Dinuclear Ni2-Schiff base complex-catalyzed asymmetric 1,4-addition of β-keto esters to nitroethylene toward γ 2,2-amino acid synthesis

Article abstract of DOI:10.1039/c0cc02152k

A homodinuclear Ni₂-Schiff base 1 complex (1-10 mol%) promoted the catalytic asymmetric 1,4-addition reactions of β-keto esters and an N-Boc oxindole to nitroethylene, giving products in 98-75% ee.

Full text of DOI:10.1039/c0cc02152k

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Dinuclear Ni2–Schiff base complex-catalyzed asymmetric 1,4-addition of
b-keto esters to nitroethylene toward c2,2-amino acid synthesisw
Harunobu Mitsunuma and Shigeki Matsunaga*
Received 28th June 2010, Accepted 16th September 2010
DOI: 10.1039/c0cc02152k
A homodinuclear Ni2–Schiff base 1 complex (1–10 mol%)
promoted the catalytic asymmetric 1,4-addition reactions of
b-keto esters and an N-Boc oxindole to nitroethylene, giving
products in 98–75% ee.
Catalytic asymmetric 1,4-additions of carbon nucleophiles are
highly useful synthetic transformations for the construction of
quaternary carbon stereocenters.1,2 Over recent years, there
has been tremendous progress in both metal catalysis and
organocatalysis for the asymmetric 1,4-additions of b-keto
esters and related compounds.2 b-Substituted nitroalkenes are
most often used as acceptors, giving b-substituted g-nitro
Fig. 1 Structures of dinucleating Schiff base 1 and homodinuclear
esters with a-quaternary carbon stereocenters.3 The use of a
M2–Schiff base 1 complexes.
b-unsubstituted acceptor (nitroethylene), however, is much
less common,4,5 possibly due to potential difficulties of
Table 1 Optimization of reaction conditionsa
enantiocontrol and competitive polymerization of nitroethylene.
Gellman et al. and Wennermers et al. independently reported
highly enantioselective organocatalytic asymmetric 1,4-additions
of aldehydes to nitroethylene and their applications to
g2-amino acid synthesis,4 but a,a-disubstituted aldehydes were
not utilized as donors. Barbas was the first to successfully
construct a quaternary carbon stereocenter via catalytic
Entry M
x
Solventb Temp/1C Time/h % Yieldc % ee
asymmetric 1,4-addition of an N-Boc oxindole to nitroethylene.5
Because g2-amino acids are potentially useful building blocks
for folder research and the synthesis of biologically active
compounds,6,7 further studies to expand the scope of donors,
especially for the synthesis of adducts with a quaternary
1
2
3
4
5
6
7
8
Co(OAc) 10 THF
Mn(OAc) 10 THF
0
0
0
0
0
0
0
0
0
0
25
25
25
25
25
25
25
25
23
48
48
5
o30
o20
75
67
67
97
68
92
90
78
98
96
89
92
93
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
Ni
10 THF
10 Toluene
10 CH2Cl2
10 CHCl3
10 CH3CN
10 AcOEt
5 AcOEt
2.5 AcOEt
2.5 AcOEt rt
2.5 AcOEt 40
94
>95
>95
78
95
91
83
87
>95
stereocenter adjacent to a carbonyl group g2,2 8,9
are highly
,
desirable. To address this issue, we herein report the utility of a
homodinuclear Ni2–Schiff base 1 complex (Fig. 1). Ni2–1
(1–10 mol%) promoted the reactions of b-keto esters to
nitroethylene, affording products in 98–75% ee.
9
10
11
12
a
b
As part of our ongoing studies of bifunctional Lewis
acid/Brønsted base catalysis in collaboration with Shibasaki,10
one of authors (S.M.) and Shibasaki recently reported the
utility of dinuclear Schiff base complexes.11–15 Among them,
homodinuclear Co2–112a,b and Mn2–112c complexes were
suitable for 1,4-additions with b-substituted nitroalkenes.
Thus, we first applied Co2–1 and Mn2–1 complexes for the
reaction of b-keto ester 2a and nitroethylene. Both of
these complexes, however, gave an unsatisfactory yield and
enantioselectivity (Table 1, entries 1 and 2, less than 30%
NMR yield and 67% ee). Among the homodinuclear12,13 and
1.2 equiv. of nitroethylene (in toluene) were used. Reactions were
run in solvent/toluene = 10 : 1, because nitroethylene stored in
toluene was used. Yield was determined by 1H NMR analysis of
the crude reaction mixture.
c
heterodinuclear14 Schiff base complexes screened, the Ni2–1
catalyst13 afforded promising results. The reaction of b-keto
ester 2a with 1.2 equiv. of nitroethylene in THF at 0 1C gave
product 3a in 75% yield and 97% ee (entry 3). Among the
solvents screened (entry 3–8), AcOEt was the best in terms of
yield and enantioselectivity (entry 8, 96% yield and 98% ee).
We then tried to reduce catalyst loading in entries 9–12. With
2.5 mol% catalyst, reactivity was decreased at 0 1C and the
reaction did not complete after 48 h (entry 10). Raising the
reaction temperature to 40 1C drastically improved the reactivity
and the reaction completed within 5 h with high enantio-
selectivity (entry 12, 93% ee).
Graduate School of Pharmaceutical Sciences,
The University of Tokyo, Hongo 7-3-1, Bunkyo-ku,
Tokyo 113-0033, Japan. E-mail: smatsuna@mol.f.u-tokyo.ac.jp;
Fax: +81-3-5684-5206; Tel: +81-3-5841-4830
w Electronic supplementary information (ESI) available: General
experimental information, spectral data of new compounds, and
copies of NMR spectral data. See DOI: 10.1039/c0cc02152k
c
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Chem. Commun., 2011, 47, 469–471 469

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The substrate scope and limitations of the reaction are
summarized in Table 2.16 Because the reactivity of b-keto
esters 2 depends on the structure, the reaction conditions, such
as catalyst loading and reaction time, were optimized for
each b-keto ester. The best results for each substrate are
summarized in Table 2. Indanone-derived b-keto esters
2b–2d showed good reactivity, and products 3b–3d were
obtained in 92–90% yield and 98–94% ee after 4.5 to 10 h
using 2.5 mol% of Ni2–1 (entries 2, 4–5). In entry 3, the
reaction was performed with 1 mol% Ni2–1 catalyst, but both
the reactivity and enantioselectivity decreased (18 h, 84%
yield, 87% ee). The reactivity of b-keto esters 2e and 2f with
a six-membered ring was lower than that of b-keto ester 2a,
and 10 mol% of Ni2–1 was required to obtain products 3e and
3f in 98–73% yield and 91–75% ee after 24 h (entries 6 and 7).
The reactivity of acyclic b-keto esters 2g and 2h was much
lower than that of cyclic b-keto esters, and products 3g and 3h
were obtained in only 35–51% yield even using 10 mol% of the
catalyst (entries 8–9, 82–85% ee). We are speculating that the
modest to poor reactivity in entries 7–10 is due to poor
nucleophilicity of Ni–enolates. The Ni2–1 catalyst was also
applicable to N-Boc oxindole 2i, giving product 3i in 99%
yield and 80% ee after 24 h. To demonstrate the synthetic
utility of the reaction, transformation of the products was
performed (Scheme 1). Reduction of 3c with RANEYs Ni
under H2 (1 atm) in the presence of Boc2O gave g2,2-amino
ester 4c in 72% yield. Reduction of 3a with Pd/C under H2
(1 atm) in MeOH gave bicyclic amino ester, which was isolated
after Boc-protection in 82% yield (5a, 2 steps).
Table 2 Catalytic asymmetric 1,4-addition of b-keto esters 2 to
nitroethylenea
cat.
(x mol%)
Time/
h
%
%
Entry
1
2
Yieldb eec
2.5
2.5
5
92
93
97
2
3
4.5 92
1
18
84
90
87
98
4
5
2.5
5
2.5
10
90
94
Scheme 1 Transformation of 1,4-adducts.
6
7
8
9
10
10
10
18
24
98
73
35
91
75
85
120
10
10
126
24
51
99
82
80
10
a
The reactions were run with 1.2 equiv. of nitroethylene (in toluene).
Isolated yield after purification by silica gel column chromato-
b
Fig. 2 Postulated catalytic cycle of Ni2–1-catalyzed 1,4-addition of
b-keto esters to nitroethylene.
c
graphy. Determined by HPLC analysis.
c
470 Chem. Commun., 2011, 47, 469–471
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In the present reaction, we assume that the two Ni centers
function cooperatively as observed in other related reactions
using Ni2–1.13 The postulated reaction mechanism is summarized
in Fig. 2. One of the Ni–O bonds in the outer O2O2 cavity is
speculated to work as a Brønsted base to generate Ni–enolate
in situ.17 The other Ni in the inner N2O2 cavity functions as a
Lewis acid to control the position of nitroethylene, similar to
conventional metal–salen Lewis acid catalysis. The C–C
bond-formation via the transition state (TS in Fig. 2), followed
by protonation, affords product and regenerates the Ni2–1
catalyst.
2008, 6, 3467; (c) T. A. Moss, B. Alonso, D. R. Fenwick and
D. J. Dixon, Angew. Chem., Int. Ed., 2010, 49, 568.
10 Recent reviews on bifunctional Lewis acid/Brønsted base
asymmetric metal catalysis: (a) S. Matsunaga and M. Shibasaki,
Bull. Chem. Soc. Jpn., 2008, 81, 60; (b) M. Shibasaki, S. Matsunaga
and N. Kumagai, Synlett, 2008, 1583.
11 For
a general review on bimetallic Schiff base catalysts:
R. M. Haak, S. J. Wezenberg and A. W. Kleij, Chem. Commun.,
2010, 46, 2713.
12 Co2–1 catalyst for 1,4-addition of b-keto esters to b-substituted
nitroalkenes: (a) M. Furutachi, Z. Chen, S. Matsunaga and
M. Shibasaki, Molecules, 2010, 15, 532; (b) Z. Chen,
M. Furutachi, Y. Kato, S. Matsunaga and M. Shibasaki, Angew.
Chem., Int. Ed., 2009, 48, 2218. Mn2–1 catalyst for 1,4-addition of
N-Boc oxindoles to b-substituted nitroalkenes: (c) Y. Kato,
M. Furutachi, Z. Chen, H. Mitsunuma, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2009, 131, 9168.
13 Ni2–1 catalyst: (a) Z. Chen, H. Morimoto, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2008, 130, 2170; (b) Y. Xu,
G. Lu, S. Matsunaga and M. Shibasaki, Angew. Chem., Int. Ed.,
2009, 48, 3353; (c) S. Mouri, Z. Chen, S. Matsunaga and
M. Shibasaki, Chem. Commun., 2009, 5138; (d) S. Mouri,
Z. Chen, H. Mitsunuma, M. Furutachi, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 1255; For the use of
Ni2–1 catalyst in 1,4-addition to b-substituted nitroalkenes with
other donors: (e) N. E. Shepherd, H. Tanabe, Y. Xu, S. Matsunaga
and M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 3666; (f) Y. Xu,
S. Matsunaga and M. Shibasaki, Org. Lett., 2010, 12, 3246.
14 Heterobimetallic transition metal/rare earth metal Schiff base
catalysts: (a) S. Handa, V. Gnanadesikan, S. Matsunaga and
M. Shibasaki, J. Am. Chem. Soc., 2007, 129, 4900; (b) S. Handa,
K. Nagawa, Y. Sohtome, S. Matsunaga and M. Shibasaki, Angew.
Chem., Int. Ed., 2008, 47, 3230; (c) H. Mihara, Y. Xu,
N. E. Shepherd, S. Matsunaga and M. Shibasaki, J. Am. Chem.
Soc., 2009, 131, 8384; (d) S. Handa, V. Gnanadesikan, S. Matsunaga
and M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 4925.
In summary, we developed a homodinuclear Ni2–Schiff
base-catalyzed enantioselective 1,4-addition of b-keto esters
to nitroethylene. The reaction proceeded with 1–10 mol%
catalyst, and products bearing a quaternary carbon stereo-
center adjacent to an ester were obtained in 98–75% ee and
99–35% yield (TON = up to 84). Further studies to improve
the poor reactivity for acyclic b-keto esters through ligand
modification are ongoing.
This work was supported by Takeda Science Foundation,
Inoue Science Research Award from Inoue Science Foundation,
and Grant-in-Aid for Young Scientists (A) from JSPS. We
thank Prof. M. Shibasaki at Institute of Microbial Chemistry,
Tokyo and Prof. M. Kanai at the University of Tokyo for
their generous supports, fruitful discussion, and unrestricted
access to analytical facilities.
Notes and references
1 Recent reviews on catalytic asymmetric construction of quaternary
carbon stereocenters: (a) J. Christoffers and A. Baro, Adv. Synth.
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2006, 369; (c) P. G. Cozzi, R. Hilgraf and N. Zimmermann, Eur. J.
Org. Chem., 2007, 5969.
2 General reviews on asymmetric 1,4-addition to electron-deficient
alkenes with metal catalysis: (a) J. Christoffers, G. Koripelly,
A. Rosiak and M. Rossle, Synthesis, 2007, 1279; With organo-
catalysis: (b) S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 1701.
3 A review on asymmetric 1,4-addition to nitroalkenes:
O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem.,
2002, 1877.
4 (a) Y. Chi, L. Guo, N. A. Kopf and S. H. Gellman, J. Am. Chem.
Soc., 2008, 130, 5608; (b) M. Wiesner, J. D. Revell, S. Tonazzi and
H. Wennemers, J. Am. Chem. Soc., 2008, 130, 5610.
5 T. Bui, S. Syed and C. F. Barbas, III, J. Am. Chem. Soc., 2009, 131,
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6 Reviews on the foldamer research: (a) C. M. Goodman, S. Choi,
S. Shandler and W. F. Degrado, Nat. Chem. Biol., 2007, 3, 252;
(b) D. Seebach, M. Brenner, M. Rueping and B. Jaun, Chem.–Eur.
J., 2002, 8, 573; (c) S. H. Gellman, Acc. Chem. Res., 1998, 31, 173.
7 A general review on asymmetric synthesis of g-amino acids:
M. Ordonez and C. Cativiela, Tetrahedron: Asymmetry, 2007, 18, 3.
8 For diastereoselective 1,4-addition of a chiral enamino ester
derived from a cyclic b-keto ester and chiral amine to nitroethylene,
see: J. d’Angelo, C. Cave, D. Desmaele, A. Gassama,
C. Thominiaux and C. Riche, Heterocycles, 1998, 47, 725.
9 For alternative highly enantioselective catalytic asymmetric
approaches to g2,2-amino acids with a-quaternary carbon stereo-
centers via ring-opening reactions of aziridines and cyclic sulfamidates
with b-keto esters, see: (a) T. A. Moss, D. R. Fenwick and
D. J. Dixon, J. Am. Chem. Soc., 2008, 130, 10076; (b) M. W. Paixao,
M. Nielsen, C. B. Jacobsen and K. A. Jørgensen, Org. Biomol. Chem.,
15 For selected examples of related bifunctional bimetallic Schiff base
complexes in asymmetric catalysis from other groups, see:
(a) V. Annamalai, E. F. DiMauro, P. J. Carroll and
M. C. Kozlowski, J. Org. Chem., 2003, 68, 1973 and references
therein; (b) M. Yang, C. Zhu, F. Yuan, Y. Huang and Y. Pan, Org.
Lett., 2005, 7, 1927; (c) J. Gao, F. R. Woolley and R. A. Zingaro,
Org. Biomol. Chem., 2005, 3, 2126; (d) W. Li, S. S. Thakur,
S.-W. Chen, C.-K. Shin, R. B. Kawthekar and G.-J. Kim, Tetra-
hedron Lett., 2006, 47, 3453; (e) C. Mazet and E. N. Jacobsen,
Angew. Chem., Int. Ed., 2008, 47, 1762; (f) J. Park, K. Lang,
K. A. Abboud and S. Hong, J. Am. Chem. Soc., 2008, 130, 16484;
(g) W. Hirahata, R. M. Thomas, E. B. Lobkovsky and
G. W. Coates, J. Am. Chem. Soc., 2008, 130, 17658; (h) B. Wu,
J. C. Gallucci, J. R. Parquette and T. V. RajanBabu, Angew.
Chem., Int. Ed., 2009, 48, 1126; For related early studies with
dinuclear Ni2–Schiff base complexes as epoxidation catalysts, see
also: (i) T. Oda, R. Irie, T. Katsuki and H. Okawa, Synlett, 1992,
641; For other examples, see ref. 11.
16 The absolute configuration of 3b was determined by comparing
with the reported data in ref. 9c after conversion into known g2,2-amino
ester. See ESIw.
17 1H NMR analysis of the bimetallic Ni2–1 complex does not show
any peaks, suggesting that at least one of Ni metal centers has
non-planar coordination mode. Based on the molecular model, we
assume that the outer Ni center has cis-b configuration due to
strain of the bimetallic complex. In other words, one of the Ni–O
bonds of the outer Ni center is speculated to be in apical position.
Thus, the weak Ni–O bond would work as a Brønsted baseto
deprotonate b-keto esters to give the Ni–enolate intermediate.
Detailed mechanistic studies to clarify the role of two Ni metal
centers are ongoing. For the utility of cis-b metal complexes of
salens in asymmetric catalysis, see a review: T. Katsuki, Chem. Soc.
Rev., 2004, 33, 437.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 469–471 471