Highly enantioselective synthesis of β-amino acid derivatives by the lewis base catalyzed hydrosilylation of β-enamino esters

Article abstract of DOI:10.1002/chem.200801582

A study was conducted to demonstrate highly enantioselective synthesis of β-amino acid derivatives by the Lewis base catalyzed hydrosilylation of βenamino esters. It was found that these catalyst and its analogue displayed excellent activities and enantioselectivities in promoting hydrosilylation of N-aryl β-enamino esters. N-picolinoylpyrrolidine derivatives and N-picolioylephedrine were also evaluated in hydrosilylation of (Z)-methyl 3-phenyl-3-(phenylamino)acrylate. The generality of the Lewis base organocatalyzed hydrosilylation of various β-enamino esters were examined under the optimized conditions. It was observed that the catalytic system exhibited a high sensitivity to the N-substituents, while all the N-aryl β-enamino esters underwent the hydrosilylation smoothly to give corresponding β-amino esters.

Full text of DOI:10.1002/chem.200801582

DOI: 10.1002/chem.200801582
Highly Enantioselective Synthesis of b-Amino AcidDerivatives by the Lewis
Base CatalyzedHydrosilylation of b-Enamino Esters
Hong-Jie Zheng,[a, b] Wen-Bing Chen,[a, b] Zhi-Jun Wu,[c] Jin-Gen Deng,[a]
[a]
Wen-Qing Lin,[a] Wei-Cheng Yuan,[a] andXiao-Mei Zhang*
Optically active b-amino acids are very important chiral
building blocks for the synthesis of b-peptides, b-lactams,
natural products, and physiologically active substances.[1]
Therefore, efficient methods for the synthesis of optically
active b-amino acids would be of great value for drug dis-
covery and organic synthesis. Among the approaches to
chiral b-amino acids,[2] the most straightforward and atom
economic one is catalytic asymmetric reduction of b-enami-
no esters. Pioneered by Noyori et al.,[3a] many chiral transi-
tion-metal complexes were developed to catalyze high-pres-
sure hydrogenation of N-acyl b-enamino esters,[3] N-aryl b-
enamino esters,[4] or N-unprotected b-enamino esters[5] with
high enantioselectivities. However, transition-metal-cata-
lyzed hydrogenation cannot get rid of the problems of metal
leaching, high pressure, the cost of the catalyst, and its re-
generation.
enantioselective hydrosilylation of b-enamino esters.[7b,8] To
our knowledge, a general, highly enantioselective Lewis
base organocatalyzed hydrosilylation of b-enamino esters
has not been reported, and thus remains an important chal-
lenge.
Herein, we describe the first general, highly enantioselec-
tive organocatalytic hydrosilylation of b-enamino esters.
Matsumura and co-workers reported the hydrosilylation of
unprotected b-enamino ester 1a catalyzed by N-picolinoyl-
pyrrolidine derivative 2a that resulted in poor yield and
enantioselectivity (Scheme 1).[7b] However, to our delight,
we found that the same catalyst 2a and its analogues dis-
played excellent activities and enantioselectivities in pro-
moting hydrosilylation of N-aryl b-enamino esters.
Recently, asymmetric reactions involving the strategy of
Lewis base activation of Lewis acids attracted much atten-
tion.[6] Among these reactions, Lewis base catalyzed enantio-
selective hydrosilylation of ketimines has become an impor-
tant alternative to transition-metal catalysis in synthesis of
chiral amines.[7] However, there is only limited examples of
Scheme 1. Enantioselective hydrosilylation of b-enamino ester 1a report-
ed by Matsumura et al.[7b]
[a] H.-J. Zheng, W.-B. Chen, Prof. Dr. J.-G. Deng, Prof. Dr. W.-Q. Lin,
Prof. Dr. W.-C. Yuan, Prof. Dr. X.-M. Zhang
Key Laboratory for Asymmetric Synthesis and
Chiraltechnology of Sichuan Province
Chengdu Institute of Organic Chemistry
Chinese Academy of Sciences
Chengdu, 610041 (China)
Fax : (+86)28-85229250
E-mail: xmzhang@cioc.ac.cn
[b] H.-J. Zheng, W.-B. Chen
Graduate School of Chinese Academy of Sciences
Beijing, 100049 (China)
[c] Dr. Z.-J. Wu
First, N-picolinoylpyrrolidine derivatives 2a–2e and N-pi-
colinoylephedrine (4)[7m] were evaluated in hydrosilylation
of (Z)-methyl 3-phenyl-3-(phenylamino)acrylate.[9] As can
be seen in Table 1, 10 mol% of catalysts 2a–2c delivered
Chengdu Institute of Biology, Chinese Academy of Sciences
Chengdu, 610041 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801582.
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COMMUNICATION
Table 1. Enantioselective hydrosilylation of b-enamino ester 1b.
Entry[a]
Cat*
Solvent
T [8C]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2a
2a
2a
2a
2b
2c
2d
2e
4
2a
2b
2a
2b
2a
2b
2b
2c
2a
CHCl3
CH2Cl2
THF
0
0
0
0
0
0
0
0
0
À10
À10
À2
À2
À30
À30
À30
À30
À40
36
36
36
36
36
36
36
36
36
36
36
0
0
36
36
48
88
93
trace
90
87
80
–
toluene
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
67
92
84
96
94
88
88
84
36
36
76
88
90
57
55
À72
89
90
90
88
91
91
92
92
92
95
Table 2. Enantioselective hydrosilylation of b-enamino esters 1 catalyzed
by 2c.
78
86
94
Entry[a]
b-Enamino ester
Yield [%][b]
ee [%][c]
Conf.
48
7290
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
94
8295
86
9292
96
97
97
NR
93
91
9292
95
84
95
95
96
84
96
93
84
95
(À)
S (À)[d]
(À)
+)
83
[a] Unless specified otherwise, reactions were carried out with 10 mol%
of catalyst and 2.0 equiv of HSiCl3 on a 0.2mmol scale in 2.0 mL of sol-
vent. [b] Isolated yield based on the b-enamino ester. [c] The ee values
were determined using chiral HPLC.
96
(
(
92(
93
92(
-
94
92(
+)
(+)
À)
–
satisfying yields and good enantioselectivities in chloroform
at 08C. The ee values (ee=enantiomeric excess) increased
slightly along with the increase of the size of the aryl groups
in the catalysts (Table 1, entries 1, 5, and 6). However, intro-
duction of a methoxy group on C4 of pyrrolidine ring of 2a
led to dramatic drop in enantioselection, no matter what the
configuration of the carbon atom is (Table 1, entries 7 and
8). Perhaps it is due to the undesired coordination of me-
thoxy group with trichlorosilane. Compound 4 gave the op-
posite enantiomer with moderate ee value (Table 1, entry 9).
Examination of the solvents revealed that chlorinated sol-
vents proved to be essential. Little reaction was observed in
nonprotic polar media such as THF (Table 1, entry 3). Reac-
tions performed in nonpolar solvent such as toluene gave
high yield but moderate ee value (Table 1, entry 4). The
most favorable solvent is chloroform (Table 1, entry 1).
Lowering the temperature from 08C to À308C resulted in
an evident improvement in enantioselectivities. The best
yield and enantioselectivity were obtained with catalyst 2c
at À308C for 48 h (Table 1, entry 17). Further lowering the
temperature to À408C led to decrease in both reactivity and
enantioselectivity (Table 1, entry 18).
Under the optimized conditions, the generality of the
Lewis base organocatalyzed hydrosilylation of various b-en-
amino esters were examined. In the presence of 10 mol% of
2c, b-enamino esters 1b–1y were reduced in chloroform at
À308C with trichlorosilane. The results were summarized in
Table 2. Interestingly, this catalytic system exhibited a high
sensitivity to the N-substituents. All of the N-aryl b-enamino
esters underwent the hydrosilylation smoothly to give corre-
sponding b-amino esters in good yields. However, N-acyl b-
(+)
À)
+)
91
90
94
95
95
70
88
(À)
(+)
(À)
(À)
(+)
(À)
(À)
(+)
(À)
(+)
+)
1s
1t
28 (dr>99:1)
54 (dr>99:1)
17
1u
1v
1w
1x
1y
91
9266
96
(
80
(+)
(+)
90
28 (dr>99:1)
[a] Unless specified otherwise, reactions were carried out with 10 mol%
of catalyst and 2.0 equiv of HSiCl3 on a 0.2mmol scale in 2.0 mL of
CHCl3 at À308C for 48 h. [b] Isolated yield based on the b-enamino
ester. [c] The ee values were determined using chiral HPLC. [d] deter-
mined by comparison of the optical rotation value of derivative of 3c
with literature data.[3n]
enamino ester 1i was totally inactive in this catalytic system
(Table 2, entry 8). Perhaps it is due to the difficulty for 1i to
isomerize from enamine tautomer to imine tautomer. Vary-
ing the N-aryl substituent resulted in marginal changes in
enantioselectivity (Table 2, entries 1–7). In most cases, high
enantioselectivities (ꢀ90% ee) were observed with b-aryl-
N-aryl b-enamino esters (Table 2, entries 9–16). However,
pyridinyl-derived 1r and thienyl-derived 1s gave lower ee
values (Table 2, entries 17 and 18), suggesting a competing
coordination of the heteroatom in the substrate with tri-
chlorosilane. As to b-alkyl-N-aryl b-enamino esters, the ee
Chem. Eur. J. 2008, 14, 9864 – 9867
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X.-M. Zhang et al.
values increased along with the increase of the size of the
alkyl groups in the substrates (Table 2, entries 21–23). Be-
sides, cyclic substrates 1t, 1u, and 1y provided poor enantio-
selectivities but very high diastereoselectivities (Table 2, en-
tries 19, 20, and 24). It seems that the rigidity of the sub-
strate is very unfavorable to the coordination between cata-
lyst and substrate.
To test the practicality of the current method for the syn-
thesis of b-amino esters, the asymmetric hydrosilylation of
b-enamino esters 1c in a gram-scale was carried out using
10 mol% of 2c. The reaction proceeded smoothly to provide
3c in 82% yield and 95% ee (1.0 g, 3.5 mmol of 1c). Fur-
thermore, the N-PMP (PMP=p-methoxyphenyl) group of
product 3c was deprotected with CAN (CAN=ceric ammo-
nium nitrate) to give b-amino ester 5 in 65% yield without
racemization (Scheme 2). Fol-
Scheme 2. Gram-scale asymmetric hydrosilylation of 1c, deprotection of
the N-PMP group in product 3c and following protection of the amino
group with acetic group. ee for 3i given in parentheses is after a single re-
crystallization; determined by HPLC with a chiral AD-H column. [a]D20
=
À79.5 (c=0.6 in CHCl3, 99% ee); literature:[3n] [a]D20 =À79.9 (c=1.0 in
CHCl3, S, 99% ee).
lowing acetylation of the amino
group of
5
generated the
known compound N-acetyl b-
aminoester 3i.[3n] The absolute
configuration of 3c was deter-
mined as S by measurement of
the optical rotation value of
compound 3i.
Although detailed structural
and mechanistic studies remain
to be carried out, based on
these facts, we propose a mech-
anism shown in Scheme 3. First,
it is supposed that the reaction
proceeds through the imine tau-
tomer rather than the enamine
tautomer. The nitrogen atom of
the pyridine ring and the car-
Scheme 3. A plausible reaction mechanism for hydrosilylation of 1c catalyzed by 2c.
bonyl oxygen atom of catalyst
to a solution of the catalyst (0.02mmol) and the corresponding b-enami-
no ester (0.20 mmol) in dry CHCl3 (2mL) at À308C. The reaction mix-
ture was stirred at À308C for 48 h. Then the reaction was quenched with
saturated aqueous solution of NaHCO3. The mixture was extracted with
EtOAc, and the combined extracts was washed with brine and dried over
anhydrous MgSO4. Concentration in vacuo followed by flash chromatog-
raphy on silica gel with petroleum ether/ethyl acetate as the eluent af-
forded the b-amino esters. The ee values were determined using estab-
lished HPLC techniques with chiral stationary phases.
2c are coordinated to Cl3SiH. Meanwhile, the imine is acti-
vated by the hydroxy group of 2c through hydrogen bond-
ing. The less hindered transition state A is consistent with
the experimentally observed si-facial selectivity of the reac-
tion. It can also be hypothesized that A will be stabilized by
arene–arene interactions between the aromatic systems of
the catalyst and the substrate.
In summary, we have demonstrated the first general,
highly enantioselective Lewis base organocatalyzed hydrosi-
lylation of b-enamino esters that enables the straightforward
and mild synthesis of a broad range of b-amino acid deriva-
tives in high yields (up to 97%) and enantioselectivities (up
to 96% ee). The absolute configuration of product 3c has
been determined as S. Finally, a plausible mechanism has
been proposed. Detailed investigations of the mechanism
are in progress.
Acknowledgements
We are grateful for the financial support from National Sciences Founda-
tion of China (20572109 and 20772122) and Sichuan Youth Science and
Technology Foundation.
Keywords: amino acids
·
asymmetric synthesis
·
hydrosilylation · lactams · organocatalysis
Experimental Section
General procedure for asymmetric hydrosilylation of N-aryl b-enamino
esters: Trichlorosilane (41 mL, 0.40 mmol, 2.0 equiv) was added dropwise
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Asymmetric Hydrosilylation
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Published online: October 1, 2008
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9867