Catalytic asymmetric ring-opening of meso- aziridines with malonates under heterodinuclear rare earth metal Schiff base catalysis

Article abstract of DOI:10.1021/ja201492x

Catalytic asymmetric ring-opening of meso-aziridines with malonates is described. The combined use of two rare earth metal sources with different properties promoted the desired ring-opening reaction. A 1:1:1 mixture of a heterobimetallic La(O-iPr)₃/Yb(OTf)₃/Schiff base 1a (0.25-10 mol %) efficiently promoted the reaction of five-, six-, and seven-membered ring cyclic meso-aziridines as well as acyclic meso-aziridines with dimethyl, diethyl, and dibenzyl malonates, giving chiral cyclic and acyclic γ-amino esters in 99-63% yield and >99.5-97% ee.

Full text of DOI:10.1021/ja201492x

COMMUNICATION
pubs.acs.org/JACS
Catalytic Asymmetric Ring-Opening of meso-Aziridines with
Malonates under Heterodinuclear Rare Earth Metal Schiff Base
Catalysis
Yingjie Xu,† Luqing Lin,† Motomu Kanai,† Shigeki Matsunaga,*,† and Masakatsu Shibasaki*,§
†Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
§Institute of Microbial Chemistry, Tokyo, Kamiosaki 3-14-23, Shinagawa-ku, Tokyo 141-0021, Japan
S Supporting Information
b
ABSTRACT: Catalytic asymmetric ring-opening of meso-
aziridines with malonates is described. The combined use of
two rare earth metal sources with different properties
promoted the desired ring-opening reaction. A 1:1:1 mix-
ture of a heterobimetallic La(O-iPr)3/Yb(OTf)3/Schiff base
1a (0.25À10 mol %) efficiently promoted the reaction of
five-, six-, and seven-membered ring cyclic meso-aziridines as
well as acyclic meso-aziridines with dimethyl, diethyl, and
dibenzyl malonates, giving chiral cyclic and acyclic γ-amino
esters in 99À63% yield and >99.5À97% ee.
Figure 1. Dinucleating Schiff base 1a and postulated structure of
heterodinuclear rare earth (RE) catalyst bearing acid/base moieties.
Schiff base complex in the present study. As shown in Figure 1, we
planned to combine a Brønsted basic rare earth metal alkoxide
mino acids are key structural motifs in many biologi-
[RE1(O-iPr)3]10 and a Lewis acidic rare earth metal triflate
γ-Acally active compounds, such as clinically used neuro-
[RE2(OTf)3]11 onto a dinucleating Schiff base 1. With the suitable
metal combination, simultaneous activation of malonates and azir-
idines with two different metal centers would be possible via a well-
organized transition state, giving products in high yield and
enantioselectivity.
transmission modulators.1 Among unnatural amino acids, cyclic
amino acids have recently received much attention in foldamer
research due to their interesting folding properties.2 Few methods
exist, however, for catalytic enantioselective synthesis of chiral cyclic
γ-amino acids.3 In 2009, Cobb et al. and Gellman et al. indepen-
dently reported the first highly enantioselective catalytic asymmetric
methods via an intramolecular Michael reaction of nitronates onto
conjugated esters3a and intermolecular Michael addition of aldehydes
onto 1-nitrocyclohexene,3b,c giving γ-amino acids with a six-mem-
bered ring in excellent enantioselectivity. Further studies toward the
synthesis of structurally diverse sets of chiral cyclic γ-amino acids,
especially those with different ring size, are highly demanded. Herein,
we report an alternative approach to chiral cyclic γ-amino acids via
desymmetrization of meso-aziridines. Heterobimetallic rare earth
metals Schiffbase 1complexes (Figure 1) promoted enantioselective
ring-opening of meso-aziridines 2 with malonate 3.
Catalytic enantioselective ring-opening of meso-aziridines with
malonates provides straightforward access to cyclic γ-amino acids.
Although racemic reactions using a stoichiometric amount of base at
elevated temperatures have been reported,4 catalytic asymmetric
methods have never been reported, possibly due to the low reactivity
of aziridines toward enolates and difficulty in differentiating the
enantiotopic center of meso-aziridines.5 Based on previous reports of
highly enantioselective ring-opening desymmetrization of meso-
aziridines6À9 with cyanide7 and azide8 nucleophiles using homodi-
nuclear rare earth metal complexes by our group and RajanBabu/
Parquette et al., as well as our ongoing projects on bimetallic Schiff
base catalysis,10À12 we envisioned using a bimetallic rare earth metal
After screening several Schiff base scaffolds to incorporate two
different rare earth metal sources, Schiff base 1 with a binaphthyl
backbone afforded promising results.13 Optimization studies using
meso-aziridine 2a and malonate 3a are summarized in Table 1. Both
rare earth metal alkoxide (entries 1À6) and rare earth metal triflate
(entries 6À10) had a significant impact on the yield of product 4a.
Among rare earth metal alkoxides screened, the most Brønsted basic
La(O-iPr)3 gave the best results (entry 6, 89% yield and >99.5% ee).
As a Lewis acidic counterpart, the most Lewis acidic Yb(OTf)3 (entry
6) and Y(OTf)3 (entry 7) gave comparably good results compared
with other less Lewis acidic Gd, Sm, and La triflates (entries 8À10).14
In the present reaction, the combined use of Brønsted basic and Lewis
acidic rare earth metals is critically important to promote the desired
reaction in good enantioselectivity and reactivity. Negative control
experiments are shown in entries 11 and 12. La(O-iPr)3/1a = 1:1 in
the absence of Yb(OTf)3 resulted in 24% yield and 4% ee (entry 11).
Yb(OTf)3 /1a = 1:1 in the absence of La(O-iPr)3 did not afford the
desired product 4aa (entry 12, 0% yield). Although aziridine 2a was
completely consumed, the rearrangement of aziridine 2a into 2-ar-
yloxazoline predominantly proceeded under the simply Lewis acidic
reaction conditions in entry 12.15 Thus, both La(O-iPr)3 and
Received: February 17, 2011
Published: March 28, 2011
r
2011 American Chemical Society
5791
dx.doi.org/10.1021/ja201492x J. Am. Chem. Soc. 2011, 133, 5791–5793
|

Journal of the American Chemical Society
COMMUNICATION
Table 1. Optimization Studies
Table 2. Catalytic Enantioselective Ring-Opening of meso-
Aziridines with Malonatesa
RE2
temp time yielda
eeb
entry RE1 source
source
solvent (°C)
(h)
(%)
(%)
1
Sc(OiPr)3 Yb(OTf)3
Er(OiPr)3 Yb(OTf)3
Gd(OiPr)3 Yb(OTf)3
Sm(OiPr)3 Yb(OTf)3
Nd(OiPr)3 Yb(OTf)3
La(OiPr)3 Yb(OTf)3
La(OiPr)3 Y(OTf)3
La(OiPr)3 Gd(OTf)3
La(OiPr)3 Sm(OTf)3
La(OiPr)3 La(OTf)3
La(OiPr)3 none
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
toluene
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
40
24
24
24
24
24
24
24
24
24
24
24
24
15
4
trace ND
2
16
24
28
83
89
90
82
21
10
24
0
>99.5
3
99
4
99
5
99
6
>99.5
>99.5
99
7
8
9
96
10
11
12
13
14
92
4
none
Yb(OTf)3
ND
>99.5
>99.5
La(OiPr)3 Yb(OTf)3
La(OiPr)3 Yb(OTf)3
92
99c
a Determined by 1H NMR analysis of the crude mixture. b Determined
by chiral HPLC analysis. c Isolated yield of 4 after purification by column
chromatography.
Yb(OTf)3 are essential for the present reaction. After further
optimization of the reaction temperature (entry 13, 40 °C) and
solvent (entry 14, toluene), 4aa was obtained in 99% isolated yield
and in >99.5% ee after 4 h.
The substrate scope of the reaction as well as trials to reduce
catalyst loading are summarized in Table 2. Catalyst loading was
successfully reduced to 2.5 mol % and 0.5 mol % without
problems (entries 2 and 3). When further reducing the catalyst
loading to 0.25 mol %, the addition of a catalytic amount of Et3N
(0.25 mol %) was effective to improve the catalyst efficiency, and
4aa was obtained in 94% yield and 99% ee after 30 h (entry 4).16
Malonates 3b and 3c also reacted well with aziridine 2a, giving
products 4ab and 4ac in 97À99% yield and 99f99.5% ee
(entries 5 and 6). Other six-membered ring meso-aziridines 2b
and 2c also reacted smoothly to give products 4ba and 4ca in
99% ee (entries 7 and 8).17 The present heterobimetallic system
was applicable to substrates with different ring sizes, giving
products in 98À99% ee (entries 9À11). In entry 11, the yield
of desired product 4fa was moderate (63% yield), because
undesired rearrangement of aziridine 2f to 2-aryloxazoline com-
peted with the desired reaction even in the presence of Et3N
additive. Acyclic meso-aziridines 2g and 2h also reacted without
problems under the heterobimetallic catalysis, giving products in
91À97% yield and 97À99% ee (entries 12 and 13). The product
was readily converted into Boc-protected cyclic γ-amino ester as
shown in Scheme 1. Decarboxylation of 4aa gave 5aa in 85%
yield. Protection of 5aa with Boc-group, followed by removal of
the 3,5-dinitrobenzoyl group with NaOMe at rt, gave 6aa in 95%
yield (2 steps).
a Isolated yield of 4 after purification by column chromatography. b Deter-
mined by chiral HPLC analysis. c Reaction was run in the presence of catalytic
amount of Et3N (0.25 mol % in entry 4 and 10 mol % in entries 8À13).
Scheme 1. Transformation of Ring-opening Adducta
a Reagents and reaction conditions: (a) LiCl, H2O, DMSO, 130 °C, 5 h,
85% yield; (b) Boc2O, Et3N, cat. DMAP, THF, rt, 24 h; (c) NaOMe,
MeOH, rt, 1 h, 95% yield (2 steps).
desymmetrization of cyclic and acyclic meso-aziridines with
dimethyl, diethyl, and dibenzyl malonates. The combined use
of two rare earth metal sources with different properties,
Brønsted basic rare earth metal alkoxide and Lewis acidic rare
earth metal triflate, was important to promote the desired
ring-opening reaction. The La(O-iPr)3/Yb(OTf)3/Schiff base
1a complex gave chiral cyclic and acyclic γ-amino esters in
99À63% yield and >99.5À97% ee. Further applications of
In summary, we developed a new heterodinuclear rare earth
metal Schiff base catalyst for an enantioselective ring-opening
5792
dx.doi.org/10.1021/ja201492x |J. Am. Chem. Soc. 2011, 133, 5791–5793

Journal of the American Chemical Society
COMMUNICATION
the heterodinuclear rare earth metal Schiff base catalysts are
ongoing.
J. Am. Chem. Soc. 2007, 129, 8103. Thiols:(c) Della Sala, G.; Lattanzi, A.
Org. Lett. 2009, 11, 3330. (d) Larson, S. E.; Baso, J. C.; Li., G.; Antilla,
J. C. Org. Lett. 2009, 11, 5186. See also a review in ref 6.
(10) For examples using Brønsted basic rare earth metal alkoxide in
combination with transition metals, see: Cu/Sm(O-iPr)3 cat:(a) Handa,
S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2007, 129, 4900. (b) Handa, S.; Gnanadesikan, V.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 4925. Pd/La(O-iPr)3 cat:
(c) Handa, S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed 2008, 47, 3230. Ni/La(O-iPr)3 cat:(d) Furutachi,
M.; Mouri, S.; Matsunaga, S.; Shibasaki, M. Chem. Asian J. 2010, 5, 2351.
(11) For an example using Lewis acidic rare earth metal triflate in
combination with a group 13 metal alkoxide, see: Ga(OiPr)3/Yb-
(OTf)3 cat:Mihara, H.; Xu, Y.; Shepherd, N. E.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2009, 131, 8384.
(12) For selected examples of bifunctional heterobimetallic Schiff
base complexes in asymmetric catalysis, see:(a) Annamalai, V.; DiMauro,
E. F.; Carroll, P. J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 1973 and
references therein. (b) Yang, M.; Zhu, C.; Yuan, F.; Huang, Y.; Pan, Y. Org.
Lett. 2005, 7, 1927. (c) Li, W.; Thakur, S. S.; Chen, S.-W; Shin, C.-K.;
Kawthekar, R. B.; Kim, G.-J. Tetrahedron Lett. 2006, 47, 3453. For related
homobimetallic Schiff base catalysts, see:(d) Hirahata, W.; Thomas, R. M.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2008, 130, 17658.
(e) Mazet, C.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2008, 47, 1762.
(f) Wu, B.; Parquette, J. R.; RajanBabu, T. V. Science 2009, 326, 1662.
(13) For the X-ray crystallographic structure of related heterobime-
tallic complex having cationic rare earth metal in the outer O2O2
cavity, see:(a) Koner, R.; Lee, G.-H.; Wang, Y.; Wei, H.-H.; Mohanta,
S. Eur. J. Inorg. Chem. 2005, 1500. For the utility of methoxy-substituted
Schiff base 1 in metal/1 = 1:1 ratio system, see:(b) Yoshino, T.;
Morimoto, H.; Lu, G.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc.
2009, 131, 17082. (c) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi,
M.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255. See
also works by RajanBabu et al. in refs 8c and 12f.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, de-
b
termination of relative and absolute configuration by X-ray
crystallographic analysis (CIF), and spectral data of new com-
pounds. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
smatsuna@mol.f.u-tokyo.ac.jp; mshibasa@bikaken.or.jp
’ ACKNOWLEDGMENT
This work was supported by Grant-in-aid for Young Scientist
(A) from JSPS, Takeda Science foundation, and Inoue Science
Research Award from Inoue Science Foundation (for S.M.). Y.X.
thanks JSPS predoctoral research fellowship and L.L. thanks
Uehera Memorial Foundation for scholarship.
’ REFERENCES
(1) (a) Bryans, J. S.; Wustrow, D. J. Med. Res. Rev. 1999, 19, 149.(b)
Cooper, J. R.; Bloom, F. E.; Roth, R. H. The Biochemical Basis of
Neuropharmacology; Oxford Press: Oxford, 2003. (c) Tassone, D. M.;
Boyce, E.; Guyer, J.; Nuzum, D. Clin. Ther. 2007, 29, 26.
(2) Reviews on the foldamer research:(a) Goodman, C. M.; Choi, S.;
Shandler, S.; Degrado, W. F. Nat. Chem. Biol. 2007, 3, 252. (b) Seebach,
D.; Brenner, M.; Rueping, M.; Jaun, B. Chem.ÀEur. J. 2002, 8, 573.
(c) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173.
(3) (a) Nodes, W. J.; Nutt, D. R.; Chippindale, A. M.; Cobb, A. J. A.
J. Am. Chem. Soc. 2009, 131, 16016. (b) Guo, L.; Chi, Y.; Almeida, A. M.;
Guzei, I. A.; Parker, B. K.; Gellman, S. H. J. Am. Chem. Soc. 2009,
131, 16018. For an alternative approach via asymmetric conjugate
addition of malonates to 3-nitro-2H-chromenes, see:(c) Chen, W.-Y.;
Ouyang, L.; Chen, R.-Y.; Li, X.-S. Tetrahedron Lett. 2010, 51, 3972.
(4) (a) Smith, P. W.; Whittington, A. R.; Cobley, K. N.; Jaxa-Chamiec, A.;
Finch, H. J. Chem. Soc., Perkin Trans. 1 2001, 21. (b) Blyumin, E. V.; Gallon,
H. J.; Yudin, A. K. Org. Lett. 2007, 9, 4677. (c) Page, M. F. Z.; Jalisatgi, S. S.;
Maderna, A.; Hawthorne, M. F. Synthesis 2008, 550.
(14) Evaluation of the relative Lewis acidity of rare earth metals:
Tsuruta, H.; Yamaguchi, K.; Imamoto, T. Chem. Commun 1999, 1703The
reactivity changed in correlation with Lewis acidity of rare earth metal
triflate (Yb, Y > Gd > Sm > La).
(15) Rearrangement of aziridine 2a to 2-aryloxazoline predomi-
nantly proceeded in the absence of La(O-iPr)3. For Lewis acid-pro-
moted rearrangement of N-acylaziridines into oxazolines, seeFerraris,
D.; Drury, W. J., III; Cox, C.; Lectka, T. J. Org. Chem. 1998, 63, 4568.
(16) The addition of catalytic amount of amine base was effective to
suppress the undesired Lewis acid-promoted intramolecular rearrange-
ment of aziridines 2 to 2-aryloxazolines, and to promote the desired
intermolecular reaction of malonate 3a with aziridines 2.
(17) The reactions were run using 10 mol % catalyst loading in
entries 7À13, because the reactivity of aziridines 2bÀ2h was lower than
that of aziridine 2a.
(5) Catalytic enantioselective alkylation of β-keto esters with un-
substituted aziridines has been reported, see:(a) Moss, T. A.; Fenwick,
D. R.; Dixon, D. J. J. Am. Chem. Soc. 2008, 130, 10076. (b) Paix~ao, M. W.;
Nielsen, M.; Jacobsen, C. B.; Jørgensen, K. A. Org. Biomol. Chem. 2008,
6, 3467.
(6) A review:Schneider, C. Angew. Chem., Int. Ed. 2009, 48, 2082.
(7) Aziridine ring-opening desymmetrization with azide:(a) Li, Z.;
Fernandez, M.; Jacobsen, E. N. Org. Lett. 1999, 1, 1611. (b) Fukuta, Y.;
Mita, T.; Fukuda, N.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 6312. (c) Rowland, E. B.; Rowland, G. B.; Rivera-Otero, E.; Antilla,
J. C. J. Am. Chem. Soc. 2007, 129, 12084. (d) Nakamura, S.; Hayashi, M.;
Kamada, Y.; Sasaki, R.; Hiramatsu, Y.; Shibata, N.; Toru, T. Tetrahedron
Lett. 2010, 51, 3820. See also ref 8c.
(8) Aziridine ring-opening desymmetrization with cyanide:(a) Mita,
T.; Fujimori, I.; Wada, R.; Wen, J.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 11252. (b) Fujimori, I.; Mita, T.; Maki, K.; Shiro, M.;
Sato, A.; Furusho, S.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2006,
128, 16438. (c) Wu, B.; Gallucci, J. C.; Parquette, J. R.; RajanBabu, T. V.
Angew. Chem., Int. Ed. 2009, 48, 1126.
(9) Aziridine ring-opening with other nucleophiles, see Grignard
reagent:(a) M€uller, P.; Nury, P. Org. Lett. 1999, 1, 439. Anilines:(b) Arai,
K.; Lucarini, S.; Salter, M. M.; Ohta, K.; Yamashita, Y.; Kobayashi, S.
5793
dx.doi.org/10.1021/ja201492x |J. Am. Chem. Soc. 2011, 133, 5791–5793