Chiral lewis base catalyzed highly enantioselective reduction of N-alkyl β-enamino esters with trichlorosilane and water

Article abstract of DOI:10.1002/chem.201003105

First, test the water! In the presence of a chiral Lewis base catalyst 2, the supposedly moisture-unfriendly reduction system with trichlorosilane was found to be highly efficient and enantioselective when using water as an additive. For the first time, this method enables the reduction of a broad range of N-alkyl β-enamino esters 1 to give N-alkyl β-amino esters 3 in good to high yields and with excellent enantioselectivities (see scheme).

Full text of DOI:10.1002/chem.201003105

DOI: 10.1002/chem.201003105
Chiral Lewis Base Catalyzed Highly Enantioselective Reduction of N-Alkyl
b-Enamino Esters with Trichlorosilane and Water
Xinjun Wu,[a, b] Yang Li,[a] Chao Wang,[a] Li Zhou,[a] Xiaoxia Lu,[a] and Jian Sun*[a]
Enantiomerically pure b-amino acid derivatives are im-
portant chiral building blocks for the synthesis of biological-
ly active molecules, such as b-peptides and b-lactams.[1]
Among the various methods for the synthesis of these tar-
gets, catalytic asymmetric reduction of b-enamino esters rep-
resents one of the most efficient and straightforward ap-
moisture-unfriendly reducing agent trichlorosilane (HSiCl3)
uses water as the most effective additive.
Recently, our group and others have developed the chiral
Lewis base catalyzed asymmetric reduction of ketimines by
HSiCl3 into a useful and viable method for the preparation
of chiral amines.[7,8] This method is also applicable for the
reduction of b-enamino esters for the preparation of chiral
b-amino esters.[5] However, for high enantioselectivity, the
substrates in the reduction of ketimines were limited to N-
aryl ones.[7,8] Similarly, the reduction of b-enamino esters by
this method was also shown to be limited to N-aryl b-enami-
no esters for high enantioselectivity.[5] Recently, we devel-
oped a novel Lewis base catalyst 1a with a dual functional
S-chiral sulfinamide group, which enabled the highly enan-
tioselective Lewis base catalyzed reduction with HSiCl3 to
be extended to a broad range of N-alkyl ketimines.[9] We
wanted to examine if this novel type of catalyst could tame
the reduction of the intractable N-alkyl b-enamino esters.
[2]
proaches. During the past decade, a number of transition-
metal catalytic systems have been developed for the asym-
metric hydrogenation of N-acyl b-enamino esters.[2,3] To
obtain high reactivity and enantioselectivity, the N-acyl
group was considered indispensable to satisfy the chelation
requirement between the substrate and the metal catalyst.
However, since the N-acyl group in the resulting b-amino
ester product is not usually the desired functional group and
needs deprotection under often harsh conditions followed
by further manipulation, it is imperative to develop effective
methods suitable for the asymmetric reduction of b-enamino
esters with different types of N-substituents. Recently, a few
catalytic systems have been presented in the literature that
enable the reduction of N-aryl b-enamino esters in high
yields and with good to high enantioselectivities through hy-
drogenation and hydrosilylation.[4,5] In addition, a few transi-
tion-metal catalysts have even proven to be applicable for
the highly enantioselective hydrogenation of N-unprotected
b-enamino esters.[6] However, to the best of our knowledge,
there are no methods available to date for the highly enan-
tioselective reduction of N-alkyl b-enamino esters. Herein,
we present an organocatalytic reduction system that, for the
first time, enables the highly enantioselective reduction of a
wide range of N-alkyl b-enamino esters, to give the corre-
sponding N-alkyl b-amino esters in high yield with excellent
enantioselectivity. An interesting feature of this system is
that the Lewis base catalyzed reduction by the supposedly
Firstly, our previously prepared catalysts 1a and 1b were
tested in the reduction of (Z)-ethyl 3-phenyl-3-(benzylami-
no)acrylate (2a) in toluene at À408C. Good enantioselectiv-
ities were obtained, but the yields were low (Table 1, en-
tries 1 and 2). We next synthesized a small set of analogous
catalysts with different groups on the amide, 1c–1 f, and ex-
amined their efficacies in the reduction of 2a. Again, these
catalysts all afforded good enantioselectivities but in low
yields (Table 1, entries 3–6). Therefore, the relatively more
reactive and enantioselective bulky aromatic amide group
catalyst 1d was selected for further studies.
[a] X. Wu, Y. Li, C. Wang, L. Zhou, Prof. Dr. X. Lu, Prof. Dr. J. Sun
Natural Products Research Center
Chengdu Institute of Biology
Based on the understanding that the b-enamino esters
themselves could not be reduced by trichlorosilane and that
the reduction proceeds through their imine tautomers, dif-
ferent Brønsted acidic additives (Table 1, entries 7–12) were
tested. We hoped that they would enhance the rate of reduc-
tion by accelerating the enamine–imine tautomerization
and, in addition, increase the electrophilicity of the imine
through protonation of the nitrogen atom. Delightfully,
every additive tested (except phenol) significantly enhanced
Chinese Academy of Sciences
Chengdu 610041 (P.R. China)
Fax : (+86)28-85222753
E-mail: sunjian@cib.ac.cn
[b] X. Wu
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences
Chengdu 610041 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003105.
2846
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Chem. Eur. J. 2011, 17, 2846 – 2848

COMMUNICATION
Table 1. Asymmetric reduction of N-benzyl b-enamino ester 2a catalyzed
by various Lewis base catalysts 1a–1 f.[a]
Under the optimal conditions, a wide variety of N-alkyl b-
enamino esters were tested as substrates in the 1d-catalyzed
reduction. As shown in Table 2, the aromatic N-benzyl b-en-
Table 2. Asymmetric reduction of various b-enamino esters 2 catalyzed
by 1d.[a]
Catalyst
Solvent Additive
[equiv][b]
Yield
[%][c]
ee
[mol%][b]
[%][d,e]
1
2
3
4
5
6
7
8
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1 f (10)
1d (10)
1d (10)
1d (10)
1d (10)
1d (10)
1d (10)
1d (10)
1d (10)
1d (10)
1d (10)
1d (10)
toluene
toluene
toluene
toluene
toluene
toluene
toluene HCl/Tol (1.0)
toluene AcOH (1.0)
toluene PhCO2H (1.0)
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH3CN
toluene
toluene
toluene
toluene
–
–
–
–
–
–
26
24
21
30
18
28
48
79
68
22
64
98
61
92
76
56
51
77
25
93
71
84
81
79
91
71
87
95
85
90
76
85
96
95
95
93
77
<5
86
81
95
94
b-enamino esters
Yield
[%][b]
ee [%]
Config.
R1
R2
R3
1
2
C6H5
Bn
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
2a
2b
2c
2d
2e
2 f
2g
2h
2i
98
85
73
94
94
96
95
98
85
87
92
90
96
92
R (+)
(+)
p-Me-C6H4
9
3[c] p-MeO-C6H4 Bn
96 (>99.9) (+)
10
11
12
13
14
15
16
17
PhOH (1.0)
EtOH (1.0)
H2O (1.0)
H2O (0.5)
H2O (1.5)
H2O (2.0)
H2O (1.0)
H2O (1.0)
H2O (1.0)
H2O (1.0)
H2O (1.0)
H2O (1.0)
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
p-F-C6H4
p-Cl-C6H4
m-Cl-C6H4
p-Br-C6H4
p-CF3-C6H4
2-naphthyl
iPr
Cy
Bn
C6H5
C6H5
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
86
94
94
95
89
96
79
51
59
97
88
74
95
95
93
94
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
(+)
2j
2k
2l
18[f] 1d (10)
19[g] 1d (10)
allyl Et
2m 97
20
21
1d (5)
1d (2)
nPr
iBu
Bn
Bn
Bn
Bn
Et
Et
Me
tBu 2q
Bn
Cy
2n
2o
2p
88
80
95
85
94
94
C6H5
C6H5
C6H5
C6H5
[a] Reactions were carried out on
a 0.2 mmol scale with HSiCl3
(3.0 equiv) in solvent (2.0 mL) at À408C for 24 h. [b] Catalyst loading
based on enamino ester. [c] Yield of isolated 3a is based on the enamino
ester. [d] The ee values were determined by using chiral HPLC.
[e] Product 3a was determined to have R configuration in all cases after
comparison of the optical rotation of N-debenzylated-3a with the litera-
ture data. [f] The reaction temperature was À208C. [g] The reaction tem-
perature wasÀ608C.
2r
2s
C6H5
[a] Reactions were carried out on a 0.2 mmol scale with 1d (10 mol%),
water (1.0 equiv), and HSiCl3 (3.0 equiv) at À408C in toluene (1 mL) for
24 h; [b] Yield of 3 isolated is based on imine. [c] Data in parentheses
was the ee value of the product after a single recrystallization in iPrOH/
hexane. Bn=benzyl, Cy=cyclohexyl.
the reactivity of the 1d-catalyzed reduction of 2a. In partic-
ular, water,
a
widely accepted adverse substance to
amino esters, 2a–2i, either with electron-donating or elec-
tron-withdrawing groups all underwent smooth reduction to
give the desired b-amino ester products in high yields (73–
98%) with high enantioselectivities (86–96% ee, Table 2, en-
tries 1–9). Notably, a single recrystallization of the obtained
chiral b-amino ester product 2c with 96% ee was able to
provide virtually pure enantiomer with >99.9% ee (Table 2,
entry 3). The aliphatic N-benzyl b-enamino esters, 2j–2l,
were also reduced in high yields (87–92%), albeit with mod-
erate enantioselectivities (51–79% ee, Table 2, entries 10–
12). Besides N-benzyl b-enamino esters, N-allyl b-enamino
ester 2m, also proved to be an excellent substrate for the
present catalytic reduction system and gave the product in
97% yield and 97% ee (Table 2, entry 13). Other N-alkyl b-
enamino esters, such as 2n and 2o, with N-propyl and N-iso-
butyl groups, also exhibited good reactivity, albeit with
slightly lower enantioselectivities (88 and 80% yield and 88
and 74% ee, respectively, Table 2, entries 14 and 15). As ex-
pected, the reduction of N-benzyl b-enamino esters 2p–2s
with different ester groups (R3 other than ethyl) proceeded
smoothly to give excellent results: 95% yield and 95% ee
for the methyl ester, 85% yield and 95% ee for the tert-
trichlorosilane, helped to drive the reaction to completion in
ACHTUNGTRENNUNG
24 h, to give the product in 98% yield, and furthermore,
boosted the enantiomeric excess (ee) to an excellent 96%
(Table 1, entry 12). Increasing the number of equivalents of
water (from 1.0 to 1.5 equiv) had marginal effects on both
the reactivity and enantioselectivity (Table 1, entry 14). A
further increase to 2.0 equiv only slightly lowered the enan-
tioselectivity, but caused a significant decrease in yield
(Table 1, entry 15), as did the use of 0.5 equiv of water
(Table 1, entry 13). Thus, 1.0 equiv of water was used as the
additive for further study.
Different solvents and reaction temperatures were also
examined for optimization (Table 1, entries 16–19), but with
no improvements. Lowering the catalyst loading from 10 to
5 mol% only slightly decreased the reactivity and enantiose-
lectivity (Table 1, entry 19), however further lowering to
2 mol% caused a significant decrease in reactivity but main-
tained a high level of enantioselectivity (Table 1, entry 21).
Thus, the optimal conditions for the reduction of 2a are as
follows: catalyst 1d (10 mol%) with water (1.0 equiv) as an
additive and toluene as the solvent at À408C.
Chem. Eur. J. 2011, 17, 2846 – 2848
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
2847

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effective method that, for the first time, enabled a broad
range of N-alkyl b-enamino esters to be reduced in high
yields and with high enantioselectivities. The use of water as
an additive proved to be crucial for high reactivity and
enantioselectivity. This method is potentially useful for the
synthesis of N-alkyl b-enamino acids and their derivatives.
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concentrated under vacuum. The crude product was purified by column
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We are grateful for financial support from the National Science Founda-
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Key Program of China during the 11th Five-Year Plan Period
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Keywords: amino esters
·
asymmetric reduction
·
enantioselectivity · organocatalysis · trichlorosilane
[1] a) Enantioselective Synthesis of b-Amino Acids (Ed.: E. Juaristi),
Wiley-VCH, New York, 2005; b) K. Gademann, T. Hintermann, J. V.
Received: October 27, 2010
Published online: February 10, 2011
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Chem. Eur. J. 2011, 17, 2846 – 2848