Chemical deracemization and (S) to (R) interconversion of some fluorine-containing α-amino acids

Article abstract of DOI:10.1016/j.jfluchem.2013.02.022

Several ω-CF₃-substituted a-amino acids have been prepared in optically pure form via two complementary approaches. Racemic fluorinated derivatives of 2-aminobutanoic acid, norvaline and norleucine were chemically deracemized by complexation with a Ni(II) salt and a chiral reagent derived from α-(phenyl)ethylamine. Additionally this procedure also allowed the conversion of readily available L-amino acids, CF₃-analogs of cysteine and methionine, into the corresponding unnatural D-series. Optically pure amino acids are obtained upon disassembly of the Ni(II) complexes with recovery of the chiral ligand.

Full text of DOI:10.1016/j.jfluchem.2013.02.022

Journal of Fluorine Chemistry 152 (2013) 114–118
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Chemical deracemization and (S) to (R) interconversion of some
fluorine-containing
a-amino acids
d
a
e
Alexander E. Sorochinsky a,b,c, Hisanori Ueki , Jose Luis Acena , Trevor K. Ellis ,
˜
*
´
Hiroki Moriwaki f, Tatsunori Sato f, Vadim A. Soloshonok a,b,
a Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, 20018 San Sebastian, Spain
b IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
c Institute of Bioorganic Chemistry & Petrochemistry, National Academy of Sciences of Ukraine, Murmanska 1, Kyiv 02660, Ukraine
d International Center for Materials Nanoarchitectonics (MANA), National Institute for Materials Science (NIMS), 1-1, Namiki, Tsukuba, Ibaraki 305-0044, Japan
e Department of Chemistry and Physics, 100 Campus Drive, Weatherford, OK 73096-3098, USA
f Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024, Japan
A R T I C L E I N F O
A B S T R A C T
Several -CF3-substituted
Article history:
v
a-amino acids have been prepared in optically pure form via two
complementary approaches. Racemic fluorinated derivatives of 2-aminobutanoic acid, norvaline and
norleucine were chemically deracemized by complexation with a Ni(II) salt and a chiral reagent derived
Received 21 January 2013
Received in revised form 21 February 2013
Accepted 24 February 2013
Available online 5 March 2013
from
a
-(phenyl)ethylamine. Additionally this procedure also allowed the conversion of readily available
-series.
L
-amino acids, CF3-analogs of cysteine and methionine, into the corresponding unnatural
D
Optically pure amino acids are obtained upon disassembly of the Ni(II) complexes with recovery of the
Keywords:
chiral ligand.
Chiral recognition
Deracemization
ß 2013 Elsevier B.V. All rights reserved.
D
-(R)-amino acids
Resolution
Diastereoselectivity
Asymmetric induction
1. Introduction
fluoro-amino acids chemistry. One particular type of fluorine-
containing
a-amino acids, linear v-trifluoromethyl derivatives
Due to the paramount importance of amino acids in the
numerous fields of biology and medicine, the development of
synthetic methods for the preparation of their fluorinated analogs
has been one of the most actively pursued research areas [1,2].
Taking into account that the biological activity of amino acids is a
function of their stereochemistry, preparation of fluorinated amino
acids in enantiomerically pure form has received particular
attention. Thus, two major approaches – asymmetric synthesis
and enzymatic resolutions of racemic amino acids – have been
extensively explored and many practical methods have been
developed [1–5]. On the other hand, chemical resolution,
deracemization, of racemic fluorinated amino acids under the
action of chiral reagents [6] remains a virtually unexplored area of
1a–c and 2a,b (Fig. 1), is of considerable interest for peptide design
due to the strong steric [7] and electrostatic [8] requirements of the
trifluoromethyl group. Amino acids 1a–c and 2a,b have been
prepared in enantiomerically pure form via asymmetric synthesis
[9] and enzymatic resolutions [10]. In this work, we report
preparation of (S)- and (R)-1a–c via deracemization of the
corresponding racemic derivatives and synthesis of (S)-2a and
(R)-2b (D-amino acids) via (S) to (R) interconversion, using new
chiral reagents (S)- and (R)-3 (Fig. 2).
During our studies of the chemistry of achiral [11,12] and chiral
[13,14] Ni(II)-complexes of amino acid Schiff bases and their
applications for general [15] asymmetric synthesis of
a-amino
acids, we discovered a modular approach to the design [16] of a
new generation of Ni(II) complexes with the general structure 4
(Fig. 2) [17]. We demonstrated that the rational combination of
four structural modules (phenone, acid, amine and amino acid)
allows for the complete control of reactivity as well as
physicochemical properties of derivatives 4. In particular, the
* Corresponding author at: Department of Organic Chemistry I, Faculty of
Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardiza´bal 3,
20018 San Sebastia´n, Spain. Tel.: +34 943015177; fax: +34 943015270.
E-mail address: vadym.soloshonok@ehu.es (V.A. Soloshonok).
chiral reagent
3 [18] can be easily assembled using very
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.02.022

A.E. Sorochinsky et al. / Journal of Fluorine Chemistry 152 (2013) 114–118
115
NH2
S
NH2
F3C
F3C
COOH
COOH
n
n
1a-c
2a,b
n = 1 (a), 2 (b), 3 (c)
n = 1 (a), 2 (b)
Fig. 1. Linear
v-trifluoromethyl amino acids 1a–c and 2a,b used in this study.
Fig. 2. Modular Ni(II) complexes 4 and chiral reagent 3.
inexpensive 2-bromoisobutyric acid, 2-aminobenzophenone and
-(phenyl)ethylamine, as a source of chirality which is readily
a
available in both enantiomerically pure forms [19].
Similar results were obtained with application of reagent
derived from (R)- -(phenyl)ethylamine. In this case the
3
a
2. Results and discussion
major diastereomeric products 5a–c had (R,RN)(S) absolute
configuration (Table 1, entries 4–6). Complex (R,RN)(S)-5c was
purified by column chromatography and upon disassembling
First, we studied deracemization of amino acids 1a-c. These
amino acids are readily available in racemic form via alkylation of
gave rise to a-(S) configured amino acid 1c in good chemical
amino malonic acid esters with the corresponding
v
-CF3-alkyl
yield. Chiroptical and spectral properties of the free amino acid
(S)-1c matched the literature data reported for this compound
[9a].
Our second goal was to study the application of reagents (S)-
and (R)-3 for (S) to (R) interconversion of fluorinated amino acids.
As an example, we chose CF3-containing (R)-cysteine 2a and (S)-
methionine 2b. It should be noted that both amino acids 2a and
iodides [20]. As shown in Scheme 1, the reactions of reagent (S)-3
with amino acids (rac)-1a–c were conducted in ethanol in the
presence of excess Ni(OAc)2 and K2CO3 while heating. Monitoring
the reaction progress by TLC revealed that initially, under
kinetically controlled conditions, a mixture of diastereomeric
products is produced. However, after allowing the reaction
mixture to continue mixing under heat for approximately 24 h
effectively provided only the thermodynamically controlled
products 5. Absolute configuration of products 5a–c was deter-
mined to be (S,SN)(R) based on the chiroptical properties of the
complexes 5a–c and by analogy with the previous results of the
reactions of reagent (S)-3 with linear non-fluorinated amino acids
[18]. Compounds 5a–c were obtained in good chemical yields
(Table 1, entries 1–3). The yield of product 5a was slightly lower as
compared with that of 5b and 5c, which can be explained by the
more profound effect of the CF3-group on the basicity of amino
group in 1a [21]. Compounds (S,SN)(R)-5a–c were purified by
column chromatography to yield chemically and diastereomeri-
cally pure materials. Free amino acids (R)-1a–c were obtained via
standard disassembly of complexes 5a–c under acidic conditions
[22] along with quantitative recovery of the chiral reagent (S)-3.
2b are of the same relative configuration (L-series) and the
difference of their absolute configurations is the result of CIP
rules [23]. Amino acids 2a,b can be easily prepared form
naturally occurring derivatives and therefore are readily avail-
able in their
corresponding compounds of the
have never been reported in the literature. Considering the
L
-configuration [9e]. On the other hand, the
D
-series [(S)-2a and (R)-2b]
importance of
preparation of
D
-amino acids in biochemical sciences [24],
D
-enantiomers of trifluoromethyl cysteine 2a
and trifluoro-methionine 2b seems to be of great interest. To this
end, we conducted the reactions of enantiomerically pure amino
acids
mixture of
L
-2a,b with reagent (S)-3. As shown in Scheme 2, heating a
-2a,b with (S)-3 and Ni(OAc)2 gave rise to
L
thermodynamically controlled products 6a,b in good chemical
yield (Table 1, entries 7 and 8). Complexes 6a,b were purified by
Ph
H
1) 3N HCl
2) cation
exchange
N
O
N
O
(rac) 1a-c
2 eq.
Ni
(S)-3
CF3
n
resin
O
N
(S)-3
(R)-1a-c
+
Ni(OAc)2 3 eq.
K2CO3 15 eq.
Ph
EtOH, 60-70 ºC
(rac) 1a-c
(R)-3
+
(S)-1a-c
(R)-3
5 (S,SN)(R)
n = 1 (a), 2 (b), 3 (c)
Scheme 1. Deracemization of racemic amino acids 1a–c.
Table 1
Reactions of reagent 3 with amino acids 1a–c and 2a,b.
Entry
Amino acid
Ligand 3
5a–c/6a,b (config.)
5a–c yield (%)
6a,b yield (%)
Amino acid (yield, %)
1
2
3
4
5
6
7
8
rac-1a
rac-1b
rac-1c
rac-1a
rac-1b
rac-1c
(R)-2a
(S)-2b
(S)-3
(S)-3
(S)-3
(R)-3
(R)-3
(R)-3
(S)-3
(S)-3
5a (S,SN)(R)
5b (S,SN)(R)
5c (S,SN)(R)
5a (R,RN)(S)
5b (R,RN)(S)
5c (R,RN)(S)
6a (S,SN)(S)
6b (S,SN)(R)
75
N/A
N/A
N/A
N/A
N/A
N/A
87
(R)-1a (63)
(R)-1b (60)
(R)-1c (66)
N/A
79
79
74
78
N/A
80
(S)-1c (69)
(S)-2a (73)
(R)-2b (74)
N/A
N/A
90

116
A.E. Sorochinsky et al. / Journal of Fluorine Chemistry 152 (2013) 114–118
Ph
H
1) 3N HCl
2) cation
exchange
resin
N
N
O
N
O
(R)-2a; (S)-2b
Ni
(S)-3
S
n
O
CF3
(S)-3
(S)-2a
+
Ni(OAc)2 3 eq.
K2CO3 15 eq.
Ph
or (R)-2b
EtOH, 60-70 ºC
6a (S,SN)(S) 6b (S,SN)(R)
n = 1 (a), 2 (b)
Scheme 2. (S) to (R) inversion of amino acids 2a,b.
column chromatography and disassembled to afford free amino
acids (S)-2a and (R)-2b. It should be noted that S-CF3 containing
amino acids 2a,b possess relatively high volatility and therefore
present quite interesting models for investigations of self-
disproportionation of enantiomers (SDE) via achiral chromatog-
raphy [25] and sublimation [26], which are currently under study
in our laboratories.
4.1.2. Ni(II) complex of (R)-2-amino-5,5,5-trifluoropentanoic acid
Schiff base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-
ethylamino)-acetamide 5b
25
M.p. 251.0 8C (decomp.). [a D
]
À811.6 (c 1.00, CHCl3). 1H NMR
(CDCl3, 300 MHz)
d
1.55(3H, s), 1.63(3H,d, J = 6.7 Hz), 2.64(1H, bm),
2.60–3.00 (4H, m), 2.88 (3H, s), 3.79 (1H, m), 4.33 (1H, bt, J = 6.3 Hz),
6.61 (1H, m), 6.73 (1H, m), 6.84 (1H, bd, J = 7.9 Hz), 7.07–7.12 (2H,
m), 7.14–7.29 (4H, m), 7.41–7.60 (3H, m), 8.03 (1H, d, J = 8.8 Hz),
8.22 (2H, bd, J = 7.3 Hz). 13C NMR (CDCl3, 75.5 MHz)
d 21.3, 22.6,
3. Conclusions
29.8, 33.3, 34.0 (q, J = 27.1 Hz), 57.7, 65.0, 65.2, 120.3, 123.1, 126.6,
127.7, 128.1, 128.3, 128.8, 128.9, 129.3, 129.6, 131.2(q, J = 275.1 Hz),
131.6, 133.8, 133.9, 140.2, 143.3, 170.7, 181.3, 183.0. HRMS [M+Na+]
found m/z 618.1502, calcd for C30H30F3N3NaNiO3 618.1490.
In conclusion, the chemical approach for deracemization and (S)
to (R) inversion of a series of
v-CF3 and v-S-CF3 amino acids has
been successfully developed with the application of new chiral
reagent (S)- or (R)-3. Good chemical yields and simple reaction
conditions render this method as
a
synthetically valuable
4.1.3. Ni(II) complex of (R)-2-amino-6,6,6-trifluorohexanoic acid
Schiff base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-
alternative to asymmetric synthesis and/or enzymatic resolutions
for preparation of these fluorinated amino acids in enantiomeri-
cally pure form.
ethylamino)-acetamide 5c
25
M.p. 264.0 8C (decomp.). [a D
]
À921.0 (c 1.12, CHCl3). 1H NMR
(CDCl3, 300 MHz)
d
1.50 (3H, s), 1.55–1.61 (2H, m), 1.67 (3H, d,
4. Experimental
J = 6.6 Hz), 1.81–1.90 (2H, m), 2.71 (1H, bm), 2.55–2.63 (2H, m), 2.88
(3H, s), 3.79 (1H, m), 4.01 (1H, dd, J = 8.5, 3.7 Hz), 6.63 (1H, m), 6.75
(1H, m), 6.83 (1H, bd, J = 7.9 Hz), 7.06–7.14 (2H, m), 7.14–7.29 (4H,
m), 7.44–7.59 (3H,m), 8.02(1H, d,J = 8.7 Hz), 8.23(2H,bd, J = 7.3 Hz).
4.1. General procedure for preparation of Ni(II)-complexes 5a–c and
6a,b by the reaction of (S)- or (R)-N-(2-benzoylphenyl)-2,2-dimethyl-
2-(1-phenyl-ethylamino)acetamide 3 with corresponding amino acids
1a–c and 2a,b
13C NMR (CDCl3, 75.5 MHz)
d 18.0, 21.3, 29.8, 33.2 (q, J = 28.8 Hz),
33.9, 57.9, 65.4, 65.9, 120.6, 123.8, 126.5 (q, J = 277.0 Hz), 126.9,
127.8, 127.9, 128.5, 128.7, 128.8, 129.2, 129.9, 131.3, 134.0, 135.8,
141.1, 142.4, 169.9, 180.7, 183.5. HRMS [M+Na+] found m/z
632.1655, calcd for C31H32F3N3NaNiO3 632.1647.
To a flask containing ethanol solution of reagent 3 (1 equiv.),
Ni(OAc)2Á4H2O (4 equiv.), racemic amino acid (2.0 equiv.), was
added K2CO3 (15 equiv.), and the reaction mixture was stirred at
60–70 8C. The progress of the reaction was monitored by TLC and
upon completion (consumption of the reagent 3), the reaction
mixture was poured into ice water. The target product was
extracted several times with CH2Cl2. The combined organic layer
was dried over anhydrous MgSO4 and evaporated under vacuum.
After evaporation of the solvents and silica–gel column chroma-
tography, the target complexes 5a–c and 6a,b were obtained in
diastereomerically pure form.
4.1.4. Ni(II) complex of (S)-2-amino-4,4,4-trifluorobutanoic acid
Schiff base with (R)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-
ethylamino)-acetamide 5a
M.p. 264.0 8C (decomp.). [a]
25 +761.3 (c 1.10, CHCl3). The NMR
D
spectra are identical to that of (R),(S)-5a enantiomer.
4.1.5. Ni(II) complex of (S)-2-amino-5,5,5-trifluoropentanoic acid
Schiff base with (R)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-
ethylamino)-acetamide 5b
4.1.1. Ni(II) complex of (R)-2-amino-4,4,4-trifluorobutanoic acid
Schiff base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-
M.p. 259.5 8C (decomp.). [a]
25 +817.0 (c 1.15, CHCl3). The NMR
D
spectra are identical to that of (R),(S)-5b enantiomer.
ethylamino)-acetamide 5a
M.p. 275.5 8C (decomp.). [
(CDCl3, 300 MHz)
a
]
D
À767.6 (c 1.11, CHCl3). 1H NMR
4.1.6. Ni(II) complex of (S)-2-amino-6,6,6-trifluorohexanoic acid
Schiff base with (R)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-phenyl-
ethylamino)-acetamide 5c
25
d
1.58 (3H, s), 1.67 (3H, d, J = 6.7 Hz), 2.53 (1H,
bm), 2.85–3.01 (2H, m), 2.95 (3H, s), 3.89 (1H, m), 4.28 (1H, dd,
J = 7.4, 5.6 Hz), 6.57 (1H, m), 6.68 (1H, m), 6.83 (1H, bd, J = 7.9 Hz),
7.04–7.14 (2H, m), 7.17–7.27 (4H, m), 7.40–7.56 (3H, m), 8.03 (1H,
M.p. 258.0 8C (decomp.). [a]
25 +915.4 (c 1.13, CHCl3). The NMR
D
spectra are identical to that of (R),(S)-5c enantiomer.
d, J = 8.8 Hz), 8.21 (2H, bd, J = 7.3 Hz). 13C NMR (CDCl3, 75.5 MHz)
d
22.1, 22.5, 33.3, 40.1 (q, J = 30.7 Hz), 57.6, 64.9, 65.0, 120.2, 123.3,
126.8, 127.4, 127.7, 128.3, 128.6, 128.8, 129.2, 129.4, 129.8 (q,
J = 277.8 Hz), 131.8, 132.8, 133.8, 140.1, 142.2, 169.7, 180.5, 181.0.
HRMS [M+Na+] found m/z 604.1358, calcd for C29H28F3N3NaNiO3
604.1334.
4.1.7. Ni(II) complex of (S)-2-amino-3-(trifluoromethylthio)propanoic
acid Schiff base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-
phenyl-ethylamino)-acetamide 6a
À1005.8 (c 1.13, CHCl3). 1H
25
M.p. 221.0 8C (decomp.). [
a
]
D
NMR (CDCl3, 300 MHz)
d
1.58 (3H, s), 1.67 (3H, d, J = 6.7 Hz), 2.53

A.E. Sorochinsky et al. / Journal of Fluorine Chemistry 152 (2013) 114–118
117
(1H, bm), 2.95 (3H, s), 3.44–3.71 (2H, m), 3.89 (1H, m), 4.38 (1H, dd,
J = 7.2, 4.7 Hz), 6.55 (1H, m), 6.72 (1H, m), 6.78 (1H, bd, J = 7.9 Hz),
3F). 13C NMR (150.9 MHz, D2O)
172.0.
d
30.5, 54.7, 131.0 (q, J = 307 Hz),
7.05–7.15 (2H, m), 7.14–7.30 (4H, m), 7.37–7.57 (3H, m), 8.02 (1H,
d, J = 8.8 Hz), 8.23 (2H, bd, J = 7.2 Hz). 13C NMR (CDCl3, 75.5 MHz)
d
4.2.6. (R)-2-amino-4-(trifluoromethylthio)butanoic 2b
À23.9 (c 1.07, 4 N HCl). 1H NMR (D2O,
25
22.1, 22.5, 30.6, 54.7, 63.9, 65.5, 121.2, 122.1, 124.5, 126.9, 127.7,
128.4, 128.7, 128.8, 129.5, 129.7, 130.3 (q, J = 305.5 Hz), 131.8,
132.4, 134.7, 140.8, 142.9, 173.7, 182.5, 183.0. HRMS [M+Na+]
found m/z 636.1014, calcd for C29H28F3N3NaNiO3S 636.1055.
M.p. 227–230 8C. [
200 MHz)
J = 6.6 Hz). 19F NMR (D2O, 188 MHz)
75.5 MHz)
a]
D
d
1.95–2.40 (2H, m), 3.04 (2H, t, J = 8.3 Hz), 4.11 (1H, t,
d
À41.5 (s, 3F). 13C NMR (D2O,
d
25.2, 30.1, 51.3, 130.4 (q, J = 306 Hz), 170.8.
4.1.8. Ni(II) complex of (R)-2-amino-4-(trifluoromethylthio)butanoic
acid Schiff base with (S)-N-(2-benzoylphenyl)-2,2-dimethyl-2-(1-
Acknowledgment
phenyl-ethylamino)-acetamide 6b
We thank IKERBASQUE, Basque Foundation for Science; Basque
Government (SAIOTEK S-PE12UN044), and Hamari Chemicals
(Osaka, Japan) for financial support.
À984.5 (c 1.13, CHCl3). 1H NMR
25
M.p. 197.5 8C (decomp.). [
a
]
D
(CDCl3, 300 MHz)
d
1.58 (3H, s), 1.67 (3H, d, J = 6.7 Hz), 1.95–2.40
(2H, m), 2.53 (1H, bm), 2.95 (3H, s), 3.00–3.05 (2H, m), 3.89 (1H, m),
4.11 (1H, m), 6.55 (1H, m), 6.72 (1H, m), 6.78 (1H, bd, J = 7.9 Hz),
7.05–7.15 (2H, m), 7.14–7.30 (4H, m), 7.37–7.57 (3H, m), 8.02 (1H,
References
d, J = 8.8 Hz), 8.23 (2H, bd, J = 7.2 Hz). 13C NMR (CDCl3, 75.5 MHz)
d
[1] (a) J.L. Acen˜a, A.E. Sorochinsky, V.A. Soloshonok, Synthesis 44 (2012) 1591–1602;
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132.0, 133.0, 134.0, 140.5, 142.3, 171.9, 180.8, 181.2. HRMS
[M+Na+] found m/z 650.1244, calcd for C30H30F3N3NaNiO3S
650.1211.
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A solution of diastereomerically pure complex 5 or 6 (25 mmol)
in MeOH (50 mL) was added to a stirring solution of 3 N HCl in
MeOH (90 mL, ratio 1:1, acid:MeOH) at 70 8C. Upon disappearance
of the red color (about 5–10 min), the reaction mixture was
evaporated in vacuum. Water (85 mL) was added and the resultant
mixture was treated with an excess of concentrated ammonium
hydroxide and extracted with methylene chloride. The methylene
chloride extracts were dried over magnesium sulfate and
evaporated in vacuum to give (>95%) ligand 3. The aqueous
solution was evaporated in vacuum, dissolved in a minimum
amount of water, and passed through cation exchange resin Dowex
50 Â 2 100 to afford analytically pure samples of the target amino
acids (91–95%) 1 and 2. The enantiomeric purity of thus prepared
amino acids 1 and 2 was determined to be >98% ee by the chiral
HPLC analysis using chiral stationary phase containing hydroxy-
proline residues. For details, see Ref. [27].
(f) P. Bravo, A. Farina, M. Frigerio, S. Valdo Meille, F. Viani, V.A. Soloshonok,
Tetrahedron: Asymmetry 5 (1994) 987–1004;
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4.2.1. (R)-2-amino-4,4,4-trifluorobutanoic acid 1a
À9.9(c 1.01, 6 N HCl). 1H NMR
25
M.p. 201–203 8C (decomp.). [a D
]
(b) V.A. Soloshonok, A.G. Kirilenko, N.A. Fokina, I.P. Shishkina, S.V. Galushko, V.P.
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(c) V.A. Soloshonok, A.G. Kirilenko, N.A. Fokina, S.V. Galushko, V.P. Kukhar, V.K.
Svedas, G. Resnati, Tetrahedron: Asymmetry 5 (1994) 1225–1228;
(d) J. Limanto, A. Shafiee, P.N. Devine, V. Upadhyay, R.A. Desmond, B.R. Foster, D.R.
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(1994) 1055–1058;
(D2O, 300 MHz)
d
2.45–3.10 (2H, m), 4.19 (1H, dd, J = 7.5, 5.5 Hz).
4.2.2. (R)-2-amino-5,5,5-trifluoropentanoic acid 1b
25
M.p. 207–209 8C (decomp.). [
NMR (D2O, 300 MHz)
a
]
D
À10.3 (c 0.93, 6 N HCl). 1H
d
2.40–3.17 (4H, m), 4.24 (1H, t, J = 6.1 Hz).
4.2.3. (R)-2-amino-6,6,6-trifluorohexanoic acid 1c
25
M.p. 194–195 8C. [
300 MHz)
a
]
D
À7.7 (c 1.12, 6 N HCl). 1H NMR (D2O,
d
1.52–1.62 (m, 2H), 1.81–1.87 (m, 2H), 2.06–2.21 (m,
2H), 3.73–3.77 (m, 1H).
(b) V.A. Soloshonok, T. Ono, Tetrahedron 52 (1996) 14701–14712;
(c) P. Bravo, S. Capelli, M. Guidetti, S.V. Meille, F. Viani, M. Zanda, A.L. Markovsky,
A.E. Sorochinsky, V.A. Soloshonok, Tetrahedron 55 (1999) 3025–3040;
(d) V.A. Soloshonok, D.V. Avilov, V.P. Kukhar’, L. Van Meervelt, N. Mischenko,
Tetrahedron Lett. 38 (1997) 4903–4904.
4.2.4. (S)-2-amino-6,6,6-trifluorohexanoic acid 1c
+7.9 (c 1.07, 6 N HCl). 1H NMR (D2O,
25
M.p. 194–195 8C. [
a
]
D
300 MHz)
d
1.51–1.62 (m, 2H), 1.81–1.86 (m, 2H), 2.05–2.20 (m,
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1547–1550;
2H), 3.74–3.77 (m, 1H).
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684–687;
4.2.5. (S)-2-amino-3-(trifluoromethylthio)propanoic acid 2a
+26.7 (c 0.9, H2O). 1H NMR (D2O,
25
M.p. 233–235 8C. [
a
]
D
300 MHz)
d
3.47 (dd, J = 7.2, 15.5 Hz, 1H), 3.64 (dd, J = 4.5, 15.5 Hz,
(b) H. Yasui, T. Yamamoto, E. Tokunaga, N. Shibata, J. Fluorine Chem. 132 (2011)
186–189;
1H), 4.34 (dd, J = 4.5, 7.2 Hz, 1H). 19F NMR (282 MHz, D2O) À41.4 (s,

118
A.E. Sorochinsky et al. / Journal of Fluorine Chemistry 152 (2013) 114–118
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7209.
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7107.
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(b) R.S. Cahn, C.K. Ingold, V. Prelog, Angew. Chem. Int. Ed. Engl. 5 (1966) 385–415;
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(b) W. Qiu, V.A. Soloshonok, C. Cai, X. Tang, V.J. Hruby, Tetrahedron 56 (2000)
2577–2582;
(c) V.A. Soloshonok, X. Tang, V.J. Hruby, L. Van Meervelt, Org. Lett. 3 (2001) 341–
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4984–4990;
(c) V.A. Soloshonok, C. Cai, V.J. Hruby, Org. Lett. 2 (2000) 747–750.
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(c) R. Sharma, R.M. Vohra, Curr. Sci. 77 (1999) 127–136;
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1396–1400;
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