Reaction of (S)-homoserine lactone with Grignard reagents: synthesis of amino-keto-alcohols and β-amino acid derivatives

Article abstract of DOI:10.1016/j.tetasy.2017.08.009

The ring-opening reaction of homoserine lactone with phenylmagnesium bromides was systematically examined. A reliable method to achieve β-amino acid precursors was developed by tuning the reaction conditions to favor mono-addition to the carbonyl moiety of the lactone.

Full text of DOI:10.1016/j.tetasy.2017.08.009

Tetrahedron: Asymmetry xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Reaction of (S)-homoserine lactone with Grignard reagents: synthesis
of amino-keto-alcohols and b-amino acid derivatives
⇑
Özlem Gündog˘du, Pınar Turhan, Aytekin Köse, Ramazan Altundasß, Yunus Kara
Department of Chemistry, Faculty of Sciences, Ataturk University, 25240 Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
The ring-opening reaction of homoserine lactone with phenylmagnesium bromides was systematically
examined. A reliable method to achieve b-amino acid precursors was developed by tuning the reaction
conditions to favor mono-addition to the carbonyl moiety of the lactone.
Ó 2017 Published by Elsevier Ltd.
Received 14 July 2017
Accepted 8 August 2017
Available online xxxx
1. Introduction
usually unable to undergo Friedel–Crafts reactions. These are the
major drawbacks in the synthesis of aryl amino-keto acids when
b-Amino acids are important compounds in Nature and syn-
thetic chemistry because they present a broad range of biological
properties. Several approaches for the efficient synthesis of these
compounds have been developed.1 One of these approaches
involves aspartic acid and methionine. (S)-Homoserine lactone
can be readily obtained from (S)-methionine,2,3 and the reaction
of this lactone with a variety of Grignard reagents yields the corre-
sponding amino alcohols,3,4 which can then be easily oxidized into
b-amino acids. However, treatment of lactone 1 with Grignard
reagents yields bis-addition, not mono-addition, of the reagent to
the carbonyl group, furnishing tertiary alcohols2 (Scheme 1).
using the Friedel–Crafts reaction. Although the reaction of organo-
metallics with lactones is well known in the literature, bis-
homoserine has not been studied in detail, and its potential in
developing easy access to b-amino acid precursors has not been
evaluated. Herein we report a straightforward and efficient synthe-
sis of
c-keto-b-amino acids via the ring-opening reaction of
homoserine lactone.
2. Results and discussion
We commenced with the synthesis of N-Boc-(S)-homoserine
lactone 1a from (S)-methionine using
a known method as
described in the literature.3 (S)-Methionine was subjected to S-
O
NH2
PhMgBr
(4.4 equiv.)
alkylation and nucleophilic displacement of a dialkyl sulfide, and
the L-homoserine obtained was then converted into lactone 1 with
Ph
Ph
NH2
O
OH
OH
HCl (Scheme 2).
1
2
Two equivalents of PhMgBr prepared7 in situ from PhBr and Mg
turnings in the presence of 1,2-dibromoethane were treated with
one equivalent of lactone 1a at room temperature (Scheme 3).
After purification of the crude material, keto-alcohols 6 and 7 were
obtained in yields of 70% and 20%, respectively. For this reaction, at
least a twofold excess of PhMgBr was necessary: one equivalent for
the acidic proton (–NHBoc) and one equivalent to achieve the addi-
tion to the carbonyl group of the lactone. In our attempts to
improve the synthesis of keto-alcohol 6, 2.3 equiv of PhMgBr were
used and the desired keto-alcohol was obtained in good yield.
It should be noted that depending on the reaction temperature
used, an increased ratio of bis-addition product 7 was found. Thus,
to eliminate 7, the reaction was repeated at 0 and ꢀ78 °C, however
these reactions failed. Despite our failure to eliminate bis-addition
product 7, the synthesis of 6 in good yield encouraged us to expand
this simple methodology to a series of in situ prepared Grignard
Scheme 1. Bis-addition of PhMgBr to homoserine lactone.
To avoid bis-addition, several methodologies have been devel-
oped.5 Seki et al. also reported the synthesis of
c-aryl or alkyl-sub-
stituted homochiral b-amino acids from N-Cbz-(S)-homoserine
lactone.3 The literature reports two main methods for synthesizing
amino-keto acids from such compounds: Friedel–Crafts acylation
and organometallic reaction with the corresponding anhydride or
acyl chloride.6 Although amino-keto acids are accessible via the
Friedel–Crafts reaction with anhydrides or acyl chlorides, the con-
trol of regioselectivity is strictly reagent-dependent. In addition,
nucleophilic groups containing aryl and alkyl compounds are
⇑
Corresponding author.
E-mail address: yukara@atauni.edu.tr (Y. Kara).
http://dx.doi.org/10.1016/j.tetasy.2017.08.009
0957-4166/Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Gündog˘du, Ö;. et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.009

2
Ö. Gündog˘du et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
NH2
NH2
NH2
NaHCO3
MeI
HO
HO
HO
S
S
OH
H2O, 24 h
reflux
MeOH/H2O,
r.t., 48 h
O
O
O
O
3
4
5
HCl, reflux
2 h
O
NHBoc
Boc2O
THF,r.t.,24 h
NH2.HCl
O
O
1a
Scheme 2. Synthesis of homoserine lactone.
1
assume that this dependence stems from the nucleophilicity and
steric effect of the aryl group.
O
NHBoc
NHBoc
PhMgBr
THF
NHBoc
Ph
Ph
O
Some of the ring-opening reactions of homoserine lactone indi-
cated that it had not completely reacted. An additional study to
investigate this phenomenon was performed using the conditions
given in Tables 2 and 3. Keto-alcohols 6 were obtained in a good
yield as judged by the 1H NMR spectra of the crude products. In
contrast to previous reports,3 the lactone was opened under mild
condition (2.7 equiv of ArMgBr at room temperature and 50 °C)
to give the amino-keto alcohols in one step. We believe that the
syntheses of amino-keto alcohols can be achieved by employing
our protocol without any obstacle.
OH
OH
OH
O
6
7
1a
Scheme 3. The ring-opening reactions of homoserine lactone with PhMgBr.
Table 1
The ring-opening reactions of homoserine lactone with Grignard reagents
Entry
ArMgBr
Products
Yielda (%)
To broaden the scope of this methodology to include alkylmag-
nesium halides, commercially available isopropylmagnesium bro-
mide and ethylmagnesium bromide were also used to obtain
amino-keto-alcohols. Treatment of lactone 1a with ethylmagne-
sium bromide at room temperature gave 8a in 60% yield and 9a
in 15% yield. The use of isopropylmagnesium bromide gave only
8b in 70% yield without any bis-addition product (Scheme 4), a
favorable result that could be attributed to the steric bulkiness of
the isopropyl group hampering the bonding of an additional iso-
propyl group to the same center.
1
2
3
4
5
6
7
8
C6H5MgBr
63
70
45
40
45
40
55
45
45
35
70
80
50
2-(MeO)C6H4MgBr
4-(MeO)C6H4MgBr
3-(F)-4-(MeO)C6H3MgBr
2-(Me)C6H4MgBr
3-(Me)C6H4MgBr
4-(Me)C6H4MgBr
2,4-(dimethyl)C6H3MgBr
4-(F)C6H4MgBr
3,4-(difluoro)C6H3MgBr
2,4,5-(trifluoro)C6H2MgBr
4-(N,N-dimethyl)-C6H4MgBr
6a
6b3
6c
6d
6e
6f3
6g
6h
6i
9
10
11
12
6j
6k
Considering the results obtained, this methodology functions
very well and is a very convenient method for preparing amino-
keto alcohol 6, which is a precursor of amino-keto-acids. For exam-
ple, we also easily obtained amino keto-alcohols 6e, 6k, and 8 via
this method; these amino-keto-alcohols cannot be synthesized
via Friedel–Crafts acylation. At this stage, the synthesized amino-
keto-alcohols were successfully converted into the corresponding
amino-keto-acids by Jones oxidation in 60%–70% yield (Scheme 5).
a
Isolated yields after column chromatography.
reagents. To prevent sudden temperature increases in the room-
temperature reactions, we used glass pieces instead of 1,2-dibro-
moethane to activate the magnesium.
As can be seen in Table 1, the substituents and their positions
on the aromatic ring affect the formation of keto-alcohols. We
Table 2
The ring-opening reactions of homoserine lactone with Grignard reagents
Entry
ArMgBr (2.7 equiv)
Lactone (1 equiv)
Temp. (°C)
Time (h)
Products
Ratio of product (%)
1
2
3
4
5
6
2-(MeO)C6H4MgBr
4-(Me)C6H4MgBr
4-(F)C6H4MgBr
3,4-(difluoro)C6H3MgBr
2,4,5-(trifluoro)C6H2MgBr
4-(N,N-dimethyl)C6H4MgBr
1a
1a
1a
1a
1a
1a
50
50
50
50
50
50
2
2
2
2
2
2
6a:7a
6f:7f
6h:7h
6i:7i
6j:7j
6k:7k
30:70
40:60
50:50
66:34
75:25
50:50
Table 3
The ring-opening reactions of homoserine lactone with Grignard reagents
Entry
ArMgBr (2.7equiv.)
Lactone (1 equiv)
Temp. (°C)
Time (h)
Products
Ratio of product (%)
1
2
3
4
5
2-(MeO)C6H4MgBr
4-(MeO)C6H4MgBr
4-(Me)C6H4MgBr
4-(F)C6H4MgBr
4-(N,N-Dimethyl)C6H4MgBr
1a
1a
1a
1a
1a
rt
2
2
2
2
2
6a:7a
6b:7b
6f:7f
6h:7h
6k:7k
85:15
60:40
65:35
66:34
66:34
rt
rt
rt
rt
Please cite this article in press as: Gündog˘du, Ö;. et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.009

Ö. Gündog˘du et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
3
R1
O
NHBoc
CH3 NHBoc
H3C
H3C
i-PrMgBr
NHBoc
R1
OH
OH
O
or EtMgBr
OH
O
R1
1
1a
8
9
a: R1: H, 60%
a
b
: R : H, 15%
b: R1: CH3, 70%
1
: R : CH3, not determined
Scheme 4. Ring-opening reactions of homoserine lactone with EtMgBr and i-PrMgBr.
NHBoc
CO2H
metal (Mg) (2.3 equiv, with glass pieces to activate the magnesium
metal) at room temperature under nitrogen. The reaction mixture
was stirred vigorously until Grignard generation occurred. The lac-
tone (1 equiv dissolved in 40 mL of THF) was added dropwise to
the Grignard reagent solution, and the mixture was stirred at room
temperature for 16 h and monitored by TLC. The mixture was trea-
ted with saturated aqueous NH4Cl (20 mL) and then extracted with
AcOEt (3 ꢁ 10 mL). The combined organic phases were dried over
Na2SO4 and the solvent was removed by an evaporator. The residue
was purified by silica-gel column chromatography (AcOEt/hexane).
In another experiment, the ring-opening reactions of homoserine
lactone with select Grignard reagents were carried out using
2.7 equiv ArMgBr at r.t. and 50 °C for 2 h.
NHBoc
Jones oxidation
Ar
Ar
OH
O
O
10
6
Scheme 5. Oxidation of amino-keto-alcohols.
Table 4
b-Amino-
c
-keto amino acid derivatives
Aryl group
Entry
Compound no
1
2
3
4
5
6
7
8
9
10
C6H5–
10
2-(OMe)C6H4–
4-(OMe)C6H4–
4-(OMe)-3-(F)C6H3–
2-(Me)C6H4–
4-(Me)C6H4–
2,4-(Dimethyl)C6H3–
4-(F)C6H4–
3,4-(Difluoro)C6H3–
2,4,5-(Trifluoro)C6H2–
10a
10b
10c
10d
10f
10g
10h
10i
10j
General procedure B: Conversion of alcohols to silylethers
In some reactions, the crude mixture was converted into
silylether to avoid the difficulties associated with separating
amino-keto-alcohol 6 from other compounds or impurities.tert-
Butylchlorodimethylsilane (1.1 equiv) was added to a solution of
alcohol 6 or 8 (1 equiv) and 1H-imidazole (2.2 equiv) in CH2Cl2
(30 ml). The mixture was stirred at room temperature for 24 h,
quenched with saturated aqueous NH4Cl (30 ml), and then
extracted with CH2Cl2 (3 ꢁ 50 ml). The combined organic layers
were dried over Na2SO4, and the crude product was purified by sil-
ica-gel column chromatography (AcOEt/hexane).
3. Conclusion
In conclusion we have developed a simple methodology to gain
access to amino-keto-alcohols from the readily available serine lac-
tone 1a and Grignard reagents. The keto-alcohols were advanta-
General procedure C: Oxidation reaction of keto-alcohols
Three milliliters of 2.67 M H2CrO4 was added to the keto-
alcohol (1 equiv) at room temperature, and the mixture was stirred
for 1.5 h. Monitoring by TLC was performed, and the reaction was
quenched with 2-propanol. The mixture was stirred until a dark
green color was achieved. The solvent was removed by an evapora-
tor, and the residue was dissolved with DCM/AcOEt (1:1). The
organic phase was dried over Na2SO4 and then filtered, and the sol-
vent was removed by evaporation. The residue was purified by sil-
ica gel column chromatography (AcOEt/hexane).
geously extended to the synthesis of b-amino-c-keto amino acid
derivatives. We believe that this procedure is not only simple
and economical, but also applicable for the large scale syntheses
of amino-keto-alcohols. The enantiomeric purity was not lost dur-
ing the ring-opening process, because we used a homochiral start-
ing material (a pure enantiomer) and we did not perform any
reactions on the stereogenic center. Therefore, we do not expect
a change in the enantiomeric purity. We performed the HPLC anal-
ysis of some of these compounds 6j0, 6k and 8a0, which confirmed
that there was no racemisation on the stereocenters. Further elab-
4.1. tert-Butyl (S)-(4-hydroxy-1-(2-methoxyphenyl)-1-oxobutan-
2-yl)carbamate 6a
oration of the keto group provided the c-functionalized-b-amino
acids. We believe that this simple and straightforward method will
find wide application in the synthesis of pharmacologically impor-
tant b-amino acid derivatives (Table 4).
Brown viscous liquid. Rf = 0.4 (50% AcOEt/hexane) [
a
]
25 = ꢀ4 (c
D
1, CH2Cl2). 1H NMR (400 MHz, CDCl3) d = 7.80 (dd, J = 7.7, 1.4 Hz,
1H), 7.50 (m, 1H), 7.03–6.96 (m, 2H), 5.85 (d, J = 7.7 Hz, 1H), 5.56
(m, 1H), 3.94 (s, 3H), 3.66 (m, 2H), 2.09 (m, 1H), 1.45 (s, 9H),
1.43 (m, 1H). 13C NMR (100 MHz, CDCl3): d = 199.6, 159.2, 157.4,
135.0, 131.6, 124.6, 121.1, 112.0, 80.4, 58.7, 56.7, 55.8, 36.6, 28.5.
IR (neat, cmꢀ1): 3411, 2976, 1697, 1600, 1493, 1248, 1165, 1024.
Elemental analysis: calc. for C16H23NO5C: 62.12; H: 7.49; N: 4.53;
found C: 62.08; H: 7.12; N: 4.59.
4. Experimental
General. All of the reagents used in the experiments are com-
mercially available unless otherwise specified, and all solvents
were distilled before use. IR spectra: PerkinElmer Spectrum One
FT-IR spectrometer. 1H and 13C NMR spectra: Varian 400 and
100 MHz and Bruker 400 and 100 MHz spectrometers. HR-MS:
electron spray technique (M+/M-) from solutions in MeOH (Waters
LCT PremierTM XE UPLC/MS TOF (Manchester, UK)).
General procedure A: Opening of the homoserine lactone 1a with
Grignard reagents
In an oven-dried flask, dried halogen-group-containing com-
pounds (2.3 equiv) were added to dry THF containing magnesium
4.2. tert-Butyl (S)-(4-((tert-butyldimethylsilyl)oxy)-1-(3-fluoro-
4-methoxyphenyl)-1-oxobutan-2-yl)carbamate 6c0
White solid, Rf = 0.45 (30% AcOEt/hexane) [a]
27 = +36 (c 1, CH2-
D
Cl2). 1H NMR (400 MHz, CDCl3): d = 7.82 (d, J = 8.8 Hz, 1H), 7.76 (dd,
J = 11.8 1.9 Hz, 1H), 6.98 (t, J = 8.4 Hz, 1H), 5.55 (d, J = 7.7 Hz, 1H),
5.30 (m, 1H), 3.94 (s, 3H), 3.75–3.65 (m, 2H), 2.08 (m, 1H), 1.71
Please cite this article in press as: Gündog˘du, Ö;. et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.009

4
Ö. Gündog˘du et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
(m, 1H), 1.42 (s, 9H), 0.89 (s, 9H), 0.03 (s, 6H). 13C NMR (100 MHz,
(m, 1H), 5.60 (d, J = 7.5 Hz, 1H), 5.34–5.29 (m, 1H), 3.75–3.65 (m,
2H), 2.13–2.02 (m, 1H), 1.76–1.66 (m, 1H), 1.40 (s, 9H), 0.87 (s,
9H), 0.02 (s, 6H). 13C NMR (100 MHz, CDCl3): d = 197.2, 155.8,
1
CDCl3): d = 197.2, 155.7, 152.3 (d, JCF = 247,8 Hz, C-3) 152.4 (C-4),
2
152. 3 (C-1), 126.3 (C-6), 116.5 (d, JCF = 8 Hz, C-2), 112.6 (C-5),
79.8, 59.6, 56.5, 52.9, 36.2, 28.5, 26.1, ꢀ5.3. IR (neat, cmꢀ1):
154.0 (dd, JCF = 256 Hz, JCF = 13 Hz, C-4) 150.6 (dd, JCF = 250 Hz,
1
2
1
3416, 2930, 2857, 1712, 1687, 1518. Elemental analysis: calc. for
2JCF = 13 Hz, C-3), 132.2 (C-1), 126.0 (m, C-6), 118.3 (d, 2JCF = 18 Hz,
2
C22H36FNO5Si C: 59.84; H: 8.22; N: 3.17; found C: 60.23; H: 8.29;
C-2), 117.8 (d, JCF = 18 Hz, C-5), 80.0, 59.6, 53.3, 35.7, 28.5, 26.0,
N: 2.99.
18.4, ꢀ5.45 IR (neat, cmꢀ1): 3355, 2956, 2931, 2858, 1700, 1612,
1518, 1283, 1170. HRMS (ESI) m/z calc. for
C15H19F2NO4:
4.3. tert-Butyl (S)-(4-hydroxy-1-oxo-1-(o-tolyl)butane-2-yl)car-
314.1209, found: 314.1201.
bamate 6d
4.8. tert-Butyl (S)-(4-((tert-butyldimethylsilyl)oxy)-1-oxo-1-
Yellow liquid, Rf = 0.4 (40% AcOEt/hexane) [
a]
25 = +18 (c 1,
(2,4,5-trifluorophenyl)butan-2-yl)carbamate 6j0
D
CH2Cl2). 1H NMR (400 MHz, CDCl3): d = 7.70 (d, J = 8.0 Hz, 1H),
7.44–7.40 (m, 1H), 7.30–7.25 (m, 2H), 5.82 (d, J = 7.0 Hz, 1H),
5.36–5.29 (m, 1H), 3.80 (brs, 1H) 3.70–3.64 (m, 2H), 2.47 (s, 3H),
2.06–1.98 (m, 1H), 1.48 (s, 9H), 1.47–1.43 (m, 1H). 13C NMR
(100 MHz, CDCl3): d = 201.9, 157.3, 139.5, 134.7, 132.4, 129.1,
126.3 (ꢁ2), 80.7, 58.4, 54.3, 36.8, 28.4, 21.4. IR (neat, cmꢀ1):
3435, 2925, 1684, 1637, 1455. HRMS (ESI) m/z calc. for
Yellow viscous, Rf = 0.4 (30% AcOEt/hexane). [
a
]
25 = ꢀ9 (c 1,
D
CH2Cl2) 1H NMR (400 MHz, CDCl3): d = 7.78–7.72 (m, 1H), 7.03–
6.96 (m, 1H), 5.76 (d, J = 8 Hz, 1H), 5.10–5.04 (m, 1H), 3.74–3.64
(m, 2H), 2.16–2.06 (m, 1H), 1.83–1.75 (m, 1H), 1.40 (s, 9H), 0.85
(s, 9H), 0.01 (s, 6H). 13C NMR (100 MHz, CDCl3): d = 195.3, 157.2
1
2
1
(dd, JCF = 262 Hz, JCF = 10 Hz, C-2), 155.7, 153.5 (dt, JCF = 259 Hz,
1
2
3
C16H23NO4: 293.1623, found: 293.1627.
2JCF = 14 Hz, C-4), 147.4 (ddd, JCF = 247 Hz, JCF = 13 Hz, JCF
=
3 Hz C-5), 120.60 (d, JCF = 16 Hz, C-1), 119.4 (d, JCF = 20 Hz, C-6),
106.9 (dd, JCF = 30.2 Hz, C-3), 79.9, 60.0, 57.9, 33.8, 28.5, 26.0,
2
2
2
4.4. tert-Butyl (S)-(4-((tert-butyldimethylsilyl)oxy)-1-oxo-1-(m-
tolyl)butan-2-yl)carbamate 6e0
ꢀ5.5.
Yellow liquid, Rf = 0.7 (30% AcOEt/hexane) [a D
]
25 = +20 (c 1, CH2Cl2).
4.9. tert-Butyl (S)-(1-(4-(dimethylamino)phenyl)-4-hydroxy-1-
1H NMR (400 MHz, CDCl3): d = 7.80–7.79 (m, 2H), 7.38–7.29 (m,
2H), 5.65 (d, J = 7.4 Hz, 1H), 5.41–5.38 (m, 1H), 3.75–3.63 (m,
2H), 3.38 (s, 3H), 2.16–2.07 (m, 1H), 1.76–167 (m, 1H), 1.43 (s,
9H). 0.89 (s, 6H), ꢀ0.03 (s, 6H). 13C NMR (100 MHz, CDCl3):
d = 199.7, 155.8, 138.7, 134.4, 129.4, 128.8, 126.5, 122.9, 79.7,
59.7, 53.4, 36.0, 28.5, 28.4, 26.1, 21.5, ꢀ5.3. IR (neat, cmꢀ1):
3414, 2955, 2929, 1717, 1686, 1499. HRMS (ESI) m/z calc. for
oxobutan-2-yl) carbamate 6k
Yellow solid, mp: 185–187 °C, Rf = 0.2 (40% AcOEt/hexane)
[a]
25 = +75 (c 1, CH2Cl2). 1H NMR (400 MHz, CDCl3): 7.91 (d,
D
J = 8.8 Hz, 2H), 6.65 (d, J = 8.8 Hz, 2H), 5.92 (d, J = 7.7 Hz, 1H),
5.36 (m, 1H), 4.10 (m, 1H), 3.72–3.69 (m, 2H), 3.07 (s, 6H), 2.11
(m, 1H), 1.46 (s, 1H), 1.40 (m, 1H). 13C NMR (100 MHz, CDCl3):
d = 196.1, 157.5, 154.1, 131.4, 121.2, 111.0, 80.4, 58.6, 51.4, 40.2,
38.6, 28.5. IR (neat, cmꢀ1): 3412, 2976, 1706, 1656, 1597, 1531,
1368, 1167. HRMS (ESI) m/z calc. for C17H26N2O4: 323.1892, found:
323.1967.
C22H37NO4Si: 408.2491, found: 408.2157.
4.5. tert-Butyl (S)-(1-(2,4-dimethylphenyl)-4-hydroxy-1-
oxobutan-2-yl)carbamate 6g
Yellow viscous liquid, Rf = 0.3 (30% AcOEt/hexane) [
a
]
20 = ꢀ3.6
4.10. tert-Butyl (S)-(1-((tert-butyldimethylsilyl)oxy)-4-oxohexa-
D
(c 1, CH2Cl2) 1H NMR (400 MHz, CDCl3): d = 7.68 (d, J = 8.0 Hz,
1H), 7.15–7.09 (m, 2H), 5.85 (d, J = 7.0 Hz, 1H), 5.44–5.40 (m,
1H), 3.95 (brs, 1H), 3.72–3.69 (m, 2H), 2.49 (s, 3H), 2.38 (s, 3H),
2.26–2.24 (m, 1H), 1.46 (s, 9H), 146–1.43 (m, 1H). 13C NMR
(100 MHz, CDCl3): d = 201.2, 157.2, 143.2, 140.1, 133.3, 131.6,
129.7, 126.9, 80.5, 58.4, 54.0, 37.0, 28.5, 28.3, 20.9. IR (neat,
cmꢀ1): 3416, 2975, 2929, 1679, 1612, 1492. HRMS (ESI) m/z calc.
for C17H25NO4: 306.1783, found: 306.1705.
n-3-yl)carbamate 8a0
20
Colorless viscous liquid. Rf = 0.63 (20% AcOEt/hexane) [
a
]
=
D
+17.3 (c 1, CH2Cl2) 1H NMR (400 MHz, CDCl3): d = 5.71 (d,
J = 6.4 Hz, 1H), 4.24–4.20 (m, 1H), 3.59 (t, J = 5.6 Hz, 2H), 2.57–
2.38 (m, 1H), 1.98–1.77 (m, 2H), 1.34 (s, 9H), 0.97 (t, J = 7.2 Hz,
3H), 0.80 (s, 9H), ꢀ0.05 (s, 6H). 13C NMR (100 MHz, CDCl3):
d = 210.3, 155.7, 79.5, 59.9, 58.1, 33.6, 32.6, 28.5, 26.0, 18.3, 7.7,
ꢀ5.5 (ꢁ2). Elemental analysis: calc. for C17H35NO4Si C: 59.09; H:
10.21; N: 4.05; found C: 59.10; H: 9.81; N: 3.99.
4.6. tert-Butyl (S)-(4-((tert-butyldimethylsilyl)oxy)-1-(4-fluor-
ophenyl)-1-oxobutan-2-yl) carbamate 6h0
4.11. tert-Butyl (S)-(1-((tert-butyldimethylsilyl)oxy)-5-methyl-
Colorless viscous liquid, Rf = 0.7 (40% AcOEt/hexane) [
a
]
26 = +22
4-oxohexan-3-yl)carbamate 8b0
D
(c 1, CH2Cl2). 1H NMR (400 MHz, CDCl3): d = 8.07–8.03 (m, 2H),
7.13–7.09 (m, 2H), 5.59 (d, J = 7.3 Hz, 1H), 5.38–5.33 (m, 1H),
3.73–3.64 (m, 2H), 2.14–2.05 (m, 1H), 1.76–1.68 (m, 1H), 1.41 (s,
9H), 0.88 (s, 9H), 0.02 (s, 6H). 13C NMR (100 MHz, CDCl3):
d = 198.0, 166.1 (d, 1JCF = 254 Hz, C-4), 155.8, 131.7 (d, 3JCF = 9.2 Hz,
20
Colorless viscous liquid. Rf = 0.66 (20% AcOEt/hexane). [
a
]
=
D
+22.3 (c 1, CH2Cl2) 1H NMR (400 MHz, CDCl3): d = 5.59 (d,
J = 6.8 Hz, 1H), 4.50–4.45 (m, 1H), 3.64 (t, J = 5.8 Hz, 2H), 2.86 (sep,
J = 6.8 Hz, 1H), 2.06–1.72 (m, 2H), 1.39 (s, 9H), 1.10 (d, J = 6.8 Hz,
1H), 1.05 (d, J = 6.8 Hz, 1H), 0.86 (s, 9H), 0.01 (s, 6H). 13C NMR
(100 MHz, CDCl3): 213.6, 155.7, 79.6, 60.2, 60.0, 56.3, 37.4, 33.9,
26.1, 19.3, 18.0, ꢀ5.5(ꢁ2). Elemental analysis: calc. for C18H37NO4Si
C: 60.12; H: 10.37; N: 3.90; found C: 59.84; H: 9.98; N: 3.58.
2
C-2/6), 116.0 (d, JCF = 22 Hz, C-3/5), 79.8, 59.6, 53.2, 35.9, 28.2,
25.9, 18.4, ꢀ5.4. IR (neat, cmꢀ1): 3355, 2956, 2930, 1693, 1600,
1509, 1367, 1233, 1156. HRMS (ESI) m/z calc. for C21H34FNO4Si:
412.2314, found: 412.2315.
4.7.
tert-Butyl
(S)-(4-((tert-butyldimethylsilyl)oxy)-1-(3,4-
4.12. (S)-3-((tert-Butoxycarbonyl)amino)-4-oxo-4-phenyl buta-
noic acid 10
difluorophenyl)-1-oxobutan-2-yl)carbamate 6i0
Yellow liquid, Rf = 0.7 (30% AcOEt/hexane) [
a]
27 = +9 (c 1, CH2-
(S)-3-((tert-Butoxycarbonyl)amino)-4-oxo-4-phenyl butanoic
acid 10 was obtained in a 70% yield. White solid. mp: 152–154 °C
D
Cl2). 1H NMR (400 MHz, CDCl3): d = 7.89–7.81 (m, 2H), 7.26–7.18
Please cite this article in press as: Gündog˘du, Ö;. et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.009

Ö. Gündog˘du et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
5
Rf = 0.3 (60% AcOEt/hexane) [
a
]
25 = ꢀ24 (c 1, CH2Cl2). 1H NMR
2.72 (d, J = 15.1 Hz, 1H), 2.51 (d, J = 16.1 Hz, 1H), 2.40 (s, 3H),
1.35 (s, 9H). 13C NMR (100 MHz, CD3OD): d = 203.7, 178.1, 156.6,
138.1, 136.8, 131.3, 130.9, 127.9, 125.3, 79.4, 55.7, 38.0, 27.5,
19.4. IR (neat, cmꢀ1): 3416, 2975, 2929, 1679, 1612, 1492. HRMS
(ESI) m/z calc. for C16H21NO5 306.1419; found 306.1383.
D
(400 MHz, CDCl3): d = 9.53 (brs, 1H), 7.95 (d, J = 7.3 Hz, 2H), 7.55
(t, J = 7.3 Hz, 1H), 7.55–7.45 (m, 2H), 5.72 (d, J = 8.4 Hz, 1H), 5.50
(brs, 1H), 2.94 (dd, AB system, J = 16.4, 4.8 Hz, 1H), 2.87–2.74 (dd,
AB system, J = 12.5, 4.4 Hz, 1H), 1.41 (s, 9H). 13C NMR (100 MHz,
CDCl3): d = 197.6, 176.2, 155.5, 134.7, 133.8, 128.7, 128.9, 80.8,
52.2, 37.0, 28.4. IR (neat, cmꢀ1): 3343, 2979, 1691, 1508, 1368,
1250, 1164. Elemental analysis: calc. for C18H37NO4Si C: 61.42;
H: 6.53; N: 4.78; found C: 61.22; H: 6.59; N: 4.63.
4.17. (S)-3-((tert-Butoxycarbonyl)amino)-4-oxo-4-(p-tolyl)buta-
noic acid 10f
(S)-3-((tert-Butoxycarbonyl)amino)-4-oxo-4-(p-tolyl)butanoic
acid 10f was obtained in a 65% yield. White solid, mp: 60–62 °C.
4.13. (S)-3-((tert-Butoxycarbonyl)amino)-4-(2-methoxyphenyl)-
4-oxo-butanoic acid 10a
Rf = 0.4 (50% AcOEt/hexane) [
a]
27 = ꢀ15 (c 1, EtOH). 1H NMR
D
(400 MHz, CDCl3): d = 7.86 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz,
2H), 5.68 (d, J = 7.6 Hz 1H), 5.51–5.47 (m, 1H), 2.93 (dd, AB system,
J = 16.4, 5.1 Hz 1H), 2.77 (dd, AB system, J = 16.1, 5.1 Hz, 1H), 2.41
(s, 3H), 1.43 (s, 9H). 13C NMR (100 MHz, CDCl3): d = 196.9, 175.6,
155.5, 145.0, 131.9, 129.7, 129.1, 80.7, 52.0, 37.4, 28.5, 21.9. IR
(KBr) (cmꢀ1): 3345, 2926, 2855, 1713, 1702, 1607, 1504. HRMS
(ESI) m/z calc. for C16H21NO5 306.1419; found 306.1383.
(S)-3-((tert-Butoxycarbonyl)amino)-4-(2-methoxyphenyl)-4-
oxobutanoic acid (10a) was obtained in a 60% yield. Yellow viscous.
Rf = 0.4 (60% AcOEt/hexane), [
a
]
D
25 = ꢀ6 (c 1, CH2Cl2). 1H NMR
(400 MHz, CDCl3): d = 7.71 (d, J = 7.7 Hz, 1H), 7.52–7.47 (m, 1H),
7.02 (t, J = 7.4 Hz, 1H), 6.95 (d, J = 8.0 Hz, 1H), 5.85 (d, J = 7.2 Hz,
1H), 5.44–5.37 (m, 1H), 3.91 (s, 3H), 2.98 (dd, AB system, J = 16.8,
4.4 Hz, 1H), 2.77 (dd, J = 16.8, 5.1 Hz, 1H), 1.43 (s, 9H). 13C NMR
(100 MHz, CDCl3): d = 198.3, 175.3, 158.2, 156.2, 134.7, 131.8,
121.3, 111.5, 80.6, 56.8, 55.8, 37.9, 28.5. IR (neat, cmꢀ1): 3416,
2978, 2929, 1713, 1599, 1487, 1248, 1163. HRMS (ESI) m/z calc.
for C16H21NO6: 322.1296, found: 322.1294.
4.18. (S)-3-((tert-Butoxycarbonyl)amino)-4-(2,4-dimethylphen-
yl)-4-oxobutanoic acid 10g
(S)-3-((tert-Butoxycarbonyl)amino)-4-(2,4-dimethylphenyl)-4-
oxobutanoic acid 10g was obtained in a 60% yield. Pale yellow vis-
4.14. (S)-3-((tert-Butoxycarbonyl)amino)-4-(4-methoxyphenyl)-
4-oxobutanoic acid 10b
cous. Rf = 0.4 (50% AcOEt/hexane) [
a]
27 = ꢀ4 (c 1, CH2Cl2). 1H NMR
D
(400 MHz, CDCl3): d = 10.82 (brs, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.05–
7.01 (m, 2H), 5.74 (d, J = 8.4 Hz, 1H), 5.29–5.25 (m, 1H), 2.94–2.82
(m, 2H), 2.39 (s, 3H), 2.32 (s, 3H), 1.40 (s, 9H). 13C NMR (100 MHz,
CDCl3): d = 200.4, 176.4, 155.7, 142.5, 139.6, 133.1, 132.3, 128.7,
126.4, 80.5, 53.9, 37.0, 28.5, 21.6, 20.8. IR (neat, cmꢀ1): 3340,
2979, 2930, 1711, 1612, 1498, 1251, 1165. HRMS (ESI) m/z calc.
for C17H23NO5 320.1503; found 320.1500.
(S)-3-((tert-Butoxycarbonyl)amino)-4-(4-methoxyphenyl)-4-
oxobutanoic acid 10b was obtained in a 70% yield. Brown viscous,
Rf = 0.4 (50% AcOEt/hexane)
[a]
26 = +1 (c 1, EtOH). 1H NMR
D
(400 MHz, CD3OD): d = 7.99 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz,
2H), 5.48–5.44 (m, 1H), 4.89–4.87 (m, 1H), 3.85 (s, 3H), 2.83 (dd,
J = 16.1, 5.9 Hz, 1H), 2.5 (dd, J = 16.0, 7.0 Hz, 1H), 1.39 (s, 9H). 13C
NMR (100 MHz, CD3OD): d = 197.3, 177.0, 164.3, 156.5, 130.9,
127.8, 113.7, 79.7, 54.9, 52.4, 38.2, 27.5. IR (neat, cmꢀ1): 3401,
2977, 1676, 1601, 1569, 1421, 1256, 1169. HRMS (ESI) m/z calc.
for C16H21NO6: 322.1296, found: 322.1294.
4.19. (S)-3-((tert-Butoxycarbonyl)amino)-4-(4-fluorophenyl)-4-
oxobutanoic acid 10h
(S)-3-((tert-Butoxycarbonyl)amino)-4-(4-fluorophenyl)-4-
oxobutanoic acid 10h was obtained in a 80% yield. White solid.
4.15. (S)-3-((tert-Butoxycarbonyl)amino)-4-(3-fluoro-4-metho-
xyphenyl)-4-oxobutanoic acid 10c
Rf = 0.4 (50% AcOEt/hexane) [
a
]
25 = ꢀ11 (c 1, CH2Cl2). 1H NMR
D
(400 MHz, CDCl3): d = 9.54 (brs, 1H), 8.03–7.98 (m, 2H), 7.16–
7.11 (m, 2H), 5.64 (d, J = 9.0 Hz, 1H), 5.48–5.42 (m, 1H), 3.28 (t,
J = 6.6 Hz, 1H), 2.79 (t, J = 6.4 Hz, 1H), 1.42 (s, 9H). 13C NMR
(S)-3-((tert-Butoxycarbonyl)amino)-4-(3-fluoro-4-methoxy-
phenyl)-4-oxobutanoic acid 10c was obtained in a 60% yield. White
1
(100 MHz, CDCl3): d = 196.5, 178.2, 166.1 (d, JCF = 254 Hz, C-4),
3
2
solid. mp: 182–184 °C Rf = 0.4 (50% AcOEt/hexane) [
a
]
26 = ꢀ3 (c 1,
155.8, 131.7 (d, JCF = 9.2 Hz, C-2/6), 116.0 (d, JCF = 22 Hz, C-3/5),
80.9, 51.9, 36.8, 33.3, 28.5. IR (neat, cmꢀ1): 3353, 2979, 2924,
1690, 1612, 1599, 1509. HRMS (ESI) m/z, calc. for C15H18FNO5
311.1169; found 311.1112.
D
MeOH) 1H NMR (400 MHz, CD3OD): d = 10.11 (brs, 1H), 7.79 (d,
J = 8.4 Hz, 1H), 7.71 (d, J = 12.0 Hz, 1H), 7.06–6.927 (m, 1H), 5.72
(d, J = 9.0 Hz, 1H), 5.44–5.42 (m, 1H), 3.92 (s, 3H), 2.90 (dd, AB sys-
tem, J = 16.4, 5.1 Hz, 1H), 2.76 (dd, AB system, J = 16.5, 4.5 Hz, 1H),
1.40 (s, 9H). 13C NMR (100 MHz, CD3OD): d = 195.3, 175.9, 155.4,
4.20. (S)-3-((tert-Butoxycarbonyl)amino)-4-(3,4-difluorophen-
yl)-4-oxobutanoic acid 10i
1
152.2 (d, JCF = 247,8 Hz, C-3) 152.4 (C-4), 152. 3 (C-1), 126.3 (C-
2
6), 116.6 (d, JCF = 19 Hz, C-2), 112.6 (C-5), 80.8, 56.5, 51.6, 36.9,
28.4. IR (neat, cmꢀ1): 3355, 2979, 1679, 1573, 1520, 1436, 1280,
1166. HRMS (ESI) m/z calc. for C16H20FNO6 340.1202; found
340.1204.
(S)-3-((tert-Butoxycarbonyl)amino)-4-(3,4-difluorophenyl)-4-
oxobutanoic acid 10i was obtained in a 70% yield. White solid. mp:
212–214 °C. Rf = 0.4 (50% AcOEt/hexane) [
a
]
25 = ꢀ4 (c 1, CH2Cl2).
D
1H NMR (400 MHz, CD3OD): d = 7.91–7.81 (m, 2H), 7.40–7.33 (m,
1H), 5.41–5.36 (m, 1H), 4.87–4.85 (m, 1H), 2.87–2.78 (m, 1H),
2.55–2.49 (m, 1H), 1.37 (s, 9H). 13C NMR (100 MHz, CD3OD):
4.16. (S)-3-((tert-Butoxycarbonyl)amino)-4-oxo-4-(o-tolyl) but-
anoic acid 10d
1
2
d = 196.4, 177.8, 156.4, 154.0 (dd, JCF = 256 Hz, JCF = 13 Hz, C-4)
1
2
(S)-3-((tert-Butoxycarbonyl)amino)-4-oxo-4-(o-tolyl) butanoic
acid 10d was obtained in a 60% yield. Pale yellow viscous.
150.6 (dd, JCF = 250 Hz, JCF = 13 Hz, C-3), 132.2 (C-1), 126.0 (m,
2
2
C-6), 118.3 (d, JCF = 18 Hz, C-2), 117.8 (d, JCF = 18 Hz, C-5),79.8,
52.9, 38.1, 27.4. IR (neat, cmꢀ1): 3416, 2975, 2929, 1679, 1612,
1492. HRMS (ESI) m/z calc. for C15H17F2NO5 328.1002; found
328.0994.
Rf = 0.4 (50% AcOEt/hexane)
[a]
27 = +7 (c 1, EtOH). 1H NMR
D
(400 MHz, CD3OD): d = 7.70 (d, J = 7.3 Hz, 1H), 7.38–7.34 (m,1H),
7.25 (d, J = 7.3 Hz, 2H), 5.19–5.15 (m, 1H), 4.88–4.85 (m, 1H),
Please cite this article in press as: Gündog˘du, Ö;. et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.009

6
Ö. Gündog˘du et al. / Tetrahedron: Asymmetry xxx (2017) xxx–xxx
4.21. (S)-3-(((Benzyloxy)carbonyl)amino)-4-oxo-4-(2,4,5-trifluo-
Supplementary data
rophenyl)butanoic acid 10j
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetasy.2017.08.
009.
(S)-3-(((Benzyloxy)carbonyl)amino)-4-oxo-4-(2,4,5-trifluo-
rophenyl)butanoic acid 10j was obtained in a 80% yield. White
solid. mp: 55–57 °C. Rf = 0.4 (50% AcOEt/hexane) [a]
25 = +5 (c 1,
D
CH2Cl2). 1H NMR (400 MHz, CDCl3): d = 9.57 (brs, 1H), 7.66–7.60
(m, 1H), 7.38–7.27 (m, 5H), 7.01–6.95 (m, 1H), 5.92 (d, J = 7.7 Hz,
1H), 5.16–5.13 (m, 1H), 5.10 (s, 6H), 3.13 (dd, J = 17.2, 4.7 Hz,
1H), 2.91 (dd, J = 17.0, 5.3 Hz, 1H). 13C NMR (100 MHz, CDCl3):
References
1. (a) Juaristi, E.; Soloshonok, V. A. Enantioselective synthesis of b-amino acids; John
Wiley & Sons Inc: New Jersey, 2005; (b) Cole, D. C. Tetrahedron: Asymmetry 2012,
23, 1111.
2. Boyle, P. H.; Davis, A. P.; Dempsey, K. J.; Hosken, G. Tetrahedron: Asymmetry
1995, 6, 2819.
3. Seki, M.; Matsumoto, K. Tetrahedron Lett. 1996, 37, 3165.
4. Seki, M.; Shimizu, T.; Matsumoto, K. J. Org. Chem. 2000, 65, 1298.
5. (a) Boutin, R. H.; Rapoport, H. J. Org. Chem. 1986, 51, 5320; (b) Fujita, M.; Hiyama,
T. J. Org. Chem. 1988, 53, 5415; (c) Basha, A.; Lipton, M. F.; Weinreb, S. M.
Tetrahedron Lett. 1977, 4171.
6. (a) Dequest, G.; Bischoff, L.; Fruit, C. Tetrahedron: Asymmetry 2006, 11, 2120; (b)
Brinknmann, T.; Gilg, A.; Hamm, A.; Lüsch, H.; Morbach, G.; Uzar, H. Tetrahedron:
Asymmetry 2000, 11, 3827.
1
2
d = 193.4, 175.5, 157.2 (dd, JCF = 262 Hz, JCF = 10 Hz, C-2), 155.9,
153.5 (dt, 1JCF = 259 Hz, 2JCF = 14 Hz, C-4), 147.4 (ddd, 1JCF = 247 Hz,
2JCF = 13 Hz, JCF = 3 Hz, C-5), 136.1, 128.8,128,5,128,3, 120.4 (d,
3
2JCF = 16 Hz, C-1), 119.4 (d, JCF = 19 Hz, C-6), 106.7 (dd, JCF
=
2
2
30,2 Hz, C-3), 67.6, 56.6, 35.8. IR (KBr) (cmꢀ1): 3371, 3067, 2983,
1719, 1625, 1513. Elemental analysis: calc. for C18H14F3NO5C:
56.70; H: 3.70; N: 3.67; found C: 56.40; H: 3.66; N: 3.42.
7. (a) Wakefield, B. J. Organomagnesium Methods in Organic Synthesis; Academic
Press: London, 1995; (b) Garst, J. L.; Swith, B. L. J. Am. Chem. Soc. 1989, 111, 241; (c)
Walborsky, H. M. Acc. Chem Res. 1990, 23, 286; (d) Silverman, G. S.; Rakita, P. E.
Handbook of Grignard-Reagents; Marcel Dekker: New York, 1996; (e) Boymond, L.;
Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem. 1998, 110, 1801. Angew.
Chem. Int. Ed. Engl. 1998, 37, 1701; (f) Gundogdu, O.; Altundas, R.; Kara, Y. Appl.
Organometal. Chem. 2017, e3719. http://dx.doi.org/10.1002/aoc.3719.
Acknowledgments
The authors would like to thank TUBITAK for financial support
(Grant No: 114Z170). The authors also thank Dr. Hasan Seçen for
his critical reading of this article.
Please cite this article in press as: Gündog˘du, Ö;. et al. Tetrahedron: Asymmetry (2017), http://dx.doi.org/10.1016/j.tetasy.2017.08.009