Asymmetric synthesis of both enantiomers of syn-(3-trifluoromethyl)cysteine derivatives

Article abstract of DOI:10.1016/j.jfluchem.2004.11.009

The use of several chiral trifluoromethylated building blocks 1a, 1b, 9a and 9b was attempted to synthesize of syn-(3-trifluoromethyl)cysteine. A novel and efficient enantioselective synthesis of both enantiomers of syn-(3-trifluoromethyl)cysteine derivat

Full text of DOI:10.1016/j.jfluchem.2004.11.009

Journal of Fluorine Chemistry 126 (2005) 499–505
www.elsevier.com/locate/fluor
Asymmetric synthesis of both enantiomers of
syn-(3-trifluoromethyl)cysteine derivatives
Zhong-Xing Jianga, Xiao-Ping Liub, Xiao-Long Qiua, Feng-Ling Qinga,c,
*
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Science, 354 Fenglin Lu, Shanghai 200032, China
bCollege of Chemistry and Chemistry Engineering, Hunan University of Science and Technology,
Xiangtan, Hunan 411201, China
cCollege of Chemistry and Chemistry Engineering, Donghua University,
1882 West Yanan Lu, Shanghai 200051, China
Received 6 September 2004; received in revised form 15 November 2004; accepted 16 November 2004
Available online 18 December 2004
Dedicated to Professor Richard D. Chambers on the occasion of his 70th birthday.
Abstract
The use of several chiral trifluoromethylated building blocks 1a, 1b, 9a and 9b was attempted to synthesize of syn-(3-trifluoromethyl)-
cysteine. A novel and efficient enantioselective synthesis of both enantiomers of syn-(3-trifluoromethyl)cysteine derivatives 12a and 12b was
successfully achieved.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Trifluoromethylated compounds; Cysteine; Amino acids; Asymmetric synthesis
1. Introduction
agents [8]. In the past 20 years, there has been a particular
interest in trifluoromethylated amino acids because replace-
ment of methyl or other groups with trifluoromethyl group is
accompanied by a substantial increase in hydrophobicity,
owing to the low polarizability of the fluorine atoms [9]. In
addition, due to the strong electron-withdrawing effect of the
trifluoromethyl group, the chemical and biological properties
of the trifluoromethylated amino acids may differ greatly
from those of their non-fluorinated analogues. Introduction
of a trifluoromethyl group into cysteine derivatives may bring
substantial conformational and physiological changes and
provide a useful probe to follow biochemical reactions.
However, to the best of our knowledge, no trifluoromethy-
lated cysteine has ever been synthesized to date, which
inspired us to pursue an asymmetric synthesis of both
enantiomers of syn-(3-trifluoromethyl)cysteine.
Cysteine is a sulfur-containing amino acid that is
distributed widely in proteins, peptides (subtilin, nisin and
ancovenin) [1] and antibiotics (griseoviridin, penicillin
family) [2]. Many cysteine-containing natural products
exhibit important biological activities. Furthermore, synthetic
orthogonally protected cyclolanthionines and methylanthio-
nines have been proposed as constrained building blocks for
the design of novel peptide mimics [3]. There are also some
reports on the synthesis and application of chemically
modified cysteines, especially b-substituted cysteines, which
show better activities in antibiotics than cysteine itself [4].
Besides being utilized as conformational modifiers in
physiologically active proteins and enzymes [5], fluorinated
amino acids, especially in an enantiomerically pure form,
have been widely used as biochemical probes [6], as
inhibitors of enzymes [7], and as antitumor and antibacterial
2. Results and discussion
* Corresponding author. Tel.: +86 21 64163300; fax: +86 21 64166128.
E-mail addresses: flq@mail.sioc.ac.cn, flq@pub.sioc.ac.cn
(F.-L. Qing).
In our previous study, we conveniently synthesized a
class of chiral trifluoromethylated building blocks through
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.11.009

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Z.-X. Jiang et al. / Journal of Fluorine Chemistry 126 (2005) 499–505
Scheme 1.
Scheme 2.
regioselective and stereoselective nucleophilic ring-opening
of trifluoromethylated cyclic sulfates [10]. From those chiral
building blocks, some trifluoromethylated amino acids
(including both enantiomers of anti-4,4,4-trifluorothreonine,
2-amino-4,4,4-trifluorobutanoic acid and syn-4,4,4-trifluor-
oisothreonine) were successfully synthesized [10]. Herein,
we sought to apply these chiral building blocks to the
synthesis of 3-trifluoromethylcysteine. Initially, chiral
building blocks 1a [10a] were chosen as starting materials.
The synthetic strategy presented here involved the following
steps: introduction of a sulfur atom into the chiral building
block 1a; removal of the benzyl group of 3a followed by
oxidation of the resultant primary alcohol 3a to the
carboxylic acid 6a; reduction of the azido group to afford
the target molecule 7a. The retrosynthetic analysis of 3-
trifluoromethyl-cysteine 7a is presented in Scheme 1.
Thus, according to our retrosynthetic analysis, trifluor-
omethylated alcohol 1a was first treated with methanesul-
fonyl chloride and pyridine to afford methanesulfonate 2 in
99% yield, which provided a leaving group for the
introduction of sulfur atom at C3 of the compound 2
(Scheme 2). However, treatment of methanesulfonate 2 with
potassium thioacetate or thioacetic acid/cesium fluoride
under various conditions resulted only in recovery of
methanesulfonate 2. The failure to afford the compound 3
should be attributed to the strong electron-withdrawing
effect and steric hindrance of trifluoromethyl group, which
blocked the SN2 replacement reaction.
In view of the above failure and corresponding analysis,
we envisaged that the trifluoromethanesulfonyl group
should probably make the replacement reaction occur
because it is a better leaving group than the methane-
sulfonyl group in SN2 replacement reaction. Thus exposure
of the alcohol 1a to trifluoromethanesulfonic anhydride and
pyridine at ꢀ40 8C gave the trifluoromethanesulfate 4a in
95% yield (Scheme 3). Then, a cesium fluoride mediated
SN2 displacement [11] was carried out on the trifluor-
omethanesulfate 4a with thioacetic acid at 0 8C and, the
desired intermediate 3a was provided in 87% yield.
Removal of the benzyl group of 3a was realized with
boron trichloride at ꢀ78 8C and the alcohol 5a was isolated
in 99% yield. Alcohol 5a was treated with Jones reagent at
Scheme 4.
Scheme 3.

Z.-X. Jiang et al. / Journal of Fluorine Chemistry 126 (2005) 499–505
501
Scheme 5.
0 8C to give acid 6a in 76% yield. Many side reactions
could take place during the reduction of the azido group of
6a (intramolecular acyl group migration from sulfur to
nitrogen resulted in a sulfhydryl group [12], the sulfhydryl
group may then trigger a set of side reactions such as the
sulfhydryl group could reduce the azido group and the
sulfhydryl group itself could be oxidized). After systematic
studies [13], we found that azide 6a was smoothly reduced
in the presence of 1,3-propanedithiol and triethylamine [14]
to a single product according to 19F NMR and TLC analysis
(this product can be detected only by 19F NMR and TLC in
the reaction mixture, and 1H NMR could not give the clear
outcome due to the existence of lots of others compounds in
the reaction mixture). However, we failed to isolate the
resultant product from the reaction mixture because it is
extremely unstable. We can provide only both the important
precursors of syn-(3-trifluoromethyl)cysteine 6a, 6b for
further use.
the protecting groups of amino acid 12a were not removed
unless further synthetic applications were needed. In the
same fashion, the other isomer 12b was also prepared in high
yield from the intermediate 9b in four steps.
3. Conclusions
In summary, we have described our attempts at the
synthesis of 3-trifluoromethylcysteine via several different
routes. After many arduous efforts, an efficient procedure
for enantioselective synthesis of both enantiomers of syn-(3-
trifluoromethyl)cysteine derivatives 12a, 12b starting from
our reported chiral trifluoromethylated building blocks was
successfully achieved.
4. Experimental
To prevent the side reactions induced by the thioacetate
group, propanethiol was used as the nucleophile for
introducing the sulfur atom (Scheme 4). To our surprise,
the unexpected compound 8 was isolated in 47% yield when
trifluoromethanesulfonate 4b was treated with propanethiol
and cesium fluoride in DMF at 0 8C. It is evident from the
formation of the compound 8 that a cesium fluoride
mediated elimination reaction first resulted in the formation
of alkene intermediate, which then underwent the Michael
addition of propanethiol to give compound 8.
19F NMR spectra were recorded on a Bruker AM300
spectrometer using CCl3F as external standard, and down-
field shifts being designed as negative. Compounds 1a, 1b,
9a and 9b were prepared according to the reported procedure
[10b].
4.1. (1R, 2R)-Methanesulfonic acid 2-azido-3-benzyloxy-
1-trifluoromethyl-propyl ester (2)
Finally, an alternative synthetic route was successfully
developed (Scheme 5). This started from our reported
trifluoromethylated alcohol 9a [10] and required only a few
straightforward steps. Thus, treatment of enantiomerically
pure alcohol 9a with trifluoromethanesulfonic anhydride
and pyridine at ꢀ40 8C, followed by a cesium fluoride
mediated SN2 displacement of trifluoromethanesulfonate
with thiolacetic acid, furnished the intermediate 10a in
almost quantitative yield. Exposure of the compound 10a in
dichloromethane to boron trichloride at ꢀ78 8C afforded a
primary alcohol 11a in 99% yield, which underwent Jones
oxidation to give the product 12a in 87% yield. Due to the
poor stability of sulfur-containing amino acids and peptides,
To a stirred solution of 1a (552 mg, 2 mmol) and pyridine
(474 mg, 6 mmol) in methylene chloride (5 ml) was added
dropwise methanesulfonyl chloride (274 mg, 2.4 mmol) in
methylene chloride (2.5 ml) at 0 8C. The reaction mixture
was stirred for 1 h at 0 8C. Then the solution was washed
with brine. The layers were separated. The organic phase
was dried over Na2SO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel
(petroleum ether:ethyl acetate = 15:1) to give 2 (701 mg,
20
99%). ½aŠ ¼ þ37:0 (c 0.290, CHCl3); 1H NMR (300 MHz,
D
CDCl3) d 7.31–7.37 (m, 5H), 5.15 (qd, J = 6.9, 6.0 Hz, 1H),
4.66 (d, J = 11.7 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 3.94–
3.99 (m, 1H), 3.88 (dd, J = 10.5, 3.3 Hz, 1H), 3.78 (dd,

502
Z.-X. Jiang et al. / Journal of Fluorine Chemistry 126 (2005) 499–505
J = 10.5, 7.2 Hz, 1H), 3.16 (s, 3H); 19F NMR (282 MHz,
CDCl3) d ꢀ73.52 (d, J = 6.9 Hz); IR (thin film) nmax 3035,
2124, 1498, 1456, 1374, 1184 cmꢀ1; MS (EI) m/z 353 (M+,
<1), 325 (6), 248 (13), 105 (5), 91 (100), 79 (10), 77 (4), 69
(1), 65 (11). Anal. Calcd for C12H14O4F3N3S: C, 40.8; H,
4.0; N, 11.9. Found: C, 41.1; H, 3.9; N, 11.9.
brine, dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography on silica gel
(petroleum ether:ethyl acetate = 30:1) to give 3a (1.00 g,
20
D
87%). ½aŠ ¼ ꢀ17:4 (c 1.41, CHCl3); 1H NMR (300 MHz,
CDCl3) d 7.32–7.41 (m, 5H), 4.57 (d, J = 11.7 Hz, 1H), 4.51
(d, J = 11.7 Hz, 1H), 4.49 (qd, J = 9.0, 1.5 Hz, 1H), 4.29 (td,
J = 6.9, 1.5 Hz, 1H), 3.60 (dd, J = 9.9, 6.9 Hz, 1H), 3.75 (dd,
J = 9.9, 6.9 Hz, 1H), 2.42 (s, 3H); 19F NMR (282 MHz,
CDCl3) d ꢀ68.67 (d, J = 9.0 Hz); IR (thin film) nmax 2112,
1715, 1498, 1455, 1267, 1176, 1118 cmꢀ1; MS (EI) m/z 305
(M+-N2, 2), 304 (5), 105 (4), 91 (100), 77 (3), 69 (<1), 43
(37). HRMS (EI) Calcd for C12H11O2F3N2S: 304.05123.
Found: 304.05313.
4.2. (1R, 2R)-Trifluoro-methanesulfonic acid 2-azido-3-
benzyloxy-1-trifluoromethyl-propyl ester (4a)
To a stirred solution of 1a (1.76 g, 6.36 mmol) and
pyridine (1.01 g, 12.72 mmol) in methylene chloride (30 ml)
at ꢀ40 8C was added dropwise trifluoromethanesulfonic
anhydride (1.98 g, 7.0 mmol) in methylene chloride (5 ml).
The reaction mixture was stirred for 1 h at ꢀ40 8C. Then the
solution was washed with brine. The layers were separated.
The organic phase was dried over Na2SO4 and concentrated
in vacuo. The residue was purified by flash chromatography
4.5. (1R, 2S)-Thioacetic acid S-(2-azido-3-benzyloxy-1-
trifluoromethyl-propyl) ester (3b)
This compound was prepared from 4b in 88% yield by
20
D
(c 1.26, CHCl3); H NMR (300 MHz, CDCl3) d 7.32–7.41
on silica gel (petroleum ether:ethyl acetate = 20:1) to give
20
using the same procedure as described for 3a. ½aŠ ¼ þ16:2
4a (2.44 g, 95%). ½aŠ ¼ þ42:6 (c 1.45, CHCl3); 1H NMR
1
D
(300 MHz, CDCl3) d 7.28–7.42 (m, 5H), 5.26 (qd, J = 6.3,
5.7 Hz, 1H), 4.67 (d, J = 11.4 Hz, 1H), 4.54 (d, J = 11.4 Hz,
1H), 4.00–4.05 (m, 1H), 3.88 (dd, J = 10.5, 3.3 Hz, 1H), 3.78
(dd, J = 10.5, 6.3 Hz, 1H); 19F NMR (282 MHz, CDCl3) d
ꢀ73.39–ꢀ73.45 (m, 3F), ꢀ73.88 to ꢀ73.92 (m, 3F); IR (thin
(m, 5H), 4.57 (d, J = 11.7 Hz, 1H), 4.51 (d, J = 11.7 Hz, 1H),
4.49 (qd, J = 9.0, 1.5 Hz, 1H), 4.29 (td, J = 6.9, 1.5 Hz, 1H),
3.60 (dd, J = 9.9, 6.9 Hz, 1H), 3.75 (dd, J = 9.9, 6.9 Hz, 1H),
2.42 (s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ68.67 (d,
J = 9.0 Hz); IR (thin film) nmax 2112, 1708, 1498, 1455,
1267, 1176, 1118 cmꢀ1; MS (EI) m/z 334 (M + 1, <1), 304
(12), 105 (4), 91 (100), 77 (3), 69 (<1), 43 (44). Anal. Calcd
for C13H14O2F3N3S: C, 46.8; H, 4.2; N, 12.6. Found: C,
46.8; H, 4.3; N, 12.1.
film) nmax 3036, 2127, 1498, 1456, 1427, 1199, 1139 cmꢀ1
;
MS (EI) m/z 407 (M+, <1), 378 (100), 302 (100), 148 (41),
105 (30), 91 (100), 79 (27), 77 (42), 69 (97), 65 (99). Anal.
Calcd for C12H11O4F3N3S: C, 35.4; H, 2.7; N, 10.3. Found:
C, 35.3; H, 2.6; N, 10.7.
4.6. (1S, 2R)-Thioacetic acid S-(2-azido-3-hydroxy-1-
trifluoromethyl-propyl) ester (5a)
4.3. (1S, 2S)-Trifluoro-methanesulfonic acid 2-azido-3-
benzyloxy-1-trifluoromethyl- propyl ester (4b)
To a stirred solution of 3a (839 mg, 2.52 mmol) in
anhydrous methylene chloride (50 ml) at ꢀ78 8C was added
dropwise borontrichloride(5 mlof1 M solutioninmethylene
chloride, 5 mmol). The reaction mixture was stirred for 2 h at
ꢀ78 8C. Then methanol (5 ml) was added. The solution was
washed with saturated aqueous sodium bicarbonate and brine,
driedover MgSO4 and concentrated invacuo. Theresiduewas
This compound was prepared from 1b in 92% yield by
20
D
(c 1.24, CHCl3); H NMR (300 MHz, CDCl3) d 7.30–7.41
using the same procedure as described for 4a. ½aŠ ¼ ꢀ43:6
1
(m, 5H), 5.24 (qd, J = 6.3, 5.7 Hz, 1H), 4.65 (d, J = 11.4 Hz,
1H), 4.53 (d, J = 11.4 Hz, 1H), 3.99–4.03 (m, 1H), 3.85 (dd,
J = 10.5, 3.3 Hz, 1H), 3.75 (dd, J = 10.5, 6.3 Hz, 1H); 19F
NMR (282 MHz, CDCl3) d ꢀ73.10 to ꢀ73.15 (m, 3F),
ꢀ73.59 to ꢀ73.63 (m, 3F); IR (thin film) nmax 3036, 2127,
1498, 1456, 1427, 1199, 1139 cmꢀ1; MS (EI) m/z 407 (M+,
<1), 378 (67), 302 (28), 148 (7), 105 (4), 91 (100), 79 (2), 77
(3), 69 (10), 65 (10). Anal. Calcd for C12H11O4F3N3S: C,
35.4; H, 2.7; N, 10.3. Found: C, 35.3; H, 2.6; N, 10.5.
purified by flash chromatography on silica gel (petroleum
20
ether:ethyl acetate = 5:1) to give 5a (610 mg, 99%). ½aŠ
¼
D
ꢀ87:3 (c 0.735, CHCl3); 1H NMR (300 MHz, CDCl3) d 4.43
(qd, J = 9.0, 1.8 Hz, 1H), 4.20 (td, J = 7.2, 1.8 Hz, 1H), 3.74
(dd, J = 11.4, 7.2 Hz, 1H), 3.59 (dd, J = 11.4, 7.2 Hz, 1H),
2.47 (s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ70.67 (d,
J = 9.0 Hz); IR (thin film) ymax 3298, 2926, 2137, 1709, 1273,
1108 cmꢀ1, MS (EI) m/z 244 (M + 1, 2), 200 (2), 174 (7), 69
(2), 43 (100). Anal. Calcd for C6H8O2F3N3S: C, 29.6; H, 3.3;
N, 17.3. Found: C, 29.9; H, 3.1; N, 17.6.
4.4. (1S, 2R)-Thioacetic acid S-(2-azido-3-benzyloxy-1-
trifluoromethyl-propyl) ester (3a)
To a stirred solution of thiolacetic acid (0.78 g,
10.25 mmol) in DMF (20 ml) at 0 8C was added anhydrous
cesium fluoride (1.56 g, 10.25 mmol). Then a solution of 4a
(1.39 g, 3.42 mmol) in DMF (5 ml) was added and reaction
mixture was stirred for 4 h at 0 8C. Then the solution was
washed with saturated aqueous sodium bicarbonate and
4.7. (1R, 2S)-Thioacetic acid S-(2-azido-3-hydroxy-1-
trifluoromethyl-propyl) ester (5b)
This compound was prepared 3b in 100% yield by using
20
D
the same procedure as described for 5a. ½aŠ ¼ þ86:8 (c

Z.-X. Jiang et al. / Journal of Fluorine Chemistry 126 (2005) 499–505
503
1
0.685, CHCl3); H NMR (300 MHz, CDCl3) d 4.43 (qd,
J = 9.0, 1.8 Hz, 1H), 4.20 (td, J = 7.2, 1.8 Hz, 1H), 3.74 (dd,
J = 11.4, 7.2 Hz, 1H), 3.59 (dd, J = 11.4 Hz, 7.2 Hz, 1H),
2.47 (s, 3H); 19F NMR (282 MHz, CDCl3) d ꢀ70.67 (d,
J = 9.0 Hz); IR (thin film) ymax 3382, 2926, 2137, 1709,
1273, 1108 cmꢀ1, MS (EI) m/z 244 (M + 1, <1), 200 (2),
174 (1), 69 (2), 43 (100). Anal. Calcd for C6H8O2F3N3S: C,
29.6; H, 3.3; N, 17.3. Found: C, 30.0; H, 3.1; N, 17.5.
4.11. (1S, 2R)-Thioacetic acid S-[3-benzyloxy-2-(1,3-
dioxo-1,3-dihydro-isoindol-2-yl)-1-trifluoromethyl-
propyl] ester (10a)
To a stirred solution of 9a (2.85 g, 7.52 mmol) and
pyridine (1.19 g, 15.04 mmol) in methylene chloride (40 ml)
at ꢀ40 8C was added dropwise trifluoromethanesulfonic
anhydride (2.33 g, 8.27 mmol) in methylene chloride
(10 ml). The reaction mixture was stirred for 2 h at
ꢀ40 8C. Then the solution was washed with 2N HCl and
brine. The layers were separated. The organic phase was
dried over Na2SO4 and concentrated in vacuo. The crude
product was used directly without further purification. To a
stirred solution of thiolacetic acid (1.72 g, 22.56 mmol) in
DMF (40 ml) at 0 8C was added anhydrous cesium fluoride
(3.43 g, 22.56 mmol). Then a solution of the crude product
in DMF (5 ml) was added and reaction mixture was stirred
for 6 h at 0 8C. Then the solution was washed with saturated
aqueous sodium bicarbonate and brine, dried over MgSO4
and concentrated in vacuo. The residue was purified by flash
4.8. (2R, 3S)-3-Acetylsulfanyl-2-azido-4,4,4-trifluoro-
butyric acid (6a)
To a mixture of 5a (0.34 g, 1.4 mmol) in acetone (50 ml)
at 0 8C was added Jones reagent (1 M, 10 ml, 10 mmol). The
mixture was stirred for 20 min at 0 8C under nitrogen. The
reaction was quenched with iso-propyl alcohol (5 ml) and
then diluted with water (30 ml) and ethyl acetate (30 ml). The
aqueous layer was extracted with ethyl acetate. The
combined organic layers were dried, filtered, and concen-
trated in vacuo. The residue was purified by column
chromatography on silica gel (petroleum ether:ethyl acet-
20
chromatography on silica gel (petroleum ether:ethyl
20
ate = 1:1) to give 6a (0.36 g, 76%). ½aŠ ¼ ꢀ26:8 (c 1.28,
acetate = 60:1) to give 10a (3.25 g, 99%). ½aŠ ¼ ꢀ67:8
D
CHCl3); H NMR (300 MHz, CDCl3) d 4.85(qd, J = 8.4,
D
1
(c 0.900, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.83–7.91
(m, 2H), 7.74–7.78 (m, 2H), 7.18–7.27 (m, 5H), 5.03–5.11
(m, 1H), 4.93 (qd, J = 9.0, 1.5 Hz, 1H), 4.54 (d, J = 12.0 Hz,
1H), 4.44 (d, J = 12.0 Hz, 1H), 4.10 (t, J = 9.0 Hz, 1H), 3.92
(dd, J = 9.0, 6.0 Hz, 1H), 2.37 (s, 3H); 19F NMR (282 MHz,
CDCl3) d ꢀ67.69 (d, J = 9.0 Hz); IR (thin film) ymax 2922,
1781, 1721, 1609, 1497, 1470, 1455, 1389, 1120 cmꢀ1; MS
(EI) m/z 438 (M + 1, <1), 437 (M+, <1), 394 (1), 107 (3), 91
(100) 77 (5), 76 (7), 43 (45). Anal. Calcd for C21H18O4F3NS:
C, 57.7; H, 4.2; N, 3.2. Found: C, 57.6; H, 4.3; N, 3.2.
2.1 Hz, 1H), 4.80 (d, J = 2.1 Hz, 1H), 2.45 (s, 3H); 19F NMR
(282 MHz, CDCl3) d ꢀ68.96 (d, J = 8.4 Hz); IR (thin film)
y
max 3500, 2937, 2127, 1720, 1260, 1118 cmꢀ1, MS (EI) m/z
258 (M + 1, <1), 212 (<1), 69 (3), 43 (100). HRMS (EI)
Calcd for C5H5OF3N3S: 212.01055. Found: 212.01231.
4.9. (2S, 3R)-3-Acetylsulfanyl-2-azido-4,4,4-trifluoro-
butyric acid (6b)
This compound was prepared from 5b in 81% yield by
20
D
(c 1.305, CHCl3); H NMR (300 MHz, CDCl3) d 4.85(qd,
using the same procedure as described for 6a. ½aŠ ¼ þ28:2
4.12. (1R, 2S)-Thioacetic acid S-[3-benzyloxy-2-(1,3-
dioxo-1,3-dihydro-isoindol-2-yl)-1-trifluoromethyl-
propyl] ester (10b)
1
J = 8.4, 2.1 Hz, 1H), 4.80 (d, J = 2.1 Hz, 1H), 2.45 (s, 3H);
19F NMR (282 MHz, CDCl3) d ꢀ68.97 (d, J = 8.4 Hz); IR
(thin film) ymax 3300, 2937, 2127, 1720, 1260, 1119 cmꢀ1
,
This compound was prepared from 9b in 98% yield by
20
D
MS (EI) m/z 258 (M + 1, <1), 212 (<1), 69 (3), 43 (100).
HRMS (EI) Calcd for C5H5OF3N3S: 212.01055. Found:
212.01022.
using the same procedure as described for 10a. ½aŠ
¼
1
þ64:1 (c 1.200, CHCl3); H NMR (300 MHz, CDCl3) d
7.83–7.91 (m, 2H), 7.73–7.78 (m, 2H), 7.18–7.28 (m, 5H),
5.03–5.11 (m, 1H), 4.91 (qd, J = 9.0, 1.5 Hz, 1H), 4.54 (d,
J = 12.0 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 4.10 (t,
J = 9.0 Hz, 1H), 3.92 (dd, J = 9.0, 6.0 Hz, 1H), 2.36 (s,
3H); 19F NMR (282 MHz, CDCl3) d ꢀ67.71 (d, J = 9.0 Hz);
IR (thin film) ymax 2921, 1781, 1722, 1609, 1498, 1470, 1455,
1374, 1122 cmꢀ1; MS (EI) m/z 437 (M+, <1), 138 (100), 107
(3), 91 (5), 77 (10), 43 (29). Anal. Calcd for C21H18O4F3NS:
C, 57.7; H, 4.2; N, 3.2. Found: C, 57.3; H, 4.2; N, 3.3.
4.10. (2-Azido-4,4,4-trifluoro-2-propylsulfanyl-
butoxymethyl)-benzene 8
This compound was prepared from 4b in 47% yield by
using the same procedure as described for 3a. Clear oil, 1H
NMR (300 MHz, CDCl3) d 7.28–7.43 (m, 5H), 4.66 (d,
J = 12.0 Hz, 1H), 4.60 (d, J = 12.0 Hz, 1H), 3.69 (d,
J = 9.9 Hz, 1H), 3.64 (d, J = 9.9 Hz, 1H), 2.63–2.84 (m,
4H), 1.58–1.73 (m, 2H), 1.04 (t, J = 7.2 Hz, 3H); 19F NMR
(282 MHz, CDCl3) d ꢀ61.09 (d, J = 10.1 Hz); IR (thin film)
4.13. (1S, 2R)-Thioacetic acid S-[2-(1,3-dioxo-1,3-
dihydro-isoindol-2-yl)-3-hydroxy-1-trifluoromethyl-
propyl] ester (11a)
y
max 3067, 2967, 2120, 1498, 1456, 1370, 1260, 1139 cmꢀ1
;
MS (EI) m/z 332 (M + ꢀ1, <1), 291 (1), 92 (11), 91 (100),
41 (12). Anal. Calcd for C14H18OF3N3S: C, 50.4; H, 5.4; N,
12.6. Found: C, 50.7; H, 5.5; N, 12.6.
To a stirred solution of 10a (2.99 g, 6.85 mmol) in
anhydrous methylene chloride (100 ml) at ꢀ78 8C was

504
Z.-X. Jiang et al. / Journal of Fluorine Chemistry 126 (2005) 499–505
added dropwise boron trichloride (13.70 ml of 1 M solution
in methylene chloride, 13.70 mmol). The reaction mixture
was stirred for 2 h at ꢀ78 8C. Then methanol (5 ml) was
added. The solution was washed with saturated aqueous
sodium bicarbonate and brine, dried over MgSO4 and
concentrated in vacuo. The residue was purified by flash
4.16. (2R, 3S)-3-Acetylsulfanyl-2-(1,3-dioxo-1,3-dihydro-
isoindol-2-yl)-4,4,4-trifluoro- butyric acid (12b)
This compound was prepared from 11b in 88% yield by
20
D
using the same procedure as described for 12a. ½aŠ
¼
1
þ56:1 (c 1.150, CHCl3); H NMR (300 MHz, CDCl3) d
7.88–7.94 (m, 2H), 7.76–7.82 (m, 2H), 5.70 (d, J = 5.4 Hz,
1H), 5.30 (qd, J = 8.5 Hz, 5.4 Hz, 1H), 2.43 (s, 3H); 19F
NMR (282 MHz, CDCl3) d ꢀ69.30 (d, J = 8.5 Hz); IR (thin
film) ymax 3522, 2929, 1780, 1724, 1611, 1471, 1386,
1166 cmꢀ1; MS (EI) m/z 319 (20), 148 (23), 76 (25), 45 (6),
43 (100). Anal. Calcd for C14H10O5F3NSꢁ(H2O)1/2: C, 45.4;
H, 3.0; N, 3.8. Found: C, 45.7; H, 3.1; N, 3.7.
chromatography on silica gel (petroleum ether:ethyl
20
acetate = 4:1) to give 11a (2.38 g, 99%). ½aŠ ¼ ꢀ63:7 (c
D
0.500, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.85–7.90 (m,
2H), 7.76–7.80 (m, 2H), 5.05 (qd, J = 8.4, 1.5 Hz, 1H), 4.84–
4.91 (m, 1H), 4.19–4.26 (m, 1H), 4.09–4.14 (m, 1H), 2.34 (s,
3H); 19F NMR (282 MHz, CDCl3) d ꢀ67.56 (d, J = 8.4 Hz);
IR (thin film) ymax 3483, 2928, 1780, 1716, 1614, 1470,
1374, 1126 cmꢀ1; MS (EI) m/z 348 (M + 1, 7), 347 (M+, 2),
330 (1), 148 (54), 76 (14), 43 (100). Anal. Calcd for
C14H12O4F3NS: C, 48.4; H, 3.5; N, 4.0. Found: C, 49.0; H,
3.6; N, 4.1.
Acknowledgments
We thank the National Natural Science Foundation of
China, the Ministry of Education of China and Shanghai
Municipal Scientific Committee for funding this work.
4.14. (1R, 2S)-Thioacetic acid S-[2-(1,3-dioxo-1,3-
dihydro-isoindol-2-yl)-3-hydroxy-1-trifluoromethyl-
propyl] ester (11b)
References
This compound was prepared from 10b in 99% yield by
20
D
using the same procedure as described for 11a. ½aŠ
¼
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Z.-X. Jiang et al. / Journal of Fluorine Chemistry 126 (2005) 499–505
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