Synthesis of new δ-(polyfluoroalkyl)-oδ-hydroxy-α-amino acids

Article abstract of DOI:10.1002/ejoc.200900684

New δ-(polyfluoroalkyl)-oδ-hydroxy-α-amino acids were synthesized from the corresponding starting 3-(benzoylamino)6-(polyfluoroalkyl)- 2H-pyran-2-ones. The key step of the synthesis was the hydrogenation of the pyrone ring. Stereoselectivity and yields de

Full text of DOI:10.1002/ejoc.200900684

FULL PAPER
DOI: 10.1002/ejoc.200900684
Synthesis of New δ-(Polyfluoroalkyl)-δ-hydroxy-α-amino Acids
Nataliya A. Tolmacheva,[a] Igor I. Gerus,*[a] Violetta G. Dolovanyuk,[a] Ivan S. Kondratov,[a]
and Günter Haufe*[b]
Keywords: Amino acids / Polyfluoroalkyl groups / 2-Pyrones / Hydrogenation / Ring-opening / Fluorine
New δ-(polyfluoroalkyl)-δ-hydroxy-α-amino acids were syn-
thesized from the corresponding starting 3-(benzoylamino)-
6-(polyfluoroalkyl)-2H-pyran-2-ones. The key step of the
synthesis was the hydrogenation of the pyrone ring. Stereo-
selectivity and yields depended dramatically on the reaction
conditions and the nature of the polyfluoroalkyl group. Vari-
ous conditions were used for the preparation of both mixtures
of diastereomers and pure diastereomers of the target amino
acids. The obtained δ-(polyfluoroalkyl)-δ-hydroxy-α-amino
acids are of interest as analogues of 2-amino-5-hydroxyva-
leric acid and glutamic acid.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
of numerous efficient inhibitors of proteolytic enzymes.[6]
By way of example, the amino acids 1a and 2a are of inter-
est as potential modulators of processes involving 2-amino-
5-hydroxyvaleric acid or glutamic acid as substrates.
Introduction
Fluorinated analogues of naturally occurring substances
play an important role in the design of new biologically
active compounds.[1] In this field, fluorinated α-amino acids
represent one of the most popular classes of compounds
that are particularly interesting as potential reversible or
irreversible inhibitors of enzymes. Moreover, these com-
pounds are useful as building blocks for peptides, to modify
their properties, and as starting materials in fluoroorganic
synthesis.[1,2] Although a large number of diverse fluori-
nated amino acids have been synthesized during the past 50
years, research interest has not decreased, and each new
synthesized fluorinated amino acid attracts considerable at-
tention.[3]
In this article we present the synthesis of the new fluoro-
alkylated δ-hydroxy-α-amino acids 1 and 2 (Scheme 1).
These compounds can be considered polyfluoroalkyl ana-
logues of 2-amino-5-hydroxyvaleric acid, which plays an im-
portant role in proline biosynthesis.[4] Moreover, com-
pounds 1 and 2 can also be regarded as glutamic acid ana-
logues, because the CF3CH(OH) unit is in some cases a
bioisostere of the CO2H group (high acidity; C–CF3 is sub-
stantially isopolar with the C=O group[5]). The properties
of the α-(trifluoromethyl) alcohol moiety as a mimetic of
the carboxylic acid function are widely used in the design
Scheme 1. Target amino acids 1a–c and 2a–c and their precursor
pyrones 3a–c.
Some fluorinated glutamate analogues have successfully
been used to study glutamate hydrolase (GH) activity,[7] to
modulate folate poly-γ-glutamate biosynthesis, and to pre-
pare methotrexate (MTX) analogues, which have been
shown to be inhibitors of dihydrofolate reductase
(DHFR).[8] Because of the great interest in glutamic acid
analogues, compounds 1a and 2a, as well as other fluori-
nated analogues such as 1b–c and 2b–c, are interesting as
potential enzyme modulators.
[a] Institute of Bioorganic Chemistry and Petrochemistry, National
Ukrainian Academy of Science,
We have previously reported the synthesis[9] and reactivi-
ties[9,10] of pyrones 3, which in this paper have served as con-
venient precursors of the target amino acids 1 and 2. The
pyrones 3 have the same carbon skeletons and necessary
functional groups. Obviously, their hydrogenation and sim-
ple functional-group transformation should be the most ef-
ficient approach to compounds 1 and 2.
Murmanska 1, Kiev 94 02660, Ukraine
Fax: +38-044-573-25-52
E-mail: igerus@hotmail.com
[b] Organisch-Chemisches Institut der Universität Münster,
Corrensstraße 40, 48149 Münster, Germany
Fax: +49-251-83-39772
E-mail: haufe@uni-muenster.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900684.
5012
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5012–5019

Synthesis of New δ-(Polyfluoroalkyl)-δ-hydroxy-α-amino Acids
Careful treatment of a mixture of the CF3 diastereomers
6a/7a with 15% HCl (Scheme 3) led to a mixture of the
corresponding diastereomeric benzoylamino acids 8 and 9.
Fractional crystallization of the mixture provided the major
compound 8 as a pure diastereomer in 43% yield. The cor-
rect assignment of structures 6a and 7a was confirmed by
X-ray analysis of 8 (Figure 1).
Results and Discussion
Catalytic reduction of double bonds of pyrones with sub-
sequent ring-opening by nucleophiles is a well-known syn-
thetic protocol.[11] Initially, we used standard conditions
(H2/PdCl2, atmospheric pressure, room temperature,
MeOH/Et3N) for the transformations of pyrones 3a–c
(Scheme 2). Accordingly, the first step led to the tetra-
hydropyrones 4 and 5, which were transformed into the cor-
responding benzoylamino acid esters 6 and 7 by meth-
anolysis. The selectivities of the reactions can be easily es-
tablished from the 19F NMR spectra of the crude product
mixtures.
Scheme 3. Preparation of diastereomerically pure benzoylamino
acid 8.
Scheme 2. Reduction of the pyrones 3a–3d.
Figure 1. X-ray structure of compound 8 (as monohydrate).
The reduction of the CF2Cl-substituted pyrone 3d under
It has been shown that both the yields and the selectivi-
ties of the reactions dramatically depend on the nature of
the polyfluoroalkyl group (Table 1, Entries 1–4). In all cases
mixtures of diastereomeric benzoylamino acid esters were the same conditions occurred in a different way (Table 1,
formed. The stereoselectivity of the reduction of the CF3- Entry 4), with hydrogenation of the pyrone ring being ac-
substituted pyrone 3a was quite low, and the reduction of companied by transformation of the CF2Cl group into a
the C3F7-substituted pyrone 3b did not show any stereo- CF2H group. Consequently, the major products were com-
selectivity at all. In contrast, high stereoselectivity was ob- pounds 6c and 7c, identical to the products obtained from
served in the case of the CHF2-substituted pyrone 3c, but pyrone 3c. Compounds 2c and 10[9] (Figure 2) were also
several inseparable by-products were also formed, and the isolated from the reaction mixture as by-products in 20%
isolated yield after column chromatography was low. All and 6% yields, respectively.
attempts to separate the diastereomers 6a/7a and 6b/7b
From the mixture of 6c and 7c, the diastereomerically
from each other by chromatography or crystallization pure amide 6c was isolated in 40% yield by fractional
failed.
crystallization from CHCl3. The structure of 6c was verified
Table 1. Reduction of the pyrones 3a–c.
Entry
Starting compound
Conditions[a]
Isolated products (ratio)
General yield [%]
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3d
3a
3a
3b
3c
3d
A
A
A
A
B
C
D
D
D
D
6a/7a (7:3)
6b/7b (1:1)
6c/7c (19:1)
6c/7c (9:1)
6c/7c (1:1)
4a
80
76
11
33
75
conversion ca. 10%[b]
4a
86
59
38
–
4b/5b (17:3)
4c
unresolved mixture
10
[a] For the conditions see Scheme 2. [b] The product was not isolated.
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I. I. Gerus, G. Haufe et al.
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Entry 10). Compounds 2c and 10 (among other by-prod-
ucts) were detected in this mixture by NMR spectroscopy,
but there was no evidence of compounds 4 or 5, nor of 6
or 7.
The configurations of the tetrahydropyrones 4 and 5
Figure 2. By-product 10 derived from the reduction of pyrone 3d were confirmed by NOE experiments (irradiation of 3-CH)
by treatment with H2/PdCl2, Et3N, MeOH (Table 1, Entry 4).
for compound 4a (Figure 4). The NOE experiments con-
firmed an interaction between 3-CH and 6-CH, which sug-
gests the cis orientation of the CF3 and NHCOPh groups.
by X-ray analysis, which confirms its relative stereochemis-
try (Figure 3). The X-ray data show that two rotamers (ra-
tio 16:84) with different orientations of the difluoromethyl
group exist in the crystal. The configurations of compounds
6a and 6b were anticipated to be the same as that of 6c
according to the similar spectroscopic data for these com-
pounds.
Figure 4. Confirmation of relative configuration of compound 4a
by NOE experiments.
Ring-opening of the diastereomerically pure lactones 4a
and 4b was easily achieved by treatment with Et3N/MeOH
(see Scheme 2). The products of the reaction were identified
as 6a and 6b, respectively, from the similarity of their spec-
troscopic data with those for the compounds obtained by
reduction in MeOH/Et3N. The two-step procedure (hydro-
genation under conditions D and ring-opening) thus pro-
vided the opportunity to obtain the pure diastereomers 6a
and 6b.
A different result was obtained on reversing the reaction
sequence (i.e., ring-opening and subsequent hydrogenation).
Ring-opening of compound 3a led to the salt 11, containing
Figure 3. X-ray structure of compound 6c.
a methoxy group adjacent to the CF3 moiety (Scheme 4).
After hydrogenation of 11 under conditions A, an insepa-
rable mixture of the diastereomers 12 and 13 (1:1) was ob-
tained.
The reduction of the CF2Cl-substituted pyrone 3d under
forced conditions and without Et3N (Table 1, Entry 5) pro-
ceeded without stereoselectivity, again giving a mixture of
the CHF2-substituted products 6c and 7c. This mixture was
not separated. It should be noted that the intermediate lac-
tones 4 or 5 were not detected, although Et3N was not used.
In order to increase the stereoselectivity and/or to allow
the separation of the diastereomeric products, we per-
formed the hydrogenation of pyrones 3a–c in aprotic sol-
vents (Table 1, Entries 6–9) and without Et3N. It was shown
that the hydrogenation of compound 3a in EtOAc (Entry 6)
proceeds slowly; after 2 weeks, the degree of conversion was
only 10%. In contrast, the reaction of 3a in THF (under
20 atm pressure, Table 1, Entry 7) proceeded in 2–3 h, and
compound 4a was isolated as a pure diastereomer in 86%
yield. Compounds 3b–c were reduced in the same way at
Scheme 4. Preparation of a mixture of diastereomers 12 and 13.
In summary, conditions A and D (with subsequent ring-
30 atm (Table 1, Entries 8–9). The C3F7-substituted pyrone opening) gave mixtures of diastereomers 6a/7a (7:3), 6b/7b
3b gave a mixture of the diastereomeric tetrahydropyrones (1:1), and 6c/7c (9:1), as well as the pure diastereomers 6a,
4b and 5b. The major diastereomer 4b was isolated in 25% 6b, and 6c by fractional crystallization.
yield (based on pyrone 3b) by fractional crystallization from
All mixtures of diastereomers and pure diastereomers
CHCl3/CCl4 (3:5). The hydrogenation of the CHF2-substi- were easily transformed into the corresponding amino acids
tuted pyrone 3c led to a complex mixture (as in the case of (either as mixtures of diastereomers 1a–c and 2a–c or as
the reaction in MeOH/Et3N, Table 1, Entry 3), and the pure pure diastereomers 1a–c) by acidic hydrolysis in HCl (30%)
diastereomer 4c was isolated in 38% yield (Table 1, En- at reflux (Scheme 5, Table 2, Entries 1–6). The isolation and
try 9). Under the same conditions, the CF2Cl-substituted purification were performed by ion-exchange chromatog-
pyrone 3d gave an inseparable mixture of products (Table 1, raphy, giving the target compounds in good yields. The
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Eur. J. Org. Chem. 2009, 5012–5019

Synthesis of New δ-(Polyfluoroalkyl)-δ-hydroxy-α-amino Acids
25 °C. TMS (for 1H and 13C NMR) and CCl3F (for 19F NMR)
were used as internal standards. IR spectra were recorded with a
Specord M-80 spectrometer. The reaction progress was monitored
by TLC (silica gel 60 F254 plates, Merck). Column chromatog-
raphy was carried out with silica gel 60 (Merck No. 109385, particle
size 0.040–0.063). Ion-exchange chromatography was performed on
Amberlite IR-120 by standard techniques.[12]
same conditions were used to obtain mixtures of the dia-
stereomeric δ-methoxy-α-amino acids 14 and 15 from the
mixture of the benzoylamino acids 12 and 13 (Scheme 5,
Table 2, Entry 7).
Starting Materials: All starting materials were of the highest com-
mercial quality and were used without further purification. The
pyrones 3a–d were prepared according to our previously published
procedures.[9]
Hydrogenation of Pyrones 3a–d
Conditions A: Hydrogen was passed through a mixture of the corre-
sponding pyrone (3a–c, 0.5 mmol), PdCl2 (17 mg, 0.1 mmol), and
triethylamine (76 mg, 0.75 mmol) in dry methanol (20 mL) for ca.
6 h. The reaction progress was monitored by TLC. After the hydro-
genation was complete, the solid residue was filtered off, and the
solvent was evaporated in vacuo. The residue was crystallized or
purified by column chromatography. Isolated yields are given in
Table 1 (Entries 1–4). In the case of hydrogenation of pyrone 3d,
compounds 2c and 10 were also isolated [column chromatography,
hexane/EtOAc (2:1)] from the reaction mixture as by-products in
20% and 6% yields, respectively. Spectral data are identical to those
described in a previous paper.[9]
Scheme 5. Preparation of amino acids 1, 2, 14, and 15.
Table 2. Deprotection of the benzamides 6a–c and 7a–c.
Entry Starting materials Isolated products[a] (ratio) Overall yield [%]
Methyl 2-(Benzoylamino)-6,6,6-trifluoro-5-hydroxyhexanoate [Mix-
ture of Diastereomers 6a/7a (7:3)]: These compounds were obtained
from pyrone 3a (141 mg) by the General Procedure and were puri-
fied by crystallization from CHCl3/hexane (1:3). The dia-
stereomeric ratio was not changed by recrystallization. Yield:
1
2
3
4
5
6
7
6a/7a (7:3)
6b/7b (1:1)
1a/2a (7:3)
1b/2b (1:1)
45
47
57
56
43
77
28
6a
6b
6c
8
1a
1b
1c
1
127 mg (80%), white solid, m.p. 143–144 °C. H NMR (300 MHz,
1a
[D6]acetone): δ = 1.79 (m, 2 H, CH2), 2.12 (m, 2 H, CH2), 3.70 (s,
3 H, OCH3), 4.12 (m, 1 H, CF3CH), 4.74 (m, 1 H, CHNH), 5.41
(br. s, 1 H, OH), 7.51 (m, 3 H, Ph), 7.93 (m, 2 H, Ph), 8.04 (br. d,
JH,H = 8.4 Hz, 1 H, NH) ppm. 19F NMR (282 MHz, [D6]acetone):
δ = –79.12 (d, JF,H = 9.2 Hz, CF3 group of compound 7a), –79.19
(d, JF,H = 9.2 Hz, CF3 group of compound 6a) ppm; integration of
these signals showed a 7:3 ratio of 6a/7a. C14H16F3NO4 (319.1):
calcd. C 52.67, H 5.05, N 4.39; found C 52.70, H 5.03, N 4.40.
12/13 (1:1)
14/15 (1:1)
[a] For the conditions see Scheme 5.
Conclusions
The new δ-(polyfluoroalkyl)-δ-hydroxy-α-amino acids 1
and 2 were prepared from the corresponding starting pyr-
ones 3. The synthetic pathway included the hydrogenation
of pyrones 3 to the tetrahydropyrones 4 with subsequent
ring-opening and hydrolysis of the amide and ester func-
tions. The first two steps can also be achieved in a one-
pot fashion under conditions A [H2, PdCl2 (10–20 mol-%),
1 atm, Et3N/MeOH, room temp., 6 h], but in this case the
stereoselectivity was low. The reaction conditions D [H2,
Pd/C (5%), 20–30 atm, THF, room temp., 2 h] are most
convenient for the preparation of the diastereomerically
pure fluorinated δ-lactones 4, which were used to synthesize
the corresponding pure δ-hydroxy-α-amino acids 1. The se-
lective preparation of the diastereomers 2, as well as the
synthesis of pure enantiomers of 1 and 2, is under investiga-
tion and will be published in due course.
Methyl 2-(Benzoylamino)-6,6,7,7,8,8,8-heptafluoro-5-hydroxyocta-
noate [Mixture of Diastereomers 6b/7b (1:1)]: These compounds
were obtained from pyrone 3b (191 mg) and were purified by
crystallization from CHCl3/hexane (1:2). The ratio of diastereomers
did not change after crystallization. Yield: 160 mg (76%), white
solid, m.p. 115–116 °C. 1H NMR (300 MHz, CDCl3): δ = 1.68–
2.32 (m, 4 H, CH2CH2), 3.80 (s, 3 H, CH3 of compound 6b), 3.82
(s, 3 H, CH3 of compound 7b), 4.22 (m, 1 H, CF2CH), 4.87 (m,
CHNH of compound 6b), 5.01 (m, CHNH of compound 7b and
OH), 7.04 (d, JH,H = 7.4 Hz, NH of compound 6b), 7.08 (d, JH,H
= 7.4 Hz, NH of compound 7b), 7.40–7.59 (m, 3 H, Ph), 7.81 (m,
2 H, Ph) ppm. 19F NMR (470 MHz, [D6]DMSO): δ = –81.44 (br.
m, 3 F, CF3), –121.43 (d, JF,F = 287 Hz, CFFCF2CF3 of compound
7b), –121.62 (d, JF,F = 283.3 Hz, CFFCF2CF3 of compound 6b),
–125.35 (d, JF,F = 293.5 Hz, CFFCF3 of compound 7b), –125.60
(d, JF,F = 293.5 Hz, CFFCF3 of compound 6b), –127.01 (d, JF,F
293.5 Hz, CFFCF3 of compound 6b), –127.35 (d, JF,F = 293.5 Hz,
CFFCF3 of compound 7b), –128.00 (d, JF,F 278.4 Hz,
=
=
CFFCF2CF3 of compound 6b), –129.48 (d, JF,F = 278.4 Hz,
CFFCF2CF3 of compound 7b) ppm; integration of these signals
showed a 1:1 ratio of 6b/7b. C16H16F7NO4 (419.3): calcd. C 45.83,
H 3.85, N 3.34; found C 45.80, H 3.87, N 3.38.
Experimental Section
General: Melting points are uncorrected. NMR spectra were re-
corded with a Varian VXR 300 instrument at 300 MHz (1H),
75.4 MHz (13C), or 282 MHz (19F) or with a Bruker Avance DRX
instrument at 500 MHz (1H), 126 MHz (13C), or 470 MHz (19F) at
Methyl 2-(Benzoylamino)-6,6-difluoro-5-hydroxyhexanoate [Mixture
of Diastereomers 6c/7c (19:1 or 9:1)]: These compounds were ob-
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I. I. Gerus, G. Haufe et al.
FULL PAPER
tained either from pyrone 3c (132 mg) or from pyrone 3d (150 mg)
and were purified by column chromatography [EtOAc/hexane (1:2),
Rf ≈ 0.3]. The ratio of diastereomers had not changed after purifi-
cation. Yield: 17 mg (11%) from pyrone 3c and 50 mg (33%) from
and the solvent was evaporated in vacuo. The residue was purified
(if necessary) by crystallization. Yields are presented in Table 1 (En-
tries 7–10). In the case of the pyrone 3d, an unresolved mixture was
obtained.
1
pyrone 3d, white solid. H NMR (500 MHz, CDCl3): δ = 1.59 (m,
(3R,6R/3S,6S)-N-[2-Oxo-6-(trifluoromethyl)-tetrahydropyran-3-yl]-
benzamide (4a): This compound was obtained from pyrone 3a
(283 mg) and was crystallized from toluene. Yield: 247 mg (86%),
1 H, CHHCH2), 1.74 (m, 1 H, CHHCH2), 2.12 (m, 1 H,
CH2CHH), 2.14 (m, 1 H, CH2CHH), 3.68 (m, CHF2CH of com-
pound 7c), 3.78 (s, CH3 of compound 6c), 3.79 (s, CH3 of com-
pound 7c), 3.82 (m, CHF2CH of compound 6c), 4.85 (m, CHNH
of compound 6c), 4.92 (m, CHNH of compound 7c), 5.60 (td, JH,F
1
white solid, m.p. 221–222 °C. H NMR (500 MHz, [D6]acetone): δ
= 2.12 (m, 2 H, CH2), 2.42 (m, 1 H, CHH), 2.54 (m, 1 H, CHH),
5.11 (m, 1 H, CHCF3), 5.33 (m, 1 H, CHNH), 7.47 (m, 2 H, Ph),
7.55 (m, 1 H, Ph), 7.92 (m, 2 H, Ph), 8.30 (br. d, JH,H = 4.9 Hz, 1
H, NH) ppm. 13C NMR (126 MHz, [D6]acetone): δ = 19.9 (CH2),
22.7 (CH2), 47.4 (CHNH), 73.5 (q, JC,F = 34.7 Hz, CHCF3), 123.4
(q, JC,F = 278.8 Hz, CF3), 127.3 (Ph), 128.3 (Ph), 131.5 (Ph), 134.1
(Ph), 166.4 (CO), 169.2 (CO) ppm. 19F NMR (470 MHz, CDCl3):
= 56.1, JH,H = 3.8 Hz, CHF2 of compound 6c), 5.62 (td, JH,F
56.1, JH,H = 3.8 Hz, CHF2 of compound 7c), 6.90 (d, JH,H
=
=
7.5 Hz, NH of compound 6c), 7.00 (d, JH,H = 7.5 Hz, NH of com-
pound 7c), 7.43 (m, 2 H, Ph), 7.51 (m, 1 H, Ph), 7.78 (m, 2 H, Ph)
ppm. 19F NMR (470 MHz, CDCl3): δ = –128.37 (ddd, JF,F = 10.1,
286.8, JF,H = 56.1 Hz, CHFF of compound 7c), –122.4 (m, CHFF
of compound 6c), –129.58 (m, CHFF of compound 6c), –121.16
(ddd, JF,F = 10.1, 286.8, JF,H = 56.1 Hz, CHFF of compound 7c)
ppm; the ratio of signal integrals for compounds 6c/7c is 19:1 or
9:1, depending on the starting material (3c or 3d, respectively).
C14H17F2NO4 (301.1): calcd. C 55.81, H 5.69, N 4.65; found C
55.78, H 5.70, N 4.62.
δ = –77.29 (d, JF,H = 6.0 Hz, CF ) ppm. IR (CHCl ): ν = 3388,
˜
3
3
1764, 1662, 1600, 1552, 1488, 1448, 1367, 1296, 1184, 1117, 1077,
984 cm–1. C13H12F3NO3 (287.1): calcd. C 54.36, H 4.21, N 4.88;
found C 54.33, H 4.17, N 4.97.
N-[6-(Heptafluoropropyl)-2-oxo-tetrahydropyran-3-yl]benzamide
[Mixture of Diastereomers 4b/5b (17:3)]: These compounds were
obtained from pyrone 3b (383 mg) without additional purification.
Methyl
(3R,6R/3S,6S)-2-(Benzoylamino)-6,6-difluoro-5-hydroxy-
1
Yield: 228 mg (59%), white solid. H NMR (500 MHz, CDCl3): δ
hexanoate (6c): This compound was obtained from a mixture of
diastereomers 6c/7c (50 mg) by fractional crystallization from
CHCl3. Yield: 20 mg (40%), white solid, m.p. 129–130 °C. 1H
NMR (500 MHz, CDCl3): δ = 1.59 (m, 1 H, CHHCH2), 1.74 (m,
1 H, CHHCH2), 2.12 (m, 1 H, CH2CHH), 2.14 (m, 1 H,
CH2CHH), 3.78 (s, 3 H, CH3), 3.82 (m, 1 H, CHF2CH), 4.85 (m,
CHNH), 5.60 (td, JH,F = 56.1, JH,H = 3.8 Hz, CHF2), 6.90 (d, JH,H
= 7.5 Hz, NH), 7.43 (m, 2 H, Ph), 7.51 (m, 1 H, Ph), 7.78 (m, 2
H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ = 25.5 (t, CH2), 28.5
(CH2), 52.1 (CH3), 52.8 (CHNH), 70.6 (t, JC,F = 23.8 Hz, CHOH),
116.1 (t, JC,F = 244.3 Hz, CHF2), 127.1 (Ph), 128.7 (Ph), 132.0
(Ph), 133.6 (Ph), 167.4 (CONH), 172.9 (CO2Me) ppm. 19F NMR
(470 MHz, CDCl3): δ = –122.4 (m, CHFF), –129.58 (m, CHFF)
ppm. C14H17F2NO4 (301.11): calcd. C 55.81, H 5.69, N 4.65; found
C 55.79, H 5.66, N 4.63.
= 1.79 (m, CHH of compound 4b), 2.06 (m, CHH of compound
5b), 2.20–2.37 (m, 2 H, CH2), 2.70 (m, CHH of compound 5b),
2.87 (m, CHH of 4b), 4.52 (m, CHCF2 of 5b) 4.98 (m, CHNH and
CHCF2 of compound 4b), 7.06 (br. d, JH,H = 5.0 Hz, 1 H), 7.46
(m, 2 H, Ph), 7.55 (m, 1 H, Ph), 7.82 (m, 2 H, Ph) ppm. 19F NMR
(470 MHz, CDCl3): δ = –81.25 (t, JF,F = 11.00 Hz, CF3 of com-
pound 4b), –81.30 (t, JF,F = 11.00 Hz, CF3 of compound 5b),
–122.60 (d, JF,F = 287.0 Hz, CFFCF2CF3 of compound 4b),
–123.23 (d, JF,F = 287.0 Hz, CFFCF2CF3 of compound 5b),
–125.89 (d, JF,F = 293.0 Hz, CFFCF3 of compound 5b), –126.03
(d, JF,F = 291.5 Hz CFFCF3 of compound 4b), –126.80 (d, JF,F
=
293 Hz, CFFCF3 of compound 5b), –126.87 (d, JF,F = 291.5 Hz,
CFFCF3 of compound 4b), –127.23 (d, JF, F = 287.0 Hz,
CFFCF2CF3 of 4b), –127.38 (d, JF,F = 287.0 Hz, CFFCF2CF3 of
compound 5b) ppm; integration of these signals showed a 17:3 ratio
of compounds 4b/5b.
Conditions B
Methyl 2-(Benzoylamino)-6,6-difluoro-5-hydroxyhexanoate [Mixture
of Diastereomers 6c/7c (1:1)]: A mixture of pyrone 3d (299 mg,
1 mmol) in MeOH (20 mL) and Pd/C (0.05 g) was stirred in an
autoclave under hydrogen pressure (50 atm) at room temp. for 6 h.
The reaction progress was monitored by TLC. After the reduction
was complete, the residue was filtered through a short pad of silica
gel, and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography [hexane/EtOAc (2:1), Rf ≈ 0.3].
Yield: 225 mg (75%). The spectroscopic data for the mixture are
presented above.
(3R,6R/3S,6S)-N-[6-(Heptafluoropropyl)-2-oxo-tetrahydropyran-3-yl]-
benzamide (4b): This compound was obtained by recrystallization
of the mixture of diastereomers 4b/5b (17:3, 228 mg) from toluene
or CHCl3/CCl4 (3:5). Yield: 97 mg (25%, based on pyrone 3b), m.p.
180–182 °C. 1H NMR (500 MHz, CDCl3): δ = 1.79 (m, 1 H, CHH),
2.20–2.37 (m, 2 H, CH2), 2.87 (m, 1 H, CHH), 4.98 (m, 2 H,
CHNH and CHCF2), 7.06 (br. d, JH,H = 5.0 Hz, 1 H), 7.46 (m, 2
H, Ph), 7.55 (m, 1 H, Ph), 7.82 (m, 2 H, Ph) ppm. 13C NMR
(126 MHz, CDCl3): δ = 19.1 (CH2), 22.7 (CH2), 47.1 (CHNH),
72.6 (t, JC,F = 28.3 Hz, CHCF2), 127.3 (Ph), 128.3 (Ph), 131.0 (Ph),
134.0 (Ph), 166.6 (CO), 169.1 (CO) ppm; low-intensity and high-
multiplicity signals of C3F7-fragment C atoms are in the δ = 110–
Conditions C
A mixture of the pyrone 3a (299 mg, 1 mmol) in EtOAc (20 mL)
and Pd/C (5%, 0.05 g) was stirred in an autoclave under hydrogen
pressure (10 atm) at room temp. The reaction progress was moni-
tored by TLC and 19F NMR spectroscopy. After 2 weeks, just 10%
conversion was observed. The reaction product 4a was not isolated.
130 ppm range. 19F NMR (470 MHz, CDCl3): δ = –81.25 (t, JF,F
11.00 Hz, 3 F, CF3), –122.60 (d, JF,F = 287.0 Hz, 1 F, CFFCF2CF3),
–126.03 (d, JF,F = 291.5 Hz, 1 F, CFFCF3), –126.87 (d, JF,F
291.5 Hz, 1 F, CFFCF3), –127.23 (d, JF,F = 287.0 Hz, 1 F,
=
=
CFFCF CF ) ppm. IR (CHCl ): ν = 3300, 1758, 1648, 1600, 1537,
˜
2
3
3
1372, 1264, 1224, 1194, 1128, 1076, 960 cm–1. C15H12F7NO3
(387.1): calcd. C 46.52, H 3.12, N 3.62; found C 46.54, H 3.10, N
3.59.
Conditions D
A mixture of a pyrone (3a–d, 1 mmol) in dry THF (30 mL) and Pd/
C (5%, 0.05 g) was stirred in an autoclave under hydrogen pressure
(10 atm) at room temp. for 2 h. The reaction progress was moni-
tored by TLC and 19F NMR spectroscopy. After complete hydro-
genation, the residue was filtered through a short pad of silica gel,
(3R,6R/3S,6S)-N-[6-(Difluoromethyl)-2-oxo-tetrahydropyran-3-yl]-
benzamide (4c): This compound was obtained from pyrone 3c
(265 mg) and was crystallized from CHCl3/hexane (1:2). Yield:
5016
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5012–5019

Synthesis of New δ-(Polyfluoroalkyl)-δ-hydroxy-α-amino Acids
1
102 mg (38%), white solid, m.p. 159–160 °C. H NMR (500 MHz, 126.4 (q, JC,F = 283.6 Hz, CF3), 127.9 (Ph), 128.7 (Ph), 132.0 (Ph),
CDCl3): δ = 1.76 (m, 1 H, CHH), 2.03 (m, 1 H, CHH), 2.16 (m, 1 134.2 (Ph), 167.2 (CONH), 172.8 (CO2Me) ppm. 19F NMR
H, CHH), 2.72 (m, 1 H, CHH), 4.64 (m, 1 H, CHNH), 4.98 (m, 1 (470 MHz, [D6]acetone): δ = –79.12 (d, JF,H = 7.1 Hz, CF3) ppm.
H, CHCHF2), 7.87 (t, JH,F = 53.1 Hz, 1 H, CHF2), 7.18 (br. s, 1
IR (CHCl ): ν = 2960, 1746, 1640, 1551, 1448, 1202, 1160, 1144,
˜
3
H, NH), 7.47 (m, 3 H, Ph), 7.81 (m, 2 H, Ph) ppm. 13C NMR 1048 cm–1. C14H16F3NO4 (319.10): calcd. C 52.67, H 5.05, N 4.39;
(126 MHz, CDCl3): δ = 19.1 (t, JC,F = 3.0 Hz, CH2), 23.5 (CH2),
48.2 (CHNH), 75.1 (t, JC,F = 27.8 Hz, CHCHF2), 113.2 (t, JC,F
244.5 Hz, CF3), 127.1 (Ph), 128.6 (Ph), 133.1 (Ph), 133.2 (Ph),
167.4 (CO), 171.0 (CO) ppm. 19F NMR (470 MHz, CDCl3): δ =
–130.44 (ddd, JF,F = 9.3, 53.3, 294.6 Hz, 1 F, CHFF), –134.80 (ddd,
found C 52.64, H 5.00, N 4.43.
=
Methyl (2R,5R/2S,5S)-2-(Benzoylamino)-6,6,7,7,8,8,8-heptafluoro-
5-hydroxyoctanoate (6b): This compound was obtained from com-
pound 4b (387 mg) and was crystallized from CHCl3/hexane (1:1),
yield 327 mg (78%), white solid, m.p. 106–108 (decomposition). 1H
NMR (500 MHz, CDCl3): δ = 1.79 (m, 1 H, CHH), 1.89 (m, 1 H,
CHH), 2.08 (m, 1 H, CHH), 2.17 (m, 1 H, CHH), 3.79 (s, 3 H,
CH3), 4.22 (m, 1 H, CHCF2), 4.87 (m, 1 H, CHNH), 7.00 (br. d,
JH,H = 7.3 Hz, 1 H, NH), 7.43 (m, 2 H, Ph), 7.53 (m, 1 H, Ph),
7.93 (m, 2 H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ = 24.7
JF,F = 9.3, 53.3, 294.6 Hz, 1 F, CHFF) ppm. IR (CHCl ): ν = 3060,
˜
3
1764, 1665, 1515, 1488, 1150, 1088 cm–1. C13H13F2NO3 (269.1):
calcd. C 57.99, H 4.87, N 5.20; found C 58.00, H 4.89, N 5.21.
Synthesis of Hydroxy-(benzoylamino) Acids 8 and 9
2-(Benzoylamino)-6,6,6-trifluoro-5-hydroxyhexanoic Acid [Mixture
of Diastereomers 8/9 (7:3)]: A mixture of the diastereomers 6a/7a
(300 mg, 0.98 mmol) was dissolved in hydrochloric acid (15 %,
15 mL). The solution was stirred at 65 °C for 4 h and was then
allowed to cool to room temp. The formed precipitate was filtered
and recrystallized from EtOH/H2O (1:4). Yield: 216 mg (72 %),
(CH2), 28.4 (CH2), 52.1 (CH3), 52.8 (CHNH), 69.3 (t, JC,F
=
28.4 Hz, CHCF2), 127.1 (Ph), 128.7 (Ph), 132.1 (Ph), 133.3 (Ph),
167.8 (CONH), 172.8 (CO2Me) ppm; low-intensity and high-multi-
plicity signals of C3F7-fragment C atoms are in the δ = 110–
130 ppm range. 19F NMR (470 MHz, CDCl3): δ = –81.44 (t, JF,F
= 9.5 Hz, 3 F, CF3), –121.62 (d, JF,F = 278.4 Hz, 1 F, CFFCF2CF3),
1
white solid. H NMR (300 MHz, [D6]acetone): δ = 1.65 (m, 1 H,
–125.71 (d, JF,F = 293.5 Hz, 1 F, CFFCF3), –127.01 (d, JF,F
293.5 Hz, 1 F, CFFCF3), –127.95 (d, JF,F = 278.4 Hz, 1 F,
=
CHH), 1.75 (m, 1 H, CHH), 2.32 (m, 2 H, CH2), 4.09 (m, 1 H,
CHNH), 4.65 (m, 1 H, CHCF3), 5.10 (br. s, 1 H, NH), 7.33 (m, 2
H, Ph), 7.41 (m, 1 H, Ph), 7.81 (m, 3 H, Ph and OH) ppm. 19F
NMR (282 MHz, [D6]acetone): δ = –80.53 (d, JF,H = 6.9 Hz, CF3
of compound 8), –80.60 (d, JF,H = 6.9 Hz, CF3 of compound 9)
ppm; integration of these signals showed a 7:3 ratio of 8/9.
CFFCF CF ) ppm. IR (CHCl ): ν = 3060, 1747, 1661, 15253, 1477,
˜
2
3
3
1429, 1356, 1210, 1110 cm–1. C16H16F7NO4 (419.3): calcd. C 45.83,
H 3.85, N 3.34; found C 45.81, H 3.89, N 3.30.
Triethylammonium Salt of 2-(Benzoylamino)-6,6,6-trifluoro-5-meth-
oxyhexa-2,4-dienoic Acid (11): The pyrone 3a (320 mg, 1.13 mmol)
was added to a solution of triethylamine (0.5 mL) in MeOH
(15 mL), and the mixture was stirred at room temp. for 5 h. The
solution was then concentrated in vacuo (bath temperature 30–
40 °C, 30–60 Torr). The residue was crystallized from CH3CN to
give compound 11. Yield: 390 mg (83%). Light yellow solid, m.p.
(2R,5R/2S,5S)-2-(Benzoylamino)-6,6-difluoro-5-hydroxyhexanoic
Acid (8): This compound was obtained by fractional crystallization
of the 8/9 mixture (7:3, 200 mg, 0.66 mmol) from EtOH/H2O (1:4).
Yield: 86 mg (43 %), white solid, m.p. 115–116 °C. 1H NMR
(300 MHz, [D6]acetone): δ = 1.63–1.95 (m, 2 H, CH2), 1.75 (m, 1
H, CHH), 2.15 (m, 2 H, CH2), 4.14 (m, 1 H, CHNH), 4.77 (m, 1
H, CHCF3), 5.39 (br. s, 1 H, NH), 7.33 (m, 2 H, Ph), 7.41 (m, 1
H, Ph), 7.81 (m, 3 H, Ph and OH) ppm. 13C NMR (126 MHz, [D6]
acetone): δ = 25.4 (CH2), 26.5 (CH2), 51.3 (CHNH), 68.2 (q, JC,F
= 29.8 Hz, CHCF3), 125.5 (q, JC,F = 280.5 Hz, CF3), 126.9 (Ph),
127.9 (Ph), 131.0 (Ph), 133.9 (Ph), 166.5 (CONH), 172.3 (CO2Me)
1
127–129 °C (decomposition). H NMR (500 MHz, [D6]DMSO): δ
= 1.15 (t, JH,H = 6.9 Hz, 9 H, 3ϫCH3), 3.05 (q, JH,H = 6.9 Hz, 6
H, 3ϫCH2), 3.56 (s, 3 H, OCH3), 5.00 (d, JH,H = 10.9 Hz, 1 H,
CH), 7.44 (m, 2 H, Ph), 7.50 (m, 1 H, Ph), 7.60 (br. m, 1 H, CH),
7.92 (m, 2 H, Ph), 8.59–9.51 (br. s, 1 H, NH) ppm. 13C NMR
(126 MHz, [D6]DMSO): δ = 9.1 (CH3), 46.3 (CH2), 46.3 (OCH3),
88.6 (CH), 111.6 (CH), 121.0 (q, JC,F = 289.3 Hz, CF3), 128.0 (Ph),
128.7 (Ph), 131.6 (Ph), 135.2 (Ph), 165.3 (CO), 166.6 (CO) ppm.
19F NMR (470 MHz, [D6]DMSO): δ = –64.65 (s, CF3) ppm. IR
ppm. 19F NMR (282 MHz, [D6]acetone): δ = –80.50 (d, JF,H
=
6.9 Hz, CF ) ppm. IR (KBr): ν = 3569, 1720, 1656, 1576, 1536,
˜
3
1491, 1464, 1430, 1336, 1288, 1272, 1224, 1192, 1168, 1136,
1040 cm–1. C13H14F3NO4 (305.1): calcd. C 51.15, H 4.62, N 4.59;
found C 51.10, H 4.59, N 4.61.
(KBr): ν = 3200, 3250, 1720, 1670, 1595, 1580, 1430, 1323, 1220,
˜
1180, 1100, 895, 715 cm–1. C20H27F3N2O3 (416.4): calcd. C 57.68,
H 6.54, N 6.73; found C 57.70, H 6.53, N 6.73.
Synthesis of Pure Diastereomers of Hydroxy-(benzoylamino) Acid
Esters 6a and 6b: Triethylamine (200 mg, 2 mmol) was added with
stirring to a solution of compound 4a or 4b (1 mmol) in MeOH
(20 mL), and the mixture was left at room temp. for 24 h. The sol-
vent was then evaporated in vacuo, and the residue was dissolved
in EtOAc and washed with citric acid solution (15%, 10 mL). The
organic layer was separated, dried with MgSO4, and concentrated
in vacuo. The residue was purified by crystallization, giving pure
compounds 6a or 6b.
2-(Benzoylamino)-6,6,6-trifluoro-5-methoxyhexanoic Acid [Mixture
of Diastereomers 12/13 (1:1)]: Hydrogen was passed through a mix-
ture of the salt 11 (400 mg, 1 mmol) in dry MeOH (30 mL) and
Pd/C (5%, 0.05 g) at room temp. for 8 h. The reaction progress
was monitored by TLC. After complete reduction, the residue was
filtered through a short pad of silica gel, and the filtrate was con-
centrated in vacuo. The residue was dissolved in EtOAc and washed
with aq. citric acid (15%). The organic layer was separated, dried
with MgSO4, and concentrated in vacuo (bath temperature 30–
40 °C, 30–60 Torr). The residue was purified by crystallization from
CHCl3/CH3CN (5:1) to give a white solid. Yield: 280 mg (88%),
Methyl (2R,5R/2S,5S)-2-(Benzoylamino)-6,6,6-trifluoro-5-hydroxy-
hexanoate (6a): This compound was obtained from compound 4a
(287 mg) and was crystallized from CHCl3/hexane (1:1). Yield:
242 mg (76%), white solid, m.p. 96–97 °C. 1H NMR (500 MHz,
[D6]acetone): δ = 1.74 (m, 1 H, CHH), 1.85 (m, 1 H, CHH), 2.12
(m, 2 H, CH2), 3.70 (s, 3 H, CH3), 4.12 (m, 1 H, CHNH), 4.75 (m,
1
m.p. 105–106 °C. H NMR (500 MHz, [D6]acetone): δ = 1.85 (m,
2 H, CH2), 2.19 (m, 2 H, CH2), 3.65 (s, 3 H, CH3), 4.10 (m, 1 H,
1 H, CHCF3), 5.35 (br. s, 1 H, OH), 7.46 (m, 2 H, Ph), 7.57 (m, 1 CHCF3), 4.73 (m, 1 H, CHNH), 5.35 (br. s, 1 H, NH), 7.46 (m, 2
H, Ph), 7.93 (m, 2 H, Ph), 8.00 (br. d, JH,H = 6.8 Hz, 1 H, NH)
H, Ph), 7.54 (m, 1 H, Ph), 7.93 (m, 2 H, Ph), 10.22 (br. s, 1 H,
ppm. 13C NMR (126 MHz, [D6]acetone): δ = 26.2 (CH2), 26.3
OH) ppm. 19F NMR (470 MHz, [D6]acetone): δ = –79.12 (d, JF,H
(CH2), 52.2 (CH3), 52.4 (CHNH), 67.9 (q, JC,F = 28.7 Hz, CHCF3), = 6.9 Hz, CF3 of compound 12), –78.20 (d, JF,H = 6.9 Hz, CF3 of
Eur. J. Org. Chem. 2009, 5012–5019
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5017

I. I. Gerus, G. Haufe et al.
FULL PAPER
compound 13) ppm; integration of these signals showed an 1:1 mix-
fragment C atoms are in the δ = 110–130 ppm range. 19F NMR
(280 MHz, D2O): δ = –83.3 (dd, JF,F = 8.2, 10.7 Hz, 3 F, CF3),
ture of compounds 12 and 13. IR (KBr): ν = 2960, 1755, 1648,
˜
1536, 1280, 1216, 1168, 1128 cm–1. C14H16F3NO4 (319.1): calcd. C –122.60 (d, JF,F = 282.9 Hz, 1 F, CFFCF2CF3), –127.55 (d, JF,F
=
52.67, H 5.05, N 4.39; found C 52.68, H 5.04, N 4.37.
294.8 Hz, 1 F, CFFCF3), –129.42 (d, JF,F = 288.8 Hz, 1 F,
CFFCF3), –129.47 (d, JF,F = 288.8 Hz, CFFCF3 of compound 2b),
–130.3 (d, JF,F = 282.9 Hz, 1 F, CFFCF CF ) ppm. IR (KBr): ν =
2943, 1680, 1592, 1537, 1464, 1412, 1342, 1226, 1184, 1121,
964 cm–1. C8H10F7NO3 (301.1): calcd. C 31.91, H 3.35, N 4.65;
found C 31.89, H 3.32, N 4.68.
Synthesis of Amino Acids 1 and 2: Either a mixture of diastereomers
(6a–b/7a–b or 12/13) or a pure diastereomer (6a–c or 8) (1 mmol)
was dissolved in HCl (30%, 6–7 mL), and the mixture was heated
at reflux for 7 h. After cooling, the precipitate of the formed ben-
zoic acid was filtered off, and the filtrate was concentrated in vacuo
(bath temperature 30–40 °C, 30–60 Torr). The residue was dis-
solved in water, and the corresponding amino acid was isolated by
ion-exchange chromatography either as a mixture of diastereomers
(1a–c/2a–c or 14/15) or as a pure diastereomer (1a–c). The obtained
ammonia solutions were concentrated, dissolved in water, and con-
centrated in vacuo again in order to remove traces of ammonia.
Yields are given in Table 2.
˜
2
3
2-Amino-6,6-difluoro-5-hydroxyhexanoic Acid (1c): This compound
was obtained from pure diastereomer 6c (300 mg). Yield: 78 mg
(43 %), white solid, m.p. Ͼ300 °C (decomposition). 1H NMR
(500 MHz, D2O): δ = 1.64 (m, 2 H, CH2), 2.07 (m, 2 H, CH2), 3.82
(m, 1 H, CHNH), 4.13 (br. m, 1 H, CHCHF2), 5.77 (br. t, JH,F
=
52.3 Hz, 1 H, CHF2) ppm. 13C NMR (126 MHz, D2O): δ = 25.8
(CH2), 26.4 (CH2), 53.6 (CHNH2), 70.1 (t, JC,F = 22.9 Hz,
CHCHF2), 117.0 (t, JC,F = 241.1 Hz, CHF2), 171.9 (CO) ppm. 19
NMR (470 MHz, D2O): δ = –128.90 (ddd, JF,H = 9.8, 55.1, JF,F
283.2 Hz, 1 F, CHFF), –131.85 (ddd, JF,H = 9.8, 55.1, JF,F
F
=
=
2-Amino-6,6,6-trifluoro-5-hydroxyhexanoic Acid [Mixture of Dia-
stereomers 1a/2a (7:3)]: These compounds were obtained from the
mixture of diastereomers 6a/7a (7:3, 319 mg). Yield: 90 mg (45%),
white solid, m.p. Ͼ300 °C (decomposition). 1H NMR (300 MHz,
D2O): δ = 1.81 (m, 4 H, CH2CH2), 3.71 (m, 1 H, CHNH2), 4.04
(br. m, 1 H, CHCF3) ppm. 19F NMR (280 MHz, D2O): δ = –79.12
(d, JF,H = 6.9 Hz, CF3 of compound 1a), –79.20 (d, JF,H = 6.9 Hz,
CF3 of compound 2a) ppm. Integration of these signals showed a
7:3 ratio of compounds 1a/2b.
283.2 Hz, 1 F, CHFF) ppm. IR (KBr): ν = 1734, 1653, 1539, 1223,
˜
1134, 1061, 879 cm–1. C6H11F2NO3 (183.15): calcd. C 39.35, H
6.05, N 7.65; found C 39.37, H 6.02, N 7.62.
2-Amino-6,6,6-trifluoro-5-methoxyhexanoic Acid [Mixture of Dia-
stereomers 13/14 (1:1)]: These compounds were obtained from a
mixture of diastereomers 11/12 (1:1, 319 mg). Yield: 60 mg (28%),
white solid, m.p. Ͼ300 °C (decomposition). 1H NMR (500 MHz,
D2O): δ = 1.94 (m, 4 H, CH2CH2), 3.76 (m, 1 H, CHNH), 4.03
(br. m, 1 H, CHCF3), 4.50 (br. s, 3 H, CH3) ppm. 13C NMR
(126 MHz, D2O): δ = 24.5 (CH2), 25.1 (CH2), 26.2 (CH2), 26.3
(CH2), 54.4 (CHNH2), 54.5 (CHNH2), 68.8 (q, JC,F = 31.8 Hz,
(2R,5R/2S,5S)-2-Amino-6,6,6-trifluoro-5-hydroxyhexanoic Acid
(1a): This compound was obtained from pure diastereomers 6a
(319 mg) or 8 (305 mg). Yield: 115 mg (57%) from 6a and 155 mg
(77 %) from 8, white solid, m.p. Ͼ300 °C (decomposition). 1H
NMR (500 MHz, D2O): δ = 1.65 (m, 1 H, CHH), 1.84–2.14 (m, 3
H, CH2 and CHH), 3.76 (t, JH,H = 6.7 Hz, 1 H, CHNH2), 4.1 (br.
m, 1 H, CHCF3) ppm. 13C NMR (126 MHz, [D6]DMSO): δ = 24.9
(CH2), 26.2 (CH2), 54.4 (CHNH2), 68.8 (q, JC,F = 30.7 Hz,
CHCF3), 125.1 (q, JC,F = 281.1 Hz, CF3), 174.2 (CO) ppm. 19F
NMR (470 MHz, D2O): δ = –79.12 (d, JF,H = 6.9 Hz, CF3) ppm.
CHCF3), 68.9 (q, JC,F = 31.8 Hz, CHCF3), 125.2 (q, JC,F
280.5 Hz, CF3), 174.2 (CO) ppm. 19F NMR (470 MHz, D2O): δ =
–74.72 (d, JF,H = 7.0 Hz, CF3 of compound 13), –74.79 (d, JF,H
=
=
7.0 Hz, CF3 of compound 14) ppm. IR (KBr): ν = 3065, 1619,
˜
1587, 1508, 1448, 1347, 1328, 1298, 1274, 1175, 1123, 1090,
1040 cm–1. C7H12F3NO3 (215.1): calcd. C 39.07, H 5.62, N 6.51;
found C 39.05, H 5.60, N 6.49.
IR (KBr): ν = 3042, 1616, 1584, 1502, 1442, 1368, 1336, 1304, 1273,
˜
1176, 1128, 1096, 1080, 944 cm–1. C6H10F3NO3 (201.1): calcd. C
35.83, H 5.01, N 6.96; found C 35.85, H 4.98, N 6.94.
X-ray Crystallographic Study: The data sets were collected with an
Xcalibur-3 diffractometer (Mo-Kα radiation, CCD detector, graph-
ite monochromator, ω-scanning) at –173 °C (for compound 8) and
at room temperature (for compound 6c). The structures were re-
fined by SHELXTL PLUS.[13] Crystals of 6c were monoclinic, a =
8.002(2), b = 22.727(3), c = 8.868(2) Å, β = 113.22(2)°, V =
2-Amino-6,6,7,7,8,8,8-heptafluoro-5-hydroxyoctanoic Acid [Mixture
of Diastereomers 1b/2b (1:1)]: These compounds were obtained
from a mixture of diastereomers 6b/7b (1:1, 420 mg). Yield: 142 mg
(47 %), white solid, m.p. Ͼ300 °C (decomposition). 1H NMR
(500 MHz, D2O): δ = 1.85 (m, 4 H, CH2CH2), 3.62 (m, 1 H,
CHNH2), 4.13 (br. m, 1 H, CHCF2) ppm. 19F NMR (470 MHz,
D2O): δ = –84.01 (br. m, 3 F, CF3), –122.61 (d, JF,F = 282.9 Hz,
CFFCF2CF3 of compound 1b), –122.72 (d, JF,F = 282.9 Hz,
CFFCF2CF3 of compound 2b), –127.67 (d, JF,F = 294.8 Hz,
CFFCF3 of compound 1b), –127.73 (d, JF,F = 294.8 Hz, CFFCF3
of compound 2b), –129.42 (d, JF,F = 288.8 Hz, CFFCF3 of com-
pound 1b), –129.47 (d, JF,F = 288.8 Hz, CFFCF3 of compound 2b),
–130.49 (d, JF,F = 282.9 Hz, CFFCF2CF3 of compound 1b),
–130.62 (d, JF,F = 282.9 Hz, CFFCF2CF3 of compound 2b) ppm.
Integration of these signals showed a 1:1 ratio of compounds 1b/
2b.
1482.1(5) Å3, Mr = 301.29, Z = 4, space group P21/n, dcalcd.
=
1.350 gcm–3, µ(Mo-Kα) = 0.114 mm–1, F(000) = 632. Crystals of 8
were triclinic, a = 7.562(1), b = 8.169(1), c = 12.395(2) Å, α =
79.16(1)°, β = 80.25(1)°, γ = 72.91(1)°, V = 713.5(2) Å3, Mr =
323.27, Z = 2, space group P1, dcalcd. = 1.505 gcm–3, µ (Mo-Kα) =
0.139 mm–1, F(000) = 336. CCDC-735717 (for 6c) and CCDC-
735718 (for 8) contain the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of compounds 4a–c, 6a–c, 1a–c; COSY and
NOE of compound 4a.
(2R,5R/2S,5S)-2-Amino-6,6,7,7,8,8,8-heptafluoro-5-hydroxyocta-
noic Acid (1b): This compound was obtained from pure dia-
stereomer 6b (420 mg). Yield: 169 mg (56 %), white solid, m.p.
Ͼ300 °C (decomposition). 1H NMR (300 MHz, D2O): δ = 1.48–
2.12 (m, 4 H, CH2CH2), 3.65 (m, 1 H, CHNH2), 4.16 (m, 1 H,
CHCF2) ppm. 13C NMR (126 MHz, D2O): δ = 24.1 (CH2), 26.3
(CH2), 54.3 (CHNH2), 68.0 (t, JC,F = 22.5 Hz, CHCF2), 174.1
(CO2H) ppm; low-intensity and high-multiplicity signals of C3F7-
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(Ha2145/9-1, AOBJ: 560896). We are grateful to Enamine Ltd.
5018
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 5012–5019

Synthesis of New δ-(Polyfluoroalkyl)-δ-hydroxy-α-amino Acids
[5] For similar arguments concerning the CF3CHNH moiety as a
bioisoster for the CONH group, see: a) M. Molteni, C. Pesenti,
M. Sani, A. Volonterio, M. Zanda, J. Fluorine Chem. 2004,
125, 1735–1743; b) S. Bigotti, S. V. Meille, A. Volonterio, M.
Zanda, J. Fluorine Chem. 2008, 129, 767–774 and references
cited therein.
(Kiev) for technical and financial support. We appreciate the assist-
ance of Mr. V. V. Polovinko (Enamine Ltd., Kiev) for special NMR
experiments and of Mrs. S. V. Shishkina and Dr. O. V. Shishkin
(STC Institute for Single Crystals, Kharkov) for performing the X-
ray diffraction study.
[6] J.-P. Bégué, D. Bonnet-Delpon, in Biomedical Frontiers of Flu-
orine Chemistry (Eds.: I. Ojima, J. McCarthy, J. T. Welch), ACS
Symposium Series 639, ACS, Washington, DC, 1996, pp. 59–
73.
[7] J. P. Alexander, T. J. Ryan, D. P. Ballou, J. K. Coward, Bio-
chemistry 2008, 47, 1228–1239.
[1] a) J.-P. Bégué, D. Bonnet-Delpon, J. Fluorine Chem. 2006, 127,
992–1012; b) J.-P. Bégué, D. Bonnet-Delpon, Bioorganic and
Medicinal Chemistry of Fluorine, John Wiley & Sons, Inc., Ho-
boken, New Jersey, 2008, p. 365; c) Fluorine and Health – Mo-
lecular Imaging, Biomedical Materials and Pharmaceuticals
(Eds.: A. Tressaud, G. Haufe), Elsevier, Amsterdam, 2008, pp.
553–778.
[2] Fluorine-Containing Amino Acids, Synthesis and Properties
(Eds.: V. P. Kukhar’, V. A. Soloshonok), Wiley, Chichester,
1995.
[8] T. Tsukamoto, T. Kitazume, J. J. McGuire, J. K. Coward, J.
Med. Chem. 1996, 39, 66–72 and references cited therein.
[9]
I. I. Gerus, N. A. Tolmachova, S. I. Vdovenko, R. Fröhlich, G.
Haufe, Synthesis 2005, 1269–1278.
[10] N. A. Tolmachova, I. I. Gerus, S. I. Vdovenko, M. Essers, R.
Fröhlich, G. Haufe, Eur. J. Org. Chem. 2006, 4704–4709.
[11] A. P. Nin, R. M. de Lederkremer, O. Varela, Tetrahedron 1996,
52, 12911–12918.
[3] For some recent reviews on the synthesis of fluorinated amino
acids, see: a) A. Sutherland, C. L. Willis, Nat. Prod. Rep. 2000,
17, 621–631; b) X.-L. Qiu, W.-D. Meng, F.-L. Qing, Tetrahe-
dron 2004, 60, 6711–6745; c) R. Smits, C. D. Cadicamo, K. [12] J. Weiss, T. Weiss, Handbook of Ion Chromatography, 3rd ed.,
Burger, B. Koksch, Chem. Soc. Rev. 2008, 37, 1727–1739.
[4] For some applications of 5-hydroxyvaleric acid for biochemical
investigations, see: a) J. Pietzsch, Biochem. Biophys. Res. Com-
mun. 2000, 270, 852–857; b) H. Luesch, D. Hoffmann, J. M.
Hevel, J. E. Becker, T. Golakoti, R. E. Moore, J. Org. Chem.
2003, 68, 83–91.
Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2004.
[13] G. M. Sheldrick, SHELXTL PLUS, PC version, A system of
computer programs for the determination of crystal structure
from X-ray diffraction data, Rev. 5.1., 1998.
Received: June 19, 2009
Published Online: September 8, 2009
Eur. J. Org. Chem. 2009, 5012–5019
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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