A novel dinuclear chiral niobium complex for Lewis acid catalyzed enantioselective reactions: Design of a tridentate ligand and elucidation of the catalyst structure

Article abstract of DOI:10.1002/anie.200462204

Two's company: By using a novel chiral ligand a dinuclear chiral niobium catalyst for highly enantioselective Mannich-type reactions was developed. Tridentate binol derivatives provide excellent asymmetric environments around the niobium atom, and the Man

Full text of DOI:10.1002/anie.200462204

Angewandte
Chemie
Asymmetric Catalysis
A Novel Dinuclear Chiral Niobium Complex for
Lewis Acid Catalyzed Enantioselective
Reactions: Design of a Tridentate Ligand and
Elucidation of the Catalyst Structure**
Shu¯ Kobayashi,* Kenzo Arai, Haruka Shimizu,
Yoichi Ihori, Haruro Ishitani, and Yasuhiro Yamashita
Development of chiral catalysts for asymmetric reactions is
one of the most important tasks in organic synthesis.[1] While
various types of catalysts have been developed, exploitation
of novel catalysts, especially those based on unusual metals
and novel ligands, applicable to new enantioselective reac-
tions, is still very important. Herein we describe the first
highly enantioselective niobium(v) Lewis acid catalyst.
Niobium lies below vanadium in Group 5 and is expected
to have high Lewis acidity,[2] there are only a few reports of
chiral niobium catalysts, which have been used in asymmetric
Diels–Alder reactions and oxidations.[3,4] This situation is in
remarkable contrast to many asymmetric transformation
catalyzed by the neighboring Group 4 metal complexes of
titanium[5] and zirconium.[6] To prepare an efficient chiral
pentavalent niobium(v) catalyst for activation of aldehydes or
imines, we designed tridentate ligands 4a–d (see Equa-
tion (1)),[7] which were synthesized according to conventional
methods).[8]
Ligands 4a–d were combined with niobium alkoxides
(Nb(OR)5), and were employed as catalysts for the Mannich-
type reaction of imines 1 with silicon enolates 2 [Eq. (1)].[9]
For the reaction of 1a with 2a, several reaction param-
eters were examined, and the results are summarized in
Table 1. It was found that N-methylimidazole (NMI) was
effective as an additional ligand.[10] Among the chiral ligands
screened, 4c gave the best enantioselectivity (Table 1,
entry 3). The selectivity was further improved in a toluene–
CH2Cl2 (1:1) mixed solvent system (Table 1, entry 6) and in
the presence of 3-ꢀ or 4-ꢀ molecular sieves (MS 3ꢀ or
MS 4ꢀ; Table 1, entries 7 and 8). We also examined several
niobium alkoxides. When Nb(OMe)5 was combined with
ligand 4c, the desired Mannich-type adduct was obtained in
86% yield with 99% ee (Table 1, entry 10). It is noteworthy
that almost complete selectivity has been achieved using this
novel chiral niobium catalyst.
[*] Prof. Dr. S. Kobayashi, K. Arai, H. Shimizu, Y. Ihori, Dr. H. Ishitani,
Dr. Y. Yamashita
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax: (+81)3-5684-0634
E-mail: skobayas@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by CREST, SORT, and ERATO,
Japan Science Technology Corporation (JST) and a Grant-in-Aid for
Scientific Research from Japan Society of the Promotion of Sciences
(JSPS).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2005, 44, 761 –764
DOI: 10.1002/anie.200462204
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Table 2: Substrate generality [Eq. (1)].[a]
Entry
Imine
Si enolate
Product
Yield [%]
ee [%]
1[b,d]
2[c,d]
3[e]
4[f]
5
1a
1a
1b
1c
1d
1e
1 f
1g
1a
1b
1h
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
3a
3a
3b
3c
3d
3e
3 f
3g
3h
3i
86
69
82
79
40
77
85
75
69[g]
44
70
99
96
98
96
95
98
93
91
84
88
87
6
7
8[f]
9[f]
10
11[f]
3j
[a] The reactions were performed using 10 mol% of Nb(OMe)5,
12 mol% of 4c, 12 mol% of NMI, and MS 3ꢀ (100 mg/0.6 mmol
substrate) at À208C for 48 h. [b] 5 mol% of the catalyst was used.
[c] 2 mol% of the catalyst was used. [d] MS 3ꢀ (50 mg/0.4 mmol
substrate) was added. [e] À108C, 18 h. [f] À108C, 48 h. [g] Determined
by 1H NMR spectroscopy.
Table 1: Effect of binol derivatives on the reaction of 1a with 2a
[Eq. (1)].[a]
Entry
Nb(OR)5
Binol
Additive[b]
Yield [%]
ee [%]
1
2
3
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OnPr
OiBu
4a
4b
4c
4d
4c
4c
4c
4c
4c
4c
4c
4c
none
none
none
none
none
none
MS 3ꢀ
MS 4ꢀ
MS 3ꢀ
MS 3ꢀ
MS 3ꢀ
MS 3ꢀ
64
71
73
34
37
84
84
74
87
86
80
28
14
35
67
6
82
85
92
88
95
99
90
73
4
5[c]
6[d]
7[d]
8[d]
9[d,e]
10[d,e]
11[d,e]
12[d,e]
[a] The reactions were carried out using 10 mol% of Nb(OR)5, 10–
12 mol% of the binol derivative, and 10–12 mol% of NMI in CH2Cl2 at
08C for 18 h. [b] Molecular sieves (100 mg/0.6 mmol substrate) were
used. [c] In toluene. [d] In toluene:CH2Cl2 =1:1. [e] À208C, 48 h.
Several other substrates were tested, and the results are
summarized in Table 2. Various imines reacted with 2a in
toluene-CH2Cl2 (1:1) between at À10 and À208C to afford the
corresponding Mannich-type adducts in high yields with
excellent enantioselectivities. When silicon
enolate 2b was used, the enantioselectivities
were good but slightly decreased (Table 2,
entries 9–11). The catalyst loading could be
reduced from 10 mol% to 5 mol% and
2 mol% without significant loss of the yield
and selectivity.[11]
Figure 1. a) 1H and b) 13C NMR spectra of a catalyst solution of
Nb(OEt)5, 4c, and NMI in CD2Cl2. A: OCH2CH3.
We next turned our attention to the
structure of the chiral catalyst. Analysis of
the 1H and 13C NMR spectra of Nb(OEt)5, 4c,
and NMI in CD2Cl2 revealed the presence of a
single species, in which Nb and 4c were a 1:1
molar ratio (Figure 1). Since two sets of
resonances (A in Figure 1) were observed for
Figure 2. Possible structures of the highly selective Nb catalyst in solution.
-OEt, structure 5 was tentatively assigned as a single unit of
the catalyst (Figure 2). Since niobium complexes are known
to form dimeric structures easily,[12] we then investigated the
nonlinear effect (NLE)[13] in the Mannich-type reaction to
confirm whether a dimeric structure existed. We conducted
the reaction using the ligand with low enantiomeric excess
(23% ee, 45% ee, 73% ee), and observed a significant pos-
&
itive NLE ( in Figure 3). We prepared optically pure R and
S chiral niobium catalysts, then mixed them together to form
the catalysts with low enantiomeric excess, and conducted the
762
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Chemie
atom while the oxygen atom of the pendent phenol moiety is
bonded to the other niobium atom (bridged structure).
Crystals of 7 thus obtained were also analyzed by 1H and
13C NMR spectroscopy in CD2Cl2 (Figure 5). Of note is that
Figure 3. Nonlinear effect. The reactions were performed using 1a and
2a as substrates in CH2Cl2 at À208C in the presence of the Nb catalyst
~
&
(10 mol%),c linear, low ee value binol ligand, mixed catalyst
solution.
same Mannich-type reaction. Interestingly, in this case a
~
slightly negative nonlinear effect was observed
(
in
Figure 3). These results suggest that a dimeric species such
as 6 is formed by combining Nb(OR)5, 4c, and NMI, and that
the R,S heterodimeric species might be less reactive than the
R,R and S,S homodimeric species. It is also assumed that no
ligand exchange occurred after formation of the dimeric
species.
Figure 5. a) 1H and b) 13C NMR spectra of 7 in CD2Cl2. B: OCH2CH3,
C:(CH3)2CH.
Single crystals of a Nb complex suitable for X-ray analysis
were obtained by the addition of petroleum ether to a
combination of Nb(OEt)5, 4c, and NMI in toluene. Crystals
formed gradually, and the X-ray structure obtained is shown
in Figure 4.[14] Surprisingly, crystal structure 7 was different
from the assumed structure in solution (6). Characteristic
features of 7 are a Nb-(m2-O)-Nb unit, and that the binol
moiety of 4c is bound in a bidentate fashion to one niobium
the spectra are quite different from those of the assumed
complex 6 (Figure 1). The principle differences are the
number of the ethoxy moieties (B in Figure 5) and the
chemical shifts of the methyl groups in the isopropyl
1
substituents (C in Figure 5) in the H NMR spectrum. The
chemical shifts of the methyl groups in 7 are at around d =
0 ppm, while the chemical shifts of the methyl groups in the
assumed complex 6 are observed at around d = 1.2 ppm.
Aromatic shielding effects might be the cause of the
significant upfield shift.
Chiral Nb complex 7 displayed lower catalytic activity in
the Mannich-type reaction of imine 1a with silicon enolate 2a
(9 mol% based on Nb atom) of 7, in dichloromethane at
À208C for 18 h). The desired product was obtained in 21%
yield with 61% ee, while the same product was obtained in
74% yield with 83% ee in the presence of 10 mol% of the
chiral niobium catalyst prepared in situ.
Since the NLE experiments suggested that no ligand
exchange occurred after formation of the dimeric species, we
propose 8 as the most plausible structure of the highly
enantioselective Nb complex (Figure 6). We assume that 7
was formed from 8 during the crystallization. A key to
understanding the mechanism for the formation of 7 from 8 is
the origin of the oxygen atom between the niobium atoms in
7. Contamination of a small amount of water might form 7
from 8, but this possibility was ruled out by several control
À
experiments. A possible mechanism is the cleavage of the C
O bond of the bridging ethoxy group of 8, followed by the Nb-
O-Nb bond formation accompanied with generation and
elimination of diethyl ether. The highly strained structure of 8
might induce the formation of 7. Further investigations to
obtain clear evidence for this mechanism are now in progress.
In summary, we have developed a novel dinuclear chiral
niobium catalyst, in which tridentate ligands have been shown
Figure 4. a) Crystal structure and b) structural formula of the niobium
complex 7.
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S. Harada, S. Okada, S. Sakamoto, K. Yamaguchi, M. Shibasaki,
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[8] Details are given in the Supporting Information. For the
synthesis of 4a, see: K. Ishihara, H. Yamamoto, J. Am. Chem.
Soc. 1994, 116, 1561.
[9] a) Review, see: S. Kobayashi, M. Ueno in Comprehensive
Asymmetric Catalysis (Eds.: E. N. Jacobsen, A. Pfaltz, H.
Yamamoto), Springer, Heidelberg, 1999, supplement 1, p. 143;
See also b) H. Ishitani, M. Ueno, S. Kobayashi, J. Am. Chem.
Soc. 1997, 119, 7153; c) H. Ishitani, M. Ueno, S. Kobayashi, J.
Am. Chem. Soc. 2000, 122, 8180; d) S. Xue, S. Yu, Y. Deng, W. D.
Wulff, Angew. Chem. 2001, 113, 2331; Angew. Chem. Int. Ed.
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Soc. 2002, 124, 12964; f) K. Ishihara, M. Miyata, K. Hattori, T.
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Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew. Chem. 2004,
116, 1592; Angew. Chem. Int. Ed. 2004, 43, 1566.
Figure 6. The most plausible structure of the highly selective niobium
catalyst in solution.
[10] We have already found that NMI is an effective additional ligand
in zirconium-catalyzed enantioselective reactions. See, for
example, ref. [9b,c].
to be effective. In the presence of a catalytic amount of this
complex, asymmetric Mannich-type reactions proceeded
smoothly to afford the desired adducts in high yields with
high enantioselectivities. A crystal structure of a chiral
binuclear niobium complex, which contains a Nb-(m2-O)-Nb
unit and a tridentate binol derivative (4c) chelates one Nb
atom while bridging to another, has been revealed. Further-
more, the most plausible structure of the highly selective
niobium complex has been proposed.
[11] Recently, several “direct” asymmetric Mannich-type reactions
have been reported; however, to our knowledge, there is no
example using simple esters as nucleophiles. In the present
method, highly enantioselective reactions of simple ester
enolates with imines have been achieved. For “direct” Man-
nich-type reactions, see a review: a) A. Cꢁrdova, Acc. Chem.
Res. 2004, 37, 102; For selected examples, see also: b) W. Notz,
K. Sakthivel, T. Bui, G. Zhong, C. F. Barbas III, Tetrahedron
Lett. 2001, 42, 199; c) K. Juhl, N. Gathergood, K. A. Jørgensen,
Angew. Chem. 2001, 113, 3083; Angew. Chem. Int. Ed. 2001, 40,
2995; d) A. Cꢁrdova, W. Notz, G. Zhong, J. M. Betancort, C. F.
Barbas III, J. Am. Chem. Soc. 2002, 124, 1842; e) A. Cꢁrdova, S.-
i. Watanabe, F. Tanaka, W. Notz, C. F. Barbas III, J. Am. Chem.
Soc. 2002, 124, 1866; f) A. Cꢁrdova, C. F. Barbas III, Tetrahedron
Lett. 2002, 43, 7749; g) S.-i. Watanabe, A. Cꢁrdova, F. Tanaka,
C. F. Barbas III, Org. Lett. 2002, 4, 4519; h) S. Matsunaga, N.
Kumagai, S. Harada, M. Shibasaki, J. Am. Chem. Soc. 2003, 125,
4712; i) Y. Hayashi, W. Tsuboi, M. Shoji, N. Suzuki, J. Am. Chem.
Soc. 2003, 125, 11208; j) Y. Hayashi, W. Tsuboi, I. Ashimine, T.
Urushima, M. Shoji, K. Sakai, Angew. Chem. 2003, 115, 3805;
Angew. Chem. Int. Ed. 2003, 42, 3677; k) S. Matsunaga, T.
Yoshida, H. Morimoto, N. Kumagai, M. Shibasaki, J. Am. Chem.
Soc. 2004, 126, 8777; For examples using modified esters, see:
l) L. Bernardi, A. S. Gothelf, R. G. Hazell, K. A. Jørgensen, J.
Org. Chem. 2003, 68, 2583; m) M. Marigo, A. Kjærsgaard, K.
Juhl, N. Gathergood, K. A. Jørgensen, Chem. Eur. J. 2003, 9,
2359; n) D. Uraguchi, M. Terada, J. Am. Chem. Soc. 2004, 126,
5356, and references therein.
Received: October 5, 2004
Published online: December 21, 2004
Keywords: asymmetric catalysis · chirality · Lewis acids ·
.
Mannich reaction · niobium
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764
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