Synthesis of enantiomerically pure α-ethyl, α-vinyl and α-ethynyl 3,3,3-trifluoro alaninates

Article abstract of DOI:10.1016/j.jfluchem.2003.11.034

We describe the first synthesis of enantiomerically pure (S)-α-vinyl and (S)-α-ethynyl 3,3,3-trifluoro alanine (TF-Ala) ethyl esters, starting from the in situ generated sulfinimine (S)-2 as key fluorinated building-block. (S)-α-Ethyl TF-Ala-OEt has been prepared as well by this route.

Full text of DOI:10.1016/j.jfluchem.2003.11.034

Journal of Fluorine Chemistry 125 (2004) 573–577
Synthesis of enantiomerically pure a-ethyl, a-vinyl and
a-ethynyl 3,3,3-trifluoro alaninates
Marcello Crucianellia,1, Francesco De Angelisa, Francesco Lazzaroa,
Luciana Malpezzib, Alessandro Volonteriob, Matteo Zandac,*
a
`
Dipartimento di Chimica, Ingegneria Chimica e Materiali, Universita di L’Aquila, via Vetoio, I-67010 Coppito, Italy
bDipartimento di Chimica, Materiali ed Ingegneria Chimica ‘‘G. Natta’’ del Politecnico di Milano, via Mancinelli 7, I-20131 Milan, Italy
cC.N.R.—Istituto di Chimica del Riconoscimento Molecolare, sezione ‘‘A. Quilico’’, via Mancinelli 7, I-20131 Milan, Italy
Received 16 October 2003; received in revised form 24 October 2003; accepted 1 November 2003
Abstract
We describe the first synthesis of enantiomerically pure (S)-a-vinyl and (S)-a-ethynyl 3,3,3-trifluoro alanine (TF-Ala) ethyl esters, starting
from the in situ generated sulfinimine (S)-2 as key fluorinated building-block. (S)-a-Ethyl TF-Ala-OEt has been prepared as well by this route.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Trifluoromethyl; a-Amino acids; Sulfinimine; Stereoselective synthesis
1. Introduction
not be obtained directly by that route. Since only racemic
a-Tfm-b,g-unsaturated [7] and a-Tfm-b,g-ethynyl-amino
acids [8–10] appeared to be known from the literature,
we decided to investigate further the topic.
In this paper we describe the stereoselective addition of
ethynyl Grignard to the key sulfinimine (S)-2 (Scheme 1),
and the transformation of the major sulfinamide 3 into (S)-a-
vinyl, (S)-a-ethynyl and (S)-a-ethyl TF-Ala ethyl esters
(Scheme 3) in enantiomerically pure form and good overall
yields.
Modification of peptides and proteins by incorporation of
fluorinated amino acids is a modern strategy, that is attract-
ing considerable interest [1,2]. In this context, trifluoro-
methyl (Tfm) amino acids are playing an increasingly
important role [3], owing to the unique properties of the
Tfm group, such as high electronegativity, electron density,
steric hindrance and hydrophobic character [4]. A major
obstacle for the progress of this fascinating area of research
is the relatively difficult availability of trifluoromethyl
amino acids in non-racemic form, whose asymmetric synth-
esis often requires complex experimental protocols and
uneasy to handle starting materials.
2. Results and discussion
Recently, we have described a novel strategy for the
synthesis of non-racemic a-Tfm-a-amino acids based on
the reaction of an enantiomerically pure sulfinimine of
trifluoropyruvate with Grignard reagents [5,6]. Although
the method proved to be quite general and effective, the
reaction with vinyl magnesium halides did not produce the
desired addition across the C¼N bond, giving rise instead
to an unexpected nucleophilic attack on the sulfur atom.
As a result, a-vinyl 3,3,3-trifluoro alanine (TF-Ala) could
The sulfinimine (S)-2 was prepared in enantiomerically
pure form by Staudinger (aza-Wittig) reaction of ethyl
trifluoropyruvate with the imino-phosphorane (S)-1, accord-
ing to the literature method. In situ addition of ethynyl
magnesium bromide, without isolation of (S)-2, occurred
effectively providing the major diastereomer (2S,SS)-3 in
84% d.e. and 75% overall yield. The enantiomeric purity of
(2S,SS)-3 (e:e: ¼ 97:5%) was checked by chiral HPLC.
The stereocontrol can be explained according to the
‘‘chelation model’’ A (Fig. 1), in analogy with alkyl
Grignard reagents, with the sulfinimine (S)-2 that is expected
to react in the predominant (E)-geometry. Such a high
stereoselectivity is very surprising if one considers that
the addition of Grignard reagents to (S)-2 generally occurred
* Corresponding author. Tel.: þ39-02-2399-3084;
fax: þ39-02-2399-3080.
E-mail address: matteo.zanda@polimi.it (M. Zanda).
1 Co-corresponding author.
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2003.11.034

574
M. Crucianelli et al. / Journal of Fluorine Chemistry 125 (2004) 573–577
CO2Et
CO2Et
CF3
N
O
CO2Et
CF3
CO2Et
CF3
N
O2
S
O
O2
S
MCPBA
CH2Cl2
S
H2, Pd/C
CF3
S
Tol
N
Tol
Tol
N
Tol
H
H
H
H
EtOAc, r.t.
(S)-5
major diast.
(S)-4
O
CO2Et
CF3
(2S,SS)-3
(2S,SS)-3
O
CF3COCO2Et
THF, 40 ˚C
MgBr
PPh3
S
+
S
Tol
N
Cleavage
of the TolSO2−
Tol
N
H2, Pd/C
CO2Et
O
S
(S)-1
(S)-2
EtOAc, -10 ˚C
CF3
Tol
N
H
Cleavage
of the TolSO2−
CO2Et
CF3
N
O2
minor diast.
(2R,SS)-3
S
X
Tol
d.r. 92:8
yield 75% from (S)-1
H
Failure under
a variety of
conditions
(S)-6
Scheme 1. Stereoselective addition of ethynyl Grignard to the Tfm-
sulfinimine (S)-2.
Scheme 2. Hydrogenation of p-toluenesulfonamide derivatives.
Br
HC
C
O
Mg
F3C
EtO2C
p-Tol
N
S
L
A
Fig. 1. Chelation model leading to (2S,SS)-3.
with rather modest stereocontrol, and that the latter became
progressively higher with increasing steric bulk of the
Grignard reagent (isobutyl magnesium bromide gave a
88:12 ratio with the same sense of stereocontrol). The
reasons for this behavior are presently unknown.
With the major diastereomer (2S,SS)-3 in hand, we
addressed its conversion into the target a-Tfm-amino acids.
In order to avoid side-reactions involving the sulfinyl group,
the p-toluenesulfinamide function was oxidized to sulfona-
mide, affording (S)-4 (Scheme 2).
Hydrogenation of the CBC bond was performed with
high chemoselectivity using commercial Pd/C as catalyst
in EtOAc, upon careful control of the reaction temperature.
Thus, at À10 8C the vinyl derivative (S)-6 was obtained
as the only detectable product, whereas at RT exhaustive
hydrogenation to the ethyl derivative (S)-5 took place.
Disappointingly, the subsequent cleavage of the p-toluene-
sulfonamide group from both 5 and 6 could not be performed
successfully, despite a number of attempts under different
reaction conditions.2
Fig. 2. Molecular structure of (S)-5 with the atom-numbering scheme;
displacement ellipsoids correspond to 20% probability; H atoms are shown
as spheres with arbitrary radius.
Chemoselective hydrogenation to (S)-a-vinyl and (S)-a-
ethyl TF-Ala-OEt (8 and 9, respectively) was performed
next under conditions similar to those discussed above.
In summary, new unsaturated enantiomerically pure
a-Tfm a-amino-acids have been synthesized in a selectively
protected form, potentially suitable for incorporation into
peptides, from a chiral sulfinimine of trifluoropyruvate.
Although this route did not lead to the target molecules,
the sulfonamide (S)-5 provided crystals suitable for X-ray
diffraction that allowed us to assign the absolute configura-
tion to the whole series of molecules described herein. An
ORTEP view of one of the two independent molecules of the
unit cell is shown in Fig. 2. The geometry of the two
molecules is very similar.
In order to complete the synthesis, the sulfinamide
(2S,SS)-3 was desulfinylated with TFA/MeOH affording
a-ethynyl-TF-Ala-OEt (S)-7 in good yields (Scheme 3).
CO2Et
CO2Et
CF3
N
TFA
O
S
.
TFA
CF3
Tol-SO2Me
+
H2N
Tol
(2S,SS)-3
MeOH
H
(S)-7
H2, Pd/C
CHCl3, 0 ˚C
H2, Pd/C
CHCl3, r.t.
CO2Et
CF3
CO2Et
CF3
.
H2N
TFA
.
H2N
TFA
2 Among the unsuccessful conditions explored, 48% HBr, phenol at
reflux and Na/liquid NH3. In both cases complex mixtures of products
were obtained, mainly as a consequence of side-reactions involving the
CBC bond.
(S)-8
(S)-9
Scheme 3. Synthesis of a-ethyl, a-vinyl and a-ethynyl trifluoroalanine
ethyl esters.

M. Crucianelli et al. / Journal of Fluorine Chemistry 125 (2004) 573–577
575
3. Experimental
Enantiomeric major diastereomer (2R,RS)-3 analogously
20
obtained starting from iminophosphorane (R)-1 had ½aŠ
D
3.1. General
À39.1 (c ¼ 0:9, CHCl3). HPLC analysis: tr ¼ 7:01 min.
20
D
(2R,SS)-3: Rf ¼ 0:37 (n-Hex/EtOAc 70/30); oil; ½aŠ
1
Chemical shifts (d) are reported in parts per million (ppm)
of the applied field. Coupling constants (J) are reported
in Hertz. Me4Si was used as internal standard (dH and
dC ¼ 0:00) for 1H and 13C nuclei, while C6F6 was used
as external standard (dF ¼ À162:90) for 19F nuclei. Peak
multiplicities are abbreviated: singlet, s; doublet, d; triplet,
t; quartet, q; multiplet, m, etc. 1H NMR spectra were
recorded at 200 MHz, 13C NMR at 50.3 MHz, 19F NMR
at 235.2 MHz. Anhydrous solvents were obtained by dis-
tillation from sodium (THF) or from calcium hydride
(dichloromethane). In all other cases commercially available
reagent-grade solvents were employed without purification.
Grignard reagents were purchased from Sigma/Aldrich/
Fluka Company. Reactions performed in dry solvents were
carried out under nitrogen atmosphere. Melting points are
uncorrected and were obtained on a capillary apparatus.
Analytical thin-layer chromatography (TLC) was routinely
used to monitor reactions. Plates precoated with E. Merck
silica gel 60 F254 of 0.25 mm thickness were used. Merck
silica gel 60 (230–400 ASTM mesh) was employed for flash
chromatography (FC). Chiral HPLC analyses were carried
out using a Chiralcel OD column, n-Hex/iso-propanol 85:15,
0.8 ml minÀ1. The iminophosphorane (S)-1 was prepared
according to the literature [5].
þ117.4 (c ¼ 0:79, CHCl3). H NMR (CDCl3): d 7.56 (d,
J ¼ 8 Hz, 2H), 7.26 (d, J ¼ 8 Hz, 2H), 5.27 (s, 1H), 4.40–
4.25 (m, 2H), 2.96 (s, 1H), 2.36 (s, 3H), 1.29 (t, J ¼ 7:2 Hz,
3H). 13C NMR (CDCl3): d 164.0, 142.1, 141.4, 129.8, 125.4,
122.0 (q, J ¼ 286:21 Hz), 81.3, 71.2, 65.1, 61.9 (q,
J ¼ 32:7 Hz), 21.4, 13.8. 19F NMR (CDCl3): d À77.7 (s).
3.3. Oxidation of (2S,SS)-3: preparation of ethyl 2-{[(4-
methylphenyl)sulfonyl]amino}-2-(trifluoromethyl)-3-
butynoate (S)-4
To 6 ml of a cooled (0 8C) dichloromethane solution
of sulfinamide (2S,SS)-3 (496 mg, 1.49 mol), 444 mg
(2.23 mmol) of m-chloro-perbenzoic acid were added under
stirring. After 15 min the mixture was allowed to warm to
RT, left under stirring for 1.5 h and then quenched. The
reaction mixture was diluted with dichloromethane and
washed with a saturated aqueous solution of Na2S2O5, the
separated organic layer was then washed with, respectively,
a saturated aqueous solution of NaHCO3 and brine, then
dried over anhydrous sodium sulfate. Purification of the
crude by FC (n-Hex/EtOAc 70/30) afforded 380 mg of (S)-4
(73% yield).
(S)-4: Rf ¼ 0:55 (n-Hex/EtOAc 70/30); mp (i-Pr2O) ¼
20
D
1
74 8C; ½aŠ þ27.8 (c ¼ 0:5, CHCl3). H NMR (CDCl3): d
3.2. Synthesis of ethyl 2-{[(4-
methylphenyl)sulfinyl]amino}-2-(trifluoromethyl)-3-
butynoates (2S,SS)- and (2R,SS)-3
7.82 (d, J ¼ 8 Hz, 2H), 7.29 (d, J ¼ 8 Hz, 2H), 5.93 (s, 1H),
4.40–4.25 (m, 2H), 2.59 (s, 1H), 2.43 (s, 3H), 1.32
(t, J ¼ 7 Hz, 3H). 13C NMR (CDCl3): d 163.4, 144.2,
137.2, 129.4, 127.9, 121.3 (q, J ¼ 287:3 Hz), 80.0, 69.9,
65.0, 61.1 (q, J ¼ 32:7 Hz), 21.6, 13.7. 19F NMR (CDCl3):
d À76.8 (s).
Neat ethyl trifluoropyruvate (111 ml, 0.83 mmol) was
added dropwise to a solution of iminophosphorane (S)-1
(313 mg, 0.75 mmol) in 1.5 ml of THF freshly distilled
from sodium. The mixture was warmed at 40 8C for 2 h;
the yellow solution containing the sulfinimine (S)-2, was
then cooled to À70 8C and a 0.5 M THF solution of ethynyl
magnesium bromide (1.66 ml, 0.83 mmol) was added
dropwise with stirring. After 15 min the reaction mixture
was quenched at À70 8C with saturated aqueous solution
of NH4Cl, extracted with ethyl acetate and dried over
anhydrous sodium sulfate. Purification of the crude by FC
(n-Hex/EtOAc from 75/25 to 70/30) afforded 173 mg of
the major diastereomer (2S,SS)-3 (Rf >) and 15 mg of
the minor (2R,SS)-3 (Rf <) (84% d.e.) with a 75% overall
3.4. Reduction of (S)-4: preparation of ethyl 20,20,20-
trifluoro-N-[(4-methylphenyl)sulfonyl]isovalinate (S)-5
and ethyl 2-{[(4-methylphenyl)sulfonyl]amino}-2-
(trifluoromethyl)-3-butenoate (S)-6
A solution of sulfonamide (S)-4 (150 mg, 0.43 mmol) in
ethyl acetate (5 ml) was stirred for 1 h at RT in the presence
of Pd/C (10%, w/w) under hydrogen atmosphere. The
solution was then filtered on a celite pad and the solvent
removed in vacuo. FC (n-Hex/EtOAc 80/20) of the crude
afforded 144 mg (94% yield) of the desired reduction pro-
duct (S)-5.
yield.
20
D
(2S,SS)-3: Rf ¼ 0:4 (n-Hex/EtOAc 70/30); oil; ½aŠ
(S)-5: Rf ¼ 0:70 (n-Hex/EtOAc 70/30); mp (i-Pr2O) ¼
20
þ44.20 (c ¼ 2, CHCl3). 1H NMR (CDCl3): d 7.62 (d,
J ¼ 8 Hz, 2H), 7.31 (d, J ¼ 8 Hz, 2H), 5.52 (s, 1H),
4.45–4.30 (m, 2H), 2.99 (s, 1H), 2.41 (s, 3H), 1.36 (t,
J ¼ 7:2 Hz, 3H). 13C NMR (CDCl3): d 163.6, 142.1,
129.8, 125.6, 121.92 (q, J ¼ 287:7 Hz), 80.8, 71.7, 64.8,
63.0 (q, J ¼ 33:2 Hz), 21.4, 13.8. 19F NMR (CDCl3): d
À76.5 (s); HPLC analysis: tr ¼ 9:05 min.
81 8C; ½aŠ þ13.46 (c ¼ 0:78, CHCl3). 1H NMR (CDCl3): d
D
7.68 (d, J ¼ 8 Hz, 2H), 7.20 (d, J ¼ 8 Hz, 2H), 5.84 (s, 1H),
4.25 (q, J ¼ 8 Hz, 2H), 2.52–2.40 (m, 1H), 2.34 (s, 3H),
2.15–1.95 (m, 1H), 1.23 (t, J ¼ 8 Hz, 3H), 0.89 (t, J ¼
7:2 Hz, 3H). 13C NMR (CDCl3): d 166.3, 143.3, 138.9, 129.3,
126.7, 123.2 (q, J ¼ 286:7 Hz), 69.1 (q, J ¼ 28:2 Hz), 63.9,
23.4, 21.4, 13.7, 7.8. 19F NMR (CDCl3): d À74.0 (s).

576
M. Crucianelli et al. / Journal of Fluorine Chemistry 125 (2004) 573–577
Working in the same experimental conditions described
3H), 4.37 (q, J ¼ 7:1 Hz, 2H), 2.35–2.00 (m, 2H), 1.33 (t,
J ¼ 7:1 Hz,3H),1.04(t,J ¼ 7:3 Hz,3H).13C NMR(CDCl3):
d165.6,123.3(q,J ¼ 284:2 Hz),65.8(q,J ¼ 28:42 Hz),64.1,
24.7, 13.8, 7.0; 19F NMR (CDCl3): d À76.9 (s, 3F), À78.3
(s, 3F). ESIþ-MS : m=z ¼ 200:2 (M þ H).
above with the only difference of temperature which was
held at aboutÀ10 8C during reaction, the vinyl derivative
(S)-6 was obtained after 2 h (89% yield).
(S)-6: Rf ¼ 0:62, (n-Hex/EtOAc 70/30); mp (i-Pr2O) ¼
20
79 8C; ½aŠ þ2.74 (c ¼ 0:62, CHCl3). 1H NMR (CDCl3): d
D
7.66 (d, J ¼ 8 Hz, 2H), 7.20 (d, J ¼ 8 Hz, 2H), 6.10–5.94
(m, 1H), 5.67 (s, 1H), 5.44–5.26 (m, 2H), 4.23 (q, J ¼7:2 Hz,
2H), 2.35 (s, 3H), 1.21 (t, J ¼ 7:2 Hz, 3H). 13C NMR
(CDCl3): d 165.4, 143.8, 138.7, 129.4, 127.2, 126.7,
123.6, 122.6 (q, J ¼ 286:46 Hz), 68.0 (q, J ¼ 28:67 Hz),
63.8, 21.6, 13.7; 19F NMR (CDCl3): d À75.2 (s).
3.7. X-ray crystallographic data for (S)-5
A colorless prismatic crystal (0:6 mm  0:5 mm Â
0:2 mm), suitable for X-ray analysis, was obtained from
diisopropyl ether. Intensities data were collected on a Sie-
mens P4 diffractometer with graphite monochromated Cu
ꢀ
Ka radiation (l ¼ 1:54179 A), using y/2y scan technique.
3.5. Synthesis of ethyl 2-amino-2-(trifluoromethyl)-3-
butynoate trifluoroacetic acid salt (S)-7
Unit cell parameters were determined using 47 reflections in
the range 19 ꢁ 2y ꢁ 72ꢀ; a total of 3363 reflections were
collected up to 1368 in 2y and index range: À1 ꢁ h ꢂ 9,
À11 ꢁ k ꢂ 11, À12 ꢁ l ꢂ 12. No crystal decay observed.
Crystal data: C14H28O4NF3S, Mr ¼ 353:3, triclinic, space
To a cooled (0 8C) flask containing a solution of (2S,SS)-3
(850 mg, 2.65 mmol) dissolved in 8 ml of methanol, 410 ml
(5.30 mmol) of trifluoroacetic acid (TFA) were added drop-
wise, under stirring. The solution was stirred for 1 h at RT,
then concentrated in vacuo. The crude was purified by FC
using a gradient n-Hex/EtOAc 95/5 to 80:20, affording
589 mg of (S)-7 (72% yield).
˚
group P1, a ¼ 8:268ð1Þ, b ¼ 10:015ð1Þꢀ, c ¼ 10:996ð1Þ A,
3
˚
a¼69:99ð1Þ, b¼80:16ð1Þ, g¼ 88:59ð1Þ , V ¼842:4ð2Þ A ,
two independent molecules in the unit cell, Dc ¼ 1:393 g
cmÀ3, m ¼ 2:166 mmÀ1, Fð0 0 0Þ ¼ 368; l ¼ 1:54179 A,
˚
room temperature. The structure was solved by direct meth-
ods (SIR97) [11] program and refined on F2 by full-matrix
least-squares procedure (SHELXL97) [12]. Owing to the
high number of parameters to be refined (429), due to the
presence in the unit cell of two independent molecules,
the last refinement, with anisotropic temperature factors for
non-H atoms, was carried out on each of the two molecule
separately. H-atoms were included in calculated positions
and refined in riding model. The C7 methyl group of one
molecule was found disordered over two positions. The final
stage converged to R1 ¼ 0:061 (Rw ¼ 0:160) for 2880
observed reflections, with I ꢂ 2sðIÞ, and R1 ¼ 0:070
(Rw ¼ 0:173) for all reflections. The goodness of fit, S,
was 1.068. The final difference map showed a maximum
(S)-7: Rf ¼ 0:35 (n-Hex/EtOAc 80/20); mp ¼ 63–65 8C;
20
½aŠ þ9.5 (c ¼ 0:5, CHCl3). 1H NMR (CDCl3): d 4.40–4.20
D
(m, 2H), 2.52 (s, 1H), 2.25 (br, s, 3H), 1.28 (t, J ¼ 7 Hz, 3H).
13C NMR (CDCl3): d 164.0, 121.7 (q, J ¼ 285:2 Hz), 73.7,
64.5, 62.9, 58.4 (q, J ¼ 31:7 Hz), 12.7; the signals of
trifluoroacetic acid counterion were undetectable due to
low intensity. 19F NMR (CDCl3): d À76.9 (s, 3F), À78.2
(s, 3F). ESIþ-MS : m=z ¼ 196:1 (M þ H).
3.6. Reduction of (S)-7: preparation of ethyl 2-amino-2-
(trifluoromethyl)-3-butenoate trifluoroacetic acid salt (S)-8
and ethyl 20,20,20-trifluoroisovalinate trifluoroacetic acid
salt (S)-9
À3
˚
and minimum residual peaks of 0.36 and À0.46 e A
,
A solution of aminoester TFA salt (S)-7 (90 mg,
0.462 mmol) in chloroform (5 ml) was stirred for 1 h at
0 8C, in the presence of Pd/C (10%, w/w) under hydrogen
atmosphere. The solution was then filtered on a celite pad
and the solvent removed in vacuo, affording 109 mg (76%
respectively. The absolute configuration was unambiguously
assigned by the Flack [13] parameter x ¼ À0:01ð3Þ for the
(S) absolute configuration and x ¼ 0:68ð3Þ for the inverse
one, and by an R-factor test R ¼ 0:061 and 0.066 for the (S)
and (R) configurations, respectively.3
yield) of the exhaustively hydrogenated TFA salt (S)-8.
20
(S)-8: Rf ¼ 0:20 (n-Hex/EtOAc 80/20); oil; ½aŠ À21.8
D
1
(c ¼ 0:72, CHCl3). H NMR (CDCl3): d 7.18 (br signal,
Acknowledgements
3H), 6.25–6.05 (m, 1H), 5.83–5.58 (m, 2H), 4.45–4.25
(m, 2H), 1.33 (t, J ¼ 7:1 Hz, 3H). 13C NMR (CDCl3):
d 165.2, 127.7, 123.0 (q, J ¼ 286:6 Hz), 122.1, 65.5
(q, J ¼ 29:7 Hz), 64.2, 13.8; 19F NMR (CDCl3): d À77.1
(s, 3F), À77.4 (s, 3F). ESIþ-MS : m=z ¼ 198:1 (M þ H).
Working in the same experimental conditions described
above with the only difference of temperature which was
held at r.t during reaction, the desired reduction product (S)-
We thank MIUR (Cofin 2002, Project ‘‘Peptidi Sintetici
Bioattivi’’), Politecnico di Milano and C.N.R. for economic
support.
3 Crystallographic data (excluding structure factors) for the structure in
this paper have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC222025. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: þ44-1223-336033.deposit@ccdc.cam.a-
c.uk).
9 was obtained after 3 h (69% yield).
D
(S)-9: Rf ¼ 0:23 (n-Hex/EtOAc 80/20); oil; ½aŠ À5.9
20
(c ¼ 0:37, CHCl3). 1H NMR (CDCl3): d 7.69 (br signal,

M. Crucianelli et al. / Journal of Fluorine Chemistry 125 (2004) 573–577
577
[6] P. Bravo, M. Crucianelli, B. Vergani, M. Zanda, Tetrahedron Lett. 39
(1998) 7771–7774.
References
[7] S.N. Osipov, O.I. Artyushin, A.F. Kolomiets, C. Bruneau, M.
Picquet, P.H. Dixneuf, Eur. J. Org. Chem. (2001) 3891–3897.
[8] K. Burger, N. Sewald, Liebigs, Ann. Chem. (1992) 947–952.
[9] K. Burger, N. Sewald, Synthesis (1990) 115–118.
[10] S.N. Osipov, A.S. Golubev, N. Sewald, K. Burger, Tetrahedron Lett.
38 (1997) 5965–5966.
[1] V.P. Kukhar, V.A. Soloshonok (Eds.), Fluorine-Containing Amino
Acids: Synthesis and Properties, Wiley, Chichester, 1995.
[2] A. Sutherland, C.L. Willis, Nat. Prod. Rep. (2000) 621–631.
[3] J.-C. Horng, D.P. Raleigh, J. Am. Chem. Soc. 125 (2003) 9286–9287,
and references therein..
[11] A. Altomare, M.C. Burla, M. Camalli, G.L. Cascarano, C.
Giacovazzo, A. Guagliardi, A.G.G. Moliteni, G.P. Polidori, R.
Spagna, J. Appl. Cryst. 32 (1999) 115–119.
[4] R.E. Banks, J.C. Tatlow, B.E. Smart, Organofluorine Chemistry:
Principles and Commercial Applications, Plenum Press, New York,
1994.
[12] G.M. Sheldrick, SHELXL97, Release 97-2, Program for the Refine-
¨
ment of Crystal Structures, University of Gottingen, Germany, 1997.
[5] A. Asensio, P. Bravo, M. Crucianelli, A. Farina, S. Fustero, J.G.
Soler, S.V. Meille, W. Panzeri, F. Viani, A. Volonterio, M. Zanda,
Eur. J. Org. Chem. (2001) 1449–1458.
[13] H.D. Flack, Acta Cryst. A39 (1983) 876–881.