Concise access to enantiopure (S)- and (R)-α-trifluoromethyl pyroglutamic acids from ethyl trifluoropyruvate-based chiral CF3-oxazolidines (Fox)

Article abstract of DOI:10.1016/j.jfluchem.2008.07.019

A straightforward synthesis of enantiopure (S)- and (R)-α-Tfm-pyroglutamic acid is reported. The strategy is based on the use of a chiral CF₃-hydroxymorpholinone intermediate conveniently obtained from ethyl trifluoropyruvate-based chiral CF

Full text of DOI:10.1016/j.jfluchem.2008.07.019

Journal of Fluorine Chemistry 129 (2008) 1104–1109
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Concise access to enantiopure (S)- and (R)-
a
-trifluoromethyl pyroglutamic
acids from ethyl trifluoropyruvate-based chiral CF3-oxazolidines (Fox)
a
a
b
a,
*
´
´
Gregory Chaume , Marie-Celine Van Severen , Louis Ricard , Thierry Brigaud
a Laboratoire de Synthe`se Organique Se´lective et Chimie Organome´tallique (SOSCO), UMR CNRS 8123, Universite´ de Cergy-Pontoise, 5, Mail Gay Lussac,
Neuville sur Oise, 95031 Cergy-Pontoise Cedex, France
b Laboratoire He´te´roe´le´ments et Coordination, UMR CNRS 7653, Ecole Polytechnique, 91128 Palaiseau, France
A R T I C L E I N F O
A B S T R A C T
Article history:
A straightforward synthesis of enantiopure (S)- and (R)-a-Tfm-pyroglutamic acid is reported. The
Received 17 June 2008
strategy is based on the use of a chiral CF3-hydroxymorpholinone intermediate conveniently obtained
from ethyl trifluoropyruvate-based chiral CF3-oxazolidines (Fox). The key step is an oxidative cyclization
followed by a reductive cleavage of the (R)-phenylglycinol chiral auxiliary.
ß 2008 Elsevier B.V. All rights reserved.
Received in revised form 18 July 2008
Accepted 24 July 2008
Available online 3 August 2008
Keywords:
a
-Trifluoromethyl amino acids
Oxazolidines
Organofluorine chemistry
Stereoselective synthesis
Ring closure
Lactams
1. Introduction
preparation of a-Tfm-pyroglutamic acids in enantiopure form has
never been reported [7].
Conformationally constrained cyclic amino acids have recently
gained considerable interest because of their ability to control the
conformation of peptides for structure–activity relationships
investigations as well as for the design of peptidomimetics [1].
In particular, incorporation of a proline unit is known to restrict the
amino acyl-proline cis/trans isomerization [2], to limit the protein
folding and consequently to modulate the biological activity of
peptides. Among the numerous proline derivatives reported in
the literature, fluorinated proline-type amino acids have received
increasing attention [3]. This is particularly due to the unique
physical and biological properties induced by the introduction
of fluorinated groups in peptides and peptidomimetics [4].
However, their use in peptide chemistry remains very limited
due to the difficulty to prepare them efficiently, particularly in
their enantiopure form. Pyroglutamic acid derivatives were also
reported to be efficient tools for the control of the peptidyl bond
geometry [5]. Although several examples of fluorine containing
pyroglutamic derivatives are reported in the literature [6], the
In the course of our studies, we recently reported several
approaches for the stereoselective synthesis of
a- and b-
trifluoromethyl amino acids (Tfm AAs) starting from chiral CF3-
oxazolidines (Fox) or imines [8]. Among them, we developed an
efficient route for the synthesis of (S)- and (R)-a-Tfm proline based
on the use of the key chiral CF3-hydroxymorpholinone 2 (Scheme
1) [9]. This compound was conveniently prepared in a few step
from the oxazolidines 1 derived from ethyl trifluoropyruvate.
We present here another feature of the use of the CF3-
hydromorpholinone 2. This versatile intermediate proved to be
also highly valuable for the synthesis of
in enantiopure form.
a-Tfm-pyroglutamic acids
2. Results and discussion
The preparation of the starting CF3-hydroxymorpholinone 2
was based on our reported procedure [9]. In addition, the first step
involving the formation of oxazolidines 1 from ethyl trifluoropyr-
uvate and (R)-phenylglycinol was significantly improved. We
observed that the yield of the direct condensation was not entirely
reproducible (65–90%) [10]. This was probably due to both bis-
nucleophilic reactivity of (R)-phenylglycinol and bis-electrophilic
reactivity of ethyl trifluoropyruvate. In order to increase the
* Corresponding author. Fax: +33 1 34 25 73 81.
E-mail address: thierry.brigaud@u-cergy.fr (T. Brigaud).
0022-1139/$ – see front matter ß 2008 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2008.07.019

G. Chaume et al. / Journal of Fluorine Chemistry 129 (2008) 1104–1109
1105
Scheme 1.
Scheme 3.
Scheme 2.
selectivity of the oxazolidine 1 formation, we designed to use a N-
protected (R)-phenylglycinol which would give an intermediate
ethyl trifluoropyruvate hemiacetal. After removal of the protecting
group, the cyclization of the hemiacetals would lead to the
expected oxazolidines. We were pleased to observe that the
reaction of the N-Boc (R)-phenylglycinol under acidic catalysis
(0.1 equiv. PPTS) gave directly the oxazolidines 1 (75:25 diaster-
eomeric mixture) in a completely reproducible high yield (93%)
(Scheme 2). Intriguingly, when reaction was performed starting
from the N-Bz phenylglycinol, the only corresponding O-Bz imine 3
was isolated in 71% yield. We postulate that in both cases, there is a
protecting group transfer from the amino to the hydroxyl group of
the (R)-phenylglycinol in the acidic reaction conditions. The free
amino group would then react selectively with the carbonyl group
of the ethyl trifluoropyruvate to give an imine intermediate. The
reaction stopped at the imine stage 3 when the stable benzoyle
protecting group was used. However, with the Boc protecting
group, the acidic mediated smooth removal of the Boc group
should undergo a selective intramolecular cyclization of the
resulting hydroxyimine into oxazolidines 1.
Scheme 4.
pyroglutamic acid 6 (50% ee) was obtained by oxidative cyclization
using Jones reagent in 32% non-optimized yield. The direct
cyclization of the intermediate amino acid is in accordance with
the observation of Burger et al. [7] since they reported in the
a-Tfm-glutamic acid gave rise to spontaneous
cyclization into -Tfm-pyroglutamic acid.
The main drawback of this synthetic pathway is that it supposes
an efficient separation of both diastereomers of the CF3-hydro-
xymorpholinone 2 in order to obtained enantiopure
racemic series that
a
a-Tfm-
The CF3-hydroxymorpholinone 2 was then obtained as a non-
separable 75:25 diastereomeric mixture following our
previously reported three-step allylation/lactonisation/hydro-
boration sequence from oxazolidines 1 (Scheme 3) [9]. The
hydroboration reaction of 4 was performed in high yield (90%)
using 9-BBN. Lowest yield were achieved using BH3ÁSMe2 or
dicyclohexylborane (30–60%).
pyroglutamic acids. As the chromatographic separation of both
diastereomers of 2 is difficult, we anticipated that the separation of
the bicyclic lactams resulting from oxidative cyclization of 2 would
be more convenient [11]. Hence the diastereomeric mixture of 2
was subjected to oxidation using the convenient Jones reagent to
give the corresponding bicyclic lactams 7 in high yield (Scheme 5)
[12].
As an explorary study, the synthesis of the
a
-Tfm-pyroglutamic
As expected, at this stage, both diastereomers of the bicyclic
lactams 7 were very easily separated by silica gel chromatography
to afford (R,S)-7 in 61% isolated yield and (R,R)-7 in 20% isolated
yield (Scheme 5) [13]. Moreover, we were pleased to observe that
both diastereomers could also be very conveniently separated by
selective crystallization and filtration. Indeed, (R,S)-7 is a white
solid poorly soluble in diethyl ether, whereas (R,R)-7 is an oil
completely soluble in this solvent. This very efficient and
convenient separation of both diastereomers will provide an easy
acid 6 from the 75:25 diastereomeric mixture of the hydro-
xymorpholinone 2 was investigated. The target compound was
obtained by the following sequence involving the removal of the
chiral auxiliary followed by the oxidation of the hydroxyl group
into the corresponding acid and the ring closure by lactamization
(Scheme 4). The hydrogenolysis of the hydroxymorpholinone 2
catalyzed by Pearlman’s catalyst led to the new
hydroxynorvaline 5 in 97% yield. Finally, the expected
a
-Tfm-5-
-Tfm-
a

1106
G. Chaume et al. / Journal of Fluorine Chemistry 129 (2008) 1104–1109
Scheme 6.
Scheme 5.
3. Conclusion
In conclusion, we have successfully developed a concise
synthesis of both enantiomers of the highly constrained -Tfm-
a
pyroglutamic acid in enantiopure form from a highly versatile
chiral CF3-hydroxymorpholinone intermediate. Further investiga-
tions about synthetic applications of this conformationally
constrained cyclic amino acid are underway and will be reported
in due course.
4. Experimental
General: Unless otherwise mentioned, all the reagents were
purchased from commercial source. THF was distilled under
nitrogen from sodium/benzophenone prior to use. 1H NMR
(400.00 MHz), 13C NMR (100.50 MHz) and 19F NMR (376.20 MHz)
were measured on a JEOL 400 spectrometer. Chemical shifts of 1H
NMR were expressed in parts per million downfield from
tetramethylsilane (
expressed in parts per million downfield from CDCl3 as internal
standard (
= 77.0). Chemical shifts of 19F NMR were expressed in
parts per million downfield from C6F6 as internal standard ( = –
d
= 0) in CDCl3. Chemical shifts of 13C NMR were
d
d
164.9). Coupling constants are reported in hertz. Column chroma-
tography was performed on Merck Kieselgel 60 (0.040–0.063 mm),
employing mixture of specified solvent as eluent. Thin-layer
chromatography (TLC) was performed on Merck silica gel (Merck
60PF254)plates. Silica TLC plates werevisualized underUVlight, bya
10% solution of phosphomolybdic acid in ethanol followed by
heating. Mass spectra (MS) were obtained on a GC/MS apparatus HP
5973 MSD with an HP 6890 Series GC. Ionization was obtained by
electronic impact (EI 70 eV). Infrared spectra (IR) were obtained by
Fig. 1. ORTEP view of (R,S)-7.
access to enantiopure derivatives of 7 in large scale. The (R,S)
configuration assignment of the major diastereomer of 7, was
confirmed by single crystal X-ray analysis (Fig. 1) [14].
¨
The removal of the (R)-phenylglycinol chiral auxiliary was then
considered. In accordance with the observations reported by Ma
et al. [15], all attempts to cleave the N-benzylic bond of the
diastereomerically pure (R,S)-7 by Pd/C or Pd(OH)2/C catalyzed
hydrogenolysis under acidic or neutral conditions failed. How-
ever, the removal of the chiral auxiliary was suitably achieved in a
three-step procedure involving the saponification of the lactone
ring by LiOH, acidification with 1N HCl followed by a reductive
cleavage of the benzylic bond using lithium in liquid ammonia
Fourier-transformation on BRUCKER TENSOR 27, wavenumbers are
given in cmÀ1. Elemental analyses were performed by the CNRS
analysis central service. Optical rotations are reported as their
specific rotations determined using a JASCO DIP-370 polarimeter.
Melting points were obtained on a Bu¨chi apparatus and are
uncorrected.
4.1. (4R)-2-Ethoxycarbonyl-2-trifluoromethyl-4-phenyl-1,3-
oxazolidine (1) [9]
[15,16]. Following this procedure, enantiopure (S)-a-Tfm-pyr-
oglutamic acid (S)-6 was obtained in 49% yield from (R,S)-7. The
enantiopurity (>98% ee) of (S)-6 was confirm by its derivatization
into the corresponding diastereomerically pure (S)-1-pheny-
lethylamide. In a similar manner, (R)-a-Tfm-pyroglutamic acid
(R)-6 was obtained in enantiopure form in 69% yield from (R,S)-7
To a stirred solution of 5.14 g of (R)-N-Boc-phenylglycinol
(21.7 mmol, 1.0 equiv.) in 200 mL of toluene at room temperature
were added 1.09 g of pyridinium p-toluenesulfonate (4.34 mmol,
0.2 equiv.) and 3.17 mL of ethyl trifluoropyruvate (23.8 mmol,
1.1 equiv.). The mixture was stirred for 1 h at room temperature,
warmed to 140 8C with a Dean–Stark apparatus for 20 h, and then
(Scheme 6).

G. Chaume et al. / Journal of Fluorine Chemistry 129 (2008) 1104–1109
1107
25
cooled to 0 8C with an ice-bath. The resulting mixture was filtered
and toluene was evaporated. Purification by flash chromatography
(95:5 cyclohexane/ethyl acetate) gave 5.80 g (93%) of 1 (75:25
diastereomeric mixture).
[
a
]
À124.4 (c 0.26, CHCl3); IR (neat): 2360, 1763, 1725, 1226,
1H NMR (400 MHz, CDCl3):
= 2.34–2.48
D
1172, 1151, 701 cmÀ1
(m, 1H), 2.60–2.74 (m, 2H), 2.86–2.98 (m, 1H), 4.40 (dd, J = 11.5,
1.4 Hz, 1H), 5.05 (dd, J = 11.5, 4.1 Hz, 1H), 5.07 (dd, J = 4.1,
1.4 Hz, 1H), 7.04–7.08 (m, 2H), 7.27–7.40 (m, 3H); 13C NMR
;
d
4.2. (E)-1-Ethoxycarbonyl-2,2,2-trifluoroethylidene (1R)-2-
(100.5 MHz, CDCl3):
71.4, 124.3 (q, J = 288.9 Hz), 125.6, 128.5, 129.2, 138.2, 165.3,
174.8; 19F NMR (376.2 MHz, CDCl3):
d = 28.6, 29.2, 53.0, 66.6 (q, J = 29.7 Hz),
benzoyloxy-1-phenylethylamine (3)
d
= À76.67 (s); MS (EI) m/z
To a stirred solution of 200 mg of (R)-N-Bz-phenylglycinol
(0.83 mmol, 1.0 equiv.) in 10 mL of toluene at room temperature,
were added 23 mg of p-toluenesulfonic acid (0.12 mmol,
299 [M+Á], 230, 212, 104 (100), 91; Anal. Calcd for C14H12F3NO3:
C, 56.12; H, 4.04; N, 4.68. Found: C, 56.03; H, 4.06; N, 4.61. (R,R)-
25
7: colorless oil; Rf = 0.29 (7:3 cyclohexane/ethyl acetate); [a]
D
0.15 equiv.) and 110
m
L of ethyl trifluoropyruvate (0.83 mmol,
À1.6 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3):
d = 2.40 (ddd,
1.0 equiv.). The mixture was warmed to 140 8C with a Dean–Stark
apparatus for 20 h, and then cooled to 0 8C with an ice-bath. The
resulting mixture was filtered and toluene was evaporated.
Purification by flash chromatography (9:1 cyclohexane/ethyl
acetate) gave 229 mg of imine 3 (71%). Colorless oil; [
J = 16.0, 9.2, 1.4 Hz, 1H), 2.60–2.78 (m, 2H), 2.87–2.92 (m, 1H),
4.49 (t, J = 12.8 Hz, 1H), 4.59 (ddd, J = 12.8, 6.9, 1.4 Hz, 1H), 5.04
(dd, J = 12.8, 6.9 Hz, 1H), 7.26–7.30 (m, 2H), 7.32–7.45 (m, 3H);
13C NMR (100.5 MHz, CDCl3):
d = 28.7, 28.8, 53.7, 66.3 (q,
20
a
]
D
J = 30.1 Hz), 68.8, 124.2 (q, J = 284.9 Hz), 127.2, 128.5, 129.1,
À3.05 (c 2.1, CHCl3); IR (neat): 2987, 1742, 1684, 1452, 1272,
134.8, 165.7, 176.6; 19F NMR (376.2 MHz, CDCl3):
MS (EI) m/z 299 [M+Á], 230, 212, 104 (100).
d
= À76.75 (s);
713 cmÀ1 1H NMR (400 MHz, CDCl3):
;
d
= 1.19 (t, J = 7.1 Hz, 3H),
4.17 (dq, J = 10.8, 7.1 Hz, 1H), 4.30 (dq, J = 10.8, 7.1 Hz, 1H), 4.50
(dd, J = 11.1, 9.3 Hz, 1H), 4.74 (dd, J = 11.1, 3.8 Hz, 1H), 5.33 (dd,
J = 9.3, 3.8 Hz, 1H), 7.37–7.47 (m, 8H), 8.02–7.99 (m, 2H); 13C NMR
4.5. (S)-a-Trifluoromethylpyroglutamic acid ((S)-6)
(100.5 MHz, CDCl3):
J = 279.0 Hz), 127.3, 128.4, 128.6, 128.9, 129.6, 133.2, 136.8,
150.2 (q, J = 36.4 Hz), 158.4, 166.0; 19F NMR (376.2 MHz, CDCl3):
d
= 13.8, 62.9, 66.3, 67.8, 118.1 (q,
To a solution of pure bicyclic diastereomer (R,S)-7 (372 mg,
1.04 mmol) in THF (6.3 mL) was slowly added at 0 8C, a 1 M
aqueous solution of LiOH (1.25 mL, 1.25 mmol, 1.2 equiv.). The
resulting mixture was vigorously stirred at 0 8C for 2 h, and then
diluted with ether (10 mL). The layers were separated and the
organic layer was washed with water (2Â 10 mL). The combined
aqueous layers were then acidified with 1N HCl until pH 2,
extracted with EtOAc (3Â 10 mL), dried over Na2SO4 and
concentrated to give 380 mg of crude acid directly used in the
next step without further purification.
d
= À72.9 (s); MS (EI) m/z 393 [M+Á], 271; 243, 198, 105 (100), 77;
Anal. Calcd for C20H18F3NO4: C, 61.07; H, 4.61; N, 3.56. Found: C,
61.01; H, 5.01; N, 3.45.
4.3.
a-Trifluoromethyl-5-hydroxynorvaline (5)
To a 75:25 diastereomeric mixture of hydroxymorpholinone
2 (207 mg, 0.68 mmol) in EtOH (20 mL) was added 380 mg of
20% Pd(OH)2/C. The reaction was stirred for 48 h under 1 bar
atmosphere pressure of hydrogen. The resulting mixture was
filtered and evaporated under reduced pressure. The crude
mixture was taken up with ether and water. The aqueous phase
was washed with ether and evaporated to afford 133 mg of 5
(97%) as white solid. 1H NMR (400 MHz, D2O):
1H), 1.34–1.49 (m, 1H), 1.80 (ddd, J = 16.7, 11.9, 5.0 Hz, 1H), 2.03
(ddd, J = 16.7, 11.9, 4.6 Hz, 1H), 3.39 (td, J = 6.0, 2.8 Hz, 2H); 13C
A solution of the above acid (1.04 mmol) in anhydrous THF
(25 mL) and absolute ethanol (2.5 mL) was added to an oven dried
three-neck round bottom flask charged with argon. The flask was
cooled to À40 8C bath, liquid NH3 (approximately 150 mL) was
condensed using an acetone/liquid nitrogen cold trap flask. Fresh
polished lithium flakes were added to the reactants at À40 8C until
the deep blue color was kept for 5 min. The reaction was quenched
by the addition of NH4Cl powder (2.7 g), and the reaction was left
in the hood until almost all the NH3 evaporated. The reaction
mixture was then diluted with EtOAc (15 mL) and water (15 mL).
The aqueous layer was washed with EtOAc (2Â 20 mL), acidified
with 1N HCl until pH 2 and extracted with EtOAc (3Â 20 mL). The
d = 1.21–1.33 (m,
NMR (100.5 MHz, D2O):
125.9 (q, J = 283.7 Hz), 169.3; 19F NMR (376.2 MHz, D2O):
= À76.2.
d = 27.7, 29.4, 63.1, 68.2 (q, J = 26.8 Hz),
d
combined organic layers were evaporated to afford 100 mg of pure
22
4.4. 8a-Trifluoromethyl-4-phenyltetrahydropyrrolo[2,1-
(S)-6 (49%). White solid; m.p.: 143–144 8C; [
a
]
D
À12.6 (c 2.2,
1H NMR
= 2.35–2.55 (m, 4H);1H NMR (400 MHz,
= 2.20–2.40 (m, 4H); 13C NMR (100.5 MHz, CD3OD):
= 26.9; 30.3; 69.0; 126.2 (q, J = 283.6 Hz), 170.2, 180.3; 13C
NMR (100.5 MHz, D2O): = 25.3, 29.0, 67.8 (q, J = 28.8 Hz), 124.2
(q, J = 283.6 Hz), 170.4, 181.3; 19F NMR (376.2 MHz, D2O):
c][1,4]oxazine-1,6-dione (7)
MeOH); IR (neat): 3139, 3049, 1670, 1402, 1155 cmÀ1
(400 MHz, CD3OD):
D2O):
;
d
To a stirred solution of 263 mg of a 75:25 diastereomeric
mixture of alcohol 2 (0.87 mmol, 1.0 equiv.) in 2.8 mL of acetone
d
d
was added dropwise at 0 8C 634
(2.74 M in 3.2:1 H2O/H2SO4 solution, 1.7 mmol, 2.0 equiv.). After
20 min at 0 8C, 250 L of solution of Jones reagent was added
m
L of solution of Jones reagent
d
d
À79.0
m
(s); MS (EI) m/z 152 (M+–CO2H) (100); Anal. Calcd for C6H6F3NO3:
once more and the reaction mixture was stirred for another
20 min at 0 8C. Finally, isopropanol was added until color turned
green and the resulting solution was diluted in 50 mL of diethyl
ether and 25 mL of water. The layers were separated and the
aqueous phase was extracted with AcOEt (3 mL Â 20 mL). The
combined organic extracts were washed with saturated aqueous
NaHCO3 solution, dried over MgSO4 and evaporated under
reduced pressure. Purification by flash chromatography (9:1
cyclohexane/ethyl acetate) gave 157 mg (61%) of the diaster-
C, 36.56; H, 3.07; N, 7.11. Found: C, 36.93; H, 3.10; N, 6.97.
4.6. (R)-a-Trifluoromethylpyroglutamic acid ((R)-6)
According to the procedure described for (S)-6, starting from
(R,R)-7 (551 mg, 1.84 mmol) in THF (11 mL) and 1 M aqueous
solution of LiOH (2.21 mL, 2.21 mmol, 1.2 equiv.), crude acid
(451 mg) was obtained. This acid was directly used in the next
reductive debenzylation step without further purification to
25
eomer (R,S)-7 as
a
white solid and 53 mg (20%) of the
afford 222 mg of pure (R)-6 (69%). White solid; [
a
]
+11.7 (c
D
diastereomer (R,R)-7 as a colorless oil. (R,S)-7: white solid;
m.p.: 189–190 8C; Rf = 0.41 (7:3 cyclohexane/ethyl acetate);
2.2, MeOH). The spectral data of (R)-6 were identical to those of
(S)-6.

1108
G. Chaume et al. / Journal of Fluorine Chemistry 129 (2008) 1104–1109
X-ray source
Mo Ka
0.71069
4.7. (S,S)-5-oxo-2-trifluoromethylpyrrolidine-2-carboxylic acid (1-
˚
l
(A)
phenyl)ethylamide ((S,S)-8)
Monochromator
T (K)
Graphite
150.0(1)
To a solution of (S)-phenylethylamine (69
1.5 equiv.) in DMF (1.5 mL) was successively added at 0 8C Et3N
(203 L, 1.45 mmol, 4.1 equiv.), HOBt (72 mg, 0.53 mmol,
mL, 0.53 mmol,
Scan mode
Phi and omega scans
Maximum
u
27.48
H K L ranges
Reflections measured
Unique data
Rint
À10 10; À9 9; À13 13
m
2790
2790
0.0000
2680
1.5 equiv.), EDCI (102 mg, 0.53 mmol, 1.5 equiv.) and pure (S)-6
(70 mg, 0.36 mmol) in DMF (1 mL). The resulting mixture was
stirred at 0 8C for 20 min and then at room temperature overnight.
Then, the reaction mixture was diluted with AcOEt (20 mL) and
washed with 1N HCl (10 mL). The layers were separated and the
aqueous layer was extracted with EtOAc (2Â 10 mL). The combined
organic layers were then washed with saturated aqueous NaHCO3
solution (10 mL) and water (10 mL), dried over MgSO4 and
evaporated under reduced pressure. The 1H and 19F NMR analysis
of the crude mixture confirmed that one single diastereomer was
obtained. Purification by flash chromatography (1:1 cyclohexane/
ethyl acetate) gave 43 mg (51%) of the diastereomer (S,S)-8 as a
Reflections used
Criterion
I > 2sI
Fsqd
Refinement type
Hydrogen atoms
Parameters refined
Reflections/parameter
wR2
Mixed
191
14
0.0932
R1
0.0322
Flack’s parameter
Weights a, b
GoF
À0.1(5)
0.0590, 0.0754
1.053
À3
˚
Difference peak/hole (e A
)
0.194(0.048)/À0.179(0.048)
colorless oil. 1H NMR (400 MHz, CDCl3):
d = 1.49 (d, J = 6.9 Hz, 3H),
2.17 (ddd, J = 14.5, 9.2, 4.8 Hz, 1H), 2.30–2.40 (m, 1H), 2.40–2.55
(m, 2H), 5.10 (dq, J = 7.8, 6.9 Hz, 1H), 7.20–7.35 (m, 5H), 7.47 (d,
References
J = 7.8 Hz, 1H), 7.87 (s, 1H); 13C NMR (100.5 MHz, CDCl3):
d = 21.4,
[1] For recent entries, see:
26.0, 29.0, 49.7, 67.5 (q, J = 28.8 Hz); 124.6 (q, J = 285.6 Hz), 126.1,
(a) P.K. Mikhailiuk, S. Afonin, A.N. Chernega, E.B. Rusanov, M.O. Platonov, G.G.
Dubinina, M. Berditsch, A.S. Ulrich, I.V. Komarov, Angew. Chem. Int. Ed. 45 (2006)
5659–5661;
(b) B.C.J. vanEsseveldt, P.W.H. Vervoort, F.L. van Delft, F.P.J.T.Rutjes, J.Org. Chem.70
(2005) 1791–1795 (and references therein);
127.6, 128.6, 142.3, 165.3, 178.6; 19F NMR (376.2 MHz, CDCl3):
d
À80.1 (s).
(c) C.L. Jenkins, G. Lin, J. Duo, D. Rapolu, I.A. Guzei, R.T. Raines, G.R. Krow, J. Org.
Chem. 69 (2004) 8565–8573 (and references therein);
Acknowledgements
(d) P. Karoyan, S. Sagan, O. Lequin, J. Quancard, S. Lavielle, G. Chassaing, Targets
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(e) J.R. Del Valle, M. Goodman, J. Org. Chem. 68 (2003) 3921–3933 (and references
therein);
The authors thank Ingrid Nativel for her experimental
contribution on the hydroboration reaction using dicylohexylbor-
ane. The authors are also grateful to Central Glass Company for
their financial support and their generous gift of ethyl trifluor-
opyruvate.
(f) J. Zhang, W. Wang, C. Xiong, V.J. Hruby, Tetrahedron Lett. 44 (2003) 1413–1415.
[2] (a) L. Moroder, C. Renner, J.J. Lopez, M. Mutter, G. Tuchscherer, in: C. Dugave (Ed.),
Cis–trans Isomerization in Biochemistry, Wiley–VCH, Weinheim, Germany, 2006;
´
(b) A. Flores-Ortega, A.I. Jimenez, C. Cativiela, C. Nussinov, R. Aleman, J. Casano-
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[3] (a) T. Kitamoto, T. Ozawa, M. Abe, S. Marubayashi, T. Yamazaki, J. Fluorine Chem.
129 (2008) 286–293;
Appendix A. X-ray crystallographic study
(b) Y. Guo, K. Fujiwara, H. Amii, K. Uneyama, J. Org. Chem. 72 (2007) 8523–8526
(and references therein);
(c) U.E.W. Lange, D. Baucke, W. Hornberger, H. Mack, W. Seitz, H.W. Ho¨ffken,
Bioorg. Med. Chem. Lett. 16 (2006) 2648–2653;
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(2005) 18121–18132;
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8145.
Data were collected at 150.0(1)K on
a
˚
Nonius Kappa CCD
diffractometer using a Mo Ka (l = 0.71070 A) X-ray source and a
graphite monochromator. All datawere measuredusing phi and omega
scans. The crystal structures were solved using SIR 9744 and Shelxl-97.
CCDC-695212 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge at www.ccdc.ca-
m.ac.uk/conts/retrieving.html or from the Cambridge Crystallographic
Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (internat.) +
44 1223/336 033; E-mail: deposit@ccdc.cam.ac.uk
[4] (a) V.P Kukhar, V.A Soloshonok, Fluorine Containing Amino Acids, Synthesis and
Properties, Wiley,, New York, 1995 (and references cited therein);
(b) X.-L. Qui, W.-D. Meng, F.-L. Qing, Tetrahedron 60 (2004) 6711–6745;
(c) M. Molteni, C. Pesenti, M. Sani, A. Volonterio, M. Zanda, J. Fluorine Chem. 125
(2004) 1735–1743.
[5] (a) G. Luppi, D. Lanci, V. Trigari, M. Garavelli, A. Garelli, C. Tomasini, J. Org. Chem.
68 (2003) 1982–1993 (and references therein);
Compound:
(R,S)-8a-Trifluoromethyl-4-phenyltetrahydropyr-
rolo[2,1-c][1,4]oxazine-1,6-dione.
(b) C. Tomasini, M. Villa, Tetrahedron Lett. 42 (2001) 5211–5214.
[6] For literature concerning fluorinated pyroglutamic acids, see:
(a) F.-L. Qing, X.-L. Qiu, Synthesis of fluorinated prolines and pyroglutamic acids,
in: V.A. Soloshonok (Ed.), Fluorine Containing Synthons, American Chemical
Society, Washington, DC, 2005 , p. 562 (and references therein);
(b) X.-L. Qiu, W.-D. Meng, F.-L. Qing, Tetrahedron 60 (2004) 5201–5206;
(c) X.-L. Qiu, W.-D. Meng, F.-L. Qing, J. Org. Chem. 68 (2003) 3614–3617;
(d) V.A. Soloshonok, C. Cai, V.J. Hruby, L. Van Meervelt, N. Mischenko, Tetrahedron
55 (1999) 12031–12044;
Molecular formula
Molecular weight
Crystal habit
C14H12F3NO3
299.25
Block colorless
Crystal dimensions (mm)
Crystal system
0.20 Â 0.18 Â 0.18
Monoclinic
Space group
P21
˚
a (A)
7.8210(10)
˚
(e) V.A. Soloshonok, C. Cai, V.J. Hruby, L. Van Meervelt, Tetrahedron 55 (1999)
12045–12058;
(f) V.A. Soloshonok, D.V. Avilov, V.P. Kukhar, L. Van Meervelt, N. Mischenko,
Tetrahedron Lett. 38 (1997) 4903–4904;
b (A)
7.5940(10)
˚
c (A)
10.6570(10)
a
b
g
(8)
(8)
(8)
90.00
93.4520(10)
(g) D. Gestmann, A.J. Laurent, E.G. Laurent, J. Fluorine Chem. 80 (1996) 27–30.
[7] a-Tfm-pyroglutamic acid has only been reported in the racemic series:
B. Koksch, D. Ullmann, H.-D. Jakubke, K. Burger, J. Fluorine Chem. 80 (1996) 53–57.
[8] (a) F. Huguenot, T. Brigaud, J. Org. Chem. 71 (2006) 7075–7078;
(b) F. Huguenot, T. Brigaud, J. Org. Chem. 71 (2006) 2159–2162;
(c) N. Lebouvier, C. Laroche, F. Huguenot, T. Brigaud, Tetrahedron Lett. 43 (2002)
2827–2830;
90.00
3
˚
V (A )
Z
631.80(13)
2
d (g cmÀ3
F (0 0 0)
)
1.573
308
m
(cmÀ1
)
0.139
Absorption corrections
Diffractometer
Multi-scan; 0.9727 min, 0.9754 max
KappaCCD
(d) T. Brigaud, G. Chaume, J. Pytkowicz, F. Huguenot, Chim. Oggi Chem. Today 25
(2007) 8–10.

G. Chaume et al. / Journal of Fluorine Chemistry 129 (2008) 1104–1109
1109
[9] G. Chaume, M.-C. Van severen, S. Marinkovic, T. Brigaud, Org. Lett. 8 (2006) 6123–
6126.
L.M. Harwood, G. Hamblett, A.I. Jimenez-Dias, D.J. Watkin, Synlett (1997) 935–
938.
[10] The formation of similar oxazolidines has already been reported in the non-
fluorinated series:
[13] Rf of (R,S)-7 = 0.41 (7:3 cyclohexane/ethyl acetate) and Rf of (R,R)-7 = 0.29 (7:3
cyclohexane/ethyl acetate).
(a) C. Agami, F. Couty, B. Prince, O. Venier, Tetrahedron Lett. 37 (1993) 7061–
7062;
[14] Crystallographic data (excluding structure factors) for compound (R,S)-7 have
been deposited with the Cambridge Crystallographic Data Centre as supplemen-
tary publication no. CCDC 695212. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: + 44
1223 336033 or email: deposit@ccdc.cam.ac.uk.
(b) L.M. Harwood, K.J. Vines, M.G.B. Drew, Synlett (1996) 1051–1053.
[11] In our previous report (Ref. 9) we observed that the chromatographic separation
of both diastereomers of similar bicyclic CF3-morpholinones was very easy.
[12] The synthesis of similar bicyclic lactams has also been reported in the non
fluorinated series by an alternative strategy:
[15] G. Tang, H. Tian, D. Ma, Tetrahedron 60 (2004) 10547–10552.
[16] D. Ma, G. Tang, H. Tian, G. Zou, Tetrahedron Lett. 40 (1999) 5753–5756.