Multinuclear zinc bisamidinate catalyzed asymmetric alkylation of α-ketoesters and its unique chemoselectivity

Article abstract of DOI:10.1039/c7cc01736g

The multinuclear Zn-bisamidinate catalyzed enantioselective addition of Et₂Zn to α-ketoesters has been developed. The steric tuning of two amidinate units as well as multiple coordination on the Zn atoms play a key role in achieving high enantioselectivity (up to 98% ee) and unique chemoselectivity. The present catalyst exhibited the preferential alkylation of α-ketoesters even in the presence of aldehydes.

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Multinuclear Zinc Bisamidinate Catalyzed Asymmetric Alkylation
of α-Ketoesters and Its Unique Chemoselectivity
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a
Masahiro Yamanaka,* Masamitsu Inaba, Ryo Gotoh, Yoshiyuki Ueki, and Kenichiro Matsui
DOI: 10.1039/x0xx00000x
www.rsc.org/
The multinuclear Zn-bisamidinate catalyzed enantioselective
addition of Et Zn to α-ketoesters has been developed. The steric
2
tuning of two amidinate units as well as multiple coordination on
the Zn atoms play a key role in achieving high enantioselectivity
(
up to 98% ee) and unique chemoselectivity. The present catalyst
exhibited the preferential alkylation of α-ketoesters even in the
presence of aldehydes.
The rational design and development of a highly efficient
catalyst for asymmetric catalytic reaction is of ongoing
considerable interest in organic chemistry. Multimetallic
catalysts, in particular, have attracted much attention due to
their potential to have a synergistic effect that is not possible
have appeared regarding the catalytic enantioselective
5
addition of Me Zn having low nucleophilic and non-reducing
2
activities. Only two catalysts for the enantioselective addition
6
,7
of more reactive Et
2
Zn to
by Kozlowski and Hoveyda.
Chiral bisamidine ligands L1
cyclohexanediamine were designed to allow multimetallic
reactive sites in cis orientation on the C -symmetric reaction
space (Fig. 2). We firstly investigated catalytic activity and
stereocontrol ability of chiral bisamidine ligands L1 L6 (Table
). The reduction product was predominantly obtained in the
α-ketoesters have been reported
1
,2
6
a-c
6d
using monometallic catalysts.
Multinuclear metals
positioned suitably on the chiral scaffold could achieve higher
level of catalytic activity and stereocontrol ability. In our effort
to develop new chiral multi-nucleating ligand, the bisamidinate
ligand found to be a promising scaffold due to the
-
L6 derived from (1R,2R)-
2
conformational versatility of metal amidinate complexes based
3
-
on
σ
and
π
coordination modes (Fig. 1).
Our designed
1
bisamidine ligand could incorporate three metals positioned in
cis arrangement to cooperatively activate the highly
coordinative substrates (e.g., dicarbonyl compound) in a site-
dependent/selective manner (Fig. 1). Furthermore, electronic
and steric properties of the amidinate moiety and the chiral
scaffold connecting them can be easily modified. To assess
catalytic activity and stereocontrol ability of our designed
multimetallic bisamidinate catalyst, we herein studied
2
reaction of Et Zn with 1a in toluene at 0 °C (89%, entry 1). L1
accelerated the addition pathway (entry 2) and lowering the
reaction temperature significantly increased the yield of
addition product 2a (74%, entry 4). A survey of various
solvents revealed the superiority of toluene in terms of yield
and ee value (Table S1 in SI). Two amidinate units in cis
orientation play a key role in the preferential addition reaction
(entry 10). This indicates the importance of the multiple and
enantioselective addition of Et Zn to α-ketoesters.
Although numerous catalysts are available for the related
4
asymmetric alkylation of aldehydes, the number of catalysts
2
simultaneous coordination of the Zn atoms in activating
ketoesters.
α-
in the α-ketoester version is scarce due to serious side
reactions; reduction and uncatalyzed reaction. Several reports
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Table 1. Optimization of reaction conditions
Table 2. Substrate scope
2
a
2a
3a
a
b
a
Entry
L
Temp (°C)
0
Yield (%)
9
ee (%)
Yield (%)
89
2
2
3
1
2
3
4
5
6
7
8
9
-
-
a
b
a
Entry
R
Yield (%)
Ee (%)
49
31
45
1
Yield (%)
L1
L1
L1
L2
L3
L4
L5
L6
L7
0
44
18 (S)
15 (S)
20 (S)
35 (S)
35 (R)
49 (R)
10 (R)
4 (S)
56
1
2
3
4
5
6
7
8
9
Ph (a)
2-Naph (b)
52
43
25
20
0
-20
-45
-45
-45
-45
-45
-45
-45
50
49
74
24
61
78
20
3,5-Me
PhCH CH
i-Pr (e)
2
C
6
H
3
(c)
63
89
11
2
2
(d)
39
52
43
c
88
88
0
73
25
c
13
84
c-C
c-C
c-C
5
6
7
H
H
H
9
(f)
88
70
12
0
[
c]
1
0
14
-
72
c
11 (g)
13 (h)
>99
>99
86
a
c
1
b
Determined by H NMR analysis of the crude mixture. Determined by chiral HPLC.
c
86
0
20 mol % of L7 was used.
d
d
e
d
o-MeOC
m-MeOC
p-MeOC
o-MeSC
6
H
4
(i)
65 (85)
94 (95)
39
13 (10)
1
1
1
0
1
2
6
H
4
(j)
(k)
(l)
56
60
35
2
The steric environment on the amidine carbon atom
6
H
4
48
exhibited a significant effect on the α-ketoester activation
ability (entries 8, 9). The most potent substituent R was Me
e
e
6
H
4
99 (85)
97 (98)
1 (15)
a
1
b
Determined by H NMR analysis of the crude mixture. Determined by chiral HPLC.
The absolute configuration was determined to be R for 2a, 2i, and 2l. All other
group due to the adequate balance between the
conformational rigidity and the flexibility, constructing an configurations were assigned by analogy. Determined by chiral GC. Reaction
c
d
2
conditions: Et Zn (6.0 eq.), MS 4A (activated with a heat gun under reduced
e
pressure, 100 mg/mmol of 1g), 10 h. 5 mol% of L4 was used
appropriate C
2
-symmetric reaction space. The Ar groups
attached to the terminal N atoms of the bisamidine ligands
have a great effect on the reactivity as well as the
enantioselectivity (entries 5-7). Increasing the steric hindrance
on the terminal Ar group (L3 and L4) reversed the absolute
stereochemistry at the quaternary carbon center with
To gain insight into the catalytically active species of the
present reaction, the relationship between the ee values of L4
and 1g, stoichiometric experiments in several ratios of
Et Zn/L1 or L4, and DFT calculations of transition state (TS)
2
increased enantioselectivity.
In particular, L4 having a
were conducted. The almost linear relationship was observed
between ee values of L4 and 1g, indicating a monomeric
catalytic species (Fig. 3). The catalytic activity was significantly
sterically demanding 9-anthryl group resulted in the promising
ee value.
Next, the scope and limitations of this reaction with various
affected by the ratio of Et Zn/bisamidine (Table 3). Whereas
2
α
-ketoesters were explored under the optimal reaction
condition (Table 2). No steric effect of the aryl group was
observed in a variety of aryl -ketoesters (entries 1-3). On the
other hand, both reactivity and enantioselectivity strongly
depend on the steric environment of alkyl -ketoesters
entries 4-8). Whereas 1d resulted in moderate yield with
the Zn-bisamidinate catalysts prepared with lower molar ratios
than Et Zn/L1 = 2/1 found to be inactive (entries 1 and 2),
2
α
those prepared with 3/1 ratio resulted in comparable ee value
to the catalytic reaction with good yield (entry 3). Almost the
same results were obtained with the higher than 3/1 ratio
α
(
(entry 4). A similar tendency was observed in the Et Zn/L4
2
nonselective transformation, 1e-h afforded the addition
product in quantitative yields with noticeably improved
enantioselectivities of 70-88% ee (entries 5-8). A significant
increase in the enantioselectivity was achieved with
introduction of the coordinating groups (e.g., OMe and SMe)
at the ortho positon of the Ph group of 1a (entries 9 and 12).
In particular, o-SMe substituted 1l exhibited higher reactivity
than o-OMe substituted 1i. A comparable product yield (85%)
was achieved remaining the enantioselectivity (98% ee) albeit
with a decrease in the catalyst loading to 5 mol%. Fortunately,
the SMe group could be removed by reductive
dethiomethylation with Raney-Ni to afford 2a in quantitative
yield without lowering the enantiomeric excess. In contrast,
both m- and p-OMe substituted 1j and 1k resulted in
comparable enantioselectivities to 1a. In accordance with our
prediction (Fig. 1), the multiple coordination of the o-OMe and
o-SMe group with Zn atoms enhances the asymmetric
induction in a site-dependent manner.
ratio effect (entries 5 and 6). The Based on these experimental
analyses, the trimetallic TS model consisting of Zn species, L4
,
and 1a in a ratio of 3 : 1 : 1 was proposed.
2
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9
-ketoesters than aldehydes, the multinuclear
Table 3. Et
2
Zn/
L
ratio effect under stoichiometric condition
reactivity of α
Zn-bisamidinate catalyst was expected to promote the
preferential alkylation of α-ketoesters through the multiple
coordination with the Zn atoms even in the presence of
aldehydes. In fact, the chiral ligands/catalysts previously
employed in the asymmetric Et
performed poorly with -ketoesters. The enantioselective
addition of Et Zn to an equimolar mixture of 1a and
benzaldehyde 4a using (-)-MIB [(2S)-3-exo-aminoisoborneol]
and (R)-BINOLate-Ti(OiPr) at 0 °C in toluene preferentially
2
Zn addition of aldehydes
2
a
2a
3a
a
b
a
Entry
L
Et
2
Zn/L
Yield (%)
ee (%)
Yield (%)
α
1
2
3
4
5
6
L1-
L1
L1
L1
L4
L4
1/1
2/1
3/1
4/1
2/1
3/1
n.r.
n.r.
82
-
-
-
2
-
27 (S)
25 (S)
-
2
1
-
89
2
n.r.
71
afforded the corresponding addition product 5a from 4a in
10
88% yield, 88% ee (S) and 74% yield, 58% ee (R), respectively.
The addition product 2a from 1a was obtained only with 5 %
61 (R)
2
a
c
1
b
Determined by H NMR analysis of the crude mixture. Determined by chiral HPLC.
20 mol % of L7 was used.
and 9%, respectively. On the other hand, in an equimolar
8
DFT calculation of the proposed TS model revealed that the
mixture of 1a and 4a, L4 achieved exclusive formation of 2a
trinuclear Zn-bisamidinate catalyst activates 1a through the
with retaining the moderate enantioselectivity observed in the
single-substrate system (entry 1, Table 4). The sterically less
demanding L1 also exhibited high molecular recognition ability
for 1a albeit with significantly reduced enantioselectivity
(entry 2). The trimetallic reactive site would be disturbed by
coordination of 4a to the Zn atoms. This indicates that the 9-
anthryl group has an essential role in sterically protecting the
multiple coordination with the Zn atoms. The C -symmetric
2
reaction space constructed by the sterically demanding 9-
anthryl groups on the terminal N atoms is suitable for the 1a
arrangement in the Si-facial attacking TS (TSmajor, Fig. 4i) which
leads to the major enantiomer (R-2). In contrast, the steric
repulsion between the 9-anthryl group of L4 and the Ph group
of 1a destabilizes the Re-facial attacking TS (TSminor, Fig. S1 in
trimetallic reactive site in the C -symmetric reaction space (Fig.
2
SI). Increasing the bulkiness of alkyl α-ketoesters (e.g., 1e-h)
would enhance the steric repulsion to destabilize the TSminor
4
). Regardless of keto groups (R) in
addition products were obtained with complete
chemoselectivity and high enantioselectivity even in the
presence of various aldehydes (entries 3-8). The more
challenging substrates and having both -ketoester and
formyl substituents was further employed using L4 (Scheme
α-ketoesters 1, the
2
and thus increase the enantioselectivity (Fig. 4ii). In addition
to the steric effect, coordinative aryl α-ketoesters (e.g., 1i and
) would allow the additional coordination with the Zn atom
4
1l
6
9
α
and stabilize TSmajor to achieve much higher enantioselectivity
in a site-dependent manner. These plausible TS models in
good agreement with the experimental results motivated us to
further investigate molecular recognition ability of the present
multinuclear Zn-bisamidinate catalyst.
1
1
1). The α-ketoester group of 6 was preferentially reacted but
unfortunately the addition reaction was significantly retarded
with reduced enantioselectivity. The electron-withdrawing
formyl group electrophilically activates the α
through the conjugated monoaryl unit in
-ketoester group
to promote
The computational TS model predicted
a unique
6
chemoselectivity in the competing asymmetric alkylation of
α
ketoesters with aldehydes. In spite of the competing or lower
-
reduction and uncatalyzed reaction.
Table 4. Chemoselective and enantioselective addition of Et
2
Zn to
2
RCOCO Me in the presence of R’CHO
2
/3
2
5
a
b
a
Entry
1
R
R’
Yield (%)
42 / 41
77 / 23
96 / 0
ee (%)
45
2
Yield (%)
Ph (1a)
Ph (1a)
Ph (4a)
Ph (4a)
Ph (4a)
<1
<1
0
c
2
3
4
5
6
7
8
c-C
c-C
c-C
6
6
6
H
H
H
11 (1g)
11 (1g)
11 (1g)
89
84
84
96
96
96
c-C
6
H
11 (4g)
99 / 0
0
o-MeSC
Ph (4a)
6
H
4
(4l)
95 / 0
0
o-MeSC
o-MeSC
o-MeSC
6
H
4
4
4
(1l)
(1l)
(1l)
97 / 3
0
6
H
c-C
6
H11 (4g)
97 / 0
0
6
H
o-MeSC
6
H
4
(4l)
97 / 3
0
1
[a] Determined by H NMR analysis of the crude mixture. [b] Determined by chiral
HPLC. L1 was used.
c
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2
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Chem., 2008, 57, 183; (b) F. T. Edelmann, Adv. Orgmet.
Chem., 2013, 61, 55; For examples of versatile coordination
modes of metal amidinate complexes, see: (a) J. R. Hagadorn
and J. Arnold, Angew. Chem. Int. Ed., 1998, 110, 1813; (b)
Hideo Kondo, Yoshitaka Yamaguchi and Hideo Nagashima, J.
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Matsuo, Chem. Comm., 2002, 958; (d) P. C. Junk and M. L.
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Cherkasov, G. K. Fukin and A. A. Trifonov, Inorg. Chem., 2014,
3
5
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001, 101, 757; (b) K. Soai and T. Shibata, In Comprehensive
4
5
2
Asymmetric Catalysis, E. N. Jacobsen, A. Pfalts and H.
Yamamoto, Eds, Springer, Berlin, 1999, pp. 911.
(a) K. Funabashi, M. Jachmann, M. Kanai, M. Shibasaki,
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Fernández, A. Marco-Aleixandre and J. R. Pedro, Org. Lett.,
2
006, 8, 1287; (c) H-L. Wu, P-Y. Wu, Y-Y. Shen and B-J. Uang,
J. Org. Chem., 2008, 73, 6445; (d) B. Zheng, S. Hou, Z. Li, H.
Guo, J. Zhong and M. Wang, Tetrahedron: Asymmetry, 2009,
In
less affect the reactivity of the
preferential alkylation of proceeded to afford 10 with the
9
built on the biaryl unit, the formyl group was expected to
α
-ketoester group. The
2
0, 2125; (e) R. Infante, J. Nieto and C. Andrés, Chem. Eur. J.,
012, 18, 4375.
9
2
same level of yield and the slightly reduced enantioselectivity
as using 2a. Even though the moderate enantioselectivity, to
the best of our knowledge, there is no precedent for the
6
7
(a) E. F. DiMauro and M. C. Kozlowski, J. Am. Chem. Soc.,
2002, 124, 12668; (b) E. F. DiMauro, M. C. Kozlowski, Org.
Lett., 2002,
O’Brien, V. Annamalai and M. C. Kozlowski, Tetrahedron,
005, 61, 6249; (d) L. C. Wieland, H. Deng, M. L. Snapper and
4, 3781; (c) M. W. Fennie, E. F. DiMauro, E. M.
2
enantioselective addition of Et Zn to the α-ketoester group
2
rather than the formyl group in a site-selective manner.
In conclusion, we have developed a newly designed
multinuclear Zn-bisamidinate catalyst for the enantioselective
A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127, 15453.
For other enantioselective organozinc additions to
α-
ketoesters, see: (a) B. Jiang, Z. Chen, and X. Tang, Org. Lett.
002, , 3451. (b) T. Hameury, J. Guillemont, L. V. Hijfte, V.
Bellosta and J. Cossy, Org. Lett. 2009, 11, 2397; For related
2
4
2
addition of Et Zn to α-ketoesters. Both the arrangement and
the steric tuning of the two amidine moieties are essential for
recent progress of Rh catalyzed enantioselective 1,2-addition
to
the high catalyst activity and enantioselectivity. The highly
α-ketoesters, see: (c) T. Ohshima, T. Kawabata, Y.
coodinative
easily removable SMe at the ortho position of the Ph group of
, yielded the highest enantioselectivities. The significant
α
-ketoesters, in which introduction of OMe or
Takeuchi, T. Kakinuma, T. Iwasaki, T. Yonezawa, H.
Murakami, H. Nishiyama, and K. Mashima, Angew. Chem. Int.
Ed. 2011, 50, 6296; (d) F. Cai, X. Pu, X. Qi, V. Lynch, A. Radha,
and J. M. Ready, J. Am. Chem. Soc. 2011, 133, 18066; (e) T.-S.
1a
site-dependent asymmetric induction is caused by the multiple
coordination with the Zn atoms of the catalyst. Furthermore,
the multimetallic reactive site exhibited high molecular
Zhu, S.-S. Jin, and M.-H. Xu, Angew. Chem. Int. Ed. 2012, 51,
80; (f) T. Wang, J.-L. Niu, S.-L. Liu, J.-J. Huang, J.-F. Gong,
7
and M.-P. Song, Adv. Synth. Catal. 2013, 355, 927.
recognition ability. The preferential alkylation of
α
-ketoesters
8
9
Computational details are shown in SI.
-ketoesters,
trifluoropyruvate esters showed selective activation over
aldehydes, see: D. A. Evans, D. W. C. MacMillan and K. R.
Campos, J. Am. Chem. Soc., 1997, 119, 10859; see also: ref.
7c
As
highly
reactive
α
pyruvate
and
even in the presence of aldehydes was achieved. Further
studies on the mechanistic detail of the unique
chemoselectivity and the application of the chiral multinuclear
Zn-bisamidinate catalyst to other catalytic asymmetric
reactions are underway.
10 For MIB and BINOLate-Ti(OiPr)
alkylation of aldehydes, see: (a) W. A. Nugent, Chem. Comm.,
999, 1369; (b) J. Balsells, T. J. Davis, P. Carroll and P. J.
2
catalyzed asymmetric
This work was supported by a Grant-in-Aid for Scientific
Research (C) from the MEXT (Japan) and MEXT-Supported
1
Walsh, J. Am. Chem. Soc., 2002, 124, 10336; (c) M. Mori and
T. Nakai, Tetrahedron Lett., 1997, 38, 6233; (d) F.-Y. Zhang,
C.-W. Yip, R. Cao and A. S. C. Chan, Tetrahedron: Asymmetry,
Program for the
ꢀStrategic Research Foundation at Private
Universities (Japan).
1
997, 8, 585.
1
1 After preliminary screening, optimal reaction temperature
was changed to -20 °C.
Notes and references
4
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