The first highly enantioselective lewis base organocatalyzed hydrosilylation of α-Imino esters

Article abstract of DOI:10.1002/ejoc.200901312

Novel, chiral Lewis base organocatalysts, which displayed poor enantioselection in the hydrosilylation of N-aryl β-enamino esters, were found to be the catalysts of choice in the hydrosilylation of a-imino esters. In the presence of 10mol-% of the best ca

Full text of DOI:10.1002/ejoc.200901312

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200901312
The First Highly Enantioselective Lewis Base Organocatalyzed Hydrosilylation
of α-Imino Esters
Zhou-Yang Xue,[a,b] Yan Jiang,[a,b] Wei-Cheng Yuan,[a] and Xiao-Mei Zhang*[a]
Keywords: Amino acids / Enantioselectivity / Hydrosilylation / Lewis bases / Organocatalysis
Novel, chiral Lewis base organocatalysts, which displayed
poor enantioselection in the hydrosilylation of N-aryl β-
enamino esters, were found to be the catalysts of choice in
the hydrosilylation of α-imino esters. In the presence of
10 mol-% of the best catalyst, various α-imino esters under-
went enantioselective hydrosilylation to provide a wide
range of chiral α-amino esters with good yields (up to 97%)
and high enantioselectivities (up to 93%ee) except for some
special substrates.
procedure was reported recently,[8e] a general, highly enan-
tioselective, Lewis base catalyzed hydrosilylation of α-imino
esters is still worth further exploration in view of the econ-
omy of this methodology and the great importance of chiral
α-amino acids.
In this paper we report the first general, highly enantiose-
lective hydrosilylation of α-imino esters catalyzed by novel
chiral Lewis base organocatalysts derived from trans-4-hy-
droxy--proline. These catalysts exhibited only moderate
enantioselectivities in the hydrosilylation of N-aryl β-en-
amino esters. However, they were found to catalyze the
hydrosilylation of α-imino esters with high enantioselectivit-
ies (up to 93%ee). It is very interesting because a poor cata-
lyst for one kind of substrate would be the catalyst of choice
for another kind of substrate. Perhaps there are no “poor”
catalysts, only “unsuitable” catalysts.
Introduction
Chiral α-amino acids constitute some of the most impor-
tant molecules in biological systems.[1] Natural and unnatu-
ral α-amino acids are also important tools in protein engi-
neering and peptide-based drug discovery.[2] Therefore, in-
tense research has been focused on the preparation of enan-
tiomerically enriched α-amino acids.[3] Among the numer-
ous approaches, the most straightforward one to chiral α-
amino acid derivatives is the catalytic asymmetric direct re-
duction of α-enamides or α-imino esters. Chiral Lewis acid
catalyzed hydrogenation of α-enamides has been well devel-
oped and utilized in industry.[4] Recently, chiral phosphoric
acids were found to accelerate Hantzsch ester reduction of
α-imino esters with excellent reactivities and enantio-
selectivities.[5] However, Hantzsch ester reduction occasion-
ally suffers from difficulties in the purification of the prod-
ucts owing to the existence of pyridine derivatives.
Results and Discussion
In recent years, the strategy of metal-free chiral Lewis
base activation of Lewis acid[6] has been widely used in
asymmetric synthesis. Many efficient chiral Lewis bases
have been developed to catalyze the enantioselective hydro-
silylation of ketimines with trichlorosilane.[7] This new or-
ganocatalytic methodology has become a promising alter-
native to transition-metal catalysis in the synthesis of chiral
amines. However, a very limited number of examples of chi-
ral Lewis base catalyzed enantioselective hydrosilylation of
α-imino esters has been reported, and the results are far
from satisfactory.[8] Although a highly diastereoselective
During our continuing studies on chiral Lewis base cata-
lyzed hydrosilylation of C=N double bond compounds,[8c,9]
we made many efforts to search appropriate catalysts for the
enantioselective hydrosilylation of α-imino esters. As can be
seen in Table 1, we found that catalysts 1a and 1b (Fig-
ure 1), which gave good results in the enantioselective
hydrosilylation of N-aryl β-enamino esters,[9] exhibited only
moderate enantioselectivities in the hydrosilylation of ethyl
2-(4-methoxyphenylimino)-2-phenylacetate (2a) at –10 °C
in chloroform (Table 1, Entries 1 and 2). Afterwards, we
were very gratified to find that catalysts 1c and 1d, which
delivered poor ee values in the enantioselective hydro-
silylation of N-aryl β-enamino esters,[9] gave much higher
enantioselectivities in this case (Table 1, Entries 3 and 4).
Inversion of the configuration at C4 of the pyrrolidine ring
from R to S only caused a slight drop in ee. Catalyst 1e
bearing a free hydroxy group at C4 of the pyrrolidine ring
also gave a good result (Table 1, Entry 5).
[a] Key Laboratory for Asymmetric Synthesis and Chiral Technol-
ogy of Sichuan Province, Chengdu Institute of Organic Chemis-
try, Chinese Academy of Sciences
Chengdu 610041, China
Fax: +86-28-85229250
E-mail: xmzhang@cioc.ac.cn
[b] Graduate School of Chinese Academy of Sciences
Beijing 100049, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901312.
616
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Eur. J. Org. Chem. 2010, 616–619

Lewis Base Organocatalyzed Hydrosilylation of α-Imino Esters
Table 1. Enantioselective hydrosilylation of α-imino ester 2a.
erate a series of novel chiral Lewis bases. However, ben-
zylation, trimethylsilylation, and isovalerylation of the hy-
droxy group only caused marginal changes in the enantiose-
lection (Table 1, Entries 6–8). To our delight, when O-pival-
oyl catalyst 1i was employed, an obvious increase in
enantioselectivity was observed (Table 1, Entry 9). Modifi-
cation of the hydroxy group with benzoyl and diphenyl
phosphoryl groups made no improvement in enantio-
selectivity (Table 1, Entries 10 and 11). Hence, pivoloylation
of the hydroxy group at C4 of the pyrrolidine ring was re-
garded as the most suitable modification. An attempt to
further enhance the ee value through enlarging the size of
the aryl groups in the catalyst proved to be in vain (Table 1,
Entry 12). Introduction of an electron-donating group or
an electron-withdrawing group at C5 of the pyridine ring
brought about dramatic decreases in the ee values in both
cases (Table 1, Entries 13 and 14). 6-Bromo catalyst 1o also
displayed poor enantioselectivity (Table 1, Entry 15). More-
over, 6-methyl catalyst 1p was totally inactive in the titled
reaction (Table 1, Entry 16), perhaps as a result of the steric
hindrance of methyl group, which made the catalyst hard
to coordinate with trichlorosilane.
Hence, catalyst 1i was determined as the most appropri-
ate catalyst in this study. Afterwards, various solvents were
screened. Chlorinated solvents were found to be superior to
other kinds of solvents (Table 1, Entries 24–26). Chloro-
form and dichloromethane were both favorable. Lowering
the temperature proved to be effective (Table 1, Entries 17–
23). When the temperature was lowered to –40 °C, the reac-
tion proceeded smoothly for 67 h to provide α-amino ester
3a with almost quantitative yield and high enantio-
selectivity of 92%ee (Table 1, Entry 26).
Subsequently, the generality of catalyst 1i was examined
in the hydrosilylation of various α-imino esters. However,
under the optimal reaction condition for α-imino ester 2a,
the hydrosilylation of other α-imino esters proceeded slug-
gishly to give low yields of the desired products, whereas
most of the starting materials decomposed. In order to acti-
vate the substrates, several acid additives were employed, of
which pentanoic acid proved to be the most effective. Thus,
in the presence of 1i (10 mol-%), trichlorosilane (2 equiv.),
and pentanoic acid (0.5 mol-%) a series of α-imino esters
were reduced in dichloromethane at –40 °C. The results are
summarized in Table 2. For substituted phenyl ethyl esters,
para or meta substituents showed no obvious deleterious
effects on reactivity and enantioselectivity, no matter
whether the substituents were electron donating or electron
withdrawing (Table 2, Entries 1–6, 9 and 10). However, or-
tho substitution on the phenyl group caused dramatic drops
in the enantioselectivities (Table 2, Entries 7 and 8). More-
over, reaction of ortho-bromo substrate 2h afforded the cor-
responding amino ester only in moderate yield. Apparently,
ortho substitution on the phenyl group made the substrates
sterically more hindered so that they exhibited lower reac-
Entry[a]
Cat*
Solvent
T [°C] t [h] Yield [%][b] ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1i
1i
1i
1i
1i
1i
1i
1i
1i
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
ClCH2CH2Cl
PhCl
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–10
–20
–30
–40
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
72
24
24
24
24
24
24
24
41
41
67
92
70
90
88
84
84
85
86
98
96
95
92
95
90
95
trace
96
91
74
86
98
96
54
98
96
97
66
62
79
76
82
79
81
83
88
84
78
86
77
51
65
–
88
82
77
56
32
55
51
90
91
92
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
toluene
CH3CN
THF
diethyl ether
CH2Cl2
CH2Cl2
CH2Cl2
1i
[a] Unless specified otherwise, reactions were carried out with the
catalyst (10 mol-%) and HSiCl3 (2.0 equiv.) on a 0.5-mmol scale in
the appropriate solvent (2.0 mL). [b] Isolated yield based on the
α-imino ester. [c] The ee values were determined by using chiral
HPLC.
Figure 1. Chiral Lewis base organocatalysts evaluated in this study.
In this study, it seemed that introduction of a bulky tivity and enantioselectivity. Owing to the same reason, re-
group at C4 of the pyrrolidine ring would be beneficial to action of 1-naphthyl derivative 2k gave the product with
the reaction. In search of more effective catalysts, we modi- inferior yield and ee value as well (Table 2, Entry 11). It
fied the hydroxy group with various bulkier groups to gen- should be noted that benzoxazinone 2l underwent enantio-
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617

Z.-Y. Xue, Y. Jiang, W.-C. Yuan, X.-M. Zhang
SHORT COMMUNICATION
selective hydrosilylation to provide the dihydrobenzoxazi- tion mechanism and the utility of this reaction in the con-
none with acceptable yield and ee value (Table 2, Entry 12). struction of complex unnatural amino acid derivatives.
Finally, an aliphatic and cyclic α-imino ester 2m was re-
duced to give the desired product with good yield but very
low ee.
Experimental Section
General Procedure for the Asymmetric Hydrosilylation of α-Imino
Esters: A solution of trichlorosilane (102 µL, 1.00 mmol, 2.0 equiv.)
in CH2Cl2 (0.5 mL) was added dropwise to a solution of the cata-
lyst (0.05 mmol), the corresponding α-imino ester (0.50 mmol), and
pentanoic acid additive (0.0025 mmol, 2.6 µL, no additive for 2a)
in dry CH2Cl2 (1.5 mL) at –40 °C. The reaction mixture was stirred
at –40 °C until the α-imino ester disappeared (by TLC). Then, the
reaction was quenched with a saturated aqueous solution of
NaHCO3. The mixture was extracted with EtOAc, and the com-
bined extract was washed with brine and dried with anhydrous
MgSO4. Concentration in vacuo followed by flash chromatography
on silica gel (petroleum ether/ethyl acetate) afforded the α-amino
ester. The ee value was determined by using established HPLC
techniques with chiral stationary phases.
Table 2. Enantioselective hydrosilylation of α-imino esters 2 cata-
lyzed by 1i.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and spectral and analytical data for
the catalysts, α-imino esters, and α-amino esters; HPLC chromato-
grams for the α-amino esters.
Acknowledgments
We are grateful for financial support from the National Sciences
Foundation of China (20772122).
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Conclusions
In summary, novel, chiral Lewis bases derived from
trans-4-hydroxy--proline were developed and found to be
highly enantioselective in catalyzing the hydrosilylation of
α-imino esters. Thus, we have established the first general,
highly enantioselective Lewis base organocatalyzed hydro-
silylation of α-imino esters. Through this approach, a broad
range of chiral α-amino esters were synthesized in good
yields and with high levels of enantioselectivity. The abso-
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as R by comparison of their rotation value with the litera-
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Published Online: December 22, 2009
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