011, 17, 12922; e) T.-L. Liu, Z.-L. He, Q.-H. Li, H.-Y. Tao, C.-
J. Wang, Adv. Synth. Catal. 2011, 353, 1713; f) Y. Yamashita, T.
Imaizumi, S. Kobayashi, Angew. Chem. 2011, 123, 4995; Angew.
Chem. Int. Ed. 2011, 50, 4893; g) Z.-Y. Xue, X. Fanga, C.-J.
Wang, Org. Biomol. Chem. 2011, 9, 3622; nickel catalysts: h) T.
Arai, N. Yokoyama, A. Mishiro, H. Sato, Angew. Chem. 2010,
122, 8067; Angew. Chem. Int. Ed. 2010, 49, 7895; calcium
catalysts: i) T. Tsubogo, S. Saito, K. Seki, Y. Yamashita, S.
Kobayashi, J. Am. Chem. Soc. 2008, 130, 13321; iron catalysts:
j) H. Wu, B. Wang, H. Liu, L. Wang, Tetrahedron 2011, 67, 1210;
gold catalysts: k) M. Martꢄn-Rodrꢄguez, C. Nꢁjera, J. M. San-
sano, A. de Cꢃzar, F. P. Cossꢄo, Chem. Eur. J. 2011, 17, 14224.
[10] For a systematic study on other types of Schiff bases of amino
acid esters, other than glycinates, see C. Nꢁjera, M. de Gracia R-
etamosa, M. J. Sansano, Angew. Chem. 2008, 120, 6144; Angew.
Chem. Int. Ed. 2008, 47, 6055. See also Ref. [8].
[11] Other types of azomethine ylide precursors have been recently
applied in catalytic asymmetric processes. Azlactones: a) A. D.
Melhado, M. Luparia, F. D. Toste, J. Am. Chem. Soc. 2007, 129,
12638. a-iminophosphonates: b) Y. Yamashita, X.-X. Guo, R.
Takashita, S. Kobayashi, J. Am. Chem. Soc. 2010, 132, 3262. a-
iminonitriles: c) R. Robles-Machꢄn, I. Alonso, J. Adrio, J. C.
Carretero, Chem. Eur. J. 2010, 16, 5286. N-(2-pyridylmethyl)i-
mines: d) S. Padilla, R. Tejero, J. Adrio, J. C. Carretero, Org.
Lett. 2010, 12, 5608.
[12] a) K. Achiwa, M. Sekiya, Tetrahedron Lett. 1982, 23, 2589; b) N.
Imai, Y. Terao, K. Achiwa, Chem. Pharm. Bull. 1987, 35, 2085;
c) O. Tsuge, S. Kanemasa, A. Hatada, K. Matsuda, Bull. Chem.
Soc. Jpn. 1986, 59, 2537; d) M. Komatsu, H. Okada, T. Akaki, Y.
Oderaotoshi, S. Minakata, Org. Lett. 2002, 4, 3505.
Received: May 17, 2012
Revised: June 28, 2012
Published online: && &&, &&&&
Keywords: asymmetric catalysis · azomethine ylides · copper ·
.
cycloaddition · silanes
[1] For reviews, see: a) J. P. Michael, Nat. Prod. Rep. 2008, 25, 139;
b) S. G. Pyne, A. S. Davis, N. J. Gates, K. B. Lindsay, T. Machan,
M. Tang, Synlett 2004, 2670; c) Y. Cheng, Z.-T. Huang, M.-X.
Wang, Curr. Org. Chem. 2004, 8, 325.
[2] For recent examples, see: a) B. Song, M. G. Bomar, P. Kibler, K.
Kodukula, A. K. Galande, Org. Lett. 2012, 14, 732; b) L. R.
Whitby, Y. Ando, V. Setola, P. K. Vogt, B. L. Roth, D. L. Boger, J.
Am. Chem. Soc. 2011, 133, 10184.
[3] a) P. Maity, B. Kçnig, Biopolymers 2008, 90, 8; b) T. Kan, Y.
Kawamoto, T. Asakawa, T. Furuta, T. Fukuyama, Org. Lett.
2008, 10, 169; c) S. Pizzarello, Acc. Chem. Res. 2006, 39, 231.
[4] For reviews, see: a) C. Grondal, M. Jeanty, D. Enders, Nat.
Chem. 2010, 2, 167; b) Proc. Natl. Acad. Sci. USA 2010, 107,
special feature issue on organocatalysis.
[13] Poorer results were obtained with other solvents such as THF
(65% conv., 12 h, 91% ee), a,a,a-trifluorotoluene (50% conv.,
12 h, 90% ee), and CH2Cl2 (85% conv., 12 h, 88% ee).
[14] No cycloaddition was observed under the optimal reaction
conditions with the phenyl-substituted a-silylmine 1s, thus
showing the key activating role of the ester moiety.
[5] For a review, see: a) M. I. Calaza, C. C. Cativiela, Eur. J. Org.
Chem. 2008, 3427. For recent references, see: b) P. Tuzina, P.
Somfai, Org. Lett. 2009, 11, 919; c) C. Caupꢀne, G. Chaume, L.
Ricard, T. Brigaud, Org. Lett. 2009, 11, 209.
[6] J. M. Longmire, B. Wang, X. Zhang, J. Am. Chem. Soc. 2002, 124,
13400.
[7] A. S. Gothelf, K. V. Gothelf, R. J. Hazell, K. A. Jørgensen,
Angew. Chem. 2002, 114, 4410; Angew. Chem. Int. Ed. 2002, 41,
4236.
[8] For recent reviews, see: a) J. Adrio, J. C. Carretero, Chem.
Commun. 2011, 47, 6784; b) C. Nꢁjera, J. M. Sansano, Top.
Heterocycl. Chem. 2008, 12, 117; c) L. M. Stanley, M. P. Sibi,
Chem. Rev. 2008, 108, 2887; d) H. Pellissier, Tetrahedron 2007,
63, 3235; e) G. Pandey, P. Banerjee, S. R. Gadre, Chem. Rev.
2006, 106, 4484; f) T. M. V. D. Pinho e Melo, Eur. J. Org. Chem.
[15] CCDC 846895 (3g) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[16] Pyrrolidine spirolactones have been used as intermediates in
natural product synthesis. For instance, see: a) M. Sun, H. Lu, Y.-
Z. Wang, H. Yang, H.-M. Liu, J. Org. Chem. 2009, 74, 2213;
b) M. H. Becker, P. Chua, R. Downham, C. J. Douglas, N. K.
Garg, S. Hiebert, S. Jaroch, R. T. Matsuoka, J. A. Middleton,
F. W. Ng, L. E. Overman, J. Am. Chem. Soc. 2007, 129, 11987.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
[17] a) N. S. Simpkins, Sulfones in Organic Synthesis, Pergamon
Press, Oxford, 1993. For a review on desulfonylation reactions,
see: b) C. Nꢁjera, M. Yus, Tetrahedron 1999, 55, 10547.
[18] In contrast, no cycloaddition was observed when typical trans-
substituted dipolarophiles such as dimethyl fumarate or b-
nitrostyrene were used as dipolarophiles.
[19] A. Lꢃpez-Pꢅrez, J. Adrio, J. C. Carretero, Angew. Chem. 2009,
121, 346; Angew. Chem. Int. Ed. 2009, 48, 340.
[20] This pyrrolidine substitution pattern is found in natural and
biologically active compounds. For selected references, see:
a) K. Shimamoto, Y. Shigeri, Cent. Nerv. Syst. Agents Med.
Chem. 2006, 6, 59; b) H. Brꢆuner-Osborne, L. Bunch, N. Chopin,
F. Couty, G. Evano, A. A. Jensen, M. Kusk, B. Nielsen, N.
Rabaso, Org. Biomol. Chem. 2005, 3, 3926; c) J. M. Ndungu, J. P.
Cain, P. Davis, S.-W. Ma, T. W. Vanderah, J. Lai, F. Porreca, V. J.
Hruby, Tetrahedron Lett. 2006, 47, 2233.
[21] Compared with the standard reaction conditions involving
3 equivalents of silyl imine, in the presence of pyridine, 2,6-
lutidine, or CsF desilylating agents we observed an erosion in the
enantioselectivity of the process (91%, 90%, and 51% ee,
respectively).
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Asymmetric Catalysis
J. Hernꢁndez-Toribio, S. Padilla, J. Adrio,*
J. C. Carretero*
&&&& — &&&&
Catalytic Asymmetric Synthesis of a-
Quaternary Proline Derivatives by 1,3-
Dipolar Cycloaddition of a-Silylimines
Going pro: The title reaction between a-
silylimines and activated olefins proceeds
in the presence of a CuI/DTBM-Segphos
catalyst system with excellent diastereo-
selectivity and enantioselectivity. This
process provides straightforward access
to highly enantioenriched 5-unsubsti-
tuted a-quaternary proline derivatives.
TMS=trimethylsilyl, DTBM-Segphos=
5,5’-bis[di(3,5-di-tert-butyl-4-methoxyphe-
nyl)phosphino]-4,4’-bi-1,3-benzodioxole.
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!