Chiral Lewis Base-Catalyzed, Enantioselective Reduction of Unprotected β-Enamino Esters with Trichlorosilane

Article abstract of DOI:10.1002/adsc.201501061

Catalytic asymmetric reduction of N-unsubstituted β-enamino esters represents a major challenge for asymmetric catalysis. In this paper, the first organocatalytic system that could be used for the asymmetric hydrosilylation of N-unsubstituted β-enamino esters has been developed. Using N-tert-butylsulfinyl-L-proline-derived amides and L-pipecolinic acid-derived formamides as catalyst, a broad range of β-aryl- and β-alkyl-substituted free β-amino esters could be prepared with high yields and enantioselectivities. The practicality was illustrated by the gram-scale asymmetric synthesis of ethyl (R)-3-amino-3-phenylpropanoate and isopropyl (S)-3-amino-4-(2,3,5-trifluorophenyl)butanoate. The resulting product can be smoothly transformed to the FDA approved medicines dapoxetine and sitagliptin in a short synthetic route.

Full text of DOI:10.1002/adsc.201501061

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DOI: 10.1002/adsc.201501061
Chiral Lewis Base-Catalyzed, Enantioselective Reduction of
Unprotected b-Enamino Esters with Trichlorosilane
Jianheng Ye,a Chao Wang,a,* Lin Chen,a Xinjun Wu,a Li Zhou,a and Jian Suna,*
a
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, Peopleꢀs Republic of China
E-mail: wangchao@cib.ac.cn or sunjian@cib.ac.cn
Received: November 18, 2015; Revised: January 12, 2016; Published online: February 23, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201501061.
Abstract: Catalytic asymmetric reduction of N-un-
substituted b-enamino esters represents a major
challenge for asymmetric catalysis. In this paper,
the first organocatalytic system that could be used
for the asymmetric hydrosilylation of N-unsubstitut-
ed b-enamino esters has been developed. Using N-
tert-butylsulfinyl-l-proline-derived amides and l-pi-
pecolinic acid-derived formamides as catalyst,
a broad range of b-aryl- and b-alkyl-substituted free
b-amino esters could be prepared with high yields
and enantioselectivities. The practicality was illus-
trated by the gram-scale asymmetric synthesis of
ethyl (R)-3-amino-3-phenylpropanoate and isopro-
pyl (S)-3-amino-4-(2,3,5-trifluorophenyl)butanoate.
The resulting product can be smoothly transformed
to the FDA approved medicines dapoxetine and si-
tagliptin in a short synthetic route.
catalyzed asymmetric hydrosilylations of b-enamino
esters for the preparation of chiral b-amino acids.[8]
Despite these advances, however, such reductions
have been limited to N-substituted enamines. Herein,
we reported the first organocatalyst catalyzed highly
enantioselective asymmetric reduction of N-unsubsti-
tuted b-enamino esters.
b-Amino acids are attracting increasing attention as
chiral building blocks, especially in the pharmaceuti-
cal and agrochemical industry. However, despite the
fact that the chiral Lewis base-catalyzed asymmetric
reduction could be done under mild reaction condi-
tions with cheap and metal-free reagents, this trans-
formation has never been considered as a mainstream
technology in this field.[9] The main reason is that the
substrate scope of the existing organocatalytic systems
was confined to N-substituted enamino esters and the
nitrogen substituent group, which is not usually the
desired functional group, needs to be removed under
often harsh reaction conditions. Thus, developing
a generally applicable and highly efficient organocata-
lytic system for the direct reduction of free b-enamino
esters has attracted considerable interest. However, to
the best of our knowledge, there are no organocata-
Keywords: b-amino esters; asymmetric hydrosilyla-
tion; Lewis bases; reduction; trichlorosilane
Enantiometrically pure b-amino acids and their deriv- lytic systems available to date and it thus remains
atives are ubiquitous important structural motifs that a major challenge.
can be found in a vast number of pharmaceutical and
In 2006, Matsumura and co-workers reported the
agrochemical substances,[1] such as dapoxetine (treat- first example of organocatalytic reduction of free b-
ment of premature ejaculation),[2] ezetimibe (reduc- enamino esters with trichlorosilane, but only 41%
tion of plasma cholesterol level), sitagliptin (anti-dia- enantiomeric excess could be achieved.[10] At the
betic), and maraviroc (treatment of HIV infection).[3] outset of our work, we hypothesized that the nitrogen
Therefore, many approaches have been developed for atom of the enamino substrate could bound to tri-
the enantioselective synthesis of chiral b-amino chlorosilane to form a complex, and it could be con-
acids,[4] among which the catalytic asymmetric reduc- verted to the reduced product under the catalysis of
tion of b-enamino esters represents the most efficient Lewis bases (Scheme 1). The steric hindrance of the
and straightforward one.[5]
catalyst and N-substituent group of the substrate are
In the past decades, transition metal[6] and organic very important for the enantioselectivity of the reduc-
Lewis base[7] catalyzed asymmetric hydrogenation of tion system. Owing to the decreased steric hindrance
b-enamines has been certified as a powerful method- of the free b-enamino esters, a catalyst with more
ology to obtain optically pure amines. Recently, we steric hindrance may be required for the asymmetric
and others reported a series of organic Lewis bases- reductions to achieve high enantioselectivity.
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Chiral Lewis Base-Catalyzed, Enantioselective Reduction
7). Satisfyingly, the desired product 4a was obtained
with 93% yield and with a high enantiomeric ratio
(er) of 88.5:11.5 under the catalysis of 10 mol% of 1a.
Catalyst 2a has a very low catalytic activity under the
existing reaction conditions, but a 90.0:10.0 er could
still be obtained. Encouraged by these results, cata-
lysts 1b–f were tested. We found that 92.5:7.5 er could
be obtained when catalysts 1e and 1f were used, re-
spectively (Table 1, entries 5 and 6). A 93% yield and
97.0:3.0 er could be achieved when 20 mol% of cata-
lyst 1e was added. After careful investigation, we
identified the best reaction conditions in which the re-
duction of b-phenyl b-enamino ester 3a is performed
Scheme 1. Strategies for the synthesis of b-amino acids.
Initially,
N-tert-butylsulfinyl-l-proline-derived using 20 mol% of catalyst 1e, trichlorosilane
amide catalyst 1a and l-pipecolinic acid-derived for- (3.0 equiv.), and H2O (1.0 equiv.) in toluene at À408C
mamide 2a were tested, respectively, in the reduction for 36 h.[11]
of b-phenyl b-amino ester 3a (Table 1, entries 1 and
With the optimized reaction conditions in hand, the
scope of the enantioselective asymmetric reduction of
N-unsubstituted b-enamino esters was next investigat-
ed (Table 2). A variety of N-unsubstituted b-enamino
esters was efficiently reduced to afford the corre-
sponding free b-amino esters with high yields and
enantioselectivity. The R2 group of the b-enamino
ester could be replaced with other groups such as
methyl, benzyl, cyclohexyl, and isopropyl. High enan-
Table 1. Asymmetric hydrosilylation of N-unsubstituted b-
phenyl-b-enamino ester 3a catalyzed by Lewis base catalysts
1a–f and 2a.[a]
Table 2. Asymmetric reduction of various unprotected b-en-
amino esters.[a]
Entry Catalyst (mol%) Solvent Yield [%][b] er[c,d]
1
2
3
4
5
6
7
8
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1f (10)
2a (10)
1c (20)
1e (20)
1f (20)
1e (20)
1e (20)
1e (20)
1e (20)
1e (20)
1e (5)
toluene 93
toluene 73
toluene 85
toluene 80
toluene 80
toluene 88
88.5:11.5
90.0:10.0
91.5:8.5
90.5:9.5
92.5:7.5
92.5:7.5
90.0:10.0
94.0:6.0
97.0:3.0
95.0:5.0
91.0:9.0
–
Entry R1
R2
Yield [%][b] er[c]
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Et
4a
4b
4c
4d
93
91
90
91
85
85
93
92
87
84
90
88
97.0:3.0
Me
Bn
Cy
94.5:5.5
94.0:6.0
95.5:4.5
94.0:6.0
92.5:7.5
95.5:4.5
91.0:9.0
93.5:6.5
95.5:4.5
93.5:6.5
94.0:6.0
95.0:5.0
94.5:5.5
91.5:8.5
85.0:15.0
60.0:40.0
toluene
7
toluene 90
toluene 93
toluene 88
Ph
i-Pr 4e
9
4-FC6H4
4-ClC6H4
3-ClC6H4
4-BrC6H4
4-CF3C6H4
4-MeC6H4
4-MeOC6H4 Et
3-MeOC6H4 Et
2-naphthyl
2-thienyl
2-furanyl
Bn
Et
Et
Et
Et
Et
Et
4f
4g
4h
4i
4j
4k
4l
10
11
12
13
14
15
16
CCl4
80
CH2Cl2 <5
9
CHCl3
THF
<5
18
–
10
11
12
13
14
15
16
17
61.0:39.0
–
81.0:19.0
CH3CN <5
toluene 70
4m 87
Et
Et
Et
Et
4n
40
4p
4q
92
86
60
95
[a]
Unless noted otherwise, reactions were performed with
3a (0.2 mmol), H2O (0.2 mmol), and HSiCl3 (0.6 mmol)
in solvent (2.0 mL) at À408C for 36 h.
[b]
[c]
Isolated yield of 4a.
[a]
The products were derivatized with TsCl and then deter-
mined by HPLC with a chiral stationary phase.
Product 4a obtained from the catalyst 1-catalyzed reac-
tions was determined to have R configuration and the
2a-catalyzed reaction gave S configuration product by
comparison of the HPLC data with the literature data.
Unless noted otherwise the reactions were set with cata-
lyst 1e, substrate 3 (0.2 mmol), H2O (0.2 mmol), and
HSiCl3 (0.6 mmol) in toluene (2.0 mL) at À408C for 36 h.
Yield of isolated product.
The products were derivatized with TsCl and then deter-
mined by HPLC with a chiral stationary phase.
[d]
[b]
[c]
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Jianheng Ye et al.
tioselectivities and yields could be obtained when
these substrates were reduced in the reaction
(Table 2, entries 1–5). Electron-donating and electron-
withdrawing substitution at the para position of the
phenyl ring are well tolerated (Table 2, entries 6–12).
When the R1 group was p-tolyl, the substrate could be
reduced in 90% yield and with an er of 93.5:6.5.
When the R1 was 4-methoxyphenyl, 88% yield and
94.0:6.0 er could be obtained (Table 2, entries 11 and
12). When the R1 groups were electron-withdrawing
group substituted phenyls such as 4-fluorophenyl, 4-
chlorophenyl, 4-bromophenyl, and 4-(trifluorome-
thyl)phenyl, the substrate could also be reduced in
high yields and enantioselectivities (Table 2, entries 6,
7, 9 and 10). Electron-donating and electron-with-
drawing substitutions at the meta position are equally
well tolerated. When the R1 were 3-chlorophenyl and
3-methoxyphenyl, the substrates could be reduced to
the corresponding amino esters in high yields and
enantioselectivities (Table 2, entries 8 and 13). How-
ever, the ortho substituted phenyls are not tolerated
(see the Supporting Information). Interestingly, we
found the R1 could be other aromatic groups such as
naphthalen-2-yl, thiophen-2-yl, and furan-2-yl. These
substrates could be reduced to the corresponding
amino esters with good to high yields and enantiose-
lectivities (Table 2, entries 14–16).
Scheme 2. Formamide-catalyzed asymmetric reduction of
(Z)-3-amino-4-phenylbut-2-enoate 3q. The products were
derivatized with PhNCS and then determined by HPLC
with a chiral stationary phase. Product 4q has an S configu-
ration by comparison of the HPLC data with the literature
data. See the Supporting Information for details of the reac-
tion conditions.
However, we found the substrate scope of this N-
tert-butylsulfinyl-l-proline-derived amide catalyst
system was limited to b-aryl-b-enamino esters. The b-
alkyl-b-enamino esters such as ethyl (Z)-3-amino-4-
phenylbut-2-enoate 3q could be reduced by this catal-
ysis system to get the corresponding product with
high yield, but poor enantioselectivities were ob-
served (Table 2, entry 17). In order to prepare chiral
b-alkyl-b-amino esters, our previously prepared Lewis
base catalysts have been rescreened. Using (Z)-3-
amino-4-phenylbut-2-enoate 3q as standard substrate,
we found it could be reduced with excellent yields
and with good enantioselectivities under the catalysis
of l-pipecolinic acid-derived formamides (Scheme 2).
Formamide 2c, in which the R group is MOM, was
shown to be the best catalyst since 3q could be re-
duced in 99% yield and with an er of 87.0:13.0.
Scheme 3. Catalyst 2c-catalyzed asymmetric reduction of b-
enamino esters.
After careful investigation, we identified the best
In order to illustrate the synthetic potential of these
reaction conditions in which the reduction of (Z)-3- methodologies, the products of the current catalytic
amino-4-phenylbut-2-enoate 3q is performed using systems have been used to prepare chiral dapoxetine
20 mol% of catalyst 2c, trichlorosilane (3.0 equiv.), and sitagliptin. As shown in Scheme 4, using the
and H2O (1.0 equiv.) in dichloromethane at 08C for asymmetric reduction product 4a as a key starting ma-
36 h. Interestingly, we found 90.5:9.5 er could be ob- terial, dapoxetine could be prepared in four steps by
tained when the ethyl in 3q was replaced with isopro- the following procedure with overall 43% yield and
pyl (3r) (Scheme 3). And it could be further improved 95.0:5.0 er.[12]
to 94.0:6.0 when it was replaced with d-menthyl (3u).
The phosphate salt of sitagliptin has been approved
More interestingly, the same major enantiomer was by the US FDA for the management of type 2 diabe-
formed in the reduction with an er of 92.5:7.5 when it tes mellitus. Numerous reports on the synthesis of si-
was replaced with l-menthyl (3v) (see the Supporting tagliptin have appeared.[13] However, to the best of
Information).
our knowledge, an inexpensive reagent-based asym-
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Chiral Lewis Base-Catalyzed, Enantioselective Reduction
the final product could be increased to 99% when it
was recrystallized from ethyl acetate and hexane.
In summary, we have developed two useful catalytic
systems which could be used to prepare chiral b-aryl-
b-amino esters and b-alkyl-b-amino esters, respective-
ly. The N-sulfinyl-l-proline amides-catalyzed asym-
metric reduction system could be used in the prepara-
tion of a broad range of b-aryl-b-amino esters with
high yields and high enantioselectivities. The l-pipe-
colinic acid-derived formamides-catalyzed system
could be used to synthesize b-alkyl-b-amino esters, es-
pecially b-benzyl-b-amino esters, with excellent yields
and with moderate to high enantioselectivities. The
synthetic potential of the current methodologies has
been proved in the synthesis of (R)-dapoxetine and
(S)-sitagliptin. The full application scope of these cat-
alytic systems and the mechanistic aspects are under
exploration and will be reported in due course.
Scheme 4. Synthesis of dapoxetine.
Experimental Section
metric synthesis of sitagliptin remains unprecedented. General Procedure for the Catalytic Reduction of b-
Our strategy for the synthesis of chiral sitagliptin was Enamino Esters
started with 2-(2,4,5-trifluorophenyl)acetic acid
(Scheme 5). The b-2,4,5-trifluorophenyl b-enamino
Under an argon atmosphere, trichlorosilane (60 mL,
0.60 mmol) was added dropwise to a stirred solution of b-en-
ester substrate 8 could be easily prepared in three
steps with an overall 84% yield. The substrate 8 could
be reduced to the chiral b-2,4,5-trifluorophenyl b-
amino ester 9 by the 2c-catalyzed asymmetric hydrosi-
lylation reaction with 95% yield and 91.0:9.0 er.[14]
With this key intermediate in hand, sitagliptin could
be synthesized in 4 steps by the reported synthetic
route with an overall 68% yield and 91.0:9.0 er. More
importantly, we also found thatr the enantiopurity of
amino ester (0.20 mmol), catalyst 1e or 2c (0.04 mmol) and
water (3.6 mL, 0.20 mmol) in the chosen solvent (2 mL) at
the chosen temperature. The mixture was allowed to stir at
the same temperature for 36 h. After completion, the reac-
tion was quenched with a saturated aqueous solution of
NaHCO3 and extracted with EtOAc. The combined organic
phase was washed with brine, dried over anhydrous MgSO4,
and concentrated under vacuum. The crude product was pu-
rified by column chromatography (silica gel, hexane/EtOAc
or DCM/MeOH) to afford pure b-amino ester 4, and then
derivatized with TsCl or PhNCS. The er values of the derva-
tives were determined by established HPLC techniques with
chiral stationary phases.
Acknowledgements
We are grateful for financial support from the Western Light
Talents Training Program of Chinese Academy of Sciences,
the National Natural Science Foundation of China (Project
Nos. 21272227 and 21402185), and the Science & Technology
Department of Sichuan Province (Project No. 2012SZ0219).
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