A general approach to the synthesis of β2-amino acid derivatives via highly efficient catalytic asymmetric hydrogenation of α-aminomethylacrylates

Article abstract of DOI:10.1002/adsc.201000122

A new strategy was developed for the synthesis of a valuable class of α-aminomethylacrylates via the Baylis-Hillman reaction of different aldehydes with methyl acrylate followed by acetylation of the resulting allylic alcohols and S_N2′-type amination of the allylic acetates. Asymmetric hydrogenation of these diverse olefinic precursors using rhodium(Et-Duphos) catalysts provided the corresponding β²-amino acid derivatives with excellent enantioselectivities and exceedingly high reactivities (up to >99.5% ee and S/C=10,000). The first hydrogenation of (Z)-configurated substrates was studied for the synthesis of β²-amino acid derivatives. The high influence of the substrate geometry and steric hindrance on the reactivity and enantioselectivity was also disclosed for this reaction. This protocol provides a highly practical, facile and scalable method for the preparation of optically pure β²- amino acids and their derivatives under mild reaction conditions.

Full text of DOI:10.1002/adsc.201000122

FULL PAPERS
DOI: 10.1002/adsc.201000122
A General Approach to the Synthesis of b2-Amino Acid
Derivatives via Highly Efficient Catalytic Asymmetric
Hydrogenation of a-Aminomethylacrylates
Yujuan Guo,a Guang Shao,a Lanning Li,a Wenhao Wu,a Ruihong Li,a Jingjing Li,a
Jian Song,a Liqin Qiu,a,* Mahavir Prashad,b and Fuk Yee Kwongc
a
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, No. 135 Xingangxi Road, Guangzhou 510275,
Peopleꢀs Republic of China
Fax : (+86)-20-8411-0996; e-mail: qiuliqin@mail.sysu.edu.cn
Process Research & Development, Chemical & Analytical Development, Novartis Pharmaceuticals Corporation, One
b
Health Plaza, East Hanover, New Jersey 07936, U.S.A
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis,
c
Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, Peopleꢀs
Republic of China
Received: February 15, 2010; Revised: May 3, 2010; Published online: June 8, 2010
Dedicated to Professor Albert S. C. Chan on the occasion of his 60th birthday.
Abstract: A new strategy was developed for the syn- tion of (Z)-configurated substrates was studied for
thesis of a valuable class of a-aminomethylacrylates the synthesis of b2-amino acid derivatives. The high
via the Baylis–Hillman reaction of different alde- influence of the substrate geometry and steric hin-
hydes with methyl acrylate followed by acetylation drance on the reactivity and enantioselectivity was
of the resulting allylic alcohols and SN2’-type amina- also disclosed for this reaction. This protocol pro-
tion of the allylic acetates. Asymmetric hydrogena- vides a highly practical, facile and scalable method
tion of these diverse olefinic precursors using rhodi- for the preparation of optically pure b2-amino acids
ACHTUNGTRENNUNGum(Et-Duphos) catalysts provided the corresponding and their derivatives under mild reaction conditions.
b2-amino acid derivatives with excellent enantiose-
lectivities and exceedingly high reactivities (up to Keywords: amino acids; asymmetric catalysis; hydro-
>99.5% ee and S/C=10,000). The first hydrogena- genation; phosphane ligands; rhodium
Introduction
comparison to the great progress in the synthesis of
b3-amino acids and their derivatives in recent
The preparation of enantiopure b-amino acids has at- years,[3a,8] only limited examples have been reported
tracted extensive attention in both academic and in- for the preparation of b2-amino acids and their deriva-
dustrial parties due to the fact that these compounds tives.[3a,9] This underdevelopment prompted us to dis-
are key moieties of a number of bioactive and phar- cover a facile, practical and scalable method for the
maceutical molecules and important building blocks synthesis of b2-amino acids and their derivatives. Al-
for the construction of new peptidomimetics.[1–4] b- though some other approaches for the catalytic syn-
Amino acids can be subdivided into b3-, b2- and b2,3- thesis of b2-amino acids can be employed nowa-
amino acids (b-substituted b-amino acids, a-substitut- days,[10–13] catalytic asymmetric hydrogenation of pro-
ed b-amino acids and a,b-substituted b-amino acids), chiral olefinic precursors of b2-amino acid derivatives
in which b2-amino acids are particularly attractive would seem to be one of the most efficient and facile
compounds since the alkyl substituent at the a-posi- methods due to its inherent efficiency and atom econ-
tion of the scaffold favors the folded conformations in omy. However, to our best knowledge, this methodol-
the b-peptides. So far the most interesting secondary ogy has been far less studied.[14]
structures of b-peptides have only been observed
In 2001, Robinson and co-workers firstly reported
when b2-amino acids are built into the backbone.[5] b2- the asymmetric hydrogenation of a,b-diamidoprope-
Amino acids were also reported as key intermediates noate substrates using Rh(Et-Duphos) catalysts to
in some antifungal drugs and PDF inhibitors.[6,7] In prepare a,b-diamidopropenoic acid derivatives with
Adv. Synth. Catal. 2010, 352, 1539 – 1553
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1539

Yujuan Guo et al.
FULL PAPERS
Scheme 1. Preparation of a-aminomethylacrylates 4
high enantioselectivity of up to 99% ee.[14a] In the mers, not only one. However, it is usually difficult to
same year, Jackson et al. developed an enantionselec- achieve high activity and enantioselectivity for a
tive hydrogenation process of a,b-unsaturated nitriles system containing both E- and Z-isomers as a catalyst
bearing a phthalimido substituent and the correspond- often favors one isomer and disfavors the other.[15]
ing phthalimido methyl esters. They found that Ru- Very recently, we published a preliminary communi-
BINAP catalyst was superior to Rh-Duphos catalysts cation, in which Rh-catalyzed asymmetric hydrogena-
for the latter substrates and the highest enantioselec- tion reactions of (E/Z)-2-[(benzyloxyamino)methyl]-
tivity was 84% ee.[14b] In contrast, Rh-DuPhos was 3-phenylacrylic acid methyl ester (4a) and (E/Z)-2-
better than Ru-BINAP catalyst in the hydrogenation [(benzyloxy-amino)methyl]-2-hexenoic acid methyl
of the nitriles (best ee up to 48%). Particularly, a-sub- ester (4s) (Scheme 1) proceeded with excellent enan-
stituted b-amidoacrylates were selected as hydrogena- tioselectivities and exceedingly high reactivities.[14h]
tion substrates using chiral bidentate phosphines as li- This success greatly encouraged us to extend this pro-
gands (BPE and Duphos), giving the products with tocol to the hydrogenation of a diverse range of sub-
modest ee values of up to 67%.[14c] Recently, Zheng strates, which have a variety of substituents with dif-
and co-workers realized good Rh-catalyzed enantiose- ferent steric and electronic properties. In addition to
lective hydrogenation reactions of b-unsubstituted the examination of a spectrum of prochiral substrates,
and b-substituted a-(phthalimidomethyl)-acrylates we were also interested to investigate the relation-
using monodentate phosphites or BoPhoz-type ligand- ships between steric and electronic properties of the
s.[14e,f] For b-unsubstituted substrates, up to 99% ee substrates on the effects of the catalytic activity and
was obtained. However, ee values decreased for the enantioselectivity. Thus, a general synthetic route to
hydrogenation of b-substituted analogues. Besides, the synthesis of b2-amino acids and their derivatives
the turnover numbers of these catalysts were not fa- can be developed. Herein, we present a full account
vorable (S/C=100, reaction time=12–24 h), and only of our studies in this asymmetric hydrogenation pro-
E-isomers of substituted b-phthalimidoacrylates were cess.
investigated. A mixed ligand system comprised of
chiral monodentate phosphoramidites and achiral
phosphines was also found to be efficient in the asym- Results and Discussion
metric rhodium-catalyzed hydrogenation of E-b-sub-
stituted a-acetylaminomethylacrylic acids, and the In order to evalulate the performance of our newly
best ee up to 91% could be obtained.[14g] As men- developed catalytic system, a spectrum of substrates
tioned above, all reported studies were focused on the which consisted of a variety of substituents having dif-
hydrogenation of E-b2-dehydroamino acids and deriv- ferent steric and electronic properties was prepared.
atives. In fact, compounds 4 are generally formed as a As reported in our previous communication, an easily
mixture of E- and Z-isomers in their preparation. We accessible approach to the synthesis of substrates 4a
should explore the hydrogenation effect of both iso- and 4s from aldehydes 1a, 1s, repectively, and methyl
1540
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1539 – 1553

A General Approach to the Synthesis of b2-Amino Acid Derivatives
acrylate through a three-step transformation was real- groups was prepared as outlined in Scheme 1. The
ized. Interestingly, the presence of an oxygen atom in synthetic route started with the Baylis–Hillman reac-
the -NHOCH2Ph group has a significant positive tion,[16] giving compounds 2 in good yields (78–95%)
effect on the hydrogenation reaction rates. In order to in most cases (Table 5). However, the methoxyaryl al-
further explore the substrate scope for catalyst selec- dehydes gave low yields for 2h, 2l, (51%, 62%, re-
tion, we attempted to synthesize a series of prochiral spectively), due to incomplete conversions, even with
substrates 4 having a similar backbone and bearing a prolonged reaction time. Acetylation[17] of the re-
different substituted groups R using the same synthet- sulting allylic alcohols and subsequent SN2’-type ami-
ic routes. A new family of a-aminomethylacrylates 4 nation[18] of the resulting acetates with O-benzylhy-
with substituted aryl groups or different aliphatic droxylamine gave a-aminomethylacrylates 4 as E/Z
mixtures. The amination yields of prochiral substrates
4 are listed in Table 1. The E/Z ratios varied with the
Table 1. Preparation of prochiral substrates 4.[a]
R group and E-isomers were produced predominate-
ly.[19] The E- and Z-isomers of 4 were simply separat-
ed by silica gel column chromatography except for
4r–4v.
Entry
R
Yield[b]
Yield[b]
of Z-4 [%]
of E-4 [%]
1
2
3
4
5
6
7
8
o-F-C6H4
o-Cl-C6H4
o-Br-C6H4
m-F-C6H4
m-Cl-C6H4
m-Br-C6H4
m-MeO-C6H4
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
p-MeO-C6H4
p-NO2-C6H4
p-CN-C6H4
p-Me-C6H4
1-naphthyl
2-naphthyl
phenylethyl
ethyl
62
46
59
60
38
66
65
69
76
62
68
47
61
62
81
45
35
26
27
25
16
24
17
26
18
26
23
33
27
25
8
In the initial model reactions,[14g] Ru-BINAP,[20a]
Ru-(Bu-PQPhos),[20b] Rh-Monophos[20c] complexes
showed poor reactivities and enantioselectivities in
the asymmetric hydrogenation of 4a (Figure 1,
Table 2, entries 1–3). Rh-Tangphos[20d] had some im-
provement in reactivity and enantioselectivity.
[Rh(Et-Duphos)
ACHTUNGTRENNUNG
9
choice among the RhAHCTUNGTRENNUNG
tries 4–7). i-PrOH was the most favored solvent.
10
11
12
13
14
15
16
17
18
19
20
Other catalytic systems such as Rh(Et-Ferro-
AHCTUNGTRENNUNG
TANE)[20g] and Rh-Josiphos[20h] were also tested for
the hydrogenation of 4s [1:1 mixture of (E) and (Z)-
isomers] and gave poor results (Table 2, entries 15
and 16). Under the optimal reaction conditions, the
asymmetric hydrogenations of E-4a and 4s (Table 2,
entries 9, 11, 13 and 14) afforded the corresponding
products 5a and 5s with satisfactory results.
To test the effectivness of the preliminary catalyst
system, a broad scope of substrates 4 were examined.
The Rh(Et-Duphos) catalyst was highly effective in
the asymmetric hydrogenation of 4, yielding products
5 almost quantitativily with unprecendented enantio-
21
78 (E/Z=1:1)
84 (E/Z=1:1)
78 (E/Z=2:1)
83
methyl
H
[a]
Reaction conditions: compounds 3, Na2CO3 and O-ben-
zylhydroxylamine hydrochloric acid salts in THF were al-
lowed to stir at room temperature under N2.
Yield of isolated product.
[b]
Figure 1. Chiral phosphane ligands evaluated in the asymmetric hydrogenation.
Adv. Synth. Catal. 2010, 352, 1539 – 1553
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1541

Yujuan Guo et al.
FULL PAPERS
Table 2. Initial screening of the hydrogenation of 4.[a]
Entry
R
Catalyst
S/C
Solvent t [h]
P [psi] Yield[b] [%] ee [%]
AHCTUNGTRENNUNG
(Config.)[c]
1
2
3
4
5
6
7
8
Ph (E)
Ph (E)
Ph (E)
Ph (E)
Ph (E)
Ph (E)
Ph (E)
Ph (E)
Ph (E)
Ph (E)
Ph (E)
Ph (E)
{Ru[(S)-BINAP]
G
100
100
100
50
100
100
100
100
100
100
i-PrOH 20
MeOH 24
1000
1000
1000
50
0
–
nd
{Ru
Rh
[(RSS)-Bu-PQPhos]
R
4[d]
7[d]
97
U
DCM
48
62 (S)
91 (R)
68 (S)
72 (R)
92 (R)
94 (S)
99 (R)
99 (R)
99 (R)
99 (R)
99.5 (R)
99.5 (R)
–
R
MeOH 48
MeOH 42
MeOH 97
MeOH 24
{Rh
{Rh
{Rh
{Rh
{Rh
{Rh
{Rh
{Rh
N
G
700
89[d]
20[d]
>99[d]
58[d]
99
N
1000
1000
1000
ACHTUNGTRENNUNG
G
DCM
90
9
A
E
E
E
G
C
i-PrOH 20 min 50
THF 20 min 50
10
11
12
13
14
15
16
99
10000 i-PrOH 78
10000 THF 44
100
1000
7
50
50
98
24[d]
99
n-Pr (E/Z) {Rh
n-Pr (E/Z) {Rh
n-Pr (E/Z)
G
U
i-PrOH 20 min 50
i-PrOH 10
MeOH 72
MeOH 24
50
50
50
30[d]
0
ACHTUNGTRENNUNG
n-Pr (E/Z) [Rh
C
100
97
10 (S)
[a]
All reactions were run at room temperature, substrate=0.1 mmol except for entries 11 and 12 (1 mmol).
Yield of isolated product.
[b]
[c]
[d]
Enantiomeric excesses were determined by HPLC analysis (Chiralcel OD-H).
1
The conversions were determined by H NMR and HPLC. nd, not determined.
selectivities and reactivities under the mild reaction ly. Notably, the hydrogenation of 4m having a strongly
conditions indicated. In order to further probe the electron-withdrawing NO2 group in the para site of
actual influence of the initial substrate configuration, the Ph ring also gave full conversion. In contrast,
structure and electronic properties, hydrogenation re- almost no reaction occurred under the same reaction
actions were conducted for single E- and Z-isomers. conditions for the hydrogenation of E-4n, which had
The data are summarized in Table 3 and Table 4 in another strongly electron-withdrawing para-CN as the
combination with those acquired via hydrogenation of substituent (Table 3, entry 26 vs. entry 27). Presuma-
4a and 4s.
bly the CN group partially complexed to the catalyst
For all of the E-isomers with aromatic rings as the and rendered the complex coordinatively saturated,
R group, except for 4n having a para-CN as the sub- hence lowering the catalytic activity of the catalyst.
stituent, the hydrogenation reactions exhibited ex- The hydrogenation reaction could be accelerated by
ceedingly high turnover frequencies and the reactions increasing the reaction temperature to 808C or in-
were completed within 20 min at room temperature creasing hydrogenation pressure to 500 psi (entries 29
under 50 psi of H2 in the presence of 1 mol% [Rh(Et- and 30). By prolonging the reaction time to 24 h, even
Duphos)ACHTUNGTRENNUNG(COD)]BF4 catalyst (Table 3). Even for sub- E-4n was completely converted to its product
strates 4p and 4q with a bulky 1-naphthyl or 2-naph- (Table 3, entry 28). In addition to the very high reac-
thyl as the R group, only 20 min were enough for full tivities, the important feature of the catalyst system in
substrate conversion under the mild reaction condi- our studies is the excellent enantioselectivties ac-
tions (Table 3, entries 31 and 32). This reaction time quired. Hydrogenation of (E)-4a–4q with an aromatic
was not further optimized. It is worthy of note that all ring as the R group provided very good ees of the cor-
substrates with a substituted phenyl group or naphthyl responding products 5a–5q. The lowest enantiomeric
group had lower reactivities than that with phenyl as excess was also up to 94% and this occurred in the
the R group. These outcomes were concluded by com- hydrogenation of 4p with 1-naphthyl as the R group
paring the hydrogenation reactivities of 4j, 4o with (Table 3, entry 31). While the R group was changed
that of 4a (Table 3, entries 14, 22–23 vs. entry 2). to 2-naphthyl, the ee value was increased to 96%
Indeed, no matter whether an electron-withdrawing (Table 3, entry 32). For other substrates with a substi-
substituent or an electron-donating group was present tuted phenyl group in the b-site, ee values ranged
on the phenyl ring, the reaction rates decreased slight- from 96 to 99%. Even for the hydrogenation of 4b–4d
1542
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1539 – 1553

A General Approach to the Synthesis of b2-Amino Acid Derivatives
Table 3. Hydrogenation of a series of a-aminomethylacrylates.[a]
Entry
R
S/C
p [psi]
T [8C]
t [min]
Yield[b] [%]
ee [%] (Config.)[c]
1[d]
2[d]
3
4
5
6
7
8
9
10
11
12
13
Ph (E)
Ph (E)
100
1000
100
100
100
100
100
100
100
100
100
500
500
1000
1000
1000
100
100
100
500
500
1000
1000
1000
1000
100
100
100
100
100
100
100
100
1000
100
1000
100
1000
100
100
50
50
50
50
50
50
50
50
50
50
50
50
50
50
1000
50
50
50
50
50
50
50
50
50
1000
50
50
50
50
500
50
50
50
50
50
50
50
50
50
50
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
80
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
80
r.t.
r.t.
r.t.
r.t.
80
r.t.
r.t.
r.t.
r.t.
50
20
10 h
20
20
20
20
20
20
20
99
>98
99
99
99
98
99
99
98
99 (R)
99 (R)
97 (À)
96 (À)
96 (À)
98 (À)
98 (À)
98 (À)
98 (À)
98 (À)
98 (À)
96 (À)
98 (À)
nd
98 (+)
98 (À)
98 (À)
98 (À)
99 (À)
99 (À)
99 (À)
nd
o-F-C6H4 (E)
o-Cl-C6H4 (E)
o-Br-C6H4 (E)
m-F-C6H4 (E)
m-Cl-C6H4 (E)
m-Br-C6H4 (E)
m-MeO-C6H4 (E)
p-F-C6H4 (E)
p-Cl-C6H4 (E)
p-Cl-C6H4 (E)
p-Cl-C6H4 (E)
p-Cl-C6H4 (E)
p-Cl-C6H4 (E)
p-Cl-C6H4 (E)
p-Br-C6H4 (E)
p-MeO-C6H4 (E)
p-Me-C6H4 (E)
p-Me-C6H4 (E)
p-Me-C6H4 (E)
p-Me-C6H4 (E)
p-Me-C6H4 (E)
p-Me-C6H4 (E)
p-Me-C6H4 (E)
p-NO2-C6H4 (E)
p-CN-C6H4 (E)
p-CN-C6H4 (E)
p-CN-C6H4 (E)
p-CN-C6H4 (E)
1-naphthyl (E)
2-naphthyl (E)
phenylethyl (E/Z)
phenylethyl (E/Z)
n-propyl (E/Z)
n-propyl (E/Z)
ethyl (E/Z)
20
20
100
100
86[e]
99
6 h
12 h
6 h
10 h
10 h
20
14
22[e]
100
98[e]
98
15[d]
16
17
18
19
20
20
20
99
99
6 h
12 h
6 h
10 h
10 h
10 h
20
20
24 h
5
5
20
20
20
7 h
20
7 h
20
7 h
20
20
91[e]
100[e]
42[e]
78
21
22
23[d]
24
98 (+)
99 (À)
99 (+)
99 (+)
nd
100[e]
100[e]
99
25[d]
26[d]
27
trace
100
100
100
98
98
99
99
99
>98
98
98
98
99
28
29
30
31
96 (À)
96 (À)
96 (À)
94 (À)
98 (À)
> 99.5 (+)
> 99.5 (+)
>99.5 (R)
>99.5 (R)
99 (À)
99 (À)
99 (À)
83 (+)
32
33[d]
34[d]
35[d]
36[d]
37[d]
38[d]
39[d]
40
r.t.
50
r.t.
50
r.t.
r.t.
ethyl (E/Z)
methyl (E/Z)
H (E/Z)
[a]
Catalyst={Rh
N
ACHTUNGTRNEUN(NG COD)}BF4, i-PrOH=1.5 mL, substrate=0.1 mmol.
[b]
[c]
[d]
[d]
ACHTUNGTRENNUNG
1
with ortho-halogened Ph groups the ees were still sat- of 4e–4g and 4i–4k with a meta- or para-halogened
isfactory, yielding products 5b–5d in 97%, 96% and phenyl group, all afforded the products in 98% ee. No
96% ee, respectively (Table 3, entries 3–5). Only significant differences in the rate of reaction and
subtle differences in the enantioselectivity existed. enantioselectivity were observed. The same ee values
Substrate 4b possessing a small ortho-F-phenyl group were acquired in the hydrogenation of 4h and 4l with
had the best result among them. The hydrogenation meta-MeO-C6H4
and
para-MeO-C6H4
groups
Adv. Synth. Catal. 2010, 352, 1539 – 1553
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1543

Yujuan Guo et al.
FULL PAPERS
(Table 3, entries 9 and 18, 98% ee). Thus, from the the enantioselectivity. For example, for (E)-4m and
aforementioned results, an ortho-substituent of the E- (E)-4o, which have an electron-withdrawing substitu-
isomers has some negative influence on the enantiose- ent para-NO2 and an electron-donating substituent
lectivity, and a small group is beneficial to get high ee para-Me, respectively in the phenyl group, however,
values. meta- and para-substitutions, which may be far hydrogenation reactions provided the corresponding
apart from the active centers of the complex and products in the same 99% ee. In contrast, 96% ee was
hence have slight or no influence on their enantiose- obtained in the hydrogennation of (E)-4n with a
lectivities were studied. After examining the experi- strongly electron-withdrawing substituent, CN.
mental data thoroughly, there were no significant in-
It was also revealed that changes of H2 pressure or
fluences of the electronic factor for the substrates on temperature have no obvious effect on the enantiose-
Table 4. Hydrogenation of Z-a-aminomethylacrylates.[a]
Entry
R
T [8C]
P [psi]
t [h]
Yield[b] [%]
ee [%] (Config.)[c]
1[d]
2
3
4
5
Ph (Z)
r.t.
r.t.
r.t.
r.t.
80
50
50
50
50
20 min
20 min
1
24
5
5
5
5
20 min
1
24
72
5
5
5
5
20 min
24
72
5
24
24
20 min
1
20 min
1
20 min
1
20 min
1
20 min
1
20 min
20 min
20 min
1
99
92 (R)
nd
nd
89 (À)
78 (À)
89 (À)
84 (À)
89 (+)
nd
o-F-C6H4 (Z)
o-F-C6H4 (Z)
o-F-C6H4 (Z)
o-F-C6H4 (Z)
o-F-C6H4 (Z)
o-F-C6H4 (Z)
o-F-C6H4 (Z)
o-Cl-C6H4 (Z)
o-Cl-C6H4 (Z)
o-Cl-C6H4 (Z)
o-Cl-C6H4 (Z)
o-Cl-C6H4 (Z)
o-Cl-C6H4 (Z)
o-Cl-C6H4 (Z)
o-Cl-C6H4 (Z)
o-Br-C6H4 (Z)
o-Br-C6H4 (Z)
o-Br-C6H4 (Z)
o-Br-C6H4 (Z)
o-Br-C6H4 (Z)
o-Br-C6H4 (Z)
m-F-C6H4 (Z)
m-F-C6H4 (Z)
m-Cl-C6H4 (Z)
m-Cl-C6H4 (Z)
m-Br-C6H4 (Z)
m-Br-C6H4 (Z)
m-MeO-C6H4 (Z)
m-MeO-C6H4 (Z)
p-F-C6H4 (Z)
p-F-C6H4 (Z)
p-F-C6H4 (Z)
p-F-C6H4 (Z)
p-Cl-C6H4 (Z)
p-Cl-C6H4 (Z)
p-Br-C6H4 (Z)
p-Br-C6H4 (Z)
p-Me-C6H4 (Z)
p-Me-C6H4 (Z)
p-NO2-C6H4 (Z)
6[e]
25[e]
100[e]
87[e]
100
77[e]
99
50
6
80
500
500
1000
50
50
50
50
500
50
500
1000
50
50
50
500
500
1000
50
50
50
50
50
7
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
80
80
80
r.t.
r.t.
r.t.
80
8[d]
9
trace
10
11
12[d]
13
14
15
16[d]
17
18
19[d]
20
21[d]
22[d]
23
24
25
26
27
28
29
30
31
32
33[d]
34[d]
35
36
37
38
39
40
41
7[e]
nd
nd
56[e]
100
50[e]
61[e]
99
77 (+)
nd
70 (À)
77 (À)
77 (+)
nd
nd
70 (+)
nd
70 (+)
70 (+)
82 (À)
84 (À)
82 (À)
83 (À)
78 (À)
79 (À)
85 (À)
86 (À)
89 (À)
90 (À)
90 (+)
90 (+)
87 (À)
88 (À)
85 (À)
87 (À)
87 (À)
90 (À)
93 (À)
99
trace
30
99
85[e]
99
80
80
99
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
76[e]
99
81[e]
99
99[e]
99
50
50
50
50
96[e]
99
98[e]
99
50
500
1000
50
50
50
50
50
50
50
99
99
99[e]
100[e]
92[e]
98
20 min
1
20 min
1
93[e]
98
20 min
99[e]
1544
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1539 – 1553

A General Approach to the Synthesis of b2-Amino Acid Derivatives
Table 4. (Continued)
Entry
R
T [8C]
P [psi]
t [h]
Yield[b] [%]
ee [%] (Config.)[c]
42
p-NO2-C6H4 (Z)
p-MeO-C6H4 (Z)
p-MeO-C6H4 (Z)
p-CN-C6H4 (Z)
p-CN-C6H4 (Z)
p-CN-C6H4 (Z)
1-naphthyl (Z)
1-naphthyl (Z)
2-naphthyl (Z)
2-naphthyl (Z)
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
50
50
50
50
500
1000
50
50
50
1
99
93 (À)
85 (+)
85 (+)
nd
nd
57 (+)
nd
65 (+)
75 (À)
76 (À)
43[d]
44[d]
45[d]
46[d]
47[d]
48[d]
49[d]
50
20 min
1
1
24
48
20 min
1
91[e]
99
trace
27[e]
99
32[e]
99
20 min
1
30[e]
99
51
50
[a]
Catalyst={Rh
A
ACHTUNGTRNE(NGNU COD)}BF4, i-PrOH=1.5 mL, substrate=0.1 mmol, S/C=100/1.
[b]
[c]
[d]
[e]
A
ACHTUNGTRENNUNG
1
lectivity of E-isomers within the range of our studies derivatives except for our preliminary communica-
(Table 3, entries 15, 16, 24, 25). It only influenced the tion.[14h] Inspired by our promising initial results, we
reactivity.
For 4r or 4t–4v, which had a phenylethyl group or drogenation reactions (Table 4). Under the same reac-
aliphatic groups as the R group in the b site, their E- tion conditions, [Rh(Et-Duphos)(COD)]BF4 offered
turned to explore a family of (Z)-4 compounds in hy-
AHCTUNGTRENNUNG
and Z-isomers could not be separated individually by lower catalytic activities and stereocommunication ca-
silica gel column chromatography. Therefore, we used pability for these (Z)-isomeric substrates than for the
the E/Z-mixtured substrates for the hydrogenation, (E)-isomers. Thus, the product configurations were
and their E/Z ratios changing from 2 to 1 based on determined by the configurations of the supporting
NMR analysis (Table 1, entris 17–19). Notably, won- ligand, Et-Duphos, but not by the geometry of the
derful results similar to that of 4s were obtained substrates. More importantly, the steric effect of the
(Table 3, entries 33–39, 99–>99.5% ee). This implied substrates significantly affected the outcome of the
that the product configuration was controlled merely catalysis, in partcular for the substrates having an
by the ligand configuration (Et-Duphos), not by the ortho-substituted aryl or naphthyl moiety as the R
substrate template. This phenomenon could be fur- group. Except for the hydrogenation of (Z)-4a, paral-
ther confirmed in the hydrogenation of pure Z-iso- lel experiments showed that most Z-form substrates
mers (Table 4). The obtained results indicated that displayed lower reactivities than their corresponding
[Rh(Et-Duphos)ACHTUNGTRENNUNG(COD)]BF4 has excellent enantiofa- E-isomers. Full conversions were obtained in 1 h in-
cial selection capability for both E- and Z-isomers for stead of 20 min for E-isomers for all studied sub-
this type of substrates. Besides the remarkable enan- strates except for selected ortho-substituted sub-
tioselectivity, the reaction activities were also very strates. These results represent the highest catalytic
high. Under S/C=100, only 20 min reaction time was activity achieved so far for the hydrogenation of the
required for full conversion of 4r–4v. In fact, the S/C (Z)-isomeric substrates for generating b2-amino acid
ratio could be increased to 1000 without deleterious derivatives. Among all Z-isomers containing halogen-
effects. As for examples of E/Z-4r and 4t, the reac- ated aryl rings, substrates with para-substituents (Z)-
tions proceeded smoothly and full conversions were 4i–4k showed the highest reactivities and gave the
obtained within 7 h at temperature 508C (Table 3, en- best ees of the desired products (Table 4, entries 31–
tries 34, 38).
38). Substrates with meta-substituents[(Z)-4e–4g] af-
In general, asymmetric hydrogenation is strongly forded moderate results. An exceptional ee decrease
sensitive to the E/Z-geometry of the substrates. The occurred in the hydrogenation of (Z)-4e (Table 4,
catalyst usually matches perfectly well in one configu- entry 24). For ortho-halogen-substituted substrates
ration of the substrate, whereas it mismatches the (Z)-4b–4d, the reactivities decreased sharply, yet the
other and affords inferior results. Yet, highly effective enantioselectivity dropped only slightly. Apart from
catalyst systems for handling both E- and Z-isomers the position of the substitution, the effect of halogens
of substrates are still limited.[15] To the best of our was investigated. The F-, Cl- or Br-substituted sub-
knowledge, there is no literature report on the asym- strates exhibited significant differences in reaction
metric hydrogenation of substrates with (Z)-configu- performance. For instance, hydrogenation of (Z)-4b–
ration for the synthesis of b2-amino acids and their 4d afforded the products in 89%, 77% and 70% ee,
Adv. Synth. Catal. 2010, 352, 1539 – 1553
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1545

Yujuan Guo et al.
FULL PAPERS
respectively (Table 4, entries 4, 12 and 19), this se- effect on the enantioselectivity was not found in the
quence is in consistent with the size order of the halo- hydrogenation of the (Z)-isomeric substrates.
gen substituent. Presumably the steric bulkiness of
Hydrogenolysis of 5a with a Pd/C catalyst under a
the ortho-substitution was significant, and thus gave a hydrogen atmosphere provided b-amino ester 6 in
relevant influence on the reactivity and enantioselec- good yield. Acetylation of the resulting compound af-
tivity. Indeed, a small group was found to be benefi- forded 7 for chiral GC tests. A 99% ee was still ob-
cial for substrate-metal complexation and hence af- tained for this derivative (Scheme 2). This means no
forded higher ee and activity. Even though the F racemization occurred during the hydrogenolysis pro-
group has small steric hindrance, the effect still exist- cess. Cleavage of the methyl ester (5a) using
ed for substrates having meta-F- and para-F-substitu- LiOH·H2O in THF, followed by hydrogenolysis gave
ents. Nevertheless, the influence was reduced obvious- free b2-amino acid 8 in 68% yield. The absolute con-
ly for those being much further apart from the center figuration of 5a and corresponding derivatives was de-
of the metal complexes. These results obviously indi- termined to compare their optical rotation direction
cated that the size and site of the subsitituent have with that of (R)-(+)-8.[21]
strong impact on the reaction activity and enantiose-
lectivity of the (Z)-isomeric substrates. However,
these effects were found to be trivial in the hydroge- Conclusions
nation of (E)-isomeric substrates.
To enhance the reactivity and further shorten the In conclusion, we have succeeded in showing a new
reaction time, reaction parameters such as tempera- strategy for the synthesis of a valuable class of a-ami-
ture and H2 pressure elevation were adopted for the nomethylacrylates. The olefinic precursors were easily
hydrogenation of (Z)-4b–4d and (Z)-4i and (Z)-4n. accessible via the Baylis–Hillman reaction of different
Recently, Bçrner[15c] and Zhang[15f] independently re- aldehydes with methyl acrylate followed by the acety-
ported that hydrogenation of Z-isomeric substrates lation of the resulting allylic alcohols and SN2’-type
was strongly dependent on H2 pressure. Higher H2 amination of the allylic acetates. The versatility of the
pressures were detrimental to the enantiomeric asymmetric hydrogenation of a-aminomethylacrylates
excess. This phenomenon, however, was not observed can be highlighted by the advantages including the
in our study. In contrast, the enantioselectivity was operationally simplicity, mild reaction conditions, the
not affected by H2 pressure variation. In fact, a higher unprecedently high enantioselectivity and reactivity
hydrogen pressure was highly beneficial on the reac- obtained for the corresponding b2-amino acid deriva-
tivity and hence decreased the reaction time (Table 4, tives (up to >99.5% ee and S/C=10,000). Notably,
entries 3, 12, 19, 32, 45 vs. entries 6 and 8, 15 and 16, we have successfully realized the first hydrogenation
21 and 22, 33 and 34, 46 and 47). Hydrogenation of of (Z)-configurated substrates for the synthesis of b2-
(Z)-4o and 4m gave the corresponding products 5m amino acid derivatives. The high dependence on the
and 5o in 90% and 93% ee, respectively. For hydroge- substrate geometry and steric hindrance of the reac-
nation of (Z)-4p and (Z)-4q having bulky naphthyl tivity and enantioselectivity was also disclosed for this
groups, the ee values dropped sharply to 65% and reaction. We anticipate that these findings will offer a
76%, respectively (Table 4, entries 49 and 51). Similar new stage of asymmetric hydrogenation of Z-configu-
to that in the hydrogenation of (E)-4, the electronic rated olefinic precursors.
Experimental Section
General
1H and 13C NMR spectra were recorded on a Varian Mercu-
ry-Plus 300 spectrometer 300 and 75 MHz or a Bruker
AVANCE 400 spectrometer at 400 and 100 MHz, respec-
tively. Chemical shifts (d) are given in ppm and are refer-
enced to residual solvent peaks. HR-MS were carried out on
a Bruker APEX 47e ESI FT-ICR mass spectrometer and
Thermo MAT95XP EI-FAB-CI mass spectro-meter. Optical
rotations were recorded on a Perkin–Elmer Model 341 po-
larimeter in a 1-cm cell. HPLC analysis was performed on
an Agilent 1200 series system using a Daicel Chiralpak OD-
Scheme 2. Synthesis of (R)-(+)-methyl 3-acetamido-2-ben-
zylpropanoate and (R)- (+)-3-amino-2-benzylpropanoic
acid.
H column. GC analysis was performed on an Agilent 6890
series system using a CP Chiralsil Dex-CB column. All re-
agents were purchased from commercial sources and used
1546
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1539 – 1553

A General Approach to the Synthesis of b2-Amino Acid Derivatives
without
(COD)}BF4 was purchased from Strem Chemicals and
{Rh[(S,S)-Et-Duphos](COD)}BF4 was obtained from
Sigmal-Aldrich. Solvents were distilled before use: i-PrOH
and CH2Cl2 were distilled from calcium hydride. Com-
pounds 2 were prepared by reacting methyl acrylate with
the corresponding aldehydes respectively according to litera-
ture reports.[16]
further
purification.
{RhACTHNGUTERN[UNG (R,R)-Et-Duphos]-
General Procedure for the Synthesis of 3
ACHTUNGTRENNUNG
Acetic anhydride (18 mmol) was added dropwise into a mix-
ture of 2 (15 mmol) and DMAP (1.5 mmol) in toluene
(20 mL) in 30 min at 0~58C. The resulting solution was al-
lowed to warm to room temperature in 1 h. After stirring
for 1 h at room temperature, the reaction mixture was
cooled to 0–58C, and 1N HCl (5 mL) was added in 20 min.
The organic layer was separated and washed sequentially
with water, saturated aqueous sodium bicarbonate and
water. The organic layer was concentrated to afford 3 as a
colorless liquid. The crude product was used in the next step
without further purification.
G
ACHTUNGTRENNUNG
General Procedure for the Synthesis of 2
To a mixture of an aldehyde (20 mmol) and DABCO
(2 mmol) in MeOH (40 mL) was added 60 mmol of methyl
acrylate. The solution was stirred at room temperature until
the reaction was complete (monitored by TLC, Table 5).
The mixture was diluted with 100 mL of ethyl acetate. The
organic layer was washed with water (100 mL), brine
(100 mL), dried on Na2SO4, filtered and concentrated. Prod-
ucts were purified by column chromategraphy (SiO2; ethyl
acetate/petroleum ether 1:5).
General Procedure for the Synthesis of 4
A mixture of 3 (17.5 mmol), Na2CO3 (52.5 mmol) and O-
benzylhydroxylamine hydrochloric acid salts (52.5 mmol) in
THF (20 mL) was allowed to stir at room temperature
under N2 until the reaction was complete (monitored by
TLC). The reaction mixture was concentrated under re-
duced pressure. The residue was dissolved in ethyl acetate
(50 mL) and washed with saturated aqueous sodium bicar-
bonate (25 mL). The ethyl acetate layer was concentrated to
afford a colorless liquid. The crude material was purified by
column chromatography (SiO2; aceton/petroleum ether
1:20) to afford the products 4 (E-isomer, Z-isomer and E/Z
mixture).
Procedure for the Synthesis of 2h, 2l and 2o[16f]
To a solution of an aldehyde (20 mmol) and a 33% (w/v)
aqueous solution of Me3N (10 mL) in MeOH (40 mL) was
added 60 mmol of methyl acrylate. The solution was stirred
for 168 h and 200 mL of CHCl3 and 50 mL H2O were added.
The layers were separated and the aqueous layer was ex-
tracted twice with 50 mL CHCl3. The organic layers were
dried on Na2SO4, filtered and concentrated. Products were
purified by column chromategraphy (SiO2; ethyl acetate/pe-
troleum ether 1:5).
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(2-fluorophe-
nyl)acrylate (4b): 1H NMR (300 MHz, CDCl3): d=7.88 (s,
1H), 7.55–7.61 (m, 1H), 7.25–7.36 (m, 6H), 7.04–7.09 (m,
2H), 6.09 (bs, 1H), 4.67 (s, 2H), 3.88 (s, 2H), 3.81 (s, 3H);
13C NMR (100 MHz, CDCl3): d=167.7, 160.5 (d, JC,F
=
160.5 Hz), 138.0, 136.2 (d, JC,F =3.6 Hz), 130.9, 130.8, 129.7,
128.4, 128.3, 127.7, 124.0 (d, JC,F =3.2 Hz), 122.9 (d, JC,F
13.5 Hz), 115.5 (d, JC,F =21.6 Hz), 75.9, 52.2, 48.9; HR-MS
(ESI): m/z=316.1357, calcd. for C18H19FNO3 [M+H]+:
316.1349.
=
Table 5. Yields and reaction times of the Baylis–Hillman re-
actions.[a]
Entry
R
t [h]
Yield of 2 [%]
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(2-fluorophe-
1
nyl)acrylate (4b): H NMR (300 MHz, CDCl3): d=7.22–7.33
1
2
3
4
5
6
7
8
o-F-C6H4
o-Cl-C6H4
o-Br-C6H4
m-F-C6H4
m-Cl-C6H4
m-Br-C6H4
m-MeO-C6H4
p-F-C6H4
p-Cl-C6H4
p-Br-C6H4
p-MeO-C6H4
p-NO2-C6H4
p-CN-C6H4
p-Me-C6H4
1-naphthyl
2-naphthyl
phenylethyl
ethyl
36
36
36
36
36
36
168
36
36
36
168
12
12
168
24
24
24
14
10
9
86
83
94
83
78
79
51
91
85
82
62
95
84
83
83
78
79
83
86
90
(m, 7H), 7.00–7.10 (m, 2H), 6.90 (s, 1H), 5.89 (bs, 1H), 4.70
(s, 2H), 3.85 (s, 2H), 3.63 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=168.3, 160.0 (d, JC,F =248.8 Hz), 137.9, 132.5,
131.1, 130.1 (d, JC,F =2.6 Hz), 130.0 (d, JC,F =8.6 Hz), 127.8,
123.7 (d, JC,F =3.3 Hz), 115.4 (d, JC,F =22.4 Hz), 76.3, 56.2,
51.6; HR-MS (ESI): m/z=316.1353, calcd. for C18H19FNO3
[M+H]+: 316.1349.
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(2-chlorophe-
nyl)acrylate (4c): 1H NMR (300 MHz, CDCl3): d=7.92 (s,
1H), 7.57 (d, J=7.5 Hz, 1H), 7.39 (d, J=7.8 Hz, 1H), 7.15–
7.30 (m, 7H), 6.11 (bs, 1H), 4.66 (s, 2H), 3.82 (s, 5H);
13C NMR (100 MHz, CDCl3): d=167.7, 140.5, 138.0, 134.2,
133.5, 130.8, 130.0, 129.5, 128.4, 128.3, 127.7, 126.6, 75.9,
52.2, 48.8; HR-MS (ESI): m/z=332.1048, calcd. for
C18H19ClNO3 [M+H]+: 332.1053.
9
10
11
12
13
14
15
16
17
18
19
20
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(2-chlorophe-
1
nyl)acrylate (4c): H NMR (300 MHz, CDCl3): d=7.15–7.38
(m, 9H), 7.04 (s, 1H), 5.91 (bs, 1H), 4.71 (s, 2H), 3.86 (s,
2H), 3.57 (s, 3H); 13C NMR (100 MHz, CDCl3): d=168.2,
137.9, 135.8, 134.8, 133.2, 132.1, 129.9, 129.3, 129.2, 128.50,
128.4, 127.8, 126.2, 76.3, 55.9, 51.6; HR-MS (ESI): m/z=
332.1048, calcd. for C18H19ClNO3 [M+H]+: 332.1053.
methyl
H
[a]
Compounds 2 are known compounds and their spectro-
scopic data matched with those in the literature.[16]
Adv. Synth. Catal. 2010, 352, 1539 – 1553
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1547

Yujuan Guo et al.
FULL PAPERS
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(2-bromophe-
nyl)acrylate (4d): 1H NMR (300 MHz, CDCl3): d=7.86 (s,
1H), 7.53–7.60 (m, 3H), 7.18–7.32 (m, 6H), 6.10 (bs, 1H),
4.65 (s, 2H), 3.82 (s, 3H), 3.80 (s, 2H); 13C NMR (100 MHz,
CDCl3): d=167.7, 142.6, 138.0, 135.3, 132.7, 130.8, 130.1,
129.3, 128.4, 128.3, 127.7, 127.2, 124.2, 75.9, 52.2, 48.7;
HRMS (ESI): m/z=376.0543, calcd. for C18H19BrNO3 [M+
H]+: 376.0548.
5.84 (bs, 1H), 4.68 (s, 2H), 3.81 (s, 2H), 3.65 (s, 3H);
13C NMR (100 MHz, CDCl3): d=168.6, 137.8, 137.7, 135.9,
131.8, 131.4, 131.1, 129.6, 128.5, 128.4, 127.9, 127.0, 122.2,
76.3, 56.4, 51.8; HR-MS (ESI): m/z=376.0553, calcd. for
C18H19BrNO3 [M+H]+: 376.0548.
(E)-Methyl
2-[(benzyloxyamino)methyl]-3-(3-methoxy-
1
phenyl)acrylate (4h): H NMR (300 MHz, CDCl3): d=7.83
(s, 1H), 7.23–7.29 (m, 6H), 7.05–7.09 (m, 2H), 6.87–6.91 (m,
1H), 6.05 (bs, 1H), 4.70 (s, 2H), 3.96 (s, 2H), 3.80 (s, 3H),
3.78 (s, 3H); 13C NMR (100 MHz, CDCl3): d=168.2, 159.7,
143.7, 137.9, 136.2, 129.5, 128.4, 128.3, 127.9, 127.8, 122.0,
114.9, 76.0, 55.3, 52.1, 48.7; HR-MS (ESI): m/z=328.1548,
calcd. for C19H22NO4 [M+H]+: 328.1549.
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(2-bromophe-
1
nyl)acrylate (4d): H NMR (300 MHz, CDCl3): d=7.52–7.55
(m, 1H), 7.08–7.36 (m, 8H), 6.99 (s, 1H), 5.91 (bs, 1H), 4.72
(s, 2H), 3.85 (s, 2H), 3.54 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=168.2, 138.1, 136.9, 132.6, 132.0, 130.1, 129.6,
128.7, 128.5, 128.0, 127.0, 123.3, 76.6, 56.1, 51.9; HR-MS
(ESI): m/z=376.0540, calcd. for C18H19BrNO3 [M+H]+:
376.0548.
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(3-fluorophe-
nyl)acrylate (4e): 1H NMR (300 MHz, CDCl3): d=7.79 (s,
1H), 7.21–7.35 (m, 8H), 7.00–7.07 (m, 1H), 6.04 (bs, 1H),
4.71 (s, 2H), 3.91 (s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=167.9, 162.7 (d, JC,F =246.4 Hz), 142.3, 137.9,
137.0 (d, JC,F =8.0 Hz), 130.0 (d, JC,F =8.2 Hz), 128.8, 128.5,
128.4, 127.8, 125.3 (d, JC,F =2.2 Hz), 116.3 (d, JC,F =22.3 Hz),
76.1, 52.2, 48.6; HR-MS (ESI): m/z=316.1356, calcd. for
C18H19FNO3 [M+H]+: 316.1349.
(Z)-Methyl
2-[(benzyloxyamino)methyl]-3-(3-methoxy-
1
phenyl)acrylate (4h): H NMR (300 MHz, CDCl3): d=7.18–
7.32 (m, 6H), 6.81–6.85 (m, 4H), 6.05 (bs, 1H), 4.69 (s, 2H),
3.82 (s, 2H), 3.78 (s, 3H), 3.65 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=169.2, 159.4, 137.9, 137.1, 136.9, 130.7, 129.2,
128.5, 128.4, 127.8, 121.0, 114.2, 113.7, 76.3, 56.6, 55.2, 51.7;
HR-MS (ESI): m/z=328.1547, calcd. for C19H22NO4 [M+
H]+: 328.1549.
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(4-fluorophe-
nyl)acrylate (4i): 1H NMR (300 MHz, CDCl3): d=7.79 (s,
1H), 7.44–7.48 (m, 2H), 7.29–7.33 (m, 5H), 6.96–7.02 (m,
2H), 6.03 (bs, 1H), 4.71 (s, 2H), 3.90 (s, 2H), 3.80 (s, 3H);
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(3-fluorophe-
13C NMR (100 MHz, CDCl3): d=168.1, 163.1 (d, JC,F
=
1
nyl)acrylate (4e): H NMR (300 MHz, CDCl3): d=7.27–7.33
250.1 Hz), 142.7, 138.1, 131.7 (d, JC,F =8.3 Hz), 130.9 (d,
JC,F =3.0 Hz), 128.4, 127.8, 127.2, 115.6 (d, JC,F =21.7 Hz),
(m, 6H), 6.94–7.03 (m, 3H), 6.80 (s, 1H), 5.73 (bs, 1H), 4.69
(s, 2H), 3.81 (s, 2H), 3.65 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=162.6 (d, JC,F =245.7 Hz), 137.8, 137.7, 136.0,
131.6, 129.6 (d, JC,F =8.3 Hz), 128.5, 128.4, 127.9, 124.2, 115.3
(d, JC,F =7.8 Hz), 115.0 (d, JC,F =6.7 Hz), 76.3, 56.4, 51.8;
HR-MS (ESI): m/z=316.1355, calcd. for C18H19FNO3 [M+
H]+: 316.1349.
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(3-chlorophe-
nyl)acrylate (4f): 1H NMR (300 MHz, CDCl3): d=7.77 (s,
1H), 7.61 (s, 1H), 7.23–7.35 (m, 8H), 6.05 (bs, 1H), 4.73 (s,
2H), 3.91 (s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=167.9, 142.2, 137.9, 136.7, 134.5, 129.8, 129.5,
129.0, 128.9, 128.5, 128.4, 127.8, 127.7, 76.1, 52.2, 48.5; HR-
MS (ESI): m/z=332.1062, calcd. for C18H19ClNO3 [M+H]+:
332.1053.
76.0, 52.2, 48.7; HR-MS (ESI): m/z=316.1356, calcd. for
C18H19FNO3 [M+H]+: 316.1349.
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(4-fluorophe-
1
nyl)acrylate (4i): H NMR (300 MHz, CDCl3): d=7.25–7.32
(m, 7H), 6.96–7.01 (m, 2H), 6.80 (s, 1H), 5.72 (bs, 1H), 4.69
(s, 2H), 3.81 (s, 2H), 3.65 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=168.8, 162.6 (d, JC,F =248.5 Hz), 137.8, 136.7,
131.6 (d, JC,F =3.4 Hz), 130.4 (d, JC,F =8.2 Hz), 130.2, 128.5,
128.4, 127.8, 115.2 (d, JC,F =21.7 Hz), 76.3, 56.6, 51.7; HR-
MS (ESI): m/z=316.1348, calcd. for C18H19FNO3 [M+H]+:
316.1349.
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(4-chlorophe-
nyl)acrylate (4j): 1H NMR (300 MHz, CDCl3): d=7.78 (s,
1H), 7.40 (d, J=8.7 Hz, 2H), 7.26–7.31 (m, 7H), 6.04 (bs,
1H), 4.70 (s, 2H), 3.89 (s, 2H), 3.80 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=167.9, 142.4, 138.0, 135.0, 133.2,
130.9, 128.7, 128.3, 128.0, 127.8, 76.0, 52.1, 48.6; HR-MS
(ESI): m/z=332.1056, calcd. for C18H19ClNO3 [M+H]+:
332.1053.
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(3-chlorophe-
1
nyl)acrylate (4f): H NMR (300 MHz, CDCl3): d=7.20–7.73
(m, 8H), 7.11–7.14 (m, 1H), 6.78 (s, 1H), 5.84 (bs, 1H), 4.69
(s, 2H), 3.81 (s, 2H), 3.65 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=168.6, 137.8, 137.4, 136.0, 134.1, 131.8, 129.4,
128.5, 128.4, 128.3, 128.2, 127.9, 126.6, 76.3, 56.4, 51.8;
HRMS (ESI): m/z=332.1054, calcd. for C18H19ClNO3 [M+
H]+: 332.1053.
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(4-chlorophe-
1
nyl)acrylate (4j): H NMR (300 MHz, CDCl3): d=7.18–7.32
(m, 9H), 6.79 (s, 1H), 5.82 (bs, 1H), 4.68 (s, 2H), 3.80 (s,
2H), 3.65 (s, 3H); 13C NMR (100 MHz, CDCl3): d=168.7,
137.8, 136.5, 134.2, 134.0, 130.9, 129.8, 128.5, 128.4, 127.9,
76.3, 56.5, 51.8; HR-MS (ESI): m/z=332.1058, calcd. for
C18H19ClNO3 [M+H]+: 332.1053.
(E)-Methyl 2-[(Benzyloxyamino)methyl]-3-(3-bromophe-
1
nyl)acrylate (4g): H NMR (300 MHz, CDCl3): d=7.78 (d,
J=6.9 Hz, 2H), 7.47 (d, J=8.4 Hz, 1H), 7.38 (d, J=7.5 Hz,
1H), 7.24–7.32 (m, 5H), 7.19 (d, J=7.80 Hz, 1H), 6.05 (bs,
1H), 4.74 (s, 2H), 3.91 (s, 2H), 3.80 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=167.8, 142.0, 137.9, 137.0, 132.3,
131.9, 130.0, 128.9, 128.4 (128.43), 128.4 (128.36), 128.1,
127.8, 122.6, 76.1, 52.2, 48.5; HR-MS (ESI): m/z=376.0555,
calcd. for C18H19BrNO3 [M+H]+: 376.0548.
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(4-bromophe-
nyl)acrylate (4k): 1H NMR (300 MHz, CDCl3): d=7.75 (s,
1H), 7.43 (d, J=8.4 Hz, 2H), 7.30–7.34ACHTNUTRGNEUNG(m, 7H), 6.03 (bs,
1H), 4.69 (s, 2H), 3.88 (s, 2H), 3.80 (s, 3H); 13C NMR
(100 MHz, CDCl3): d=168.0, 142.5, 138.0, 133.7, 131.7,
131.1, 128.4, 128.1, 127.9, 123.4, 76.1, 52.2, 48.6; HR-MS
(ESI): m/z=376.0558, calcd. for C18H19BrNO3 [M+H]+:
376.0548.
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(3-bromophe-
1
nyl)acrylate (4g): H NMR (300 MHz, CDCl3): d=7.35–7.41
(m, 2H), 7.27–7.32 (m, 5H), 7.16–7.18 (m, 2H), 6.78 (s, 1H),
1548
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1539 – 1553

A General Approach to the Synthesis of b2-Amino Acid Derivatives
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(4-bromophe-
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-p-tolylacrylate
1
nyl)acrylate (4k): H NMR (300 MHz, CDCl3): d=7.42 (d,
J=8.4 Hz, 2H), 7.26–7.32 (m, 5H), 7.13 (d, J=8.4 Hz, 2H),
6.77 (s, 1H), 5.84 (bs, 1H), 4.68 (s, 2H), 3.80 (s, 2H), 3.64 (s,
3H); 13C NMR (100 MHz, CDCl3): d=168.8, 137.9, 136.6,
134.6, 131.5, 131.2, 130.3, 128.6, 128.5, 128.0, 122.6, 76.6,
56.8, 52.1; HR-MS (ESI): m/z=376.0555, calcd. for
C18H19BrNO3 [M+H]+: 376.0548.
(4o): 1H NMR (300 MHz, CDCl3): d=7.24–7.33 (m, 5H),
7.09–7.19 (m, 4H), 6.82 (s, 1H), 5.85 (bs, 1H), 4.69 (s, 2H),
3.81 (s, 2H), 3.66 (s, 3H), 2.34 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=169.4, 138.5, 138.0, 137.9, 132.7, 129.4, 129.1,
128.7, 128.5, 128.0, 76.5, 57.1, 52.0, 21.7; HR-MS (ESI):
m/z=334.1417, calcd. for C19H21NO3Na [M+Na]+: 334.1419.
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(naphthalen-1-
yl)acrylate (4p): 1H NMR (300 MHz, CDCl3): d=8.37
(s,1H), 7.83–7.91 (m, 3H), 7.38–7.58 (m, 4H), 7.12–7.21 (m,
4H), 6.14 (bs, 1H), 4.56 (s, 2H), 3.87 (s, 5H); 13C NMR
(75 MHz, CDCl3): d=168.0, 142.2, 138.0, 133.6, 132.2, 131.7,
130.0, 129.4, 128.7, 128.5, 128.4, 127.8, 127.1, 126.7, 126.4,
125.4, 124.8, 76.0, 52.5, 49.2; HR-MS (ESI): m/z=348.1616,
calcd. for C22H22NO3 [M+H]+: 348.1600.
(E)-Methyl
2-[(benzyloxyamino)methyl]-3-(4-methoxy-
phenyl)acrylate (4l): 1H NMR (300 MHz, CDCl3): d=7.79
(s, 1H), 7.46 (d, J=8.4 Hz, 0.5H), 7.29–7.34 (m, 5H), 6.83
(d, J=8.4 Hz, 2H), 6.01 (bs, 1H), 4.74 (s, 2H), 3.97 (s, 2H),
3.82 (s, 3H), 3.78 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
168.5, 160.5, 143.8, 138.2, 131.6, 128.5, 128.4, 127.7, 127.4,
124.9, 114.0, 76.0, 55.3, 52.0, 48.8; HR-MS (ESI): m/z=
328.1547, calcd. for C19H22NO4 [M+H]+: 328.1549.
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(naphthalen-1-
1
(Z)-Methyl
2-[(benzyloxyamino)methyl]-3-(4-methoxy-
yl)acrylate (4p): H NMR (300 MHz, CDCl3): d=7.82–7.98
1
phenyl)acrylate (4l): H NMR (300 MHz, CDCl3): d=7.27–
7.35 (m, 5H), 6.84–6.95 (m, 4H), 6.81 (s, 1H), 4.73 (s, 2H),
3.83 (s, 5H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
169.1, 159.5, 137.7, 130.1, 128.3, 128.2, 127.6, 113.4, 76.1,
56.8, 55.2, 51.6; HR-MS (EI): m/z=327.1466, calcd. for
C19H21NO4: 327.1465.
(m, 3H), 7.34–7.53 (m, 10H), 6.06 (bs, 1H), 4.84 (s, 2H),
4.02 (d, J=0.9 Hz, 2H), 3.48 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=168.5, 137.8, 137.7, 133.9, 133.3, 132.2, 131.1,
128.5, 128.4 (128.41), 128.4 (128.40), 128.3, 127.8, 126.2,
125.9, 125.7, 125.1, 124.7, 76.3, 56.1, 51.4; HR-MS (EI):
m/z=347.1518, calcd. for C22H21NO3: 347.1516.
(E)-Methyl
2-[(benzyloxyamino)methyl]-3-(4-nitrophe-
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(naphthalen-2-
yl)acrylate (4q): H NMR (300 MHz, CDCl3): d=8.02–8.03
1
1
nyl)acrylate (4m): H NMR (300 MHz, CDCl3): d=8.12 (d,
J=8.7 Hz, 2H), 7.82 (s, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.29–
7.32 (m, 5H), 6.07 (bs, 1H), 4.69 (s, 2H), 3.85 (s, 2H), 3.83
(s, 3H); 13C NMR (100 MHz, CDCl3): d=167.4, 147.7, 141.2,
140.9, 137.9, 130.9, 130.3, 128.4, 128.0, 123.6, 76.2, 52.4, 48.6;
HR-MS (ESI): m/z=343.1299, calcd. for C18H19N2O5 [M+
H]+: 343.1294.
(m, 2H), 7.75–7.84 (m, 4H), 7.57–7.60 (m, 1H), 7.45–7.53
(m, 2H), 7.23–7.35 (m, 4H), 6.17 (bs, 1H), 4.76 (s, 2H), 4.04
(s, 2H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
168.4, 144.1, 138.1, 133.5, 133.3, 132.6, 129.8, 128.7, 128.5,
128.3, 128.0, 127.9, 127.1, 127.0, 126.7, 76.3, 52.5, 49.1;
HRMS (ESI): m/z=348.1616, calcd. for C22H22NO3 [M+
H]+: 348.1600.
(Z)-Methyl
2-[(benzyloxyamino)methyl]-3-(4-nitrophe-
1
nyl)acrylate (4m): H NMR (300 MHz, CDCl3): d=8.14 (d,
J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.19–7.32 (m, 5H),
6.89 (s, 1H), 5.88 (bs, 1H), 4.69 (s, 2H), 3.85 (s, 2H), 3.64 (s,
3H); 13C NMR (75 MHz, CDCl3): d=168.1, 147.4, 142.6,
137.8, 135.3, 134.1, 129.3, 128.7, 128.6, 128.1, 123.6, 76.6,
56.4, 52.2; HR-MS (ESI): m/z=343.1287, calcd. for
C18H19N2O5 [M+H]+: 343.1294.
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-(4-cyanophe-
nyl)acrylate (4n): 1H NMR (300 MHz, CDCl3): d=7.79 (s,
1H), 7.51–7.58 (m, 4H), 7.24–7.34 (m, 5H), 6.06 (bs, 1H),
4.68 (s, 2H), 3.84 (s, 2H), 3.82 (s, 3H); 13C NMR (100 MHz,
CDCl3): d=167.5, 141.3, 139.3, 137.9, 132.1, 130.4, 130.0,
128.4, 127.9, 118.5, 112.3, 76.1, 52.3, 48.5; HR-MS (ESI):
m/z=323.1400, calcd. for C19H19N2O3 [M+H]+: 323.1396.
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(4-cyanophe-
(Z)-Methyl 2-[(benzyloxyamino)methyl]-3-(naphthalen-2-
1
yl)acrylate (4q): H NMR (300 MHz, CDCl3): d=7.73–7.80
(m, 4H), 7.44–7.47 (m, 2H), 7.27–7.38 (m, 6H), 7.01 (s, 1H),
5.95 (bs, 1H), 4.71 (s, 2H), 3.88 (s, 2H), 3.64 (s, 3H);
13C NMR (100 MHz, CDCl3): d=169.4, 138.0, 137.9, 133.2,
130.7, 128.7, 128.6, 128.4, 128.0, 127.8, 126.7, 126.5, 126.2,
76.6, 57.0, 52.0; HR-MS (ESI): m/z=348.1609, calcd. for
C22H22NO3 [M+H]+: 348.1600.
AHCTUNGTREG(NNUN E/Z)-Methyl 2-[(benzyloxyamino)methyl]-5-phenylpent-
2-enoate (4r): 1H NMR (300 MHz, CDCl3, E/Z=1:1): d=
7.10–7.31 (m, 10H), 6.96 (t, J=7.5 Hz, 0.5H), 6.16 (t, J=
6.9 Hz, 0.5H), 5.80 (bs, 1H), 4.64 (s, 2H), 3.71 (s, 3H), 3.64
(d, J=10.8 Hz, 2H), 2.69–2.84 (m, 3H), 2.49–2.57 (m, 1H);
13C NMR (75 MHz, CDCl3): d=175.8, 142.1, 138.0, 128.7,
128.5, 128.0, 126.0, 76.5, 54.2, 51.9, 44.1, 36.1, 30.3, 29.4; HR-
MS (ESI): m/z=326.1754, calcd. for C20H24NO3 [M+H]+:
326.1756.
1
nyl)acrylate (4n): H NMR (300 MHz, CDCl3): d=7.61 (d,
J=8.3 Hz, 2H), 7.29–7.39 (m, 7H), 6.87 (s, 1H), 5.87 (bs,
1H), 4.71 (s, 2H), 3.85 (d, J=0.9 Hz, 2H), 3.66 (s, 3H);
13C NMR (100 MHz, CDCl3): d=167.8, 140.1, 137.4, 135.5,
133.2, 131.7, 128.8, 128.3, 128.2, 127.8, 118.5, 111.5, 76.2,
56.1, 51.9; HR-MS (EI): m/z=322.1314, calcd. for
C19H18N2O3: 322.1312.
AHCTUNGTREG(NNNU E/Z)-Methyl 2-[(benzyloxyamino)methyl]pent-2-enoate
(4t): 1H NMR (300 MHz, CDCl3, E/Z=1:1): d=7.24–7.32
(m, 5H), 6.92 (t, J=7.6 Hz, 0.5H), 6.11 (t, J=7.3 Hz, 0.5H),
5.87 (bs, 1H), 4.66 (s, 2H), 3.71–3.72 (m, 4H); 3.64 (s, 1H),
2.50–2.55 (m, 1H), 2.44–2.49 (m, 1H), 1.02–1.07 (m, 3H);
13C NMR (75 MHz, CDCl3): d=168.0, 149.1, 138.2, 128.6,
128.5, 127.9, 127.1, 76.2, 56.2, 52.0, 47.9, 23.5, 22.4, 14.1, 13.7;
HR-MS (ESI): m/z=250.1440, calcd. for C14H20NO3 [M+
H]+: 250.1443.
(E)-Methyl 2-[(benzyloxyamino)methyl]-3-p-tolylacrylate
1
(4o): H NMR (300 MHz, CDCl3): d=7.82 (s, 1H), 7.39 (d,
J=8.0 Hz, 2H), 7.28–7.34 (m, 5H), 7.15 (d, J=8.0 Hz, 2H),
6.07 (bs, 1H), 4.72 (s, 2H), 3.96 (s, 2H), 3.79 (s, 3H), 2.38 (s,
3H); 13C NMR (75 MHz, CDCl3): d=168.5, 144.1, 139.5,
138.2, 132.2, 129.9, 129.4, 128.6, 128.5, 127.9, 126.7, 76.2,
52.4, 49.0, 21.8; HR-MS (ESI): m/z=312.1594, calcd. for
C19H22NO3 [M+H]+: 312.1600.
A
2-[(benzyloxyamino)methyl]but-2-enoate
(4u): 1H NMR (300 MHz, CDCl3, E/Z=2:1): d=7.24–7.35
(m, 5H), 7.00–7.07 ( m, 0.67ꢂ1H), 6.21–6.29 (m, 0.33ꢂ1H),
5.87 (bs, 1H), 4.67 (s, 0.67ꢂ2H), 4.66 (s, 0.33ꢂ2H), 3.75 (s,
Adv. Synth. Catal. 2010, 352, 1539 – 1553
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1549

Yujuan Guo et al.
FULL PAPERS
0.67ꢂ2H), 3.73 (s, 0.33ꢂ3H), 3.71 (s, 0.67ꢂ3H), 3.64 (s,
0.33ꢂ2H), 2.04, (d, 0.33ꢂ3H, J=7.2 Hz), 1.84 (d, 0.67ꢂ3H,
J=7.2 Hz); 13C NMR (75 MHz, CDCl3): d=167.8, 142.5,
138.2, 128.7, 128.6, 128.5, 127.9, 76.2, 56.1, 52.0, 51.6, 47.6,
16.3, 14.9; HR-MS (ESI): m/z=236.1280, calcd. for
C13H18NO3 [M+H]+: 236.1287.
alpak OD-H, i-PrOH/hexane=5/95, UV 220 nm, flow rate
0.5 mLminÀ1): t (minor)=20.1 min, t (major)=22.6 min.
Methyl 3-(benzyloxyamino)-2-(3-fluorobenzyl)propanoate
(5e): oil; [a]2D0: À18.6 (c 1.4, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.22–7.37 (m, 5H), 7.11–7.20 (m, 1H), 6.83–6.92
(m, 3H), 5.70 (bs, 1H), 4.64 (d, J=1.7 Hz, 2H), 3.60 (s,
3H), 2.77–3.20 (m, 5H); 13C NMR (100 Hz, CDCl3): d=
174.7, 162.9 (d, JC,F =245.8 Hz), 141.4 (d, JC,F =7.3 Hz),
137.7, 129.9 (d, JC,F =8.3 Hz), 128.5, 128.4, 127.9, 124.6, 115.8
(d, JC,F =21.0 Hz), 113.5 (d, JC,F =21.0 Hz), 76.3, 53.2, 51.7,
45.5, 35.9; HR-MS (ESI): m/z=318.1499, calcd. for
C18H21FNO3 [M+H]+: 318.1505; ee=98%, determined by
HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane=5/95, UV
220 nm, flow rate 0.5 mLminÀ1): t (minor)=19.4 min, t
(major)=21.9 min.
Methyl
2-[(benzyloxyamino)methyl]acrylate
(4v):
1H NMR (300 MHz, CDCl3, Z/E=1:1): d=7.24–7.33 (m,
5H), 6.28 (s, 1H), 5.95 (bs, 1H), 5.77 (s, 1H), 4.68 (s, 2H),
3.75 (s, 3H), 3.71 (s, 2H); 13C NMR (75 MHz, CDCl3): d=
167.3, 137.2, 136.8, 129.1, 128.6, 128.4, 128.0, 75.9, 58.9, 52.1;
HRMS (ESI): m/z=222.1125, calcd. for C12H16NO3 [M+
H]+: 222.1130.
Methyl 3-(benzyloxyamino)-2-(3-chlorobenzyl)propanoate
(5f): oil; [a]2D0: À12.9 (c 1.4, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.17–7.29 (m, 5H), 7.05–7.13 (m, 3H), 6.90–6.97
(m, 1H), 5.64 (bs, 1H), 4.56 (d, J=1.6 Hz, 2H), 3.52 (s,
3H), 2.56–3.01 (m, 5H); 13C NMR (100 Hz, CDCl3): d=
174.7, 140.9, 137.7, 134.3, 129.7, 129.1, 128.5, 128.4, 127.9,
127.1, 126.7, 76.3, 53.1, 51.7, 45.4, 35.8; HR-MS (ESI): m/z=
334.1208, calcd. for C18H21ClNO3 [M+H]+: 334.1210; ee=
98%, determined by HPLC (Daicel Chiralpak OD-H, i-
PrOH/hexane=5/95, UV 220 nm, flow rate 0.5 mLminÀ1): t
(minor)=19.8 min, t (major)=22.4 min.
Methyl 3-(benzyloxyamino)-2-(3-bromobenzyl)propanoate
(5g): oil; [a]2D0: À21.2 (c 1.7, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.19–7.27 (m, 7H), 7.06–7.17 (m, 2H), 5.63 (bs,
1H), 4.56 (d, J=1.6 Hz, 2H), 3.52 (s, 3H), 2.65–3.11 (m,
5H); 13C NMR (100 Hz, CDCl3): d=174.7, 140.9, 137.7,
134.3, 129.7, 129.1, 128.5, 128.4, 127.9, 127.1, 126.7, 76.3,
53.1, 51.7, 45.4, 35.8; HR-MS (ESI): m/z=378.0708, calcd.
for C18H21BrNO3 [M+H]+: 378.0705; ee=98%, determined
by HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane=5/95,
UV 220 nm, flow rate 0.5 mLminÀ1): t (minor)=20.8 min, t
(major)=23.6 min.
General Procedures for the Asymmetric
Hydrogenation
The catalyst was added to a solution of the substrate and de-
gassed solvent in a glass-lined stainless steel autoclave under
a nitrogen atmosphere. After purging three times with H2,
the autoclave was pressurized to the desired pressure with
H2. The solution was stirred well at the given temperature
for the time specified in Table 3 or Table 4. After releasing
the hydrogen pressure, reaction mixture was concentrated.
The residue was filtered through a short SiO2 column with
ethyl acetate/petroleum ether (1/1) to remove the catalyst.
The filtrate was concentrated. The conversion of the reac-
1
tion was determined by H NMR and HPLC. The enantio-
meric excess was determined by chiral HPLC.
Methyl 3-(benzyloxyamino)-2-(2-fluorobenzyl)propanoate
(5b): oil; [a]2D0: À16.0 (c 1.0, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.11–7.35 (m, 7H), 6.97–7.05 (m, 2H), 5.72 (bs,
1H), 4.64 (d, J=0.9 Hz, 2H,), 3.59 (s, 3H), 2.92–3.23 (m,
5H); 13C NMR (100 Hz, CDCl3): d=174.9, 161.3 (d, JC,F
=
245.5 Hz), 137.9, 131.3 (d, JC,F =4.5 Hz), 128.6, 128.5, 128.4,
127.9, 125.8 (d, JC,F =15.7 Hz), 124.1 (d, JC,F =3.1 Hz), 115.4
(d, JC,F =22.1 Hz), 76.4, 53.3, 51.7, 44.4, 29.7; HR-MS (ESI):
m/z=318.1500, calcd. for C18H21FNO3 [M+H]+: 318.1505;
ee=97%, determined by HPLC (Daicel Chiralpak OD-H, i-
PrOH/hexane=5/95, UV 220 nm, flow rate 0.5 mLminÀ1): t
(minor)=16.7 min, t (major)=18.5 min.
Methyl 3-(benzyloxyamino)-2-(2-chlorobenzyl)propanoate
(5c): oil; [a]2D0: À19.0 (c 1.0, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.22–7.37 (m, 6H), 7.12–7.19 (m, 3H), 5.65 (bs,
1H), 4.64 (d, J=1.8 Hz, 2H), 3.57 (s, 3H), 2.94–3.23 (m,
5H); 13C NMR (100 Hz, CDCl3): d=174.9, 137.8, 136.6,
134.2, 131.2, 129.7, 128.5, 128.4, 128.1, 127.8, 126.8, 76.3,
53.4, 51.6, 43.9, 34.0; HR-MS (ESI): m/z=334.1213, calcd.
for C18H21ClNO3 [M+H]+: 334.1210; ee=96%, determined
by HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane=5/95,
UV 220 nm, flow rate 0.5 mLminÀ1): t (minor)=18.4 min, t
(major)=20.6 min.
Methyl 3-(benzyloxyamino)-2-(2-bromobenzyl)propanoate
(5d): oil; [a]2D0: À7.5 (c 2.3, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.50–7.53 (m, 1H), 7.22–7.37 (m, 5H), 7.15–7.20
(m, 2H), 7.03–7.10 (m, 1H), 5.72 (bs, 1H), 4.65 (d, J=
2.2 Hz, 2H), 3.57 (s, 3H), 2.94–3.24 (m, 5H); 13C NMR
(100 Hz, CDCl3): d=174.8, 138.3, 137.8, 133.0, 131.2, 128.5,
128.4, 128.3, 127.8, 127.4, 124.7, 76.3, 53.4, 51.7, 44.0, 36.5;
HR-MS (ESI): m/z=378.0703, calcd. for C18H21BrNO3 [M+
H]+: 378.0705; ee=96%, determined by HPLC (Daicel Chir-
Methyl
3-(benzyloxyamino)-2-(3-methoxybenzyl)propa-
noate (5h): oil; [a]D20: À13.3 (c 0.9, EtOH); 1H NMR
(300 MHz, CDCl3): d=7.19–7.29 (m, 5H), 7.08–7.13 (m,
1H), 6.61–6.69 (m, 3H), 5.63 (bs, 1H), 4.56 (d, J=1.6 Hz,
2H), 3.70 (s, 3H), 3.54 (s, 3H), 2.67–3.14 (m, 5H); 13C NMR
(100 Hz, CDCl3): d=175.1, 159.8, 140.4, 137.8, 129.5, 128.5,
128.4, 127.9, 121.4, 114.7, 112.0, 76.3, 55.2, 53.2, 51.7, 45.6,
36.4; HRMS (ESI): m/z=330.1700, calcd. for C19H24NO4
[M+H]+: 330.1705; ee=98%, determined by HPLC (Daicel
Chiralpak OD-H, i-PrOH/hexane=5/95, UV 220 nm, flow
rate 0.5 mLminÀ1):
32.5 min.
t
(minor)=29.1 min,
t
(major)=
Methyl 3-(benzyloxyamino)-2-(4-fluorobenzyl)propanoate
(5i): oil; [a]2D0: À23.3 (c 0.9, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.18–7.27 (m, 5H), 7.00–7.04 (m, 2H), 6.84–
6.90
3H), 2.67–3.13 (m, 5H); 13C NMR (100 Hz, CDCl3): d=
174.84, 161.65 (d, JC,F =244.4 Hz), 137.75, 134.34 (d, JC,F
ACHTUNGTREN(NGNU m, 2H), 5.63 (bs, 1H), 4.57 (d, J=1.7 Hz, 2H), 3.51 (s,
=
2.8), 130.33 (d, JC,F =7.8 Hz), 128.47, 128.39, 127.87, 115.26
(d, JC,F =21.2 Hz), 76.28, 53.16, 51.63, 45.78, 35.41; HRMS
(ESI): m/z=318.1507, calcd. for C18H21FNO3 [M+H]+:
318.1505; ee=98%, determined by HPLC (Daicel Chiralpak
OD-H, i-PrOH/hexane=5/95, UV 220 nm, flow rate
0.5 mLminÀ1): t (minor)=19.0 min, t (major)=21.7 min.
1550
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1539 – 1553

A General Approach to the Synthesis of b2-Amino Acid Derivatives
Methyl 3-(benzyloxyamino)-2-(4-chlorobenzyl)propanoate
(5j): oil; [a]2D0: À14.4 (c 1.8, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.27–7.34 (m, 5H), 7.22 (d, J=7.9 Hz, 2H), 7.05
(d, J=7.9 Hz, 2H), 5.70 (bs, 1H), 4.63 (d, J=1.1 Hz, 2H),
3.58 (s, 3H), 2.74–3.19 (m, 5H); 13C NMR (100 Hz, CDCl3):
d=174.7, 137.7, 137.3, 132.3, 130.3, 128.6, 128.5, 128.4, 127.9,
76.3, 53.2, 51.7, 45.6, 35.5; HR-MS (ESI): m/z=334.1215,
calcd. for C18H21ClNO3 [M+H]+: 334.1210; ee=98%, deter-
mined by HPLC (Daicel Chiralpak OD-H, i-PrOH/
76.5, 53.5, 51.9, 46.1, 36.2; HR-MS (ESI): m/z=314.1750,
calcd. for C19H24NO3 [M+H]+: 314.1756; ee=99%, deter-
mined by HPLC (Daicel Chiralpak OD-H, i-PrOH/
hexane=5/95, UV 220 nm, flow rate 1 mLminÀ1):
(minor)=8.3 min, t (major)=9.6 min.
t
Methyl
3-(benzyloxyamino)-2-(naphthalen-1-ylmethyl)-
1
propanoate (5p): oil; [a]2D0: À13.0 (c 1.0, EtOH); H NMR
(300 MHz, CDCl3): d=8.00–8.04 (m, 1H), 7.83–7.86 (m,
1H), 7.72 (d, J=8.0 Hz, 1H), 7.44–7.53 (m, 2H), 7.21–7.38
(m, 7H), 5.71 (bs, 1H), 4.61 (d, J=1.9 Hz, 2H), 3.57 (s,
3H), 3.38–3.44 (m, 1H), 3.20–3.31 (m, 3H), 3.08–3.13 (m,
1H); 13C NMR (75 Hz, CDCl3): d=175.3, 137.9, 135.0,
134.2, 132.0, 129.1, 128.7, 128.5, 128.0, 127.6, 127.3, 126.3,
125.8, 125.6, 123.8, 76.5, 53.8, 52.0, 45.2, 33.8; HR-MS (ESI):
m/z=350.1753, calcd. for C22H24NO3 [M+H]+: 350.1756;
ee=94%, determined by HPLC (Daicel Chiralpak OD-H, i-
PrOH/hexane=5/95), UV 220 nm, flow rate 0.5 mLminÀ1): t
(minor)=33.9 min, t (major)=39.4 min.
hexane=5/95, UV 220 nm, flow rate 0.5 mLminÀ1):
(minor)=20.1 min, t (major)=23.3 min.
t
Methyl 3-(benzyloxyamino)-2-(4-bromobenzyl)propanoate
(5k): oil; [a]2D0: À8.4 (c 1.9, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.37 (d, J=8.3 Hz, 2H), 7.24–7.32 (m, 5H), 7.01
(d, J=8.3 Hz, 2H), 5.70 (bs, 1H), 4.64 (d, J=1.5 Hz, 2H),
3.59 (s, 3H), 2.72–3.19 (m, 5H); 13C NMR (100 Hz, CDCl3):
d=174.7, 137.8, 137.7, 131.6, 130.7, 128.5, 128.4, 127.9, 120.4,
76.3, 53.2, 51.7, 45.5, 35.6; HR-MS (ESI): m/z=378.0701,
calcd. for C18H21BrNO3 [M+H]+: 378.0705; ee=98%, deter-
mined by HPLC (Daicel Chiralpak OD-H, i-PrOH/
Methyl
3-(benzyloxyamino)-2-(naphthalen-2-ylmethyl)-
1
propanoate (5q): oil; [a]2D0: À10.6 (c 1.7, EtOH); H NMR
(300 MHz, CDCl3): d=8.00–8.04 (m, 1H), 7.83–7.86 (m,
1H), 7.72 (d, J=8.0 Hz, 1H), 7.44–7.53 (m, 2H), 7.21–7.38
(m, 7H), 5.71 (bs, 1H), 4.61 (d, J=1.9 Hz, 2H), 3.57 (s,
3H), 3.38–3.44 (m, 1H), 3.20–3.31 (m, 3H), 3.08–3.13 (m,
1H); 13C NMR (100 Hz, CDCl3): d=175.1, 137.8, 136.3,
133.6, 132.3, 128.5, 128.4, 128.1, 127.8, 127.7, 127.6, 127.4,
127.3, 126.1, 125.5, 76.3, 53.3, 51.7, 45.6, 36.4; HR-MS (ESI):
m/z=350.1751, calcd. for C22H24NO3 [M+H]+: 350.1756;
ee=98%, determined by HPLC (Daicel Chiralpak OD-H, i-
PrOH/hexane=5/95, UV 220 nm, flow rate 0.5 mLminÀ1): t
(minor)=30.7 min, t (major)=40.5 min.
hexane=5/95, UV 220 nm, flow rate 0.5 mLminÀ1):
(minor)=21.2 min, t (major)=25.0 min.
t
Methyl
3-(benzyloxyamino)-2-(4-methoxybenzyl)propa-
noate (5l): oil; [a]D20: À19.2 (c 1.3, EtOH); 1H NMR
(300 MHz, CDCl3): d=7.23–7.35 (m, 5H), 7.05 (d, J=
8.7 Hz, 2H), 6.79 (d, J=8.7 Hz, 2H), 5.69 (bs, 1H), 4.64 (d,
J=1.7 Hz, 2H), 3.77 (s, 3H), 3.59 (s, 3H), 2.71–3.20 (m,
5H); 13C NMR (100 Hz, CDCl3): d=175.2, 158.4, 137.9,
130.9, 130.0, 128.6, 128.5, 127.9, 114.0, 76.3, 55.4, 53.2, 51.7,
46.0, 35.5; HR-MS (ESI): m/z=330.1711, calcd. for
C19H24NO4: 330.1705 [M+H]+; ee=98%, determined by
HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane=5/95, UV
220 nm, flow rate 0.5 mLminÀ1): t (minor)=25.9 min, t
(major)=30.2 min.
Methyl 2-[(benzyloxyamino)methyl]-5-phenylpentanoate
(5r): oil; [a]2D0: +16.3 (c 0.8, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.11–7.31 (m, 10H), 4.64 (d, J=1.0 Hz, 2H),
3.64 (s, 3H), 2.95–3.18 (m, 2H), 2.71–2.80 (m, 1H), 2.59 (t,
J=7.7 Hz, 2H), 1.47–1.70 (m, 4H); 13C NMR (100 Hz,
CDCl3): d=175.8, 142.1, 138.0, 128.7, 128.5, 128.0, 126.0,
76.5, 54.2, 51.9, 44.1, 36.1, 30.3, 29.4; HR-MS (ESI): m/z=
328.1905, calcd. for C20H26NO3 [M+H]+: 328.1913; ee
>99.5%, determined by HPLC (Daicel Chiralpak OD-H, i-
PrOH/hexane=5/95, UV 220 nm, flow rate 0.5 mLminÀ1): t
(major)=23.3 min, t (minor)=40.0 min.
Methyl 2-[(benzyloxyamino)methyl]pentanoate (5t): oil;
[a]2D0: À15.0 (c 1.0 , EtOH); 1H NMR (300 MHz, CDCl3):
d=7.25–7.34 (m, 5H), 5.69 (bs, 1H), 4.66 (d, J=1.5 Hz,
2H), 3.66 (s, 3H), 2.97–3.19 (m, 2H), 2.71–2.81 (m, 1H),
1.25–1.65 (m, 6H), 0.90 (t, J=7.2 Hz, 3H); 13C NMR
(75 Hz, CDCl3): d=175.8, 137.7, 128.4, 128.3, 127.8, 76.3,
54.0, 51.6, 43.8, 32.6, 20.6, 14.2; HR-MS (ESI): m/z=
252.1594, calcd. for C14H22NO3 [M+H]+: 252.1600; ee=
98%, determined by HPLC (Daicel Chiralpak OD-H, i-
PrOH/hexane=5/95, UV 220 nm, flow rate 0.5 mLminÀ1): t
(major)=12.7 min, t (minor)=13.6 min.
Methyl 3-(benzyloxyamino)-2-(4-nitrobenzyl)propanoate
1
(5m): oil; [a]2D0: +16.3 (c 0.8, EtOH); H NMR (300 MHz,
CDCl3): d=8.10 (d, J=8.5 Hz, 2H), 7.24–7.35 (m, 7H), 5.71
(bs, 1H), 4.65 (d, J=1.5 Hz, 2H), 3.59 (s, 3H), 2.92–3.22 (m,
5H); 13C NMR (75 Hz, CDCl3): d=174.4, 146.9 (146.94),
146.9 (146.87), 137.7, 129.9, 128.7, 128.6, 128.1, 123.9, 76.6,
53.5, 52.1, 45.6, 36.1; HR-MS (ESI): m/z=345.1441, calcd.
for C18H21N2O5 [M+H]+: 345.1450; ee=99%, determined
by HPLC (Daicel Chiralpak OD-H, i-PrOH/hexane=5/95,
UV 220 nm, flow rate 1 mLminÀ1): t (major)=27.8 min, t
(minor)=33.9 min.
Methyl 3-(benzyloxyamino)-2-(4-cyanobenzyl)propanoate
(5n): oil; [a]2D0: À21.4 (c 0.7, EtOH); 1H NMR (300 MHz,
CDCl3): d=7.53 (d, J=8.2 Hz, 2H), 7.27–7.32 (m, 5H),
7.23(d, J=8.1 Hz, 2H), 4.64 (d, J=1.4 Hz, 2H), 3.58 (s, 3H),
2.83–3.20 (m, 5H); 13C NMR (75 Hz, CDCl3): d=174.4,
144.7, 137.8, 132.4, 129.9, 128.6 (128.64), 128.6 (128.58),
128.1, 119.0, 110.7, 76.6, 53.5, 52.1, 45.5, 36.4; HR-MS (ESI):
m/z=325.1546, calcd. for C19H21N2O3 [M+H]+: 325.1552;
ee=96%, determined by HPLC (Daicel Chiralpak OD-H, i-
PrOH/hexane=5/95), UV 220 nm, flow rate 1 mLminÀ1): t
(minor)=28.5 min, t (major)=36.6 min.
Methyl 2-[(benzyloxyamino)methyl]butanoate (5u): oil;
1
[a]2D0: À15.8 (c 1.9, EtOH); H NMR (300 MHz, CDCl3): d=
7.24–7.33 (m, 5H), 5.64 (bs, 1H), 4.66 (s, 2H), 3.66, (s, 3H),
2.98–3.20 (m, 2H), 2.63–2.72 (m, 1H), 1.50–1.68 (m, 2H),
0.91 (t, J=7.4 Hz, 3H); 13C NMR (75 Hz, CDCl3): d=176.7,
138.0, 128.6, 128.5, 128.0, 76.5, 53.8, 51.8, 45.6, 23.8, 12.0;
HR-MS (ESI): m/z=238.1447, calcd. for C13H18NO3 [M+
H]+: 238.1443; ee=99%, determined by HPLC (Daicel Chir-
Methyl
3-(benzyloxyamino)-2-(4-methylbenzyl)propa-
noate (5o): oil; [a]D20: À22.2 (c 0.9, EtOH); 1H NMR
(300 MHz, CDCl3): d=7.17–7.30 (m, 5H), 6.99–7.06 (m,
4H), 5.67 (bs, 1H), 4.62 (d, J=1.5 Hz, 2H), 3.57 (s, 3H),
2.71–3.18 (m, 5H), 2.29 (s, 3H); 13C NMR (75 Hz, CDCl3):
d=175.2, 138.0, 136.1, 135.8, 129.4, 129.0, 128.7, 128.6, 128.0,
Adv. Synth. Catal. 2010, 352, 1539 – 1553
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1551

Yujuan Guo et al.
FULL PAPERS
alpak OD-H, i-PrOH/hexane=2/98, UV 220 nm, flow rate
0.5 mLminÀ1): t (major)=16.2 min, t (minor)=18.1 min.
Methyl 3-(benzyloxyamino)-2-methylpropanoate (5v): oil;
troduced to the flask at an initial pressure of about 1 atm.
The suspension was stirred for 8 h at ambient temperature.
After filtration and evaporation of MeOH, the residue was
subjected to column chromatography (SiO2; MeOH) to
afford 8 as a white solid; yield: 49 mg (68%). [a]2D5: +12.7 (c
0.9, 1M HCl) {lit.[21a] [a]D25: +11.3 (c 1.0, 1M HCl), lit.[21b]
[a]2D5: +16.9 (c 2.3, 1M HCl)}; 1H NMR (300 MHz, D2O):
d=7.22–7.34 (m, 5H), 2.95–3.08 (m, 3H), 2.80–2.85 (m,
2H).
1
[a]2D0: +15.0 (c 1.2, EtOH); H NMR (300 MHz, CDCl3): d=
7.23–7.32 (m, 5H), 5.71 (bs, 1H), 4.66 (s, 2H), 3.65 (s,3H),
2.92–3.20 (m, 2H), 2.77–2.88 (m, 1H), 1.16 (d, J=7.1 Hz,
3H); 13C NMR (75 Hz, CDCl3): d=176.2, 138.0, 128.6,
128.5, 128.0, 76.4, 55.3, 52.0, 38.0, 15.6; HR-MS (ESI): m/z=
224.1283, calcd. for C12H17NO3 [M+H]+: 224.1287; ee=
83%, determined by HPLC (Daicel Chiralpak OD-H, i-
PrOH/hexane=5/95, UV 220 nm, flow rate 0.5 mLminÀ1): t
(minor)=16.5 min, t (major)=15.5 min.
Acknowledgements
(R)-Methyl 3-Amino-2-benzylpropanoate (6)
We thank the National Natural Science Foundation of China
(No. 20842005) and the Hong Kong Polytechnic University
(No. A-SA55) for financial support.
In a flask was placed with Pd/C (10%, 15 mg), (R)-5a
(149 mg, 0.5 mmol), and anhydrous MeOH (5 mL), Then,
hydrogen gas was introduced to the flask at an initial pres-
sure of about 1 atm. The suspension was stirred for 8 h at
ambient temperature. After filtration and evaporation of
MeOH, the residue was subjected to column chromatogra-
phy (SiO2; CH2Cl2) to afford 6 as a colorless oil; yield:
82 mg (85%). [a]D20: +19.6 (c 2.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.16–7.19 (m, 2H), 7.05–7.11 (m,
3H), 3.54 (s, 3H), 2.6–2.89 (m, 5H), 1.36 (bs, 2H); 13C NMR
(75 Hz, CDCl3): d=174.8, 138.7, 128.5, 128.2, 126.1, 51.3,
50.5, 43.1, 35.6; HR-MS (ESI): m/z=194.1188, calcd. for
C11H16NO2 [M+H]+: 194.1181.
References
[1] I. Ojima, S. N. Lin, T. Wang, Curr. Med. Chem. 1999, 6,
927–954.
[2] G. I. Georg, (Ed.), The Organic Chemistry of b-Lac-
tams, Verlag Chemie, New York, 1993.
[3] a) E. Juaristi, V. A. Soloshonok, (Eds.), Enantioselective
Synthesis of b-Amino Acids, 2nd edn., Wiley-VCH,
Weinheim, 2005; b) S. H. Gellman, Acc. Chem. Res.
1998, 31, 173–180; c) D. C. Cole, Tetrahedron 1994, 50,
9517–9582; d) E. Juaristi, H. Lopez-Ruiz, Curr. Med.
Chem. 1999, 6, 983–1004; e) E. A. Porter, X. Wang, H.-
S. Lee, B. Weisblum, S. H. Gellman, Nature 2000, 404,
565; f) X. Wang, J. F. Espinosa, S. H. Gellman, J. Am.
Chem. Soc. 2000, 122, 4821–4822; g) S. Abele, D. See-
bach, Eur. J. Org. Chem. 2000, 1–15.
[4] a) D. Seebach, M. Overhand, F. N. M. Kuhlne, B. Marti-
noni, L. Oberer, U. Hommel, H. Widmer, Helv. Chim.
Acta 1996, 79, 913–941; b) D. Seebach, P. E. Ciceri, M.
Overhand, B. Jaun, D. Rigo, L. Oberer, U. Hommel, R.
Amstutz, H. Widmer, Helv. Chim. Acta 1996, 79, 2043–
2065; c) D. H. Appella, L. A. Christianson, I. L. Karle,
D. R. Powell, S. H. Gellman, J. Am. Chem. Soc. 1996,
118, 13071–13072; d) S. Borman, Chem. Eng. News
1997, 75, 32–35; e) D. L. Steer, R. A. Lew, P. Perlmut-
ter, A. I. Smith, M.-I. Aguilar, Curr. Med. Chem. 2002,
9, 811–822.
(R)-Methyl 3-Acetamido-2-benzylpropanoate (7)
Acetyl chloride (32 mg, 0.41 mmol) in CH2Cl2 (2 mL) was
added dropwise to a stirred solution of compound 6 (77 mg,
0.4 mmol) and Et3N (0.167 mL, 1.2 mmol) in CH2Cl2 (8 mL)
at 08C. The reaction mixture was then stirred for 1 h at 08C,
and for a further hour at room temperature. After removal
of the solvent under reduced pressure, the residue was treat-
ed with ethyl acetate (3ꢂ20 mL) and passed through a short
silica gel plug. The combined filtrate was concentrated
under reduced pressure to afford 7; yield: 87 mg
(0.37 mmol, 92%). [a]2D0: +14.7 (c 2.0, CHCl3); 1H NMR
(300 MHz, CDCl3): d=7.07–7.22 (m, 5H), 5.98 (m, 1H),
3.57 (s, 1H), 3.41–3.47 (m, 1H), 3.24–3.31 (m, 1H), 2.84–
2.91 (m, 2H), 2.72–2.78 (m, 1H), 1.86 (s, 3H); 13C NMR
(75 Hz, CDCl3): d=174.8, 170.3, 138.1, 128.8, 128.6, 126.7,
51.8, 46.7, 40.3, 36.1, 23.2; HR-MS (ESI): m/z=258.1103,
calcd. for C13H17NNaO3 [M+Na]+: 258.1106; ee=99%, de-
termined by chiral GC (CP Chiralsil Dex-CB column, iso-
thermal at 708C for 1.0 min, 78CminÀ1 to 1608C): tR
(major)=16.3 min, tR (minor)=18.5 min).[22]
[5] G. Lelais, D. Seebach, Biopolymers (Peptide Sci.) 2004,
76, 206–243.
[6] a) G. V. Subbaraju, T. Golakoti, G. M. L. Patterson,
R. E. Moore, J. Nat. Prod. 1997, 60, 302–305; b) S.
Chaganty, C. Heltzel, T. Golakoti, R. E. Moore, W. Y.
Yoshida, J. Nat. Prod. 2004, 67, 1403–1406; c) R. E.
Schwartz, C. F. Hirsch, D. F. Sesin, J. E. Flor, M. Char-
train, R. E. Fromtling, G. H. Harris, M. J. Salvatore,
J. M. Liesch, K. Yudin, J. Ind. Microbiol. 1990, 5, 113–
124.
[7] a) J. D. Park, D. H. Kim, S. J. Kim, J. R. Woo, S. E.
Ryu, J. Med. Chem. 2002, 45, 5295–5302; b) D. H.
Kim, Y. Jin, Bioorg. Med. Chem. Lett. 1999, 9, 691–
696; c) J. A. Robl, L. M. Simpkins, M. M. Asaad,
Bioorg. Med. Chem. Lett. 2000, 10, 257–260; d) L. M.
Pratt, R. P. Beckett, S. J. Davies, S. B. Launchbury, A.
(R)-3-Amino-2-benzylpropanoic Acid (8)
To a solution of 5a (120 mg, 0.4 mmol) in THF/H2O (4:1)
(7.5 mL) at room temperature was added LiOH·H2O
(50 mg, 1.2 mmol). After 24 h at room temperature, reaction
mixture was acidified to pH 2 with 0.5 mmol HCl and ex-
tracted with CH2Cl2 (3ꢂ20 mL). The combined CH2Cl2
layers were washed with brine (1ꢂ30 mL) and dried over
Na2SO4. The evaporation of the solvent gave the crude acid
that was used without further purification for the next step.
In a flask was placed with Pd/C (10%, 25 mg), crude acid,
and anhydrous MeOH (5 mL), Then, hydrogen gas was in-
1552
asc.wiley-vch.de
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1539 – 1553

A General Approach to the Synthesis of b2-Amino Acid Derivatives
Miller, Z. M. Spavold, R. S. Todd, M. Whittaker,
Bioorg. Med. Chem. Lett. 2001, 11, 2585–2588; e) M.
Prashad, H. Y. Kim, B. Hu, J. Slade, P. K. Kapa, M. J.
Girgis, Patent WO 2004/076053, 2004.
Zhang, Org. Lett. 2002, 4, 4159–4161; g) Y.-G. Zhou,
W. Tang, W. B. Wang, W. Li, X. Zhang, J. Am. Chem.
Soc. 2002, 124, 4952–4953; h) D. PeÇa, A. J. Minnaard,
J. G. de Vries, B. L. Feringa, J. Am. Chem. Soc. 2002,
124, 14552–14553.
[8] For a review, see: H. J. Drexler, J. You, S. Zhang, C.
Fisher, W. Baumann, A. Spannenberg, D. Heller, Org.
Process Res. Dev. 2003, 7, 355–361.
[16] a) D. Basavaiah, P. D. Rao, R. S. Hyma, Tetrahedron
1996, 52, 8001–8062; b) Y. Fort, M. C. Berthe, P. Cau-
bere, Tetrahedron 1992, 48, 6371–6384; c) H. M. R.
Hoffmann, J. Rabe, J. Org. Chem. 1985, 50, 3849–3859;
d) G. E. Keck, D. S. Welch, Org. Lett. 2002, 4, 3687–
3690; e) W. Pei, H.-X. Wei, G. Li, Chem. Commun.
2002, 1856–1857; f) J. Cai, Z. Zhou, G. Zhao, C. Tang,
Org. Lett. 2002, 4, 4723–4725; g) D. Basavaiah, A. J.
Rao, T. Satyanarayana, Chem. Rev. 2003, 103, 811–891;
h) B. Das, G. Mahender, N. Chowdhury, J. Banerjee,
Synlett 2005, 1000–1002; i) C. Z. Yu, B. Liu, L. Q. Hu,
J. Org. Chem. 2001, 66, 5413–5418.
[9] M. Liu, M. P. Sibi, Tetrahedron 2002, 58, 7991–8035.
[10] a) A. Duursma, A. J. Minnaard, B. L. Feringa, J. Am.
Chem. Soc. 2003, 125, 3700–3701; b) U. Eilitz, F. Less-
mann, O. Seidelmann, V. Wendisch, Tetrahedron:
Asymmetry 2003, 14, 189–191; c) U. Eilitz, F. Less-
mann, O. Seidelmann, V. Wendisch, Tetrahedron:
Asymmetry 2003, 14, 3095–3097; d) A. Rimkus, N.
Sewald, Org. Lett. 2003, 5, 79–80; e) M. P. Sibi, H. Ta-
tamidani, K. Patil, Org. Lett. 2005, 7, 2571–2573.
[11] M. P. Sibi, K. Patil, Angew. Chem. 2004, 116, 1255–
1258; Angew. Chem. Int. Ed. 2004, 43, 1235–1238.
[12] H. M. L. Davies, C. Venkataramani, Angew. Chem.
2002, 114, 2301–2303; Angew. Chem. Int. Ed. 2002, 41,
2197–2199.
[17] a) R. Annunziata, M. Benaglia, M. Cinquini, F. Cozzi,
L. Raimondi, J. Org. Chem. 1995, 60, 4697–4706; b) D.
Basavaiah, R. S. Hyma, Tetrahedron 1996, 52, 1253–
1258.
[13] a) J. F. Bower, J. M. J. Williams, Synlett 1996, 685–686;
b) J. F. Bower, R. Jumnah, A. C. Williams, J. M. J. Wil-
liams, J. Chem. Soc. Perkin Trans. 1 1997, 1411–1420.
[14] a) A. J. Robinson, C. Y. Lim, J. Org. Chem. 2001, 66,
4141–4147; b) D. Saylik, E. M. Campi, A. C. Donohue,
W. R. Jackson, A. J. Robinson, Tetrahedron: Asymme-
try 2001, 12, 657–667; c) J. Elaridi, A. Thaqi, A. Pross-
er, W. R. Jackson, A. J. Robinson, Tetrahedron: Asym-
metry 2005, 16, 1309–1319; d) H.-J. Drexler, W. Bau-
mann, T. Schmidt, S. L. Zhang, A. L. Sun, A. Spannen-
berg, C. Fischer, H. Buschmann, D. Heller, Angew.
Chem. 2005, 117, 1208–1212; Angew. Chem. Int. Ed.
2005, 44, 1184–1188; e) H. Huang, X. Liu, J. Deng, M.
Qiu, Z. Zheng, Org. Lett. 2006, 8, 3359–3362; f) J.
Deng, X.-P. Hu, J.-D. Huang, S.-B. Yu, D.-Y. Wang, Z.-
C. Duan, Z. Zheng, J. Org. Chem. 2008, 73, 2015–2017;
g) R. Hoen, T. Tiemersma-Wegman, B. Procuranti, L.
Lefort, J. G. de Vries, A. J. Minnaard, B. L. Feringa,
Org. Biomol. Chem. 2007, 5, 267–275; h) L. Qiu, M.
Prashad, B. Hu, K. Prasad, O. Repic, T. J. Blacklock,
F. Y. Kwong, S. H. L. Kok, H. W. Lee, A. S. C. Chan,
Proc. Natl. Acad. Sci. USA 2007, 104, 16787–16792.
[15] a) W. D. Lubell, M. Kitamura, R. Noroyi, Tetrahedron:
Asymmetry 1991, 2, 543–554; b) M. Yasutake, I. D.
Gridnev, N. Higashi, T. Imamoto, Org. Lett. 2001, 3,
1701–1704; c) D. Heller, J. Holz, H. J. Drexler, J. Lang,
K. Drauz, H.-P. Krimmer, A. Bçrner, J. Org. Chem.
2001, 66, 6816–6817; d) G. Zhu, Z. Chen, X. Zhang, J.
Org. Chem. 1999, 64, 6907–6912; e) S.-G. Lee, Y. J.
Zhang, Org. Lett. 2002, 4, 2429–2431; f) W. Tang, X.
[18] a) S. Hbaıeb, Z. Latiri, H. Amri, Synth. Commun. 1999,
29, 981–988; b) P. Perlmutter, M. Tabone, J. Org.
Chem. 1995, 60, 6515–6522; c) S. E. Drewes, M. M.
Horn, N. Ramesar, Synth. Commun. 2000, 30, 1045–
1055.
[19] Assignments of the configurations of E- and Z-4 were
1
based on H NMR spectra. For the E-isomers, the vinyl
proton in b site shifts further down field.
[20] a) R. Noyori, M. Kitamura, T. Ohkuma, Proc. Natl.
Acad. Sci. USA 2004, 101, 16787–16792; b) L. Qiu,
F. Y. Kwong, J. Wu, W. H. Lam, S. Chan, W.-Y. Yu, R.
Guo, A. S. C. Chan, J. Am. Chem. Soc. 2006, 128,
5955–5965; c) B. L. Feringa, Acc. Chem. Res. 2000, 33,
346–353; d) W. Tang, X. Zhang, Angew. Chem. Int. Ed.
2002, 41, 16162–11614; e) M. J. Burk, J. E. Feaster,
W. A. Nugent, R. Harlow, J. Am. Chem. Soc. 1993, 115,
10125–10138; f) M. J. Burk, Acc. Chem. Res. 2000, 33,
363–372; g) U. Berens, M. J. Burk, A. Gerlanch, W.
Hems, Angew. Chem. 2000, 112, 2057–2060; Angew.
Chem. Int. Ed. 2000, 39, 1981–1984; h) A. Togni, C.
Breutel, A. Schnyder, F. Spindler, H. Lanbert, A.
Tijani, J. Am. Chem. Soc. 1994, 116, 4062–4066.
[21] a) E. Juaristi, D. Quintana, M. Balderas, E. Garcia-
Perez, Tetrahedron: Asymmetry 1996, 7, 2233–2246;
b) D. Y. Ma, D. X. Wang, Q. Y. Zheng, M. X. Wang,
Tetrahedron: Asymmetry 2006, 17, 2366–2376.
[22] a) J. Meeuwissen, M. Kuil, A. M. van der Burg, A. J.
Sandee, J. N. H. Reek, Chem. Eur. J. 2009, 15, 10272–
10279; b) J. Wassenaar, J. N. H. Reek, J. Org. Chem.
2009, 74, 8403–8406.
Adv. Synth. Catal. 2010, 352, 1539 – 1553
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1553