A bench-stable homodinuclear Ni2-Schiff base complex for catalytic asymmetric synthesis of α-tetrasubstituted anti-α,β- diamino acid surrogates

Article abstract of DOI:10.1021/ja710398q

Catalytic asymmetric direct Mannich-type reactions of α-substituted nitroacetates using a new bench-stable homodinuclear Ni₂-Schiff base 1b complex are described. The Ni₂-1b complex gave Mannich products, precursors for anti-α,β-diam

Full text of DOI:10.1021/ja710398q

Published on Web 01/29/2008
A Bench-Stable Homodinuclear Ni2-Schiff Base Complex for Catalytic
Asymmetric Synthesis of r-Tetrasubstituted anti-r,â-Diamino Acid Surrogates
Zhihua Chen, Hiroyuki Morimoto, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received November 27, 2007; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
Chiral R,â-diamino acids are key structural components in many
biologically active compounds.1 Among methods for their synthesis,
catalytic asymmetric direct Mannich-type reactions2 of a glycine
Schiff base are one of the most efficient and straightforward
methods for producing chiral syn-R,â-diamino acids.3 Recently,
Johnston4a and Willis4b reported alternative approaches for produc-
ing anti-R,â-diamino acids via Mannich-type reactions of a nitro-
acetate and an R-isothiocyanate acid derivative. Although high
diastereo- and enantioselectivity were realized, R,â-diamino acids
with an R-tetrasubstituted carbon stereocenter cannot be produced
using those reactions.3-5 Jørgensen reported an exceptional example
using an R-methyl nitroacetate,6 but only an R-imino ester was
utilized as an electrophile. Considering the importance of R,R-
disubstituted R-amino acids as chiral building blocks for pharma-
ceuticals and artificial peptides,7 a new catalyst for chiral R-tetra-
substituted R,â-diamino acid synthesis with a broad substrate scope
is in high demand. Herein, we report a new bench-stable homodi-
nuclear Ni2-Schiff base 1b complex (Figure 1) that promoted
Mannich-type reactions of N-Boc imines and R-substituted nitro-
acetates to afford R-tetrasubstituted anti-R,â-diamino acid surro-
gates in high ee (up to >99% ee). Ni2-1b was also applicable to
asymmetric Mannich-type reactions of malonates and â-keto ester.
We recently reported the utility of the dinucleating Schiff base
1a-H4 (Figure 1) in aza-Henry reactions of nitroethane and
nitropropane.8 Schiff base 1a-H4 selectively incorporated Cu into
the N2O2 inner cavity and oxophilic rare earth metal with a large
ionic radius into the O2O2 outer cavity. Cooperative functions of
the two metals9 in the heterobimetallic Cu-Sm-1a complex (Fig-
ure 1, M1 ) Cu, M2 ) Sm) were key to achieving high enantio-
selectivity in aza-Henry reactions. Thus, we initiated optimizations
using Schiff base 1a, imine 2a, and nitroacetate 3a (Table 1). The
Cu-Sm-1a complex, however, gave product 4aa in poor selectiv-
ity (entry 1, anti:syn ) 49:51, 5% ee). Although we screened various
heterobimetallic combinations of late transition metals and rare earth
metals using Schiff base 1a, there were no promising results. During
chiral ligand screening, we found that Schiff base 1b with a 1,1′-
binaphthyl-2,2′-diamine unit can incorporate metals with a smaller
ionic radius than that of rare earth metals into the O2O2 outer cavity,
possibly due to conformational difference between 1a-H4 and 1b-
H4. After rescreening metal combinations using 1b (entries 3-7),
a homobimetallic Ni2-1b complex, prepared from Schiff base
1b-H4 and 2 equiv of Ni(OAc)2, gave the best result.10-12 Ni2-1b
(10 mol %) gave 4aa in anti:syn ) 90:10 and 98% ee (entry 5).
Other metal combinations using 1b, such as M1 ) Ni, M2 ) Sm
(entry 4, 59% ee), M1, M2 ) Cu (entry 6, 9% ee), M1, M2 ) Pd
(entry 7), gave much less satisfactory results. The addition of MS
4Å improved reaction rate, giving 4aa in 95% isolated yield, anti:
syn ) 91:9, and 98% ee after 12 h (entry 8).
Figure 1. Structures of dinucleating Schiff bases 1a-H4 and 1b-H4, and
postulated structures of bimetallic M1-M2-1 and (R)-Ni2-1b complexes.
Table 1. Optimization of Reaction Conditions
metal sources
Schiff
base
time
(h)
yieldb
(%)
drc
% ee
(anti)
entry
M1a
M2a
additive
(anti/syn)
1
2
3
4
5
6
7
8
Cu
Ni
Cu
Ni
Ni
Cu
Pd
Ni
Sm
Sm
Sm
Sm
Ni
Cu
Pd
1a
1a
1b
1b
1b
1b
1b
1b
none
none
none
none
none
none
none
MS 4Å
18
18
18
18
18
18
18
12
75
36
33
42
92
95
49:51
50:50
34:66
61:39
90:10
34:66
ND
5
15
17
59
98
9
ND
98
trace
Ni
95d
91:9
a Cu(OAc)2, Ni(OAc)2, Pd(OAc)2, and Sm(O-iPr)3 were used as metal
sources. b Conversion yield determined by 1H NMR analysis (entries 1-6).
c Diastereomeric ratio was determined by 1H NMR analysis. d Isolated yield.
temperature for at least 3 months without loss of activity. Substrate
scope in Table 2 was investigated using the Ni2-1b complex stored
under air for more than 3 months.13 The optimized reaction con-
ditions were applicable to non-isomerizable aryl and heteroaryl
imines, giving products in 91-99% ee (entries 1-6). Nitroacetates
3b-3d also gave high diastereo- and enantioselectivity (entries 7-9,
94:6-88:12, >99-94% ee). For isomerizable aliphatic imines, the
reactions were performed at a lower temperature to prevent the
undesired isomerization of imines to enamides, giving products in
85-67% yield and 95-91% ee (entries 10-12). Reaction pro-
ceeded without problem in 2 mmol scale (entry 13). Catalyst loading
was successfully reduced to 1 mol %, while maintaining high enan-
tio-selectivity (entry 14, 98% ee). The NO2 moiety in product 4aa
was readily reduced with NaBH4/NiCl2 at room temperature, giving
R-tetrasubstituted anti-R,â-diamino ester 5aa in 94% yield (eq 1).
In contrast to the previously reported heterobimetallic Schiff base
1a complex including rare earth metals, the present bimetallic
Ni2-1b complex was bench-stable and storable under air at room
9
2170
J. AM. CHEM. SOC. 2008, 130, 2170-2171
10.1021/ja710398q CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric Mannich-Type Reaction of
Nitroacetates 3 and N-Boc Iminesa
Scheme 1 . Control Experiments Using Mononuclear Ni-Schiff
Base 1b-H2 or Ni-Salen 10a-10c Complexes
cat
temp time yieldb
C) (h) (%)
drc
(anti/syn) (anti)
% ee
entry
imine R1
Nu 3
(
×
mol %)
(°
1
2
3
4
5
6
7
8
9
Ph-
2a 3a
4-MeO-C6H4- 2b 3a
5
5
5
5
5
5
5
5
5
10
10
10
5
0
12 95
12 92
12 90
12 87
12 91
12 96
12 91
12 92
12 94
91:9
98
98
97
97
91
99
99
0
0
0
0
0
0
0
0
87:13
89:11
86:14
90:10
91:9
94:6
92:8 >99
88:12
4-Me-C6H4- 2c 3a
4-Cl-C6H4-
4-F-C6H4-
3-thienyl
Ph-
2d 3a
2e 3a
2f 3a
2a 3b
2a 3c
2a 3d
2g 3a
2h 3a
2i 3a
2a 3a
2a 3a
Acknowledgment. This work was supported by Grant-in-Aid
for Specially Promoted Research from MEXT. We thank Prof. S.
Kobayashi, Dr. R. Matsubara (X-ray crystallographic analysis), and
Prof. T. Ohwada, Dr. S. Uchiyama, and Mr. S. Handa (ESI-MS) at
the University of Tokyo for their kind help.
Ph-
Ph-
94
95
93
91
98
98
10d PhCH2CH2-
11d n-butyl
12d i-butyl
13e Ph-
-40 36 73 >97:3
-40 36 67 >97:3
-20 24 85 >97:3
0
13 91
90:10
88:12
14 Ph-
1
rt 12 93
Supporting Information Available: Experimental procedures,
spectral data of new compounds, determination of relative and absolute
configurations, ESI-MS data of Ni2-1b, and CIF of 4aa. This material
is available free of charge via the Internet at http://pubs.acs.org.
a Reaction was performed in THF (0.4 M on imines 2, 0.2-0.3 mmol
scale) with MS 4Å using the Ni2-1b complex stored over 3 months under
air at room temperature; 1.1 equiv of 3 was utilized unless otherwise noted.
b Isolated yield. c Determined by 1H NMR analysis of crude mixture. d Two
equivalents of 3a were utilized. e Reaction was run in 2.0 mmol scale.
References
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The utility of the Ni2-1b complex was further demonstrated in
the Mannich-type reactions of other donors, such as malonates and
â-keto ester (eqs 2 and 3).14 High diastereo- and enantioselectivities
were achieved at room temperature using 2.5 mol % of Ni2-1b
(99-91% ee).15
Control experiments (Scheme 1) indicated that neither a mono-
nuclear Ni-1b-H2 complex nor Ni-salen 10a-10c complexes are
effective for the present reaction, resulting in poor reactivity,
diastereoselectivity, and enantioselectivity. We assume that coop-
erative functions of the two Ni metal centers in the Ni2-1b complex
would be important for achieving high stereoselectivity as well as
reactivity. Further mechanistic studies to elucidate the precise role
of the two Ni centers are ongoing.
In summary, we developed a bench-stable homodinuclear
Ni2-1b complex for direct Mannich-type reactions of nitroacetates,
giving R-tetrasubstituted anti-R,â-diamino acid surrogates in >99-
91% ee. The Ni2-1b complex was also applicable to Mannich-
type reactions of malonates and â-keto ester. Preliminary mecha-
nistic experiments suggested the importance of the two Ni centers
in the catalyst. Further mechanistic studies as well as applications
of the Ni2-1b complex in other asymmetric reactions are ongoing.
Soc. 2007, 129, 4900.
(9) Review of bifunctional metal catalysis: Shibasaki, M.; Matsunaga, S.
Chem. Soc. ReV. 2006, 35, 269 and references therein.
(10) ESI-MS analysis indicated that Schiff base 1b incorporated two Ni to
afford homodinuclear Ni2-1b complex. See Supporting Information.
(11) For a related bimetallic Ni-Cs2-salen complex in asymmetric Michael
reaction of malonates, see: Annamalai, V.; DiMauro, E. F.; Carroll, P.
J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 1973 and references therein.
(12) For other recent examples of bifunctional chiral mono-Ni(II) catalyst for
activation of 1,3-dicarbonyl compounds in Michael addition, see: (a)
Evans, D. A.; Seidel, D. J. Am. Chem. Soc. 2005, 127, 9958. (b) Evans,
D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583.
(13) Freshly prepared Ni2-1b complex gave comparable results.
(14) There are many excellent chiral catalysts for direct Mannich-type reactions
with malonates, â-keto esters, and 1,3-diketones. For selected examples,
see: (a) Marigo, M.; Kjærsgaard, A.; Juhl, K.; Gathergood, N.; Jørgensen,
K. A. Chem.sEur. J. 2003, 9, 2359. (b) Uraguchi, D.; Terada, M. J. Am.
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Ye, J.; Dixon, D. J. Chem. Commun. 2006, 1191. For other examples,
see reviews in ref 2.
(15) For the determination of relative and absolute configurations of products
4, 7, and 9, and ORTEP structure of 4aa, see Supporting Information.
JA710398Q
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