Evolution of chiral Lewis basic N-formamide as highly effective organocatalyst for asymmetric reduction of both ketones and ketimines with an unprecedented substrate scope

Article abstract of DOI:10.1039/b703307a

L-Pipecolinic acid derived Lewis basic N-formamide 5e has been developed as a first highly effective catalyst for the asymmetric reduction of aromatic and aliphatic ketones as well as aromatic and aliphatic ketimines in good to high enantioselectivity. The Royal Society of Chemistry.

Full text of DOI:10.1039/b703307a

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Evolution of chiral Lewis basic N-formamide as highly effective
organocatalyst for asymmetric reduction of both ketones and ketimines
with an unprecedented substrate scope{
Li Zhou,ac Zhouyu Wang,abc Siyu Weia and Jian Sun*a
Received (in Cambridge, UK) 5th March 2007, Accepted 24th April 2007
First published as an Advance Article on the web 9th May 2007
DOI: 10.1039/b703307a
Catalyst 4 was previously observed to be slightly more
enantioselective than its diastereomer 5a in the reduction of
ketimines.9c In contrast, in the reduction of ketone 6a, the latter
was found to be more enantioselective (entry 4 vs. 3). Thus our
attention was next directed to fine-tuning the structure of 5a in
hope of achieving high efficiency and enantioselectivity for the
reduction of ketones.
L-Pipecolinic acid derived Lewis basic N-formamide 5e has
been developed as a first highly effective catalyst for the
asymmetric reduction of aromatic and aliphatic ketones as
well as aromatic and aliphatic ketimines in good to high
enantioselectivity.
Catalytic asymmetric reductions of prochiral ketones and imines
have been among the central topics in asymmetric synthesis over
the past few decades. A number of highly efficient and
enantioselective catalytic methods have been developed for the
reduction of either ketones or imines.1 However, there have been
only a few examples of catalytic methods that allow for highly
enantioselective reductions of both ketones and imines.2–5 The
currently available methods mainly use transition metal complexes
as catalysts and all have narrow substrate scopes.2 Matsumura and
co-workers reported the first organocatalytic enantioselective
reduction method applicable to both ketone and imines, which
employed a chiral organic Lewis base as the catalyst and
trichlorosilane (HSiCl3) as the reducing agent, affording low to
moderate enantioselectivities.4 Recently, Malkov, Kocovsky and
co-workers disclosed that significantly improved enantioselectivies
could be obtained for this method with the newly designed catalyst
1.5 The substrates were, however, limited to aromatic ketones and
ketimines. We report here a first catalytic system that allows for
efficient reduction of aliphatic and aromatic ketones as well as
aliphatic and aromatic ketimines with HSiCl3 in good to high
enantioselectivity.6–8
We previously reported that chiral Lewis bases 2,9a 3,9b 49c and
5a9c (Fig. 1) all catalyzed the reduction of ketimines with HSiCl3
with high efficiency and enantioselectivity. We were interested in
testing the efficacies of these catalytic systems in the reduction of
ketones. Thus these catalysts were examined in the reduction of
para-trifluoromethylphenyl methyl ketone 6a with HSiCl3 at 0 uC
with toluene as the solvent. To our surprise, extremely low
reactivity was observed with 2 and 3 (,5% yield, entries 1 and 2,
Table 1). In contrast, the L-pipecolinic acid derived catalyst 4 and
its diastereomer 5a both exhibited good reactivity and enantio-
selectivity (entries 3 and 4).
Analogous catalysts 5b–h bearing different R groups were easily
prepared (see ESI{ for experimental details) and examined in the
reduction of 6a. Catalysts 5e–g with R as alkyl groups turned out
to be more enantioselective than the other analogues (entries 4–11).
Catalyst 5e bearing the smallest alkyl group (R = Me) displayed
the best overall efficacy, affording the product in 99% yield and
89% ee (entry 8).
We thus selected catalyst 5e for further studies. To optimize the
reaction conditions, the temperature and solvent effects were
examined (entries 12–17, Table 1). When the reaction temperature
was lowered from 0 to 220 uC, the enantioselectivity was lifted
from 89 to 92% whereas the high reactivity was almost unaffected
(entry 12 vs. 8). Further lowering the temperature to 240 uC
caused
a substantial decrease in enantioselectivity and an
unacceptable loss of reactivity (entry 13). A survey of solvents
proved toluene to be the best choice (entries 12 and 14–17).
Having established the optimal reaction conditions, we next
examined other ketones to expand the substrate scope of catalyst
5e. Various ketones were reduced by HSiCl3 in the presence of
10 mol% 5e in toluene at 220 uC. As shown in Table 2, high yields
(92–98%) and enantioselectivities (82–93%) were obtained for
typical electron-deficient and electron-rich aromatic ketones 6a–j
(entries 1–10). Remarkably, the notoriously difficult aliphatic
aChengdu Institute of Biology, Chinese Academy of Sciences, Chengdu,
610041, China. E-mail: sunjian@cib.ac.cn; Fax: +86-28-85222753;
Tel: +86-28-85211220
bDepartment of Chemistry, Xihua University, Chengdu, 610039, China
cGraduate School of Chinese Academy of Sciences, Beijing, China
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b703307a
Fig. 1 Structures of the catalysts.
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Table 1 Asymmetric reduction of ketone 6aa
Table 3 Asymmetric reduction of ketimines 8 with catalyst 5ea
Entry Ketimine R2, Ar
Yieldb (%) eec (%)
Entry
Catalyst
Solvent
T/uC
Yieldb (%)
ee (%)c,d
1d
2e
3f
4
5
6
7
8
9
8a
8a
8a
8a
8b
8c
8d
8e
8f
Ph, Ph
Ph, Ph
Ph, Ph
Ph, Ph
Ph, PMP
4-MeOC6H4, Ph
4-CF3C6H4, Ph
2-Naphthyl, Ph
94
85
93
94
93
96
98
92
90 (R)
93 (R)
91 (R)
93 (R)
89 (R)
93 (R)
88 (R)
89 (R)
90 (R)
92 (R)
89 (R)
83 (R)
1
2
3
4
5
6
7
8
2
3
4
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
ClCH2CH2Cl
CHCl3
0
0
0
0
0
0
0
0
0
,5
,5
86
87
89
90
91
99
85
89
89
92
20
77
82
75
36
—
—
74
80
78
71
80
89
89
85
83
92
80
86
84
79
33
5a
5b
5c
5d
5e
5f
5g
5h
5e
5e
5e
5e
5e
5e
6-MeO-2-naphthyl, Ph 86
9
10g
11h
12h
a
8g
8h
8i
c-C6H11, Ph
i-Pr, Ph
i-Pr, PMP
93
93
88
10
11
12
13
14
15
16
17
a
0
0
220
240
220
220
220
220
Unless specified otherwise, reactions were carried out with 2.0 of
equiv. of HSiCl3 on a 0.2 mmol scale in 1.0 mL of toluene at 220 uC
for 24 h. Isolated yield based on the imine. The ee values were
b
c
d
determined using chiral HPLC. The reaction was carried out in
e
CH3CN
CH2Cl2 at 0 uC. The reaction was carried out in CH2Cl2 at 220 uC.
f
g
The reaction was carried out in toluene at 0 uC. The imine is a
10 : 1 (E/Z) mixture. The imine is a 6 : 1 (E/Z) mixture.
Unless specified otherwise, reactions were carried out with 10 mol%
catalyst and 2.0 equiv. of HSiCl3 on a 0.2 mmol scale in 1.0 mL of
solvent for 16 h. Isolated yield based on the ketone. The ee
h
b
c
d
values were determined using chiral HPLC. Product 7a was R
configured in all cases, as revealed by comparison of the optical
rotation with the literature data.
the solvent.9c Delightfully, high yield of 94% and ee value of 90%
were obtained (entry 1, Table 3). The enantioselectivity was
enhanced to 93% when the reaction temperature was lowered to
220 uC (entry 2). Further survey of solvents revealed that the
overall performance of 5e in toluene is slightly better than in
dichloromethane (entries 3 and 4 vs. 1 and 2).
ketones 6k–m also reacted well to produce the desired alcohol in
high yields (81–99%) with moderate to good enantioselectivities
(53–88%, entries 11–13).10
To examine the substrate scope of 5e for the reduction of
ketimines, a variety of ketimines were reduced under the optimal
conditions. As illustrated in Table 3 (entries 4–9), all the typical
aromatic ketimines 8a–f gave high yields (86–98%) and ee values
(88–93%). Moreover, the difficult aliphatic ketimines 8g–i that
exist as E/Z isomeric mixtures also reacted well to afford high
yields (88–93%) and ee values (83–92%, entries 10–12).6,9,11
Thus, the present catalyst system represents the most general
one for the asymmetric reduction of both aromatic and aliphatic
ketones and ketimines known to date. To rationalize the
exceptional efficacy of this catalyst system, the methoxy group
on C29 (see 5e in Scheme 1 for labeling) seems to be an important
factor to take into account. It has been shown that replacement of
this group with either a bigger alkoxy group (5f and 5g in Fig. 1) or
a group with a less electron-rich 29-oxygen atom (5a, 5b, and 5d)
led to decreased reactivity and/or enantioselectivity of the catalyst
for the reduction of ketone 6a (vide supra). Further reversing the
stereochemistry of C29 (10) that bears this group or removing it
To check if catalyst 5e still retains the high efficiency and
enantioselectivity of the original catalyst 4 for the reduction of
ketimines, 8a was reduced in the presence of 10 mol% 5e under the
optimal conditions for 4, namely at 0 uC with dichloromethane as
Table 2 Asymmetric reduction of ketones 6 with catalyst 5ea
Entry
Ketone
R1
Yieldb (%)
ee (%)c
1
2
3
4
5
6
7
8
6a
6b
6c
6d
6e
6f
6g
6h
6i
4-CF3C6H4
4-NO2C6H4
3-NO2C6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
3-BrC6H4
Ph
4-MeC6H4
2-Naphthyl
c-C6H11
2-PhCH2CH2
i-Pr
92
92
95
95
94
96
96
94
95
98
90
99
81
92 (R)
91 (R)
93 (R)
88 (R)
87 (R)
88 (R)
87 (R)
81 (R)
87 (R)
82 (R)
88 (R)
76 (R)
53 (R)
9
10
11d
12
13d
a
6j
6k
6l
6m
Unless specified otherwise, reactions were carried out with
2.0 equiv. of HSiCl3 on a 0.2 mmol scale at 220 uC for 16 h.
b
c
Isolated yield based on the ketone.
The ee values were
d
determined using chiral HPLC. The product was converted to its
para-nitrobenzoate for ee determination due to its inefficient
visibility for UV detection of HPLC.
Scheme 1
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Lett., 1999, 40, 7507.
Fig. 2 Proposed transition states.
(11) resulted in a significant decrease in both reactivity and
enantioselectivity (Scheme 1). Although detailed structural and
mechanistic studies remain to be carried out, on the basis of these
results we propose that catalyst 5e could work as a tridentate
activator and promote the hydrosilylation of ketones through the
heptacoordinate silicon transition structure A (Fig. 2).12 For the
hydrosilylation of ketimines, similar transition structure B should
not be favorable due to the steric repulsion between the N-Ar
group and the methoxyl group, and the hexacoordinate silicon
structure C should be preferred, which is justified by the
observation that both the diastereomer 10 and the
C29-deoxygenated analogue 11 displayed the same high level of
reactivity and enantioselectivity as 5e for the reduction of ketimine
8a (Scheme 1).13
5 A. V. Malkov, A. Liddon, P. Ramirez-Lopez, L. Bendova, D. Haigh
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hydrosilylation of ketimines, see: (a) A. V. Malkov, S. Stoncius,
K. N. MacDougall, A. Mariani, G. D. McGeoch and P. Kocovsky,
Tetrahedron, 2006, 62, 264; (b) A. V. Malkov, A. Mariani,
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H. B. Kagan, Synlett, 1997, 1175; (d) D. Pini, A. Iuliano and
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In summary, we have developed the L-pipecolinic acid derived
N-formamide (5e) as a highly effective Lewis basic organocatalyst
for the enantioselective reduction of both ketones and ketimines
with an unprecedented substrate scope. The methoxy group on
C29 has proven to be critical for the high efficacy of this catalyst
for the reduction of ketones, but not indispensable for the
reduction of ketimines. A heptacoordinate silicon transition
structure and a hexacoordinate one were proposed for the
reduction of ketones and ketimines, respectively.
We are grateful for financial support from the National Natural
Science Foundation of China (20402014 and 20672107) and from
the Chinese Academy of Sciences (Hundreds of Talents Program).
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Notes and references
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2 For transition metal catalyzed highly enantioselective reduction of both
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13 For other transition state models proposed previously for Lewis base
catalyzed asymmetric hydrosilylations, see refs. 4–7.
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Chem. Commun., 2007, 2977–2979 | 2979