New stereoconservative syntheses of β,β,β- and γ,γ,γ-trifluoro-α-amino, α-hydroxy, and α-mercapto acids and their incorporation into a peptide and depsipeptide fragment

Article abstract of DOI:10.1055/s-2000-8198

Syntheses of β,β,β- and γ,γ,γ-trifluoro-α-amino, α-hydroxy and a-mercapto acids using hexafluoroacetone as protecting and activating reagent are described. The key step of the syntheses is the transformation of an ω-carboxy group into a trifluoromethyl group on treatment with sulfur tetrafluoride. The carboxy activated species obtained are suitable for direct incorporation into peptide and depsipeptide fragments. RP-HPLC experiments and Mosher's TMPA method (¹H and ¹⁹F) demonstrate that the reaction sequence occurs without racemization.

Full text of DOI:10.1055/s-2000-8198

PAPER
1681
New Stereoconservative Syntheses of , , - and , , -Trifluoro- -amino,
-Hydroxy, and -Mercapto Acids and Their Incorporation into a Peptide
and Depsipeptide Fragment
Hartmut Schedel,a Wojciech Dmowski,b Klaus Burger*a
aInstitut für Organische Chemie, Universität Leipzig, Johannisallee 29, 04103 Leipzig, Germany
Fax +49(341)9736599; E-mail: burger@organik.chemie.uni-leipzig.de
bInstitute of Organic Chemistry of the Polish Academy of Sciences, Kasprzaka St. 44, 01-224 Warsaw, Poland
Received 10 March 2000; revised 28 June 2000
activated ester moiety. Consequently, the -carboxy
group can be regioselectively derivatized on reaction with
a variety of nucleophiles.8 On the other hand, the -car-
boxy group in 1 can be selectively activated on transfor-
Abstract: Syntheses of
- and
-trifluoro- -amino, -hy-
droxy and a-mercapto acids using hexafluoroacetone as protecting
and activating reagent are described. The key step of the syntheses
is the transformation of an -carboxy group into a trifluoromethyl
group on treatment with sulfur tetrafluoride. The carboxy activated mation into an acid chloride or an isocyanate.9
species obtained are suitable for direct incorporation into peptide
In this paper, we describe a preparative simple two step
and depsipeptide fragments. RP-HPLC experiments and Mosher's
synthesis of -carboxy activated -trifluoromethyl -N-
methylamino, -hydroxy and -mercapto alkanoic acids
and some of their derivatives starting from the corre-
sponding -carboxy substituted -functionalized alkanoic
acids, using hexafluoroacetone as protecting and activat-
TMPA method (1H and 19F) demonstrate that the reaction sequence
occurs without racemization.
Key words: amino acids, heterocycles, hexafluoroacetone, lac-
tones, peptides, sulfur tetrafluoride
ing agent. -Carboxy substituted -N-methylamino,10
-
hydroxy and -mercapto acids are readily transformed
into lactones 1 upon reaction with hexafluoroacetone in
dimethyl sulfoxide at room temperature.11
Fluorine is a unique tool for modifying profiles of bioac-
tive compounds.1 Consequently, there is a growing inter-
est in the synthesis of chiral fluorine containing building
blocks. In this context, new synthetic routes to fluorine
containing amino,2 hydroxy,3 keto4 and mercapto acids,5
their incorporation into peptides and depsipeptides, and
their application in combinatorial chemistry are of current
interest.6
Several strategies for the synthesis of trifluoromethyl sub-
stituted amino and hydroxy acids using fluorinated build-
ing blocks have been developed.2,3 In most cases racemic
mixtures were obtained. Therefore, the development of
enzymatic methodology for enantiomeric resolution was
necessary.2a,h Enantiopure -trifluoromethyl -functional-
ized acids were obtained on catalytic hydrogenation of
chiral fluoro substituted , -dehydro amino acid deriva-
tives,2d trifluoromethylation of Garner’s aldehyde with
Ruppert’s reagent2e and asymmetric synthesis via chiral
chromium complexes.3a A direct transformation of the -
carboxy group of hydantoin-protected -carboxy- -ami-
no acids into a trifluoromethyl group on treatment with
sulfur tetrafluoride has been described,7 but hydantoin-
protected amino acids are notoriously sensitive to racem-
ization.
Scheme 1
Transformation of the unprotected -carboxy group of
compounds 1 into a trifluoromethyl group was accom-
plished in respectable yields on treatment with sulfur
tetrafluoride12 in an autoclave at temperatures between
25-60 °C (Schemes 1,2, Tables 1, 2). At lower tempera-
tures, acid fluorides were the main products, at higher
temperatures a mixture of undefined side products is
formed. From the reaction mixtures obtained, compounds
2 can be easily separated by distillation.
Application of hexafluoroacetone as protecting reagent in
multifunctional -amino, -hydroxy and -mercapto acid
chemistry allows efficient orthogonal functionalization.
The functional groups present in the -position and the ad-
jacent carboxy group are simultaneously protected on re-
action with hexafluoroacetone, while the -carboxy
group remains unaffected. The -carboxy group incorpo-
rated into the five membered heterocyclic system 1 is an
The yield of the transformation 1e 2e was low (8%) be-
cause of side reactions at the unprotected NH function
present in the molecule. When hexafluoroacetone-pro-
tected glutamic acid 1f was treated with sulfur tetrafluo-
ride, the pyroglutamic acid derivative 3 was obtained as
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1682
H. Schedel et al.
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main product. Compound 2f could only be traced by Since compounds 2 are a-carboxy group activated species,
GCMS and 19F NMR spectroscopy.
deprotection can be achieved under mild conditions. The
carboxy group and the functional group in the -position
of compounds 2 are deprotected in one step to give direct-
ly the -trifluoromethyl -functionalized acids 4 (Scheme
3, Tables 3, 4). Cleavage of the five-membered lactone
can be achieved with various nucleophiles providing a
general access to the corresponding esters (5a, 5c), amides
(7), depsipeptide (6a, 6b) and peptide fragments (6c, 6d).
The formation of the alkanoic acid derivatives is always
coupled with the deprotection of the functional group
Scheme 2
Table 1 Compounds 2a-e, g, Analytical Data
[ ]D IR [cm−1] 1H NMR (CDCl3) (ppm), J (Hz) 19F NMR (CDCl3) (ppm), J (Hz)
a
Com-
pound
Condi-
tions
Yield
[%]
mp / bp
(torr) [°C]
(°C) / (h)
2a
2b
2c
2d
2e
2g
44 / 24
44 / 23
60 / 24
60 / 25
25 / 20
50 / 22
57
50
44
26
8
74 (175)
68 (70)
- 8
- 8
1861b
1850b
2.48-2.97 (m, 2 H), 4.93 (dd, 1 H, J -3.29 (q, 4JFF = 7), -3.08 (q, 4JFF = 7),
= 10, 10)
13.04 (t, 3JHF = 10)
1.76 (s, 3 H), 2.50-2.80 (m, 2 H)
-3.09 (q, 4JFF = 6), -2.95 (q, 4JFF = 6),
17.18 (t, 3JHF = 9)
75-77 (22)c +29 1848b
84 (17)c +22 1840b
2.50-2.95 (m, 2 H), 2.79 (m, 3 H), -1,04 (q, 4JFF = 9), 4.39 (q, 4JFF = 9),
3.81 (dd, 1 H, J = 5, 5)
14.64 (t, 3JHF = 11)
1.90-2.43 (m, 4 H), 2.73 (m, 3 H), -0.86 (q, 4JFF = 9), 4.36 (q, 4JFF = 9),
3.73 (m, 1 H)
11.28 (t, 3JHF = 11)
37 / 75 (104) +1
1834b
1824b
2.43 (m, 1 H), 2.81 (m, 1 H), 3.35 -3.36 (q, 4JFF = 9), -2.31 (q, 4JFF = 9),
(m, 1 H), 4.29 (m, 1 H)
12.92 (t, 3JHF = 11)
45
82-84 (70)
–
2.63 (m, 1 H), 3.21 (m, 1 H), 4.40 0.92 (q, 4JFF = 9), 1.86 (q, 4JFF = 9),
(dd, 1 H, J = 11, 2)
12.02 (t, 3JHF = 11)
a c = 2, CH2Cl2.
b film.
c An analytically pure sample was obtained on column chromatography, eluent: petroleum ether/EtOAc (20/1).
Table 2 Compounds 2a−e, g , 13C NMR and MS Data
Compound
13C NMR (CDCl3) d (ppm), J (Hz)
EI-MS [m/z]
2a
36.99 (q, 2JCF = 36), 70.15 (q, 3JCF = 4), 98.53 (m), 119.06
287 [2, (M-F)+], 259 (4), 237 (24), 209 (54), 115 (56), 97 (19),
69 (100)
(q, 1JCF = 287), 119.73 (q, 1JCF = 287), 124.58 (q, 1JCF
=
276), 166.29
2b
2c
2d
2e
2g
22.51, 40.96 (q, 2JCF = 31), 78.44 (q, 3JCF = 2), 97.84 (m),
119.10 (q, 1JCF = 278), 119.36 (q, 1JCF = 288), 119.41 (q,
1JCF = 288), 169.15
305 [2, (M-CH3)+], 251 (21), 223 (54), 195 (5), 131 (17),
111 (19), 107 (16), 69 (64), 65 (12), 42 (100)
30.86, 35.22 (q, 2JCF = 30), 56.32 (q, 3JCF = 3), 90.15 (m),
120.72 (q, 1JCF = 287), 122.04 (q, 1JCF = 295), 125.18 (q,
1JCF = 277), 168.30
319 (18, M+), 272 (18), 250 (57), 236 (31), 222 (100), 202
(19), 156 (9), 139 (12), 124 (16), 110 (35), 69 (48)
21.60 (q, 3JCF = 3), 28.04 (q, 2JCF = 28), 33.10 (q, 4JCF
=
333 (9, M+), 286 (10), 264 (14), 236 (100), 216 (4), 138 (9),
119 (7), 110 (13), 69 (18)
2), 59.27, 89.90 (m), 120.95 (q, 1JCF = 287), 122.04 (q,
1JCF = 295), 127.06 (q, 1JCF = 276), 169.03
38.43 (q, 2JCF = 30), 50.12 (q, 3JCF = 3), 88.76 (m), 120.36
305 (<1, M+), 258 (24), 236 (35), 222 (19), 208 (100), 192
(11), 188 (23), 177 (18), 96 (31), 90 (24), 69 (71)
(q, 1JCF = 288), 121.43 (q, 1JCF = 287), 125.76 (q, 1JCF
=
277), 169.19
38.72 (q, 2JCF = 31), 40.18, 83.84 (m), 121.03 (q, 1JCF
284), 121.66 (q, 1JCF = 285), 125.16 (q, 1JCF = 277),
169.36
=
322 (30, M+), 275 (33), 253 (33), 225 (58), 205 (23), 163 (10),
128 (89), 113 (34), 97 (18), 69 (84), 44 (100)
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New Stereoconservative Syntheses of , , - and , , -Trifluoro- -amino Acids
1683
placed in a-position, which can be directly transformed
without further manipulation.
Reagents and conditions: a) (F3CSO2)2O, pyridine, 0 °C, 90%; b) 1.
MeOH, Pd-C, H2, 2. EtOH, propene oxide, 87%; c) 1. MeOH, Pd-
C, H2 (13 Mpa), 3 days, 2. aq HCl, 60 °C, 2 days; 3. EtOH, propene
oxide, 26%.
Scheme 4
Scheme 3
A variety of N-substituted w-trifluoromethyl a-amino ac-
ids (13, 14) and some of their derivatives (11a-d, 15) are
now available from trifluoromethyl -hydroxy acid 5a via
triflate13 10. Hydrogenolytic debenzylation of 11b to give
the 4,4,4-trifluoro-2-methylaminobutyric acid (14) needs
more drastic conditions and was achieved in an autoclave
at 13 MPa. We were not able to remove traces of metal
ions, dissolved from the autoclave, from compounds 14,
1514 because they form stable complexes. After derivati-
zation, 15 17, they can be removed by extraction with
aqueous citric acid.
TMPA = (S)-a-trifluoromethyl-a-methoxyphenylacetyl chloride
Scheme 5
that the (S,S) and the (R,S) configured compounds were
nicely separable (Figure). Furthermore, it is possible to
identify 6a and 9 unequivocally on the basis of their
Compounds 5c and 15 were subjected to a racemization
test. For this purpose they were converted into the Mosher
derivatives. Derivatization according to the standard pro-
tocol using N,N´-dicyclohexylcarbodiimide failed.2h,15
Transformation of 5c into 16, and 15 into 17 was achieved
in good yields with Mosher acid chloride in the presence
of N-methylmorpholine (Scheme 5). The shift differences
of compounds 16 and 17 in their 1H and 19F NMR spectra
are of a size that allows determination of the optical puri-
ty. NMR analysis of crude compound 16 proves optical
purity. Hence, the multi-step reaction sequence 1c 5c
proceeds in a strictly stereoconservative manner. Analysis
of crude compound 17 revealed that the sample contained
about 10% of 16. Consequently, partial racemization
takes place, during the reaction sequence 5a 15.
A racemization test was also developed for compound
6a (Scheme 5). The configuration of the -hydroxy
acid substructure was inverted by a Mitsunobu reaction
Figure RP-HPLC analysis, with UV detection at = 220 nm.
A) Chromatogram: (S,S) 5a (crude peptide).
B) Chromatogram: co-injection of (S,S) 5a and (R,S) 9.
(6a
8
9). Subsequent RP-HPLC experiments revealed
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1684
H. Schedel et al.
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Table 3 Compounds 4a−d, g, 6a−d, 7 Analytical Data
Com-
pound
yield (%)
mp (°C)
75-77
[ ]D
-4d
IR (cm−1)
3067, 1741e
3430, 1741e
1604e
1H NMR (ppm), J (Hz)
19F NMR δ =
4a
4b
4c
4d
4g
6a
91
70
70
69
75
67
(D2O) 2.32-2.80 (m, 2 H), 4.44 (dd, 1 H,
J = 9, 4)
(D2O) 14.37
(t, 3JHF = 11)
d
120-123
296f
11
(D2O) 1.36 (s, 3 H), 2.37-2.61 (m, 1 H),
2.63-2.87 (m, 1 H)
(D2O) 16.28
(t, 3JHF = 11)
8g
16g
–
(D2O) 2.62 (s, 3 H), 2.70-2.89 (m, 2 H),
3.75 (dd, 1 H, J = 5, 5)
(D2O) 13.99
(t, 3JHF = 11)
f
304
1591e
(D2O / 1% DCl) 1.97-2.34 (m, 4 H), 2.60 (s,
3 H), 3.79 (dd, 1 H, J = 7, 7)
(D2O / 1% DCl) 11.22
(t, 3JHF = 11)
66-69
159
3422, 1710e
3372, 1657e
(CDCl3) 2.42 (d, 1 H, J = 10), 2.57 (m,
1 H), 2.95 (m, 1 H), 3.64 (m, 1 H)
(D2O) 12.71
(t, 3JHF = 11)
12h
(DMSO-d6) 2.00-2.43 (m, 2 H), 2.86 (dd, 1
H, J = 14, 8), 3.02 (dd, 1 H, J = 14, 5), 4.13
(m, 1 H), 4.48 (m, 1 H), 6.16 (d, 1 H, J = 6),
7.15-7.28 (m, 6 H), 7.52 (s, 1 H), 7.81 (d, 1
H, J = 9)
(DMSO-d6) 16.12
(t, 3JHF = 11)
6b
6c
56
80
160
38h
3400, 1663,
1525e
(DMSO-d6) 1.26 (s, 3 H), 2.25-2.70 (m,
2 H), 2.91 (m, 2 H), 4.45 (m, 1 H), 5.94 (s,
1 H), 7.14-7.24 (m, 6 H), 7.46 (s, 1 H), 7.64
(d, 1 H, J = 8)
(DMSO-d6) 18.92
(t, 3JHF = 11)
118-120
4h
3423, 1654e
3433, 1650e
(DMSO-d6) 1.84 (s, 3 H), 2.20-2.45 (m,
2 H), 2.75 (dd, 1 H, J = 14, 10), 3.02 (dd,
1 H, J = 14, 5), 3.20 (dd, 1 H, J = 6, 6), 4.52
(m, 1 H), 7.10 (s, 1 H), 7.14-7.23 (m, 5 H),
7.45 (s, 1 H), 8.26 (d, 1 H, J = 9)
(DMSO-d6) 20.97
(t, 3JHF = 11)
6d
71
75
132-133
8h
(DMSO-d6) 1.51 (m, 2 H), 1.90-2.20 (m,
2 H), 1.98 (s, 3 H), 2.76 (dd, 1 H, J = 14,
10), 2.85 (dd, 1 H, J = 6, 6), 3.03 (dd, 1 H,
J = 14, 4), 4.55 (m, 1 H), 7.08 (s, 1 H), 7.13-
7.23 (m, 5 H), 7.52 (s, 1 H), 8.00 (d, 1 H, J
= 9)
(DMSO-d6) 13.26
(t, 3JHF = 11)
7
87
3274, 1651,
1563e
(DMSO-d6) 2.50-2.76 (m, 1 H), 2.84-3.15
(m, 1 H), 3.45 (s, 1 H), 3.64 (m, 1 H), 4.29
(d, 2 H, J = 6), 7.22-7.35 (m, 5 H), 8.70 (dd,
1 H, J = 6, 6);
(DMSO-d6) 14.59
(t, 3JHF = 11);
d c = 2, H O.
2
e KBr.
f sealed glass capillary.
g c = 2, 1N aq HCl.
h c = 2, DMSO.
chemical shift differences in their 1H and 19F NMR spec- stereoconservative orthogonal group transformations of
tra. Thus, we could demonstrate that crude 6a did not con- multifunctional -functionalized alkanoic acids.
tain traceable amounts of the diastereomeric compound 9
and vice versa. Likewise, no evidence for racemization
could be found in the NMR spectra of crude compound
6d.
Mps (uncorrected) were determined on a Boetius heating table. Op-
tical rotations were measured at 589 nm (Na D line). 1H NMR spec-
tra were recorded at 200 MHz. Chemical shifts are reported in ppm
relative to TMS in CDCl3, D2O, CD3OD and DMSO-d6; J values are
In the case of the thiomalic acid only the racemate was
available for our experiments, therefore compounds 1g,
2g, 4g and 7 are racemates.
given in Hz. 13C NMR spectroscopy was performed at 50 MHz. 19
F
NMR spectra were recorded at 188 MHz with trifluoroacetic acid
(TFA) as an external standard. Reactions with sulfur tetrafluoride
were carried out in a high-pressure stainless steel autoclave with a
needle valve. For flash chromatography, silica gel (32-63 mm) was
used with the solvent system given in the text. Analytical HPLC
In conclusion, we have shown that hexafluoroacetone rep-
resents an interesting protecting and activating reagent for
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New Stereoconservative Syntheses of , , - and , , -Trifluoro- -amino Acids
1685
Table 4 Compounds 4a−d, g, 6a−d, 7 13C NMR and MS Data
Compound
13C NMR (ppm), J (Hz)
EI-MS [m/z]
4a
(D2O) 37.26 (q, 2JCF = 28), 65.39 (q, 3JCF = 3), 126.40 (q, 1JCF = 277),
176.04 (q, 4JCF = 3)
113 [84, (M-CO2H)+], 39 (57), 65 (100)
4b
4c
4d
4g
6a
6b
6c
(D2O) 29.06, 44.75 (q, 2JCF = 27), 74.37 (q, 3JCF = 3), 128.39 (q, 1JCF
= 277), 180.70
127 [31 (M-HCO2)+], 111 (11), 91 (5), 69 (6), 63
(20), 42 (100)
(D2O) 35.00, 35.48 (q, 2JCF = 30), 58.32 (q, 3JCF = 3), 127.83 (q, 1JCF
= 277), 171.94
(FAB-MS) 172 [(M+1)+]
(D2O / 1% DCl) 21.52 (q, 3JCF = 4), 29.12 (q, 2JCF = 30), 31.76, 59.55,
126.78 (q, 1JCF = 276), 170.49
140 [100 (M-HCO2)+], 120 (17), 115 (5), 100
(8), 88 (9), 69 (19)
(D2O) 34.36 (q, 3JCF = 3), 38.86 (q, 2JCF = 27), 125.94 (q, 1JCF = 278),
176.34
174 (44, M+), 156 (22), 129 (62), 109 (34), 77
(29), 69 (21), 65 (38), 44 (100)
(CD3OD) 37.88 (q, 2JCF = 28), 38.16, 54.16, 66.68 (q, 3JCF = 3), 126.66
(q, 1JCF = 277), 127.25, 128.79, 129.69, 136.94, 173.78, 175.24
(FAB-MS) 305 [(M+1)+], 327 [(M+Na)+]
(FAB-MS) 319 [(M+1)+], 274 [(M-CO2)+]
(FAB-MS) 318 [(M+1)+]
(CD3OD) 27.33, 39.66, 43.50 (q, 2JCF = 27), 55.57, 73.33, 127.45 (q,
1JCF = 277), 129.76, 128.20, 130.74, 138.08, 175.88, 176.89
(DMSO-d6) 33.69, 36.24 (q, 2JCF = 27), 38.75, 54.40, 58.25 (q, 3JCF
3), 127.18, 127.53 (q, 1JCF = 277), 128.94, 130.19, 138.77, 172.26,
173.82
=
6d
7
(DMSO-d6) 25.70, 30.17 (q, 2JCF = 28), 34.57, 38.79, 53.94, 63.04,
(FAB-MS) 332 [(M+1)+]
127.17, 128.53 (q, 1JCF = 277), 128.98, 130.12, 138.82, 173.43, 174.05
(CD3OD) 35.08 (q, 3JCF = 3), 39.77 (q, 2JCF = 28), 43.40, 125.97 (q,
1JCF = 277), 127.46, 127.65, 128.67, 138.55, 172.70
FAB-MS 525 [(2×M-1)+], 264 [(M+1)+]
was equipped with a Capcell column (C18, SG 120, 4,6 × 250 mm,
5µm), monitoring at l = 220 nm. Mixtures of MeCN, H2O and 0.1%
TFA were used as the solvent system, with a gradient starting at
95% H2O, and decreasing to 50% within 30 min. Organic solvents
were dried and distilled prior to use. Palladium on carbon (10% Pd-
C) was purchased from Aldrich.
Hydrolysis of 1,3-Oxazolidin-4-ones 2c and 2d; General Proce-
dure C
Compound 2c or 2d (1.5 mmol) was dissolved in a mixture of diox-
ane (10 mL), concd HCl (1.0 mL) and H2O (1.0 mL). Then the mix-
ture was stirred at 60 °C for 24-84 h (19F NMR analysis). The
solvent was removed under reduced pressure and the remaining sol-
id was dissolved in EtOH (4.0 mL), then propene oxide (0.5 mL)
was added. The resulting precipitate was collected by filtration and
washed with Et2O to obtain 4c and 4d.
Fluorination of Hexafluoroacetone-Protected -Functional
Carboxylic Acids with Sulfur Tetrafluoride; General Proce-
dure A
Autoclaves with a capacity of 30 cm3 for 15 g of starting material
and a capacity of 200 cm3 for 33-72 g of starting material were used.
1a-g was placed into an autoclave, the reactor was evacuated,
cooled to -70 °C and SF4 (3 equiv) was condensed into it. The auto-
clave was heated (25-60 °C/20-25 h) in a rocking muffle furnace,
then cooled to r.t., and the gaseous products were released. The re-
maining liquid was dissolved in CH2Cl2 and the organic phase was
washed with sat. NaHCO3, and dried (MgSO4). The solvent was re-
moved and the residue was subjected to fractional distillation to
give 2a-e, g.
(rac)-4,4,4-Trifluoro-2-mercaptobutyric Acid (4g)
Compound 2g (1.0 g, 3.1 mmol) was dissolved in dioxane (4.0 mL),
H2O (6.0 mL), concd HCl (1.0 mL) and stirred at r.t. for 50 h. H2O
(15 mL) was added and the mixture was extracted with Et2O (4 × 10
mL). The organic layer was dried (MgSO4) and the solvent evapo-
rated. Recrystallization from light petroleum afforded 4g as color-
less crystals.
Peptides and Amides (6a-d, 7); General Procedure D
To a solution of the nucleophile, L-phenylalanine amide (468 mg,
2.9 mmol) or benzylamine (216 mg, 2 mmol) in i-PrOH (7.0 mL),
the hexafluoroacetone protected derivative 2a-d (2.0 mmol) or 2g
(500 mg, 1.6 mmol) was added with stirring at r.t. After completion
of the reaction (19F NMR analysis), the solvent was evaporated in
vacuo. The resulting crude product was purified by column chroma-
tography (CH2Cl2/MeOH, for 6b, 6c, 20:1; 6d, 8:1; and 7, 10:1).
Compound 6a crystallizes from the mixture, the crystalline solid
was collected by filtration. Stirring with Et2O (15 mL) for 24 h and
filtration gave the pure product.
Hydrolysis of 1,3-Dioxolan-4-ones 2a and 2b; General Proce-
dure B
A mixture of 2a or 2b (1.0 mmol), i-PrOH (5.0 mL), H2O (1.0 mL)
and four drops of concd HCl was stirred at r.t. for 24 h. After remov-
al of the solvent in vacuo, the residue was dissolved in H2O (25 mL)
and lyophilized to give 4a, 4b. Lyophilization was repeated until
hexafluoroacetone hydrate could not be detected by 19F NMR spec-
troscopy.
(S)-4,4,4-Trifluoro-2-hydroxybutyric Acid Methyl Ester (5a)
Compound 2a (13.3 g, 43 mmol) was dissolved in neat MeOH (10
mL) and kept at r.t. After 12 h the excess of MeOH was removed.
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H. Schedel et al.
PAPER
The residue was dissolved in CH2Cl2 (100 mL) and washed with
H2O (2 × 50 mL). The water phase was extracted with CH2Cl2
(4 × 20 mL). Drying of the combined organic phase (MgSO4), evap-
oration of the solvent, and distillation in vacuo gave 5a (5.9 g, 80%)
as a colorless liquid; bp = 48 °C (4.0 torr); [ ]21D = -3 (c 2, CH2Cl2).
1H NMR (DMSO-d6): = 2.19-2.65 (m, 2H), 2.90 (dd, 1H, J = 14,
8), 3.06 (dd, 1H, J = 14, 5 Hz), 4.14 (m, 1H), 4.52 (m, 1H), 6.16 (d,
1H, J = 7), 7.16-7.32 (m, 6H), 7.54 (s, 1H), 7.93 (d, 1H, J = 9).
13C NMR (CD3OD): = 39.34 (q, 2JCF = 28), 39.54, 55.55, 67.84 (q,
1
3JCF = 3), 128.07 (q, JCF = 276), 128.20, 129.80, 130.67, 138.33,
IR (film): = 3446, 1747 cm-1.
174.58, 175.91.
1H NMR (CDCl3): = 2.44 (m, 1H), 2.68 (m, 1H), 3.04 (d, 1H,
J = 5), 3.84 (s, 3H), 4.48 (m, 1H).
19F NMR (DMSO-d6): = 16.25 (t, 3JHF = 12).
FAB-MS: m/z = 327 [(M+Na)+], 305 [(M+1)+].
2
13C NMR (CDCl3): = 38.61 (q, JCF = 29), 53.70, 65.98 (q,
3JCF = 3), 126.02 (q, 1JCF = 277), 173.63.
19F NMR (CDCl3): = 14.14 (t, 3JHF = 9).
(S)-4,4,4-Trifluoro-2-(trifluoromethanesulfonyloxy)butyric
Acid Methyl Ester (10)
Compound 5a (1.0 g, 6.0 mmol) and anhyd pyridine (554 mg, 7.0
mmol) was dissolved in light petroleum (10 mL) and CH2Cl2 (1 mL)
and added dropwise to a stirred, ice-cold solution of trifluo-
romethanesulfonic acid anhydride (1.97 g, 7.0 mmol) in light petro-
leum (20 mL) and stirred for additional 10 min. Filtration from the
precipitated salt and evaporation in vacuo afforded 10 (1.59 g, 90%)
as slightly yellow liquid (stable at 0 °C for long time); [ ]21D = -54
(c 2, CH2Cl2).
EI-MS: m/z (%) = 172 (2, M+), 144 (3), 135 (4), 113 (87), 93 (61),
89 (11), 69 (14), 65 (100), 59 (42).
(S)-4,4,4-Trifluoro-2-methylaminobutyric Acid Methyl Ester
Hydrochloride (5c)
Compound 2c (200 mg, 0.63 mmol) was dissolved in MeOH (5
mL). The solution was saturated with anhyd HCl and kept at r.t. Af-
ter 24 h, the excess of MeOH was removed in vacuo and the residue
was stirred with Et2O (5 mL). Filtration after 24 h gave 5c (130 mg,
94%) as a white crystalline product; mp = 154-155 °C; [ ]21D = 9 (c
2, MeOH).
IR (film): = 1766, 1428 cm-1.
1H NMR (CDCl3): = 2.75-3.00 (m, 2H), 3.91 (s, 3H), 5.36 (dd,
1H, J = 8, 4).
2
IR (KBr): = 1747 cm-1.
1H NMR (DMSO-d6): = 2.60 (s, 3H), 3.00-3.25 (m, 2H), 3.78 (s,
3H), 4.42 (dd, 1H, J = 7, 5), 9.90 (br s, 2H).
13C NMR (CDCl3): = 36.65 (q, JCF = 31), 54.55, 76.63 (q,
3JCF = 3), 118.70 (q, 1JCF = 310), 124.63 (q, 1JCF = 269), 166.16.
19F NMR (CDCl3): = 2.82 (s), 13.28 (m).
13C NMR (CD3OD): = 32.04, 33.03 (q, 2JCF = 31), 53.44, 55.42 (q,
EI-MS: m/z (%) = 285 [4, (M-F)+], 245 (11), 235 (26), 207 (14), 79
(92), 69 (79), 59 (100).
3JCF = 3), 125.52 (q, 1JCF = 277), 167.50.
19F NMR (DMSO-d6): = 15.92 (t, 3JHF = 11).
EI-MS: m/z (%) = 185 [4, (M-HCl)+], 126 (100), 102 (9), 62 (7).
(R)-2-Benzylamino-4,4,4-trifluorobutyric Acid Methyl Ester
(11a)
To benzylamine, (707 mg, 6.6 mmol) dissolved in CH2Cl2 (40 mL),
10 (1.0 g, 3.3 mmol) in CH2Cl2 (10 mL) was added dropwise with
stirring at r.t. After an additional 30 min, the solvent was distilled
off and the residue was subjected to column chromatography (light
petroleum/EtOAc, 7:1) to give 11a (782 mg, 90%) as colorless, oily
liquid.
[ ]21D = +44 (c 2, CH2Cl2).
IR (film): = 1742 cm-1.
(1R)-Formic Acid 1-(1S)-1-Carbamyl-2-phenylethylcarbamoyl-
3,3,3-trifluoropropyl Ester (8)
THF (40 mL) was added to a mixture of 6a (600 mg, 1.97 mmol),
Ph3P (629 mg, 2.40 mmol), and HCO2H (184 mg, 4.0 mmol). Dieth-
yl azodicarboxylate (418 mg, 2.40 mmol) was added dropwise to
the stirred and cooled (-5 °C) suspension over 20 min. A clear yel-
low solution resulted and was stirred at r.t. for additional 15 h. The
solution was evaporated and purified by column chromatography
(light petroleum/CH2Cl2/EtOAc/i-PrOH, 16:16:7:1) and recrystal-
lized from CHCl3/EtOAc to give 8 (500 mg, 76%) as a white crys-
talline product; mp = 140-142 °C; [a]D = +4 (c 2, DMSO).
1H NMR (CDCl3): = 1.92 (br s, 1H), 2.30-2.70 (m, 2H), 3.59 (dd,
1H, J = 6, 6), 3.68 (d, 1H, J = 13), 3.76 (s, 3H), 3.84 (d, 1H, J = 13),
7.26-7.34 (m, 5H).
IR (KBr): = 1739, 1672, 1647 cm-1.
13C NMR (CDCl3): = 37.83 (q, 2JCF = 33), 52.25, 52.72, 55.65 (q,
1
1H NMR (DMSO-d6): d = 2.30-2.65 (m, 2H), 2.75 (dd, 1H, J = 14,
10), 3.02 (dd, 1H, J = 14, 5 Hz), 4.47 (m, 1H), 5.28 (dd, 1H, J = 9,
4), 7.10-7.30 (m, 6H), 7.48 (s, 1H), 8.28 (s, 1H), 8.54 (d, 1H, J = 9).
13C NMR (DMSO-d6): d = 35.72 (q, 2JCF = 29), 38.48, 54.62, 67.04
(q, 3JCF = 3), 126.56 (q, 1JCF = 276), 127.29, 128.95, 130.19, 138.69,
161.86, 167.14, 173.37.
19F NMR (DMSO-d6): d = 15.75 (t, 3JHF = 11).
FAB-MS: m/z = 333 [(M+1)+], 355 [(M+Na)+].
3JCF = 3), 126.18 (q, JCF = 277), 127.84, 128.72, 128.98, 139.54,
174.06.
19F NMR (CDCl3): = 14.08 (t, 3JHF = 11).
EI-MS: m/z (%) = 261 (6, M+), 202 (37), 107 (36), 92 (100), 65 (5).
(R)-2-(Benzylmethylamino)-4,4,4-trifluorobutyric Acid Methyl
Ester (11b)
In analogy to 11a, benzylmethylamine (933 mg, 6.6 mmol) and 10
(1.0 g, 3.3 mmol) gave, after column chromatography (light petro-
leum/EtOAc, 10:1), 11b (690 mg, 76%) as a colorless, oily liquid.
(1R)-N-[(1S)-1-Carbamoyl-2-phenylethyl]-4,4,4-trifluoro-2-hy-
droxybutyramide (9)
[a]21D = +88 (c 2, CH2Cl2).
To 8 (300 mg, 0.90 mmol) dissolved in MeOH (10 mL) were added
MeOH saturated with anhyd HCl (10 drops) and Pd-C (50 mg). The
mixture was stirred under H2 (normal pressure) at r.t. for 48 h. The
catalyst was removed by filtration and the solvent was evaporated
in vacuo. Recrystallization from CHCl3/EtOAc gave 9 (269 mg,
98%) as a white powder; mp = 140-141 °C; [ ]D = +38 (c 2,
DMSO).
IR (film): n = 1737 cm-1.
1H NMR (CDCl3): d = 2.23 (s, 3H), 2.40-2.60 (m, 1H), 2.65-2.85
(m, 1H), 3.60-3.77 (m, 3H), 3.80 (s, 3H), 7.26-7.34 (m, 5H).
13C NMR (CDCl3): d = 34.66 (q, JCF = 28), 37.81, 52.07, 59.60,
2
60.43 (q, 3JCF = 3), 126.65 (q, 1JCF = 277), 127.78, 128.84, 129.15,
138.98, 171.08.
IR (KBr): = 3325, 3188, 1686, 1639 cm-1.
19F NMR (CDCl3): d = 13.69 (t, 3JHF = 11).
Synthesis 2000, No. 12, 1681–1688 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
New Stereoconservative Syntheses of , , - and , , -Trifluoro- -amino Acids
1687
EI-MS: m/z (%) = 275 (5, M+), 216 (12), 91 (100).
1H NMR (D2O): d = 2.43-2.82 (m, 2H), 4.06 (dd, 1H, J = 8, 4).
13C NMR (D2O): d = 33.62 (q, 2JCF = 30), 47.70 (q, 3JCF = 3), 125.39
(q, 1JCF = 277), 169.77.
19F NMR (D2O): d = 13.65 (t, 3JHF = 11).
FAB-MS: m/z = 158 [(M+1)+].
(R)-4,4,4-Trifluoro-2-hydroxyaminobutyric Acid Methyl Ester
(11c)
In analogy to 11a (THF as solvent), hydroxylamine (436 mg, 50%
aq solution, 6.6 mmol) and 10 (1.0 g, 3.3 mmol) gave, after column
chromatography (CH2Cl2/EtOAc, 7:1), 11c (370 mg, 60%) as a
white, crystalline solid (decomposition to a brown oil at r.t. within
weeks); mp = 73-74 °C; [ ]21D = +27 (c 2, MeOH).
IR (KBr): = 3435, 3260, 1741 cm-1.
1H NMR (DMSO-d6): = 2.50-2.74 (m, 2H), 3.66 (s, 3H), 3.69 (dd,
1H, J = 13, 7), 6.10 (dd, 1H, J = 7, 3), 7.72 (d, 1H, J = 3).
(R)-4,4,4-Trifluoro-2-methylaminobutyric Acid (14)
Compound 11b (1.2 g, 4.2 mmol) was dissolved in MeOH (50 mL).
The catalyst (Pd-C, 150 mg) and anhyd HCl (until pH of the solu-
tion < 7) were added and the mixture was stirred in an autoclave at
r.t. under 13 MPa H2 pressure for 3 days. After releasing the pres-
sure, the catalyst was removed by filtration, and the solution evap-
orated. The residue was dissolved in aq HCl (8 mL, 20%) and stirred
at 60 °C for 2 days. After evaporation, the resulting solid was dis-
solved in EtOH and treated with propene oxide (0.5 mL). The pre-
cipitate was collected by filtration. Washing with Et2O gave 14 (185
mg, 26%) as a pale brown powder.
2
13C NMR (DMSO-d6): = 33.40 (q, JCF = 28), 52.86, 60.00 (q,
3JCF = 3), 127.28 (q, 1JCF = 277), 172.78.
19F NMR (DMSO-d6): = 15.70 (t, 3JHF = 12).
EI-MS: m/z (%) = 187 (7, M+), 128 (100), 108 (34), 90 (9), 72 (6).
Mp = 214-216 °C; [ ]21D = -6 (c 2, 1 N aq HCl).
IR (KBr): n = 3435, 1604 cm-1.
(R)-4,4,4-Trifluoro-2-[2-(tert-butoxycarbonyl)hydrazino]bu-
tyric Acid Methyl Ester (11d)
1H NMR (D2O/1% DCl): d = 2.58 (s, 3H), 2.75-3.00 (m, 2H), 4.17
(dd, 1H, J = 5, 5).
Hydrazinecarboxylic acid tert-butyl ester (Boc-hydrazine) (1.0 g,
6.6 mmol) and 10 (1.0 g, 3.3 mmol) were dissolved in CH2Cl2 (50
mL) and refluxed during 6 days to give, after column chromatogra-
phy (light petroleum/EtOAc, 5:1), 11d (941 mg, 93%) as a white,
crystalline solid; mp = 75-78 °C; [ ]21D = 29 (c 2, CH2Cl2).
IR (KBr): = 3374, 3244, 1743, 1696 cm-1.
1H NMR (CDCl3): = 1.45 (s, 9H), 2.40-2.79 (m, 2H), 3.78 (s, 3H),
3.95 (m, 1H), 4.52 (m, 1H), 6.17 (m, 1H).
2
13C NMR (D2O/1% DCl): d = 34.99, 35.45 (q, JCF = 31), 58.27,
127.64 (q, 1JCF = 247), 172.08.
19F NMR (D2O/1% DCl): d = 16.78 (t, 3JHF = 11).
FAB-MS: m/z = 172 [(M+1)+].
(R)-4,4,4-Trifluoro-2-methylaminobutyric Acid Methyl Ester
Hydrochloride (15)
2
13C NMR (CDCl3): = 28.60, 35.20 (q, JCF = 29), 53.11, 58.03,
81.68, 126.19 (q, 1JCF = 277), 156.96, 171.64.
19F NMR (CDCl3): = 14.22 (t, 3JHF = 11).
Compound 14 (100 mg, 0.58 mmol) was dissolved in MeOH (4 mL)
saturated with anhyd HCl and kept overnight at r.t. Evaporation of
the solvent in vacuo and storing over P2O5 gave 15 (129 mg, 99%)
as a pale green, crystalline solid; mp = 151 °C; [ ]21D = -4 (c 2,
MeOH).
EI-MS: m/z (%) = 286 (1, M+), 271 (2), 230 (16), 213 (6), 186 (25),
171 (24), 153 (11), 127 (64), 57 (100).
IR (KBr): = 3433, 1746 cm-1.
1H NMR (DMSO-d6): = 2.59 (s, 3H), 3.07-3.25 (m, 2H), 3.78 (s,
3H), 4.43 (dd, 1H, J = 7, 5), 9.91 (br s, 2H).
(R)-2-Benzylamino-4,4,4-trifluorobutyric Acid Hydrochloride
(12)
Compound 11a (416 mg, 1.6 mmol) was dissolved in a mixture of
aq HCl (4 mL, 20%) and dioxane (1 mL) and stirred for 3 days at
60 °C. Evaporation of the solvent in vacuo gave 12 (447 mg, 99%)
as slightly brown crystals; mp = 250 °C (dec.); [ ]21D = 0 (c 2, 1 N
aq HCl).
13C NMR (DMSO-d6): = 33.14, 34.04 (q, 2JCF = 30), 54.50, 56.45,
126.45 (q, 1JCF = 277), 168.44.
19F NMR (DMSO-d6): = 20.12 (t, 3JHF = 12).
IR (KBr): = 3420, 1746 cm-1.
EI-MS: m/z (%) = 185 [3, (M-HCl)+], 126 (100), 103 (6), 62 (4).
1H NMR (D2O): d = 2.71-2.92 (m, 2H), 4.06 (s, 2H), 4.13 (dd, 1H,
J = 5, 5), 7.17 (m, 5H).
(S)-4,4,4-Trifluoro-2-[(3,3,3-trifluoro-(R)-2-methoxy-2-phenyl-
propionyl)amino]butyric Acid Methyl Ester (16)
2
13C NMR (CD3OD): = 33.62 (q, JCF = 31), 51.03, 54.19 (q,
Compound 5c (90 mg, 0.40 mmol) was suspended in Et2O (5 mL),
N-methylmorpholine (45 mg, 0.45 mmol) was added and the mix-
ture was sonificated for 15 min. (S)-a-Trifluoromethyl-a-methox-
yphenylacetyl chloride (114 mg, 0.45 mmol) was added and the
mixture stirred for 1 day. The mixture was diluted with EtOAc (30
mL) and washed with NaHCO3 solution (3 × 10 mL), aqueous citric
acid (3 × 10 mL, 5%) and brine (3 × 10 mL). Drying (MgSO4) and
removing of the solvents gave 16 (91 mg, 72%) as colorless crys-
tals; mp = 104-106 °C; [ ]21D = -120 (c 2, CH2Cl2).
1
3JCF = 3), 125.47 (q, JCF = 277), 129.44, 130.12, 130.62, 130.84,
168.16.
19F NMR (DMSO-d6) = 16.16 (t, 3JHF = 11).
FAB-MS: m/z = 248 [(M-HCl)+].
(R)-2-Amino-4,4,4-trifluorobutyric Acid (13)
Compound 12 (300 mg, 1.1 mmol) was dissolved in MeOH (7 mL)
and HOAc (1 drop), the catalyst (Pd-C) was added and the mixture
was stirred in an H2 atm. After 2 days, the solvent was distilled off,
and the residue was dissolved in a small amount of EtOH (~2-3 mL)
and treated with propene oxide (0.5 mL). The precipitate was fil-
tered off and washed with Et2O to give 13 (145 mg, 87%) as a white
powder; mp = 244-247 °C (Lit.2d (S)-enantiomer): mp = 244 °C;
[ ]21D = -4 (c 2, 1 N aq HCl), [Lit.2d (S)-enantiomer: [ ]D = +3.4 (c
1, 5% aq HCl)].
IR (KBr): = 1759, 1647 cm-1.
1H NMR (CDCl3): = 2.70-3.20 (m, 2H), 2.77 (s, 3H), 3.73 (q, 3H,
5JHF = 2), 3.82 (s, 3H), 4.42 (dd, 1H, J = 10, 2), 7.37-7.44 (m, 3H),
7.50-7.73 (m, 2H).
2
13C NMR (CDCl3): = 32.97 (q, JCF = 29), 36.25, 53.33, 55.97,
3
2
1
57.61 (q, JCF = 3), 84.90 (q, JCF = 26), 123.93 (q, JCF = 290),
1
126.50 (q, JCF = 276), 127.31, 128.65, 129.95, 133.38, 166.88,
IR (KBr): = 3443, 1641 cm-1.
169.12.
Synthesis 2000, No. 12, 1681–1688 ISSN 0039-7881 © Thieme Stuttgart · New York

1688
H. Schedel et al.
PAPER
Osipov, S. N.; Golubev, A. S.; Sewald, N.; Michel, T.;
19F NMR (CDCl3): = 7.17 (br s), 13.26 (t, 3JHF = 12).
Kolomiets, A. F.; Fokin, A. V.; Burger, K. J. Org. Chem.
1996, 61, 7521.
FAB-MS: m/z = 424 [(M+Na)+], 402 [(M+1)+], 370 [(M-OCH3)+].
(5) Hrib, N. J.; Jurcak, J. G.; Bregna, D. E.; Burgher, K. L.;
Hartman, H. B.; Kafka, S.; Kerman, L. L.; Kongsamut, S.;
Roehr, J. E.; Szewczak, M. R.; Woods-Kettelberger, A. T.;
Corbett, R. J. Med. Chem. 1996, 39, 4044;
(R)-4,4,4-Trifluoro-2-[(3,3,3-trifluoro-(R)-2-methoxy-2-phenyl-
propionyl)amino]butyric Acid Methyl Ester (17)
In analogy to 16, compound 15 (55 mg, 0.25 mmol) was derivatized
with N-methylmorpholine (27 mg, 0.27 mmol) and (S)- -trifluo-
romethyl- -methoxyphenylacetyl chloride (70 mg, 0.28 mmol) to
give 17 (90 mg, 90%) as colorless crystalline solid (contains ap-
prox. 10% 16, 1H and 19F NMR analysis).
Ishizaki, Masahiko (Tokuyama Soda Kk) Jpn. Kokai, Tokyo,
Koho, JP 06122671, Chem. Abstr. 1994, 121, 179098;
Hrib, Nicholas J.; Jurcak, J. G. (Hoechst-Roussel
Pharmaceuticals, Inc.) U.S. US 5229388, Chem. Abstr. 1994,
120, 270452.
1H NMR (CDCl3): = 2.70-3.20 (m, 2H), 2.74 (s, 3H), 3.76 (s, 3H),
3.77 (s, 3H), 4.58 (dd, 1H, J = 10, 2), 7.38-7.54 (m, 5H).
19F NMR (CDCl3): = 7.09 (br s), 13.40 (t, 3JHF = 11).
Hrib, Nicholas J.; Jurcak, J. G. (Hoechst-Roussel Pharma-
ceuticals, Inc.) U.S. US 4933453, Chem. Abstr. 1991, 114,
81887.
Enomoto, M.; Kojima, A.; Komuro, Y.; Morooka, S.; Aono,
S.; Sanemitsu, Y.; Mizutani, M.; Tanabe, Y. (Sumitomo
Pharmaceuticals Co., Ltd.) Eur. Pat. Appl. EP 292305, Chem.
Abstr. 1989, 110, 144829.
Acknowledgement
We gratefully acknowledge financial support by Deutsche Fors-
chungsgemeinschaft and Bayer AG. We wish to thank Dipl. Chem.
Sven Tust for RP-HPLC analyses, Mr. Adam Wolniewicz (Inst. of
Org. Chem. of the Polish Academy of Sciences) for assistance with
GC analyses and helpful advice.
(6) Ojima, I.; Kato, K.; Jamieson, F. A.; Conway, J.; Nakahashi,
K.; Hagiwara, M.; Miyamae, T.; Radunz, H. E. Bioorg. Med.
Chem. Lett. 1992, 2, 219.
Ojima, I.; Jameison, F. A.; Pete, B.; Radunz, H. E.;
Schittenhelm, C.; Lindner, H. J.; Emith, A. E. USA Drug Des.
Discovery 1994, 11, 91.
Koksch, B.; Sewald, N.; Jakubke, H. -D.; Burger, K. In
Biomedical Frontiers of Fluorine Chemistry; Ojima, I.;
McCarthy, J. R.; Welch, J. T., Eds.; ACS Symposium Series
639; American Chemical Society: Washington, DC 1996, 42.
Winkler, D.; Sewald, N.; Burger, K.; Chung, N. N.; Schiller,
P. W. J. Peptide Sci. 1998, 4, 496.
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(14) Different chemical shifts, mps, and analyses of the
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Synthesis 2000, No. 12, 1681–1688 ISSN 0039-7881 © Thieme Stuttgart · New York