New stereoselective synthesis of thiamphenicol and florfenicol from enantiomerically pure cyanohydrin: a chemo-enzymatic approach

Article abstract of DOI:10.1016/j.tet.2008.05.113

Thiamphenicol and florfenicol have been synthesized stereoselectively from enantiomerically pure 4-methylsulfanyl-mandelonitrile, which was obtained by hydrocyanation reaction of 4-methylsulfanyl-benzaldehyde catalyzed by (R)-hydroxynitrile lyase of Badamu (Prunus communis L. var. dulcis Borkh, almond from Xinjiang, China). It was found to be a highly effective bio-catalyst for this reaction after an extensive screening.

Full text of DOI:10.1016/j.tet.2008.05.113

Tetrahedron 64 (2008) 7822–7827
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New stereoselective synthesis of thiamphenicol and florfenicol from
enantiomerically pure cyanohydrin: a chemo-enzymatic approach
,
,
Wenya Lu a, Peiran Chen a b, Guoqiang Lin a
*
a Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
b Laboratory of Fluorine Organic Chemistry, College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Thiamphenicol and florfenicol have been synthesized stereoselectively from enantiomerically pure 4-
methylsulfanyl-mandelonitrile, which was obtained by hydrocyanation reaction of 4-methylsulfanyl-
benzaldehyde catalyzed by (R)-hydroxynitrile lyase of Badamu (Prunus communis L. var. dulcis Borkh,
almond from Xinjiang, China). It was found to be a highly effective bio-catalyst for this reaction after an
extensive screening.
Received 28 March 2008
Received in revised form 28 May 2008
Accepted 28 May 2008
Available online 19 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Thiamphenicol
Fluorfenicol
4-Methylsulfanyl-mandelonitrile
(R)-Hydroxynitrile lyase
Badamu (Prunus communis L. var. dulcis
Borkh)
1. Introduction
D
-(ꢀ)-threo-2-amino-1-(4-methylsulfonylphenyl)-1,3-propanediol
as the starting material. Clark and co-workers8b achieved a resolu-
Thiamphenicol 2, a member of chloramphenicol 1 family (Fig.1),
is a broad spectrum antibiotics against many Gram negative and
Gram positive microorganisms. Thiamphenicol possesses high in
vivo activity for having a good property of unbinding with glucur-
onic acid in liver and has been used clinically. The first synthesis of
racemic thiamphenicol was reported in 1950s.1,2 Currently, com-
tion of DL-threo-2-amino-1-(4-methylthiophenyl)-1,3-propanediol
in its D-isomer in high ee value byusing a protease fromStreptomyces
griseus. Later on, they8c,d disclosed a procedure for the synthesis of
diastereomerically pure florfenicol, which was based on an in-
termediate, 10-(R,R)-(dichloromethyl)oxazoline, obtained in the
resolution process for thiamphenicol. In 1997, Wu and co-workers8e
have developed a new asymmetric total synthesis of thiamphenicol
and florfenicol based on the diastereoselective Sharpless epoxida-
tion followed by a series of transformations to (3S,4R)-2-(dichloro-
mercially available optically active
a resolution process with unnatural
recycle of the
D-thiamphenicol is obtained by
D
-(ꢀ)-tartaric acid.3,4 However,
L-isomer generated as a by-product in the resolution
has been unsatisfactory due tothe tediousand ineffectiveprocedure.
Florfenicol 3 (Fig. 1) is a fluorinated derivative of thiamphenicol,
which was discovered in 1979.5 Compared to thiamphenicol, flor-
fenicol shows significant superiority in antibacterial spectrum,
antibacterial activity, and considerably lower side effect, its anti-
bacterial potency is 10 times higher than that of thiamphenicol.
Since their discovery, there has been continuous interest in de-
veloping asymmetric synthesis of these two compounds.6,7 Nagab-
hushan and co-workers4b reported a diastereospecific synthesis of
thiamphenicol in racemic form. Schumacher and co-workers8a
reported an asymmetric synthesis of florfenicol by using
methyl)-4,5-dihydro-a-[4-(methylsulfonyl)phenyl]-oxazole-4-
methanol, a common intermediate for both thiamphenicol and
florfenicol. In 2006, two Indian groups reported the stereoselective
syntheses of (ꢀ)-chloramphenicol and (þ)-thiamphenicol, re-
spectively. Hajra and co-workers8f commenced the synthesis of
(þ)-thiamphenicol by using
a silver(I)-promoted asymmetric
bromomethoxylation of (2R)-N-[(2-methanesulfonyl-pheny)-
OH
OH
F
OH
NHCOCHCl2
D-(ꢀ)-threo-2-amino-1-(4-methylthiophenyl)-1,3-propanediol or
NHCOCHCl2
MeO2S
R
R = NO2
1 chloramphenicol
3 florfenicol
R = SO2Me 2 thiamphenicol
* Corresponding author. Tel.: þ86 21 54925169; fax: þ86 21 64166263.
E-mail address: lingq@mail.sioc.ac.cn (G. Lin).
Figure 1.
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.113

W. Lu et al. / Tetrahedron 64 (2008) 7822–7827
7823
propenoyl]-bornanesultam to afford anti-(2R,20R,3R)-N-[20bromo-
30methoxy-30(2-methnesulfonyl-phenyl)-propionyl]-bornane-
sultam, which, after a series of transformations, gave the target
compound. Sudalai and co-workers8g performed the enantiose-
lective synthesis of (þ)-thiamphenicol by converting 4-(methyl-
sulfanyl)-benzaldehyde into 1-(4-methylsulfanylphenyl)-2-
propen-1-ol, which, after being converted into the corresponding
sulfonyl derivative, was subjected to Sharpless asymmetric epoxi-
dation. The epoxide was then converted into the target compound
by a series of chemical manipulations.
Table 1
4-Methylsulfanyl-mandelonitrile formed under the catalysis of some representative
(R)-HNL-containing plants as the enzyme source
OH
CN
O
DIPE/HCN
HNL
MeS
MeS
Yielda (%)
4
5
Entry
HNL source
ee (%)b
Configuration
1
2
3
4
Malus pumila Mill., seeds
Eriobotrya japonica Lindl., seeds
Prunus armeniaca L., kernels
Prunus communis L. var. dulcis
Borkh, kernels
92
70
81
98
65
74
39
96
R
R
R
R
The enzyme-catalyzed asymmetric syntheses of cyanohydrins
have been remarkably developed by Effenberger9 and Brussee.10
b-
Hydroxy-a-amino acids were diastereoselectively synthesized from
cyanohydrins by Brussee and co-workers in 1992.10b As a result of
our investigation of biologically catalyzed hydrocyanation of alde-
hydes and ketones,11 we now report a new route to the asymmetric
total synthesis of thiamphenicol and florfenicol starting from
enantiomerically pure 4-methylsulfanyl-mandelonitrile.
a
Isolation yield on silica gel column.
Determined on chiral HPLC after acetylation of the obtained cyanohydrins.
b
2.2. Syntheses of thiamphenicol and florfenicol starting from
the enantiomerically pure 4-methylsulfanyl-mandelonitrile
Both thiamphenicol and florfenicol have 1R chiral carbon and
threo configuration. As shown in Scheme 1, the enantioselective
formation of 5 establishes the 1R form stereochemistry. The sub-
sequent transformations were performed by a modification of the
procedure reported by Brussee and van der Gen.10c One-pot se-
quential manipulations of DIBAL reduction of the 2-methoxy-iso-
propyl (MIP) protected (R)-cyanohydrin 6 at low temperature,
benzylamine addition, and hydrocyanation generated the second
chiral carbon in threo configuration almost exclusively to afford 7 in
75%. The diastereoselective ratio (dr) of this hydrocyanation re-
action was found to be higher than 20:1 (determined by 1H NMR,
the erythro isomer’s signals were not observed) when the reaction
was conducted at 0 ꢁC. Compound 7 was converted into the oxa-
zolidone derivative 8 in an overnight reaction with 1,10-carbonyl-
diimidazole. The NOE and coupling constant of the oxazolidone 8
supported the assigned threo (trans) configuration10b,13 of the
major product. Conventional treatment of 8 produced 10, which
was used as a common intermediate for the formation of both of
the target compounds.
2. Results and discussion
2.1. Discovery of an enzyme source to catalyze highly
enantioselective formation of the key starting compound 4-
methylsulfanyl-mandelonitrile
As shown in Scheme 1, the enantioselective transformation of 4-
methylsulfanyl-benzaldehyde to 4-methylsulfanyl-mandelonitirle
is a key point in this synthesis. In our previous publications,11 we
reported a number of (R)-cyanohydrins formed in a bio-catalytic
process, in which various (R)-hydroxynitrile lyase (HNL) containing
plants were investigated and used as the crude enzyme source.
However, these investigated plants were found to be unable to give
the desired enantiomeric excess in 4-methylsulfanyl-mandeloni-
trile formation. Fortunately, after an extensive search and screen-
ing, we finally found that the kernel of Badamu (almond from
Xingjiang, China) (Prunus communis L. var. dulcis Borkh)12 is
a highly effective enzyme source for our goal.
As shown in Scheme 2, oxidation of 10 with meta-chloro-
perbenzoic acid (m-CPBA) converted the methylsulfanyl group into
a methylsulfonyl group to give 11, resulting in the formation of the
skeleton of thiamphenicol. Hydrolysis with aqueous KOH, catalytic
debenzylation, and acylation produced thiamphenicol in 26%
overall yield starting from 4-methylsulfanyl-benzaldehyde 4.
As shown in Scheme 3, fluorination of 10 with diethyl-
aminosulfur trifluoride (DAST) gave the fluorinated derivative 13. It
is interesting that the alkaline ring opening of the oxazolidone ring
in 15, which was used by Brussee for the same conversion10b and
used by us for the ring opening of 11, caused cleavage of the F–C
The plant originated enzyme source, shown in Table 1 (entry 4),
was soaked in distilled water for 2 h, peeled, air-dried, and ho-
mogenized. The homogenate was defatted with ethyl acetate and
washed with isopropyl ether to give a soft powder, which was
stored in a refrigerator for use. A mixture of the crude enzyme-
containing meal, aldehyde, and HCN in isopropyl ether was stirred
at room temperature for 12 h.9 Filtration, evaporation in vacuo, and
chromatography on silica gel gave the cyanohydrin with 96% ee in
98% yield. Recrystallization from petroleum ether and diethyl ether
gave 4-methylsulfanyl-mandelonitrile 5 as a colorless needle
crystal with 99% ee in 86% yield.
O
OH
OH
O
OMe
CN
a
CN
b
CN
O
c,d,e,f
NHBn.HCl
MeS
MeS
MeS
MeS
4
5
6
7
O
O
O
O
O
H
NBn
H
NBn
COOEt
NBn
OH
i
g
h
CN
No NOE
MeS
MeS
MeS
8
9
10
observed
Scheme 1. Synthesis of the common intermediate 10 for thiamphenicol and florfenicol. Reaction and conditions: (a) HCN/HNL, 98%, 96% ee; 86%, 99% ee after recrystallization; (b)
MIP, POCl3, 95%; (c) DIBAL; (d) BnNH2; (e) NH4Br, NaCN; (f) HCl, H2O, ethanol; a through f, overall yield 75%; (g) (im)2CO, TEA, 82%; (h) K2CO3, ethanol; then 1 N HCl, 91%; (i) NaBH4,
methanol, 85%.

7824
W. Lu et al. / Tetrahedron 64 (2008) 7822–7827
O
O
OH
OH
O
O
a
NBn
OH
NBn
OH
OH
NHBn
OH
NHCOCHCl2
b
c
MeO2S
MeO2S
MeO2S
MeS
10
11
12
2 thiamphenicol
Scheme 2. Synthesis of thiamphenicol 2 from intermediate 10. Reaction and conditions: (a) m-CPBA, 90%; (b) 2 N KOH, reflux, 85%; (c) Pd/C, H2, 90%; MeOH, CHCl2COOEt, TEA, 100%.
O
O
OH
OH
O
O
a
NBn
F
NBn
d,e
F
b
c
10
NHBn
NHCOCHCl2
MeO2S
MeO2S
F
F
MeO2S
MeS
13
14
15
3 florfenicol
Scheme 3. Synthesis of florfenicol 3 from intermediate 10. Reaction and conditions: (a) DAST, THF, 85%; (b) m-CPBA, 90%; (c) 8 N H2SO4, 140 ꢁC, 71%; (d) Pd/C, H2 85%; (e) MeOH,
CHCl2COOEt, TEA, 100%.
bond. Careful study showed that substitution of the fluoro group by
hydroxy group was quicker than ring opening of oxazolidone under
the alkaline condition. Finally, the ring opening was accomplished
with aqueous 8 N H2SO4 to give 16 in moderate yield. Florfenicol 3
was thus obtained in 18% overall yield starting from 4-methyl-
sulfanyl-benzaldehyde 4.
HCN in IPE (1.5 equiv, 5 mL, added by a syringe) (caution: highly
toxic! For details, see http://www.cdc.gov/niodh/ipcsneng/
neng0492.html). The resulting mixture was stirred at room tem-
perature for 12 h, filtered, and washed with ethyl acetate. The
combined organic phase was washed with aqueous saturated FeCl3
solution until the color of FeCl3 kept unchanged, dried over Na2SO4,
and evaporated under reduced pressure. Flash chromatography on
silica gel (ethyl acetate/petroleum ether¼1:2) of the residue gave
the title compound as a white solid (yield 98%, ee¼96%). Crystal-
lization from petroleum ether and diethyl ether gave 5 as colorless
crystals (920 mg, 86% yield, ee¼99%).
3. Conclusion
With the aid of (R)-hydroxynitrile lyase (HNL) in the kernel of
Badamu (Prunus communis L. var. dulcis Borkh), we were able to
obtain 4-methylsulfanyl-mandelonitrile in high chemical yield and
high optical purity. With this cyanohydrin as the starting point, we
have developed a new and efficient route to the asymmetric syn-
theses of thiamphenicol and florfenical, in 26% and 18% overall
yields, respectively.
Mp 73–74 ꢁC; [
a
]
20 50.4 (c 0.83, CHCl3), ee¼99%. Determined on
D
chiral HPLC after acetylation of the obtained cyanohydrins (Chir-
alcel AD, 15% IPA/hexanes, 0.7 mL/min, tR (major)¼11.1 min, tR
(minor)¼12.1 min); FTIR (KBr): 3390, 2917, 1602, 1496, 1405, 1238,
1184, 1094, 1029, 1014, 932, 838, 801, 618, 502 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz): d 2.50 (s, 3H, CH3), 3.00 (br s, 1H, OH), 5.49 (s, 1H,
CHOH), 7.29 (d, J¼8.5 Hz, 2H, Ar), 7.43 (d, J¼8.5 Hz, 2H, Ar); 13C NMR
4. Experimental section
4.1. Material and methods
(75 MHz, CDCl3):
d 15.3, 63.2, 118.7, 126.5, 127.1, 131.7, 141.1; EIMS:
m/z (rel intensity %) 181 (Mþ, 2.5), 179 (Mþ, 79), 162 (MþꢀOH, 39),
153 (MþꢀCN, 55), 152 (MþꢀHCN, 100), 151 (MþꢀHCNꢀH, 88), 132
(29), 123 (16), 109 (20), 105 (17), 91 (7), 77 (17). Anal. Calcd for
C9H9NOS: C, 60.31; H, 5.06; N, 7.82. Found: C, 60.40; H, 5.06; N, 7.73.
The acetylation was carried out by treating the cyanohydrin with
acetyl chloride in pyridine to obtain a clear oil. 1H NMR (CDCl3,
Prunus communis L. var. dulcis Borkh was obtained from Xinjiang,
China. Prunus armeniaca, Malus pumila, and Eriobotrya japonica
were purchased from market as fresh fruits. All other chemicals
were of the highest purity, commercially available, and used with-
out further purification unless otherwise mentioned. NMR spectra
were recorded on a Bruker AM 300 spectrometer (300 MHz). The 1H
NMR chemical shifts are reported relative to 0 (TMS). 13C NMR
chemical shifts are reported relative to the center of the solvent
resonance 77.0 (CDCl3). Mass spectra were recorded on a Bruker
APEXIII 7.0 TESLA FTMS using ESI mode. IR spectra were recorded on
a Digital FTIR instrument. Optical rotations were measured using
Perkin–Elemer 241 MC polarimeter or Jasco P-1030.
300 MHz):
d 2.15 (s, 3H, CH3CO), 2.50 (s, 3H, SCH3), 6.36 (s, 1H,
CHO), 7.29 (d, J¼8.5 Hz, 2H, Ar), 7.43 (d, J¼8.5 Hz, 2H, Ar); EIMS: m/z
(rel intensity %) 221 (Mþ, 93), 179 (38), 162 (100), 161 (98), 151 (16),
147 (44), 146 (32), 132 (9).
4.4. (R)-O-Methoxy-iso-propyl-4-methylsulfanyl-
mandelonitrile (6)
To a round-bottomed flask were added compound 5 (900 mg,
5.0 mmol), 2-methoxypropene (2 mL, 20 mmol), diethyl ether
(5 mL), and POCl3 (20 mg, 0.1 mmol). The resulting mixture was
stirred at room temperature for 2 h. Et3N (1 mL) was added and
stirring was continued for 30 min. The organic phase was washed
with aqueous saturated NaCl solution (3ꢂ50 mL), dried (Na2SO4),
and evaporated under reduced pressure. Flash chromatography on
silica gel (ethyl acetate/petroleum ether¼1:10) afforded 6 as a yel-
low oil (1.09 g, 96% yield).
4.2. Preparation of defatted Prunus communis L. var. dulcis
Borkh powder
Prunus communis L. var. dulcis Borkh (100 g) was soaked in
distilled water (200 mL) for 4 h then air-dried, peeled, and ho-
mogenized in cold ethyl acetate. The resultant powder was col-
lected by filtration, subsequently washed with ethyl acetate
(2ꢂ100 mL) and di-iso-propyl ether (IPE) (2ꢂ60 mL), and stored in
a refrigerator for use.
[a]
20 25.2 (c 0.83, CHCl3) (Chiralcel AD, 2% IPA/hexanes, 0.7 mL/
D
min, tR (major)¼14.1 min, tR (minor)¼17.7 min); FTIR (KBr): 2993,
4.3. (R)-4-Methylsulfanyl-mandelonitrile (5)
2924, 2835, 1594, 1562, 1495, 1438, 1378, 1268, 1216, 1146, 1095,
1014, 876, 838, 813, 766, 544 cmꢀ1; 1H NMR (CDCl3, 300 MHz):
d 1.4
In a well-ventilated hood, to a 25 mL round-bottomed flask
were added 4-methylsulfanyl-benzaldehyde (400 mg, 2.6 mmol),
the above-prepared P. dulcis Borkh kernel powder (150 mg), and
(s, 3H, CH3), 1.58 (s, 3H, CH3), 2.50 (s, 3H, SCH3), 3.2 (s, 3H, OCH3),
5.42 (s, 1H, CH), 7.25–7.41 (m, 4H, Ar–H); 13C NMR (75 MHz, CDCl3):
d
15.3, 24.3, 24.9, 49.8, 60.9, 102.8, 119.2, 126.4, 127.5, 129.9, 140.4;

W. Lu et al. / Tetrahedron 64 (2008) 7822–7827
7825
EIMS: m/z (rel intensity %) 251 (Mþ, 1.63), 219 (MþꢀHꢀOCH, 2.01),
760, 670, 564 cmꢀ1
;
1H NMR (300 MHz, CDCl3):
d
2.47 (s, 3H,
179 (100.00), 162 (76.27), 151 (21.93), 132 (82.14), 109 (22.98), 105
(28.48), 86 (49.45), 45 (27.76); HRMS calcd for C13H17NO2S: m/z
251.0980, found: 251.0973.
SCH3), 4.06 (d, J¼6.3 Hz, 1H, CHCN), 4.20 (d, J¼14.9 Hz, 1H, Ar–
CHH), 5.02 (d, J¼14.9 Hz, 1H, Ar–CHH), 5.57 (d, J¼6.3 Hz, 1H, CHO),
7.15–7.38 (m, 9H, Ar–H); 13C NMR (75 MHz, CDCl3):
d 14.3, 46.4,
51.9, 113.7, 124.8, 125.6, 127.5, 127.9, 128.3, 130.6, 132.5, 140.6, 154.5;
EIMS: m/z (rel intensity %) 324 (Mþ), 286 (0.57), 243 (0.52), 215
(1.81), 175 (14.70), 151 (2.77), 91 (100), 77 (4.73), 65 (41.498.08);
HRMS (MALDI) calcd for C18H17N2O2Sþ: m/z 325.1005, found:
325.1020.
4.5. (2R,3R)-2-Benzylamino-3-hydroxy-3-(4-methyl-
sulfanylphenyl)-propionitrile$HCl (7)
Under argon atmosphere, to a dried three-necked flask con-
taining 6 (3.6 g, 14 mmol) and anhydrous diethyl ether (90 mL) was
added dropwise DIBAL-H (35 mL, 1 M in toluene) at ꢀ70 ꢁC. The
mixture was stirred at the same temperature for 2.5 h and then was
added NH4Br (3.43 g) in MeOH (50 mL). After removal of the dry
ice/acetone bath was added benzylamine (7.5 mL). The mixture was
stirred at room temperature for 1 h, cooled in an ice bath, and was
added a solution of NH4Br (4.2 g) and NaCN (2.1 g) in MeOH (90 mL)
(caution must be taken: HCN formed in situ!) and stirred for an-
other 1.5 h. MeOH was removed below 30 ꢁC, and then aqueous 2 N
NaOH (100 mL) was added and extracted with diethyl ether
(4ꢂ60 mL). The combined organic phase was washed with water
(2ꢂ15 mL) and aqueous saturated NaCl solution (2ꢂ15 mL), and
dried (Na2SO4). Column chromatography on silica gel (ethyl ace-
tate/petroleum ether¼1:6) to remove the benzylamine afforded
pale yellow oil, which was dissolved in EtOH (100 mL) and then 1 N
HCl (20 mL) was added. Evaporation under reduced pressure to
remove the ethanol and co-evaporation with toluene gave a pale
4.7. Ethyl (4R,5R)-2,3,4,5-tetrahydro-5-(4-methyl-
sulfanylphenyl)-2-oxo-3-benzyl-4-oxazolecarboxylate (9)
A mixture of 8 (121 mg, 0.37 mmol) and potassium carbonate in
96% ethanol (3.2 mL) was stirred at room temperature for 6 h. Po-
tassium carbonate was removed by filtration and to the filtrate was
added hydrochloric acid (1 N, 3.5 mL). The solution was stirred for
30 min and then was added saturated aqueous sodium bicarbonate
(4 mL). The mixture was diluted with methylene chloride (30 mL)
and water (30 mL), and the organic phase was separated. The
aqueous phase was extracted with methylene chloride (2ꢂ30 mL).
The combined organic phase was washed with water and dried
over sodium sulfate. Removal of the solvent gave a crude product,
which was purified by column chromatography on silica gel (pe-
troleum ether/ethyl acetate¼4:1) to afford 9 (99 mg, 80% yield) as
a yellow oil.
yellow solid. Crystallization from iso-PrOH produced 7 as white
crystals (3.46 g, 75% yield). Mp 156–158 ꢁC (decomposed); [
ꢀ36.4 (c 0.85, CH3OH); FTIR (KBr): 3308, 3037, 2920, 2703, 2621,
2532, 2322, 1683, 1602, 1496, 1439, 1404, 1329, 1312, 1286, 1236,
1192, 1091, 1066, 1050, 1029, 966, 816, 748, 697, 625 cmꢀ1; 1H NMR
Mp 64–65 ꢁC; [
1495, 1436, 1417, 1289, 1226, 1182, 1091, 1064, 1043, 819, 757, 704,
617, 500 cmꢀ1 1H NMR (300 MHz, CDCl3):
a]
20 154.4 (c 0.90, CHCl3); FTIR (KBr): 1752, 1602,
D
20
a]
D
;
d
1.29 (t, J¼7.2 Hz, 3H,
CH3), 2.47 (s, 3H, SCH3), 3.90 (d, J¼5.4 Hz, 1H, CHCOOEt), 4.21–4.30
(m, 3H, Ar–CHH and OCH2), 4.96 (d, J¼14.4 Hz, 1H, Ar–CHH), 5.42
(d, J¼5.4 Hz, 1H, CHO), 7.14–7.31 (m, 9H, Ar–H); 13C NMR (75 MHz,
(CD3OD, 300 MHz):
d
2.52 (s 3H), 4.47 (AB, J¼28 Hz, 2H), 4.70 (d,
J¼9 Hz, 1H), 5.11 (d, J¼9 Hz, 1H), 7.33–7.58 (m, 9H); ESIMS: m/z (rel
intensity %): 299.0 (MþþH); HRMS calcd for C17H19OSN2 (MþH):
m/z 299.1218, found: 299.1213. Because of the low solubility and
equilibrium between amine and ammonium salt, we failed to col-
CDCl3): d 14.0, 15.3, 47.3, 62.2, 63.4, 76.6, 125.8, 126.4, 128.1, 128.3,
128.8,134.3,134.7, 140.0,157.0, 168.9. Anal. Calcd for C20H21NO4S: C,
64.67; H, 5.70; N, 3.77. Found: C, 64.85; H, 5.76; N, 3.62. HRMS
(MALDI) calcd for C20H21NO4SNa: m/z 394.1084, found: 394.1085.
lect a clear 13C NMR of 7. Therefore, 100 mg of 7 was neutralized
20
with NaOH to afford the corresponding free base as a clear oil. [
a
]
4.8. (4R,5R)-2,3,4,5-Tetrahydro-5-(4-methylsulfanylphenyl)-
2-oxo-3-benzyl-4-oxazole-methanol (10)
D
ꢀ113.8 (c 0.85, CHCl3); 1H NMR (CDCl3, 300 MHz):
d
2.47 (s, 3H,
SCH3), 3.56 (d, J¼7.8 Hz, 1H, CHCN), 3.93 (dd, J¼69.0, 13.2 Hz, 2H,
Ar–CH2), 4.66 (d, J¼7.8 Hz, 1H, CHOH), 7.23 (d, J¼8.1 Hz, 2H, Ar–H),
7.31–7.34 (m, 7H, Ar–H), de>20 (1H NMR does not show the erythro
To an ice-cooled solution of 9 (0.95 g, 2.6 mmol) in methanol
(50 mL) was added sodium borohydride (0.6 g, 15 mmol). The re-
action mixture was warmed to room temperature and stirred for
2 h. Then water (20 mL) was added and methanol was removed
under reduced pressure. The residue was extracted with ethyl ac-
etate (160 mL). The organic phase was washed with water
(2ꢂ10 mL) and saturated brine (2ꢂ10 mL), and dried over sodium
sulfate. Removal of the solvent gave a crude product (0.89 g).
isomer); 13C NMR (CDCl3, 75 MHz):
d 15.5, 51.2, 56.5, 73.0, 117.9,
126.4, 127.3, 127.8, 128.3, 128.7, 134.7, 137.6, 139.6; the erythro iso-
mer could be isolated with 5% yield when the hydrocyanation re-
action was conducted at room temperature. 1H NMR (CDCl3,
300 MHz):
d
2.49 (s, 3H, SCH3), 3.66 (d, J¼3.6 Hz, 1H, CHCN), 4.47
(dd, J¼81.9, 13.5 Hz, 2H, Ar–CH2), 4.94 (d, J¼3.6 Hz, 1H, CHOH),
7.23–7.38 (m, 9H, Ar–H).
Crystallization from methanol afforded 10 (0.72 g, 85% yield) as
20
a white crystal. [
a
]
101.5 (c 1.2, CHCl3); FTIR (KBr): 3398, 2945,
D
4.6. (4R,5R)-2,3,4,5-Tetrahydro-5-(4-methylsulfanylphenyl)-
2-oxo-3-benzyl-4-oxazole-carbonitrile (8)
2916, 2897, 1717, 1602, 1495, 1450, 1434, 1417, 1367, 1249, 1197, 1109,
1081, 1059, 1006, 961, 828, 753, 707, 672, 634 cmꢀ1 1H NMR
(300 MHz, CDCl3): 2.45 (s, 3H, SCH3), 2.90 (br, 1H, OH), 3.47–3.50
;
d
In a stirred solution of 7 (0.6 g, 1.8 mmol) in methylene chloride
(7 mL) was added triethylamine (0.1 mL). The mixture was stirred
for 30 min, N,N0-carbonyldiimidazole (0.6 g, 3.6 mmol) was added,
and stirring was continued overnight. Water (5 mL) was added
under stirring for phase separation. The organic phase was sepa-
rated and the aqueous phase was extracted with ethyl acetate
(3ꢂ30 mL). The combined organic phase was washed with 0.1 N
HCl and dried over anhydrous sodium sulfate. Evaporation under
reduced pressure gave a crude (0.32 g). Crystallization from a mix-
ture of methylene chloride and petroleum ether (1:8) afforded 8
(m, 1H, CHN), 3.57 (dd, J¼12.6, 3.6 Hz, 1H, CH2O), 3.81 (dd, J¼12.6,
3.6 Hz, 1H, CH2O), 4.61 (dd, J¼134, 15.6 Hz, 2H, Ar–CH2), 5.36 (d,
J¼6.3 Hz, 1H, CHO), 7.15–7.32 (m, 9H, Ar–H); 13C NMR (75 MHz,
CDCl3):
d 15.6, 51.3, 56.6, 73.1, 117.9, 126.5, 127.3, 127.8, 128.3, 128.7,
134.8, 137.6, 139.6. Anal. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N,
4.25. Found: C, 65.63; H, 5.83; N, 4.17. HRMS (MALDI) calcd for
C18H19NO3SNa: m/z 352.0978, found: 352.0973.
4.9. (4R,5R)-2,3,4,5-Tetrahydro-5-(4-methylsulfonylphenyl)-
2-oxo-3-benzyl-4-oxazole-methanol (11)
(276 mg, 86% yield) as white crystals.
20
[
a]
160.1 (c 0.81, CHCl3); FTIR (KBr): 3087, 3030, 2921, 1748,
To a solution of 10 (140 mg, 0.42 mmol) in tetrahydrofuran
(15 mL) was added m-chloroperbenzoic acid (350 mg, 1.2 mmol).
D
1602, 1495, 1437, 1410, 1364, 1325, 1181, 1039, 1050, 1014, 991, 808,

7826
W. Lu et al. / Tetrahedron 64 (2008) 7822–7827
The mixture was stirred at temperature for 2 h. The solvent was
removed by rotatory evaporator. The residue was dissolved in ethyl
acetate (100 mL). The solution was washed with saturated aqueous
sodium sulfite (10 mL), water (10 mL), and saturated brine
(2ꢂ10 mL), and dried over sodium sulfate. Column chromatography
on silica gel (petroleum ether/ethyl acetate¼1:2) afforded 11
66.1, 70.1, 126.8, 126.9, 139.5, 149.0, 165.1; HRMS (MALDI) calcd for
12H15NO5SCl2Na: m/z 377.99402, found: 377.9937.
C
4.12. (4R,5R)-5-(4-Methylsulfanylphenyl)-2-oxo-3-benzyl-4-
fluoromethyl-oxazolidine (13)
(145 mg, 94% yield) as a white solid.
Under argon atmosphere, to a flask containing 10 (255 mg,
0.77 mmol) was added anhydrous THF (10 mL). To the resultant
solution, DAST (0.3 g, 1.8 mmol) was then added slowly via a sy-
ringe. The reaction mixture was stirred at room temperature for
12 h. The reaction was quenched by adding 2 N NaOH (10 mL) and
extracted with ethyl acetate (3ꢂ30 mL). The combined organic
phases were washed with water (8 mL) and saturated brine
(2ꢂ8 mL), and dried over sodium sulfate. The solvent was removed
and the residue was purified by flash column chromatography on
silica gel (petroleum ether/ethyl acetate¼4:1) to afford 13 (260 mg,
20
[a
]
91.3 (c 1.42, CHCl3); FTIR (KBr): 3495, 1738, 1725, 1454,
D
1422, 1324, 1305, 1247, 1153, 1087, 1055, 952, 775, 709, 669, 589,
564 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
2.50 (br, 1H, OH), 3.06 (s,
3H, SO2CH3), 3.49–3.53 (m, 1H, CHN), 3.70 (dd, J¼12.0, 3.0 Hz, 1H,
CH2O), 3.84 (dd, J¼12.0, 3.0 Hz, 1H, CH2O), 4.61 (dd, J¼110, 15.3 Hz,
2H, Ar–CH2), 5.50 (d, J¼5.7 Hz, 1H), 7.28–7.37 (m, 5H, Ar–H), 7.49
(d, J¼8.7 Hz, 2H, Ar–H), 7.90 (d, J¼8.7 Hz, 2H, Ar–H); 13C NMR
(75 MHz, CDCl3):
d 44.4, 46.8, 60.2, 64.0, 126.5, 127.9, 128.1, 128.3,
129.1, 135.72, 140.9, 144.9, 157.9; ESIMS: m/z (MþNaþ) (384.10);
HRMS (MALDI) calcd for C18H20NO5Sþ: m/z 362.1057, found:
362.1063.
90% yield) as a yellow solid.
20
[
a
]
132.2 (c 0.65, CHCl3); FTIR (KBr): 3004, 2878, 2737, 2626,
D
1771, 1754, 1559, 1459, 1371, 1216, 1108, 1038, 933, 750, 698,
548 cmꢀ1 1H NMR (300 MHz, CDCl3):
;
d
2.45 (s, 3H, SCH3), 3.57–
4.10. (2R,3R)-2-Benzylamino-3-(4-methylsulfonylphenyl)-
propane-1,3-diol (12)
3.66 (m, 1H, CHN), 4.26 (d, J¼15.0 Hz, 1H, Ar–CH2), 4.31–4.62 (m,
2H, CH2F), 4.89 (d, J¼15.0 Hz, 1H, Ar–CH2), 5.20 (d, J¼6.6 Hz, 1H,
CHO), 7.15–7.37 (m, 9H, Ar–H); 13C NMR (75 MHz, CDCl3):
d 15.3,
To a solution of 11 (110 mg, 0.30 mmol) in ethanol (5 mL) was
added aqueous potassium hydroxide (4 N, 5 mL). The mixture
was heated in reflux under argon atmosphere for 45 min and
cooled to room temperature. Ethanol was evaporated and the
residue was extracted with methylene chloride (3ꢂ30 mL). The
combined organic phase was washed with water (8 mL) and
saturated brine (2ꢂ8 mL), and dried over sodium sulfate. Purifi-
cation of the crude product by column chromatography on silica
gel (ethyl acetate) afforded 12 (98 mg, 96% yield) as a white
46.7, 61.9 (d, JC–C–F¼15.1 Hz), 75.7 (d, JC3–F¼4.4 Hz), 80.4 (d, JC–
¼132 Hz), 126.2, 126.5, 127.9, 128.1, 128.8, 134.0, 135.3, 140.1, 157.4.
F
Anal. Calcd for C18H18FNO2S: C, 65.24; H, 5.47; N, 4.23. Found: C,
65.04; H, 5.63; N, 4.02. HRMS (EI) calcd for C18H18NO2FS: m/z
331.1042, found: 331.1045.
4.13. (4R,5R)-5-(4-Methylsulfonylphenyl)-2-oxo-3-benzyl-4-
fluoromethyl-oxazolidine (14)
solid.
20
[a
]
ꢀ47.1 (c 1.5, ethanol); FTIR (KBr): 3467, 2927, 1653,
1H
2.74–2.76 (m, 1H, CHN), 3.05 (s, 3H,
D
To a solution of 14 (150 mg, 0.45 mmol) in THF (6 mL) was added
m-perbenzoic acid (250 mg, 0.90 mmol). The reaction mixture was
stirred at room temperature for 2 h and concentrated to remove
THF. The residue was dissolved in ethyl acetate (100 mL). The so-
lution was washed with saturated sodium sulfite (10 mL), water
(10 mL), and saturated brine (2ꢂ10 mL), and dried over sodium
sulfate. Removal of the solvent followed by column chromato-
graphy on silica gel (petroleum ether/ethyl acetate¼3:2) afforded
1600, 1456, 1406, 1307, 1150, 1089, 958, 771, 701, 544 cmꢀ1
NMR (300 MHz, CDCl3):
;
d
SO2CH3), 3.43 (dd, J¼11.4, 3.9 Hz, 1H, CH2O), 3.70 (dd, J¼44,
13.2 Hz, 2H, Ar–CH2), 3.75 (dd, J¼11.4, 3.9 Hz, 1H, CH2O), 4.74 (d,
J¼6.9 Hz, 1H, CHO), 7.22–7.35 (m, 5H, Ar–H), 7.58 (d, J¼9.0 Hz,
2H, Ar–H), 7.90 (d, J¼9.0 Hz, 2H, Ar–H); 13C NMR (75 MHz,
CDCl3):
d 44.51, 51.63, 63.30, 63.56, 71.29, 71.35, 79.24, 81.47,
127.58, 127.79, 128.16, 128.68, 139.05, 140.10, 147.95; ESIMS: m/z
(MþHþ) 336.15; HRMS (ESI) calcd for C17H22NO4S: m/z 336.1264,
found: 336.1271.
14 (149 mg, 89% yield) as a white solid.
20
[
a
]
99.0 (c 1.10, CHCl3); FTIR (KBr): 2970, 2923, 1746, 1457,
D
1421, 1308, 1212, 1150, 1089, 1041, 1032, 956, 825, 756, 706,
582 cmꢀ1; 1H NMR (300 MHz, CDCl3):
d
3.05 (s, 3H, SO2CH3), 3.59–
3.68 (m, 1H, CHN), 4.27 (d, J¼15.3 Hz, 1H, Ar–CH2), 4.31–4.62 (m,
2H, CH2F), 4.86 (d, J¼15.3 Hz, 1H, Ar–CH2), 5.37 (d, J¼6.0 Hz, 1H,
CHO), 7.25–7.34 (m, 5H, Ar–H), 7.48 (d, J¼8.4 Hz, 2H, Ar–H), 7.95 (d,
4.11. Thiamphenicol (2)
To a solution of 12 (35 mg, 0.10 mmol) in ethanol (3 mL) were
added concd hydrochloric acid (0.05 mL) and 10% Pd/C (20 mg). The
hydrogenation was carried out at room temperature in atmospheric
hydrogen for 2 h. The catalyst was separated via filtration and
ethanol was removed. To the residue were added anhydrous
methanol (1 mL), ethyl dichloroacetate (0.2 mL, 1.5 mmol), and
J¼8.4 Hz, 2H, Ar–H); 13C NMR (75 MHz, CDCl3):
d 44.4, 47.0, 61.8 (d,
JC–C–F¼19 Hz), 75.2 (d, JC3–F¼4.1 Hz), 80.4 (d, JC–F¼132 Hz), 126.4,
128.0, 128.2, 128.4, 129.1, 135.1, 141.3, 144.0, 157.0; ESIMS: m/z
(MþNaþ) 386.10; HRMS (MALDI) calcd for C18H19NO4FSþ: m/z
364.1019, found: 364.1013.
triethylamine (25 m
L). The mixture was stirred at 30 ꢁC for 6 h. The
solvent was removed by evaporation. Purification of the crude
product by column chromatography on silica gel (methylene
chloride/methanol¼9:1) afforded 2 (38 mg, 96% yield) as a white
4.14. (1R,2R)-1-(4-Methylsulfonylphenyl)-2-benzylamino-3-
fluoro-1-propanol (15)
solid.
To a solution of 14 (60 mg, 0.165 mmol) in dioxane (3 mL) was
added 8 N sulfuric acid (3 mL). The solution was heated in a sealed
tube under argon atmosphere at 140 ꢁC for 6 h. After being cooled
to room temperature, the tube was cooled in an ice-water bath and
aqueous 4 N sodium hydroxide (14 mL) was added. The mixture
was extracted with methylene chloride (3ꢂ30 mL). The combined
organic phase was washed with water (8 mL) and saturated brine
(2ꢂ8 mL), and dried over sodium sulfate. Removal of the solvent
followed by column chromatography on silica gel (petroleum
20
Mp 164–165 ꢁC; [
a]
12.5 (c 0.38, ethanol) (lit.1 mp 164.3–
D
166.3 ꢁC; [
3080, 2918, 1691, 1561, 1408, 1281, 1144, 1067, 1034, 974, 808, 771,
753, 684, 545 cmꢀ1 1H NMR (300 MHz, CD3OD):
3.07 (s, 3H,
a]
20 12.9 (c 1.0, ethanol)); FTIR (KBr): 3493, 3449, 3258,
D
;
d
SO2CH3), 3.59 (dd, J¼10.8, 6.0 Hz, 1H, CH2O), 3.81 (dd, J¼10.8,
7.2 Hz, 1H, CH2O), 4.10–4.14 (m, 1H, CHN), 5.14 (d, J¼3.3 Hz, 1H,
CHO), 6.23 (s, 1H, CHCl2), 7.66 (d, J¼8.4 Hz, 2H, Ar–H), 7.88 (d,
J¼8.4 Hz, 2H, Ar–H); 13C NMR (75 MHz, CD3OD):
d 43.1, 57.2, 60.9,

W. Lu et al. / Tetrahedron 64 (2008) 7822–7827
7827
ether/ethyl acetate¼1:1) afforded 13 (42 mg, yield 75%) as a white
solid.
Supplementary data
20
[
a]
ꢀ79.2 (c 1.10, CHCl3); FTIR (KBr): 3469, 3311, 2924, 1599,
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2008.05.113.
D
1456, 1318, 1148, 1087, 962, 838, 775, 746, 547 cmꢀ1
;
1H NMR
(300 MHz, CDCl3): 2.71–2.83 (m, 1H, CHN), 3.05 (s, 3H, SO2CH3),
d
3.83 (dd, J¼56.0, 12.9 Hz, 2H, Ar–CH2), 4.10–4.60 (m, 2H, CH2F), 4.62
(d, J¼7.9 Hz, 1H, CHO), 7.28–7.35 (m, 5H, Ar–H), 7.59 (d, J¼8.4 Hz,
2H, Ar–H), 7.92 (d, J¼8.4 Hz, 2H, Ar–H); 13C NMR (75 MHz, CDCl3):
References and notes
1. Culter, R. A.; Stenger, R. J.; Suter, C. M. J. Am. Chem. Soc. 1952, 74, 5475–5481.
2. Suter, C. M.; Schalit, S.; Cutler, R. A. J. Am. Chem. Soc. 1953, 75, 4330–4333.
3. Tobiki, H.; Okamoto, T.; Akiyama, H. U.S. Patent 3,927,054, 1975.
4. For racemic syntheses of thiamphenicol, see: (a) Horak, V.; Moezie, F.; Klein,
R. F. X.; Giordano, C. Synthesis 1984, 839–841; (b) McCombie, S. W.;
Nagabhushan, T. L. Tetrahedron Lett. 1987, 28, 5395–5398; (c) Giordano, C.;
Cavicchioli, S.; Levi, S.; Villa, M. Tetrahedron Lett. 1988, 29, 5561–5564.
5. (a) Nagabhushan, T. L. U.S. Patent 4,235,892, 1980; (b) Jommi, G.; Pagliarin, R.;
Chiarino, D.; Fantucci, M. Gazz. Chim. Ital. 1985, 115, 653–658.
d
44.5, 51.6, 63.4 (d, JC–C–F¼19 Hz), 71.3 (d, JC3–F¼4.6 Hz), 80.4 (d, JC–
¼168 Hz), 127.6, 127.8, 128.2, 128.7, 139.1, 140.1, 148.0; ESIMS: m/z
F
(MþHþ) 338.0; HRMS (ESI) calcd for C17H21N1O3FS: m/z 338.1221,
found: 338.1221.
4.15. Florfenical (3)
6. For chiral syntheses of thiamphenicol, see: (a) Giordano, C.; Cavicchioli, S.; Levi,
S.; Villa, M. J. Org. Chem. 1991, 56, 6114–6118; (b) Davis, F. A.; Zhou, P. Tetra-
hedron Lett. 1994, 35, 7525–7528; (c) Gennari, C.; Pain, G. Tetrahedron Lett. 1996,
37, 3747–3750; (d) Gennari, C.; Vulpetti, A.; Pain, G. Tetrahedron 1997, 53, 5909–
5924; (e) Bhaskar, G.; Kumar, V. S.; Rao, B. V. Tetrahedron: Asymmetry 2004, 15,
1279–1283; (f) Boruwa, J.; Borah, J. C.; Gogoi, S.; Barua, N. C. Tetrahedron Lett.
2005, 46, 1743–1746.
7. For chemo-enzymatic syntheses of thiamphenicol, see: (a) Kaptein, B.; van
Dooren, T. J. G. M.; Boesten, W. H. J.; Sonke, T.; Duchateau, A. L. L.; Broxterman,
Q. B.; Kamphuis, J. Org. Process Res. Dev. 1998, 2, 10–17; (b) Liu, J. Q.; Odani, M.;
Dairi, T.; Itoh, N.; Shimizu, S.; Yamada, H. Appl. Microbiol. Biotechnol. 1999, 51,
586–591; Clark, J. E.; Fisher, P. A.; Schumacher, D. P. Synthesis 1991, 10, 891–894.
8. (a) Schumacher, D. P.; Clark, J. E.; Murphy, B. F.; Fischer, P. A. J. Org. Chem. 1990,
55, 5291–5294; (b) Clark, J. E.; Fischer, P. A.; Schumacher, D. P. Synthesis 1991,
10, 891–894; (c) Wu, G.-Z.; Tormos, W. I. PTC Int. Appl. WO 94/14764, 1994; (d)
Clark, J. E.; Schumacher, E. P.; Wu, G.-Z. U.S. Patent 5,382,673, 1995; (e) Wu,
G.-Z.; Schumacher, D. P.; Tormos, W.; Clark, E. J.; Murphy, B. L. J. Org. Chem. 1997,
62, 2996–2998; (f) Hajra, S.; Karmakar, A.; Maji, T.; Medda, A. K. Tetrahedron
2006, 62, 8959–8965; (g) George, S.; Narina, S. V.; Sudalai, A. Tetrahedron 2006,
62, 10202–10207.
9. For Effenberger’s work in this area, only a few articles are cited herein as ex-
amples: (a) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555–1564; (b)
Effenberger, F. Biocatal. Biotransform. 1997, 14, 167–179; (c) Effenberger, F.
Stereoselective Biocatalysis; Patel, R. N., Ed.; Marcel Dekker: New York, NY, 2000;
Chapter 12, pp 321–342.
10. (a) Brussee, J.; Loos, W. T.; Kruse, C. G.; van der Gen, A. Tetrahedron 1990, 46,
979–986; (b) Zandbergen, P.; Brussee, J.; van der Gen, A.; Kruse, C. G. Tetrahe-
dron: Asymmetry 1992, 3, 769–774; (c) Brussee, J.; van der Gen, A. Stereoselective
Biocatalysis; Patel, R. N., Ed.; Marcel Dekker: New York, NY, 2000; Chapter 12,
pp 289–320.
To a solution of 15 (22 mg, 0.065 mmol) in ethanol (3 mL) were
added concd sulfuric acid (0.05 mL) and 10% Pd/C (12 mg). The
suspension was hydrogenated under atmospheric hydrogen at
room temperature for 2 h. The Pd/C was separated via filtration
and ethanol was removed by evaporation. Anhydrous methanol
(1 mL) was added to the residue. To the solution were added ethyl
dichloroacetate (0.12 mL) and triethylamine (15 mL). The reaction
mixture was stirred at 30 ꢁC for 6 h. Removal of the solvent fol-
lowed by purification of the residue on silica gel (petroleum
ether/ethyl acetate¼1:1) afforded 14 (19 mg, 96% yield) as a white
solid.
Mp 151–152 ꢁC; [
a
]
ꢀ18.0 (c 0.35, DMF) (lit.5b mp 151–152 ꢁC,
20
D
20
[
a]
ꢀ18.4 (c 0.5, DMF)); FTIR (KBr): 3455, 3320, 2931, 1683, 1535,
D
1276, 1190, 1150, 1091, 1018, 859, 809, 769, 537 cmꢀ1
;
1H NMR
(300 MHz, DMSO-d6): 3.17 (s, 3H, CH3), 4.26–4.33 (m, 1H,
d
CHNHCO), 4.44–4.76 (m, 2H, CH2F), 4.99 (d, J¼2.4 Hz, 1H, CHOH),
6.46 (s, 1H, COHCl2), 7.62 (d, J¼8.4 Hz, 2H, Ar–H), 7.85 (d, J¼8.4 Hz,
2H, Ar–H), 8.62 (d, J¼9 Hz, 1H, NHCO); 13C NMR (75 MHz, DMSO-
d6):
d
44.1, 55.1 (d, JC–C–F¼19 Hz), 66.7, 69.8 (d, JC3–F¼5.3 Hz), 82.8
(d, JC–F¼169 Hz), 127.0, 127.6, 140.0, 148.4, 164.2; ESIMS: m/z
(MþNaþ) 380.0; HRMS (ESI) calcd for C12H14N1O4FSCl2Na: m/z
399.9897, found: 379.9906.
11. (a) Han, S.; Lin, G.; Li, Z. Tetrahedron: Asymmetry 1998, 9, 1835–1838; (b) Lin, G.;
Han, S.; Li, Z. Tetrahedron 1999, 55, 3531–3540; (c) Han, S.; Chen, P.; Lin, G.;
Huang, H.; Li, Z. Tetrahedron: Asymmetry 2001, 12, 843–846; (d) Chen, P.; Han, S.;
Lin, G.; Huang, H.; Li, Z. Tetrahedron: Asymmetry 2001, 12, 3273–3279; (e) Chen,
P.; Han, S.; Lin, G.; Li, Z. J. Org. Chem. 2002, 67, 8251–8253.
12. Flora Reipublicae Popuplaris Sinicae; Te-Tsun, Y., Ed.; Science: Beijing, 1896;
Tomus 38, p 12.
13. Compound 8, J¼6.3 Hz; cis-oxazolidone, J¼8–9 Hz; trans-oxazolidone, J¼5–
7 Hz; (a) Wenger, R. M. Helv. Chim. Acta 1983, 66, 2308–2321; (b) Saeed, A.;
Yound, D. W. Tetrahedron 1992, 48, 2507–2514.
Acknowledgements
Financial support is from The National Natural Science Foun-
dation of China (203900506) and the Major State Basic Research
Development Program (G2000077506). We would like to thank
Prof. Yaoquan Chen for his valuable help during the various stages
of the research.