Asymmetric transfer hydrogenations of β-N-substituted enamino esters with ammonia borane

Article abstract of DOI:10.1016/j.tetlet.2019.03.060

Optically active β-amino acids and their derivatives are very useful building blocks in synthetic and medicinal chemistry. The catalytic asymmetric reduction of β-enamino esters is one of the most efficient approaches for their synthesis. Ammonia borane w

Full text of DOI:10.1016/j.tetlet.2019.03.060

Accepted Manuscript
Asymmetric Transfer Hydrogenations of β-N-Substituted Enamino Esters with
Ammonia Borane
Weiwei Zhao, Xiangqing Feng, Jing Yang, Haifeng Du
PII:
S0040-4039(19)30289-8
https://doi.org/10.1016/j.tetlet.2019.03.060
TETL 50701
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
15 February 2019
23 March 2019
25 March 2019
Please cite this article as: Zhao, W., Feng, X., Yang, J., Du, H., Asymmetric Transfer Hydrogenations of β-N-
Substituted Enamino Esters with Ammonia Borane, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.03.060
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2
Graphical Abstract
With ammonia borane as hydrogen source, an asymmetric transfer hydrogenation of β-N-substituted enamino esters was
successfully realized to give β-amino acid derivatives in 51−90% yields with up to 91% ee by using a combination of Piers’
Asymmetric Transfer Hydrogenations of
β-N-Substituted Enamino Esters with
Ammonia Borane
Weiwei Zhao,a,b Xiangqing Feng,b,c Jing Yanga,* and Haifeng Dub,c,*
borane and (S)-tert-butylsulfinamide as a chiral catalyst.

1
Tetrahedron Letters
Asymmetric Transfer Hydrogenations of β-N-Substituted Enamino Esters with
Ammonia Borane
Weiwei Zhaoa,b , Xiangqing Fengb,c , Jing Yanga,* and Haifeng Dub,c,*
a State Key Laboratory of Chemical Resource, Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing University of Chemical
Technology, Beijing 100029, China
b Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China
c School of Chemical Science, University of Chinese Academy of Sciences, Beijing 100049, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Optically active β-amino acids and their derivatives are very useful building blocks in synthetic
and medicinal chemistry. The catalytic asymmetric reduction of β-enamino esters is one of the
most efficient approaches for their synthesis. Ammonia borane with low molecular weight, high
hydrogen capacity, and good stability, is an ideal hydrogen source for the transfer
hydrogenation. However, only a few successful examples have been reported for the asymmetric
reduction with ammonia borane. In this work, an asymmetric metal-free transfer hydrogenation
of β-N-substituted enamino esters with ammoinia borane was successfully realized by using a
frustrated Lewis pair of Piers’ borane and (S)-tert-butylsulfinamide as a chiral catalyst. A variety
of β-amino acid derivatives were obtained in 51−90% yields with up to 91% ee.
Available online
Keywords:
Transfer hydrogenation
Frustrated Lewis pair
Ammonia borane
β-N-substituted enamino ester
2009 Elsevier Ltd. All rights reserved.
Optically active β-amino acids and their derivatives are
extremely important building blocks in synthetic and medicinal
chemistry.1 Clinical medicines ezetimibe and sitagliptin are
among the most representative examples.2 Various
methodologies have been established for the synthesis of
optically active β-amino acids.3 The catalytic asymmetric
reduction of β-enamino esters is among the most efficient and
straightforward approaches.4 A great success has been achieved
for the asymmetric hydrogenation with chiral transition-metal
highly effective for asymmetric transfer hydrogenations of imines
and 2,3-disubstituted quinoxalines (Scheme 1).13 The hydrogen
transfer between FLP and imine occurred via an 8-memberered
transition state TS1, and the FLP catalyst was regenerated with
ammonia borane through a concerted 6-membered transition state
TS2. Very recently, our group disclosed a chiral ammonia borane
by the dehydrogenation of ammonia borane with chiral
phosphoric acid, which was a regenerable hydrogen donor for
asymmetric transfer hydrogenations of imines and β-enamino
esters.14 As our ongoing interest in the FLP catalysis,15 herein, we
wish to report our preliminary results on the FLP-catalyzed
asymmetric transfer hydrogenation of β-enamino esters for the
synthesis of optically active β-amino acid derivatives.
catalysts.5
Alternatively,
the
asymmetric
metal-free
hydrosilylation with trichlorosilane as hydrogen source using
chiral Lewis base as catalyst is also a very promising approach.6
However, trichlorosilane is extremely flammable and moisture
sensitive, and its hydrogen capacity is low. Exploring stable and
easily handling hydrogen donors with high hydrogen capacities is
therefore still of great importance.
Ammonia borane (NH3·BH3, AB) with some unique features
including low molecular weight, high hydrogen capacity, and
good stability, has been widely studied as a potential solid
hydrogen-storage material.7 Moreover, ammonia borane has also
been employed as an effective hydrogen source in
transition-metal
catalyzed
or
catalyst-free
transfer
hydrogenations.8 But only a few successful examples have been
reported for the asymmetric reaction.9 For example, in 1984,
Williams and co-workers realized an asymmetric reduction of
ketones which the complex of ammonia borane and chiral
18-crown-6. Recently, our group developed a novel type
frustrated Lewis pair (FLP)10 by the combination of
(S)-tert-butylsulfinamide (1)11 and Piers’ borane (2)12, which was
Scheme 1. Our previous work on the FLP-catalyzed transfer
hydrogenation with ammonia borane.
 Corresponding author. Tel: +86-10-62652117; fax: +86-10-62554449; e-mail: yangj@mail.buct.edu.cn, haifengdu@iccas.ac.cn.

2
The initial study was conducted by subjecting ethyl
(Z)-3-(4-methoxyphenyl)amino)-3-phenylacrylate (3a) to the
asymmetric hydrogenation with NH3·BH3 (2.0 equiv) in toluene
at 60 °C for 48 h by using (S)-tert-butylsulfinamide (1) (30 mol
%) and HB(C6F5)2 (2) (10 mol %) as a FLP catalyst (Scheme 2).
Despite the excess of (S)-tert-butylsulfinamide (1), product 4a
was obtained with a disappointing enantioselectivity. A control
experiment indicates the reaction between ammonia borane and
3a without catalyst was not very fast under the same condition
(Scheme 2).
Pyridines and diethylamine slowed down the reaction and
lowered the ee (Table 1, entries 10-12). While, triethylamine can
give 85% ee without loss of reactivity (Table 1, entry 13). With
triethylamine as additive, reducing the loading of
(S)-tert-butylsulfinamide (1) to 10 mol % resulted in a slight drop
of ee (Table 1, entry 14). Adjusting the addition sequence by
treating 3a with (S)-tert-butylsulfinamide (10 mol %) and Piers’
borane at 30°C for 12 h before the addition of triethylamine and
ammonia borane afforded product 4a in 88% conversion with
84% ee (Table 1, entry 15). In contrast to adding in one portion,
the two-step addition sequence possibly inhibited the racemic
background reaction with ammonia borane catalyzed by Piers’
borane more effectively, which resulted in a higher ee.13a
Moreover, when NEt3·BH3 instead of NH3·BH3 was used, much
lower conversion and ee were obtained (Table 1, entry 16).
Subsequently,
a
variety
of
ethyl
(Z)-3-amino-3-phenylacrylates 3a-o with diverse N-substituents
were subjected to the asymmetric transfer hydrogenation under
the optimal reaction condition. As shown in Scheme 3, all the
reactions proceeded smoothly to furnish the desired products
4a-o in 51-79% yields with 41-85% ee’s. Both electron-donating
and withdrawing substituents on the phenyl group were well
tolerated for this reaction. β-Enamino ethyl esters 3k-m with the
ortho-substituted phenyl group were also effective substrates, but
gave relatively lower yields and ee’s. When using benzyl group
as the N-substituent, product 4o was obtained in 76% yield with
54% ee.
Scheme 2. Initial study on transfer hydrogenation of 3a.
Table 1. Optimization of reaction conditionsa
Entry Additive
(10 mol %)
Solvent
Conv. Ee
(%)b (%)c
95
1
--
Toluene
16
19
38
10
73
76
71
78
76
64
73
68
85
73
84
61
2
--
p-Xylene
Chloroform
78
93
3
--
4
--
Dichloromethane 99
5
--
n-Hexane
89
88
85
90
60
50
88
71
89
89
88
33
6
--
n-Heptane
7
--
n-Decane
8
--
Cyclohexane
Cyclohexane
Cyclohexane
9d
10
11
12
13
14e
15f
16g
--
Pyridine
2-Phenylpyridine Cyclohexane
Diethylamine
Triethylamine
Triethylamine
Triethylamine
--
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
a
All reactions were carried out with 3a (0.10 mmol),
(S)-tert-butylsulfinamide (1) (0.03 mmol, 30 mol %), HB(C6F5)2 (2) (0.01
mmol, 10 mol %), NH3·BH3 (0.20 mmol) in solvent (1.5 mL) at 60 °C for 48
h unless other noted.
b The conversion was determined by crude 1H NMR.
c The ee was determined by chiral HPLC.
Scheme 3. Asymmetric transfer hydrogenations of β-enamino
esters with diverse N-substituents.
d NH3·BH3 (1.0 equiv) was used.
e (S)-tert-butylsulfinamide (1) (0.01 mmol, 10 mol %) was used.
f Treating 3a (0.1 mmol) with 1 (10 mol %) and 2 (10 mol %) at 30 °C for 12
h before addition of NH3·BH3 and triethylamine, and the mixture was stirred
at 60 °C for 48 h.
The effect of ester group was investigated by subjecting
β-enamino esters 3p-v to the transfer hydrogenation. It was found
that the size of alkyl groups influenced the enantioselectivity
obviously, the ee values were varied from 78% to 91% (Scheme
4). The bulky tert-butyl group gave the highest enantioselectivity.
A variety of β-enamino tert-butyl esters 3w-c’ were therefore
employed as substrates for the asymmetric transfer
hydrogenation to afford the corresponding products 4w-c’ in
70-86% yields with 72-91% ee’s (Scheme 4). Moreover,
β-enamino esters 3d’-f’ with different aryl groups at the
β-positions were also effective substrates for this reaction to
furnish the corresponding products 4d’-f’ in 59-83% yields with
66-91% ee’s (Scheme 4). According to the reported methods,16
β-lactam 5 can be easily accessed in 88% yields with >99% ee
g NEt3·BH3 was used instead of NH3·BH3.
Solvents were next optimized to reduce the background
reaction and improve the enantioselectivity. As shown in Table 1,
solvents were found to have
a large impact on the
enantioselectivity (entries 1-8). Alkane solvents gave much
higher ee’s, and cyclohexane gave the optimal result (Table 1,
entries 5-8). When 1.0 equivalent of ammonia borane was used,
an obvious drop of conversion was observed (Table 1, entry 9).
Various Lewis bases were further studied as additives for the
asymmetric transfer hydrogenation in cyclohexane to inhibit the
possible racemic reaction catalyzed by free Piers’ borane.13a

3
after a recrystallization in hexanes by treating compound 4r (93%
ee after recrystallization in hexanes) with Grignard reagent in
THF for 0.5 h (Scheme 5).
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Scheme 5. Synthesis of β-lactam 5.
In summary, a metal-free asymmetric transfer hydrogenation
of β-N-substituted enamino esters with ammonia borane as a
hydrogen source and a frustrated Lewis pair of HB(C6F5)2 and
(S)-tert-butylsulfinamide as
a
chiral catalyst has been
successfully realized. A variety of optically active β-amino acid
derivatives were obtained in 51−90% yields with 41-91% ee’s.
Enantiomer-pure β-lactam was easily prepared via a single step
reaction. Further efforts on searching for novel chiral FLPs and
expanding their applications in asymmetric reactions are
underway in our laboratory.
Acknowledgments
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Chem. Soc., Chem. Commun. 1984, 1461-1464.
We are grateful for the financial support by the National
Natural Science Foundation of China (21572231, 21521002 and
21825108).
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Supplementary Material
Supplementary data (the procedures for the synthesis of
substrates and metal-free transfer hydrogenation of
β-N-substituted enamino esters, the characterization of the
substrates and products and data for the determination of ee’s
along with the NMR spectra) associated with this article can be
found, in the online version.
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Highlights
1. Asymmetric transfer hydrogenations with
ammonia borane were realized.
2. β-Amino acid derivatives were obtained in high
yields with up to 91% ee.
3. A frustrated Lewis pair was used as an effective
chiral catalyst.