A short enantioselective synthesis of (-)-chloramphenicol and (+)-thiamphenicol using tethered aminohydroxylation

Article abstract of DOI:10.1016/j.tet.2006.08.019

An efficient enantioselective synthesis of (-)-chloramphenicol (1) and (+)-thiamphenicol (2) is described. These antibiotics have been synthesized from commercially available 4-nitrobenzaldehyde and 4-(methylthio)benzaldehyde, respectively, using tethered aminohydroxylation and Sharpless asymmetric epoxidation as the chirality inducing steps.

Full text of DOI:10.1016/j.tet.2006.08.019

Tetrahedron 62 (2006) 10202–10207
A short enantioselective synthesis of (L)-chloramphenicol and
(D)-thiamphenicol using tethered aminohydroxylation
*
Shyla George, Srinivasarao V. Narina and Arumugam Sudalai
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 12 May 2006; revised 17 July 2006; accepted 3 August 2006
Available online 6 September 2006
Abstract—An efficient enantioselective synthesis of (ꢀ)-chloramphenicol (1) and (+)-thiamphenicol (2) is described. These antibiotics have
been synthesized from commercially available 4-nitrobenzaldehyde and 4-(methylthio)benzaldehyde, respectively, using tethered amino-
hydroxylation and Sharpless asymmetric epoxidation as the chirality inducing steps.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
naturally occurring and cheaply available (+)-diisopropyl
tartrate for the enantioselective syntheses of 1 and 2.
(ꢀ)-Chloramphenicol 1 and (+)-thiamphenicol 2 (Fig. 1)
are broad-spectrum antibiotics with a range of biological ac-
tivities.1 The antibiotic chloramphenicol is active only in its
D-threo configuration and is especially effective in the treat-
ment of typhus, dysentery and ocular bacterial infections.2
(+)-Thiamphenicol 2, a synthetic analogue of chloramphen-
icol 1, is bacteriostatic for both Gram-positive and Gram-
negative aerobes and for some anaerobes.3 Owing to their
potential biological activity, a number of syntheses have
been described.4–7
The tethered aminohydroxylation (TA),8 an intramolecular
asymmetric aminohydroxylation of alkenes, has become
a reliable method in recent years for achieving excellent
levels of syn selectivity while providing at the same time
complete control over the regio- and chemoselectivity of
the oxidation. We describe herein a new, short approach
for the stereoselective synthesis of (ꢀ)-chloramphenicol 1
and (+)-thiamphenicol 2 by employing two key reactions,
namely, Sharpless asymmetric epoxidation11 and the teth-
ered aminohydroxylation.8
OH
OH
2. Result and discussion
NHCOCHCl2
R
Our synthesis of (ꢀ)-chloramphenicol 1 (Scheme 1) starts
with the reaction of 4-nitrobenzaldehyde 3a with divinyl-
zinc9 to give 1-(4-nitrophenyl)allyl alcohol 4a in 68% yield.
Allylic alcohol 4a was then subjected to Sharpless asymmet-
ric epoxidation under kinetic resolution conditions10 using
the naturally occurring (+)-diisopropyl tartrate [(+)-DIPT]
to furnish the corresponding chiral allylic alcohol, 1-(S)-4-
(nitrophenyl)-2-propen-1-ol 6a, in 44% chemical yield and
98% ee (optical purity was determined by 1H NMR analysis
of the corresponding Mosher’s ester 10a, see Section 4 for
details) along with the corresponding epoxide 7a in 49%
yield. Both chiral alcohol 6a and epoxide 7a could be easily
separated by column chromatographic purification. Alcohol
6a was then treated with trichloroacetyl isocyanate11 in
CH2Cl2 to give the corresponding isocyanate, which on
treatment with K2CO3 and methanol in the presence of
H2O gave the carbamate 8a in 90% yield.
R= NO2; (-)-Chloramphenicol, 1
R= SO2Me; (+)-Thiamphenicol, 2
Figure 1.
Sharpless asymmetric epoxidation has previously been used
for the syntheses of 1 and 2.5c,d,j,7c,e In one of these reports,
the authors made use of a Z-cinnamyl alcohol for which the
asymmetric epoxidation required a long reaction time.5c
Further, in some cases, the use of E-cinnamyl alcohol re-
sulted in the increase of the number of steps.5d,7c,e In another
report, the use of Sharpless asymmetric epoxidation under
kinetic resolution conditions required expensive, unnatural
(ꢀ)-diisopropyl tartrate [(ꢀ)-DIPT].5j However, we are
able to replace the unnatural (ꢀ)-diisopropyl tartrate with
Keywords: Asymmetric synthesis; Asymmetric epoxidation; Kinetic resolu-
tion; Tethered aminohydroxylation.
The carbamate 8a thus obtained was converted into the ox-
azolidinone 9a by a tethered aminohydroxylation protocol8b
* Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676;
e-mail: a.sudalai@ncl.res.in
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.019

S. George et al. / Tetrahedron 62 (2006) 10202–10207
OH
10203
OH
OH
CHO
a or a'
c
O
+
R
R
R
R
3a R= NO2
3b R= SMe
(method a, 68%) 4a R= NO2
(method a', 96%) 4b R= SMe
(95%) 5 R= SO2Me
(49%) 7a R= NO2
(48%) 7b R= SO2Me
(44%) 6a R= NO2
(43%) 6b R= SO2Me
b
O
OH
O
NH2
O
O
OH
NHCOCHCl2
f
d
OH
e
6a,6b
NH
R
R
R
(69%) 9a R= NO2
(65%) 9b R= SO2Me
(90%) 8a R= NO2
(86%) 8b R= SO2Me
(78%) 1 R= NO2
(77%) 2 R= SO2Me
Scheme 1. Reagents and conditions: (a) divinylzinc, THF, Et2O, ꢀ78–25 ꢁC, 10 h; (a0) vinylmagnesium bromide, THF, 0–25 ꢁC, 2 h; (b) oxone, THF/MeOH/
H2O (1:1:1), 0–25 ꢁC, 30 min, 95%; (c) (+)-DIPT, Ti(OiPr)4, TBHP, CH2Cl2, ꢀ20 ꢁC, 14–24 h; (d) (i) trichloroacetyl isocyanate, CH2Cl2, 0–25 ꢁC, 2 h; (ii)
K2CO3, MeOH, H2O, 0–25 ꢁC, 18 h; (e) K2Os(OH)4O2, t-BuOCl, NaOH, EtN-i-Pr2, n-PrOH/H2O (1:1), 25 ꢁC, 3 h; (f) (i) 1 N NaOH, MeOH, 25 ꢁC, overnight;
(ii) methyl dichloroacetate, 90 ꢁC, 3 h.
using tert-butyl hypochlorite as the oxidant in the presence
of potassium osmate, 0.08 M NaOH, diisopropyl ethylamine
and propan-1-ol as the solvent. The reaction proceeded
smoothly to furnish the protected aminoalcohol 9a as a single
isomer with complete regiocontrol and excellent syn selec-
tivity (syn:anti>20:1, determined by 1H NMR analysis) giv-
ing 69% yield. The compound 9a was then hydrolyzed using
1 N NaOH in methanol5h to furnish the crude aminoalcohol,
which was then taken in methyl dichloroacetate4a,5h and
heated at 90 ꢁC for 3 h to give (ꢀ)-chloramphenicol 1
in 78% yield. [a]D25 ꢀ25.4 (c 1, EtOAc) [lit.12 [a]2D3 ꢀ25.5
(c 1, EtOAc)]. The spectral data of 1 was in complete agree-
ment with the reported values.1b
(+)-thiamphenicol (overall yield 34%, 98% ee) using
tethered aminohydroxylation and Sharpless asymmetric ep-
oxidation as the two key chirality inducing steps. The major
advantages of this work are the use of naturally occurring
(+)-DIPT for the kinetic resolution and the use of tethered
aminohydroxylation for the induction of second chiral centre
in the molecule in a highly diastereoselective fashion
(dr¼98:2).
4. Experimental
4.1. General
The same strategy was extended to the synthesis of
(+)-thiamphenicol 2 (Scheme 1). Commercially available
4-(methylthio)benzaldehyde 3b was converted to the allyl
alcohol 4b using vinylmagnesium bromide in THF.5j The
thioether 4b was then oxidized using oxone13 to give the cor-
responding sulfonyl ester 5 in 95% yield. Allyl alcohol 5 was
then subjected to Sharpless asymmetric epoxidation10 using
(+)-diisopropyl tartrate under kinetic resolution conditions to
furnish the chiral alcohol 6b in 43% yield and 98% ee (the
Solvents were purified and dried by standard procedures
before use;15 petroleum ether of boiling range 60–80 ꢁC
was used. Melting points are uncorrected. Optical rotations
were measured using sodium D line on a JASCO-181 digital
polarimeter. Infrared spectra were recorded on Shimadzu
FTIR-8400 spectrometer. 1H NMR and 13C NMR were
recorded on Bruker AV-200, AV-400 and BRX-500 NMR
spectrometers, respectively. Elemental analysis was carried
on a Carlo Erba CHNS-O analyzer.
1
optical purity was determined by H NMR analysis of the
corresponding Mosher’s ester 10b, see Section 4 for details)
along with the epoxide 7b. Both alcohol 6b and epoxide 7b
could be easily separated by column chromatography. The
carbamate 8b obtained from 6b under the same experimental
conditions11 as explained earlier was converted into the oxa-
zolidinone 9b using tethered aminohydroxylation.8b The de-
sired isomer of the oxazolidinone 9b was obtained with high
4.2. 1-(4-Nitrophenyl)-2-propen-1-ol (4a)
To a stirred solution of vinylmagnesium bromide [prepared
from vinyl bromide (8.49 g, 79.4 mmol) and magnesium
(1.93 g, 79.4 mmol)] in THF (90 mL), freshly fused ZnCl2
(5.40 g, 39.7 mmol) dissolved in THF (30 mL) was added
at 0 ꢁC under nitrogen atmosphere. This solution was stirred
at 55 ꢁC for 18 h, after which it was cooled to 10 ꢁC and dry
ether (150 mL) was added and stirred for 10 min. The reac-
tion mixture was allowed to settle for 30 min. The superna-
tant liquid was transferred through a canula to another flask.
This solution was allowed to cool to ꢀ78 ꢁC, then 4-nitro-
benzaldehyde 3a (1.5 g, 9.92 mmol) in THF (20 mL) was
added over a period of 15 min. The reaction mixture was
allowed to warm to room temperature and stirring continued
for 10 h. The reaction mixture was then quenched at ꢀ20 ꢁC
by the addition of aqueous ammonium chloride. The aque-
ous layer was extracted with ethyl acetate (3ꢂ100 mL)
and the combined organic fractions collected and washed
with water and brine solution, then dried over Na2SO4 and
1
stereoselectivity (syn:anti>20:1, determined by H NMR
analysis) giving 65% yield. Finally, the hydrolysis of 9b
with 1 N NaOH in methanol5h followed by the treatment
with methyl dichloroacetate4a,5h gave the final product
thiamphenicol 2 in 77% yield. [a]2D5 +12.7 (c 1, EtOH) [lit.3
[a]2D5 +12.9 (c 1, EtOH)]. The spectral data of 2 was in com-
plete agreement with the reported values.5j,14
3. Conclusion
In conclusion, we have achieved an efficient synthesis
of (ꢀ)-chloramphenicol (overall yield 29%, 98% ee) and

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S. George et al. / Tetrahedron 62 (2006) 10202–10207
concentrated under reduced pressure. The crude compound
was purified by column chromatography using petroleum
ether/EtOAc (8:2) to afford compound 4a (1.21 g, 68%) as
a pale yellow amorphous solid. Mp: 48–49 ꢁC; IR (CHCl3)
nmax 3433, 2858, 1606, 1519, 1348, 1217, 1108, 1041,
through a syringe. It was allowed to stir for additional
10 min, followed by dropwise addition of (R)-a-methoxy-
a-trifluoromethylphenyl acetic acid (46 mg, 0.196 mmol)
in CH2Cl2 (2 mL). This reaction mixture was then stirred at
0 ꢁC for additional 1 h and then at room temperature over-
night. The reaction mixture was diluted with CH2Cl2
(50 mL), washed with saturated sodium bicarbonate solution
(50 mL), dried over Na2SO4 and then concentrated under re-
duced pressure to give Mosher’s ester of the alcohol (53 mg,
70%) as a thick syrup. [a]2D5 +39.5 (c 0.4, CHCl3); IR (CHCl3)
nmax 3158, 2952, 2927, 2850, 2250, 1753, 1606, 1519, 1495,
1348, 1268, 1242, 1217, 1153, 1122, 1015, 957, 911, 735,
650 cmꢀ1; 1H NMR (200 MHz, CDCl3) d 8.15 (d, J¼9 Hz,
2H), 7.32–7.53 (m, 7H), 6.48 (d, J¼6.6 Hz, 1H), 5.90–6.06
(m, 1H), 5.36–5.47 (m, 2H), 3.55 (s, 3H). 13C NMR
(100 MHz, CDCl3) d 165.27, 147.98, 144.53, 134.09, 133.87,
132.04, 129.79, 128.45, 127.68, 127.24, 123.86, 119.95,
77.06, 55.56. Anal. Calcd for C19H16F3NO5 (395.10): C,
57.72; H, 4.08; F, 14.42; N, 3.54. Found: C, 57.94; H, 3.82;
F, 14.68; N, 3.21.
1
989, 854, 757 cmꢀ1; H NMR (200 MHz, CDCl3) d 8.21
(d, J¼8.8 Hz, 2H), 7.56 (d, J¼8.5 Hz, 2H), 5.91–6.05 (m,
1H), 5.25–5.45 (m, 3H), 2.04 (br s, 1H); 13C NMR
(50 MHz, CDCl3) d 149.6, 147.1, 139.1, 126.9, 123.5,
116.6, 74.4. Anal. Calcd for C9H9NO3 (179.18): C, 60.33;
H, 5.06; N, 7.82. Found: C, 60.45; H, 5.09; N, 7.94%.
4.3. 1-(S)-(4-Nitrophenyl)-2-propen-1-ol (6a)
˚
To a stirred suspension of powdered 4 A molecular sieves
(1.5 g) in dry CH2Cl2 (25 mL), Ti(OiPr)4 (1.27 g,
4.47 mmol) was added under nitrogen atmosphere. The
reaction mixture was cooled to ꢀ20 ꢁC and (+)-diisopropyl
tartrate (1.25 g, 5.36 mmol) was added and stirred for
10 min, after which allyl alcohol 4a (0.8 g, 4.5 mmol) dis-
solved in CH2Cl2 (20 mL) was added and stirred at ꢀ20 ꢁC
for 30 min. To the above solution tert-butyl hydroperoxide
(0.22 g, 2.5 mmol) dissolved in toluenewas added and stirred
at ꢀ20 ꢁC for 14 h. After completion of half of the reaction
(monitored by TLC), the reaction mixture was quenched
with 10% aqueous solution of tartaric acid (25 mL), after
which stirring was continued for 1 h at ꢀ20 ꢁC and 2 h at
room temperature. The organic layer was separated, washed
with water and dried over Na2SO4, and concentrated under
reduced pressure. The residue was diluted with ether
(75 mL) and stirred with 1 M NaOH (25 mL) for 1 h at
0 ꢁC. The organic layer was then separated, washed with
brine solution, dried over Na2SO4 and concentrated under
reduced pressure. The crude compound was purified by
column chromatography using petroleum ether/EtOAc
(8:2) to afford compound 6a (0.35 g, 44%) as a pale yellow
amorphous solid. Mp: 48–49 ꢁC; [a]D25 +41.3 (c 1, CHCl3);
IR (CHCl3) nmax 3433, 2858, 1606, 1519, 1348, 1217,
4.6. 1-(S)-(4-Nitrophenyl)allyl carbamate (8a)
To a stirred solution of alcohol 6a (0.45 g, 2.5 mmol) in
dichloromethane (12 mL) at 0 ꢁC was added dropwise tri-
chloroacetyl isocyanate (0.36 mL, 3 mmol). The resulting
solution was stirred for 2 h and then concentrated in vacuo.
The residue was diluted with MeOH (13 mL), cooled
to 0 ꢁC and a solution of potassium carbonate (1.04 g,
7.5 mmol) in H2O (2.4 mL) was added. The resulting suspen-
sion was stirred at 0 ꢁC for 2 h, then at room temperature for
16 h. The reaction was concentrated in vacuo, diluted with
H2O (50 mL) and brine (50 mL) and extracted with dichloro-
methane (2ꢂ50 mL). The combined organic extracts were
dried over MgSO4 and concentrated in vacuo. The crude ma-
terial was purified by column chromatography using petro-
leum ether/EtOAc (6:4) to give 8a (0.5 g, 90%) as a pale
yellow crystalline solid. Mp: 101 ꢁC; [a]D25 +12.39 (c 1,
CHCl3); IR (CHCl3) nmax 3471, 3280, 3178, 1724, 1620,
1108, 1041, 989, 854, 757 cmꢀ1 1H NMR (200 MHz,
;
1
CDCl3) d 8.21 (d, J¼8.8 Hz, 2H), 7.56 (d, J¼8.5 Hz, 2H),
5.91–6.05 (m, 1H), 5.25–5.45 (m, 3H), 2.04 (br s, 1H); 13C
NMR (50 MHz, CDCl3) d 149.6, 147.1, 139.1, 126.9,
123.5, 116.6, 74.4. Anal. Calcd for C9H9NO3 (179.18):
C, 60.33; H, 5.06; N, 7.82. Found: C, 60.45; H, 5.09; N,
7.94%.
1514, 1386, 1346, 1328, 1215, 925, 854, 756 cmꢀ1; H
NMR (200 MHz, CDCl3) d 8.23 (d, J¼8.8 Hz, 2H), 7.53
(d, J¼8.7 Hz, 2H), 6.23 (d, J¼6 Hz, 1H), 5.89–6.06 (m,
1H), 5.35 (t, J¼7.3 Hz, 2H), 4.86 (br s, 2H); 13C NMR
(50 MHz, CDCl3) d 155.5, 147.5, 146.3, 135.2, 127.5,
123.7, 118.2, 75.7. Anal. Calcd for C10H10N2O4 (222.22):
C, 54.05; H, 4.54; N, 12.62. Found: C, 54.16; H, 4.50; N,
12.61%.
4.4. (1R,2S)-1-(4-Nitrophenyl)oxiranemethanol (7a)
White amorphous solid. Mp: 74–75 ꢁC; [a]D25 +60.8 (c 1,
4.7. (5R,6R)-4-(Hydroxymethyl)-5-(4-nitrophenyl)-2-
oxazolidinone (9a)
1
CHCl3); H NMR (200 MHz, CDCl3) d 8.23 (d, J¼9.0 Hz,
2H), 7.57 (d, J¼9.0 Hz, 2H), 5.01 (br d, J¼3.0 Hz, 1H),
3.20 (ddd, J¼2.6, 3.0, 4.2 Hz, 1H), 2.88 (dd, J¼2.6,
4.9 Hz, 1H), 2.72 (dd, J¼4.2, 4.9 Hz, 1H), 2.45 (br s, 1H).
A fresh aqueous solution of sodium hydroxide (0.08 M,
0.9 equiv) was prepared. All but a few drops of this were
added in one portion to a stirred solution of the allylic carba-
mate (0.222 g, 1 mmol) in propan-1-ol (12 mL). The solu-
tion was allowed to stir for 5 min, before freshly prepared
tert-butyl hypochlorite (0.114 mL, 1 mmol) was added.
The mixture was again allowed to stir for 5 min. To this
was added diisopropyl ethylamine (5 mol %) in one portion.
The mixture was allowed to stir for a further 5 min before the
final addition of a solution of potassium osmate (4 mol %) in
the remainder of the sodium hydroxide solution made ear-
lier. The reaction was monitored by TLC and halted when
4.5. Preparation of Mosher’s ester of 1-(S)-(4-nitro-
phenyl)-2-propen-1-ol (10a)
A two-neck 10 mL flask with septum was charged with
(44 mg, 0.21 mmol) N,N0-dicyclohexylcarbodiimide (DCC),
catalytic amount of 4-dimethylaminopyridine (DMAP) and
CH2Cl2 (2 mL) under argon atmosphere. The flask was
allowed to cool at 0 ꢁC for 10 min and a solution of alcohol
6a (32 mg, 0.18 mmol) in CH2Cl2 (2 mL) was introduced

S. George et al. / Tetrahedron 62 (2006) 10202–10207
10205
no further change was detected. The reaction was quenched
by the addition of sodium sulfite (500 mg), and allowed to
stir for 30 min. The mixture was extracted with ethyl acetate
(2ꢂ50 mL). The combined organics were washed with
brine, dried over sodium sulfate and concentrated under re-
duced pressure. The crude material was purified by flash col-
umn chromatography on silica using petroleum ether/EtOAc
(4:6) to give 9a (0.16 g, 69%) as a gum. [a]2D5 ꢀ4.08 (c 1.1,
EtOH); IR (CHCl3) nmax 3351, 2944, 2832, 2523, 1755,
815 cmꢀ1 1H NMR (200 MHz, CDCl3) d 7.30 (d,
;
J¼8.7 Hz, 2H), 7.24 (d, J¼8.7 Hz, 2H), 5.95–6.11 (m, 1H),
5.17–5.39 (m, 3H), 2.48 (s, 3H), 1.97 (br s, 1H); 13C NMR
(50 MHz, CDCl3) d 139.9, 139.4, 137.5, 126.7, 126.5,
114.9, 74.6, 15.74. Anal. Calcd for C10H12OS (180.27): C,
66.63; H, 6.71; S, 17.79. Found: C, 66.79; H, 6.89; S,
17.68%.
4.10. 1-(4-Methylsulfonylphenyl)-2-propen-1-ol (5)
1
1607, 1527, 1450, 1416, 1351, 1112, 666 cmꢀ1; H NMR
(200 MHz, acetone-d6) d 8.33 (d, J¼8.3 Hz, 2H), 7.75 (d,
J¼8.7 Hz, 2H), 6.96 (s, 1H), 5.61 (m, 1H), 4.49 (s, 1H),
3.81 (m, 3H); 13C NMR (125 MHz, acetone-d6) d 158.3,
148.6, 148.3, 127.3, 124.4, 78.6, 63.7, 62.1. Anal. Calcd
for C10H10N2O5 (238.22): C, 50.42; H, 4.23; N, 11.77.
Found: C, 50.36; H, 4.36; N, 11.86%.
To a vigorously stirred solution of sulfide 4b (3.78 g,
21 mmol) in THF (20 mL), MeOH (20 mL) and H2O
(20 mL) at 0 ꢁC was added oxone (36 g, 59 mmol) portion-
wise. After 5 min at 0 ꢁC, the white suspension was warmed
to room temperature and stirred for 30 min. The reaction was
poured into H2O (200 mL) and extracted with CH2Cl2
(3ꢂ100 mL), and the combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The
crude compound was purified by column chromatography
using petroleum ether/EtOAc (6:4) to give sulfone 5
(4.25 g, 95%) as a white amorphous solid. Mp: 56.5–
57.5 ꢁC; IR (CHCl3) nmax 3481, 3020, 2927, 2360, 1639,
4.8. (1R,2R)-2-(Dichloroacetamido)-1-(4-nitrophenyl)-
1,3-propanediol (1)
A solution of 1 N NaOH was made in methanol. The above
solution (10 mL) was added to 9a (0.95 g, 0.4 mmol) and
stirred overnight at room temperature. The reaction mixture
was filtered and the filtrate concentrated in vacuum. The
crude compound was taken in methyl dichloroacetate
(2 mL) and heated at 90 ꢁC for 3 h. The excess ester was re-
moved under reduced pressure and the crude compound was
purified by column chromatography using petroleum ether/
EtOAc (3:7) to give the product 1 (0.1 g, 78%) as a white
amorphous solid. Mp: 151–152 ꢁC [lit.11 149.7–150.7 ꢁC];
[a]D25 ꢀ24.9 (c 1, EtOAc) [lit.11 [a]2D3 ꢀ25.5 (c 1, EtOAc)];
IR (CHCl3) nmax 3420, 3020, 2929, 1686, 1604, 1523,
1
1598, 1407, 1303, 1149, 1087, 958, 761 cmꢀ1; H NMR
(200 MHz, CDCl3) d 7.91 (d, J¼8.5 Hz, 2H), 7.58 (d,
J¼8.2 Hz, 2H), 5.99 (m, 1H), 5.23–5.43 (m, 3H), 3.03 (s,
3H), 2.20 (br s, 1H); 13C NMR (50 MHz, CDCl3) d 149.0,
139.3, 139.1, 127.3, 127.1, 116.2, 74.34, 44.39. Anal. Calcd
for C10H12O3S (212.27): C, 56.58; H, 5.69; S, 15.11. Found:
C, 56.69; H, 5.76; S, 15.23%.
4.11. 1-(S)-(4-Methylsulfonylphenyl)-2-propen-1-ol (6b)
1454, 1403, 1348, 1216, 1049, 850 cmꢀ1
;
1H NMR
To a stirred suspension of powdered 4 A molecular sieves
˚
(400 MHz, DMSO-d6) d 8.31 (d, J¼9 Hz, 1H), 8.15 (d,
J¼8.3 Hz, 2H), 7.58 (d, J¼8.5 Hz, 2H), 6.47 (s, 1H), 6.04
(br s, 1H), 4.83–5.05 (m, 2H), 3.90–3.95 (m, 1H), 3.56–
3.61 (m, 1H), 3.33–3.40 (m, 1H); 13C NMR (100 MHz, ace-
tone-d6) d 164.3, 150.1, 147.3, 128.2, 123.2, 70.6, 66.6, 61.6,
56.9. Anal. Calcd for C11H12Cl2N2O5 (323.15): C, 40.89; H,
3.74; Cl, 21.94; N, 8.68. Found: C, 40.93; H, 3.82; Cl, 21.89;
N, 8.66%.
(7 g) in dry CH2Cl2 (75 mL), Ti(OiPr)4 (3.12 g, 11 mmol)
was added under nitrogen atmosphere. The reaction mixture
was cooled to ꢀ20 ꢁC and (+)-diisopropyl tartrate (3.1 g,
13.2 mmol) was added and stirred for 10 min, after which al-
lyl alcohol 5 (2.3 g, 11 mmol) dissolved in CH2Cl2 (60 mL)
was added and stirred at ꢀ20 ꢁC for about 30 min. To the
above solution tert-butyl hydroperoxide (0.59 g, 6.6 mmol)
dissolved in toluene was added and stirred at ꢀ20 ꢁC for
about 24 h. After completion of half of the reaction (moni-
tored by TLC), the reaction mixture was quenched with
10% aqueous solution of tartaric acid (80 mL), after which
stirring was continued for 1 h at ꢀ20 ꢁC and 2 h at room tem-
perature. The organic layer was separated, washed with water
and dried over Na2SO4 and concentrated under reduced pres-
sure. The residue was diluted with ether (250 mL) and stirred
with 1 M NaOH (100 mL) for about 1 h at 0 ꢁC. The organic
layer was then separated, washed with brine solution, dried
over Na2SO4 and then concentrated under reduced pressure.
The crude compound was purified by column chromato-
graphy using petroleum ether/EtOAc (6:4) to afford
compound 6b (1 g, 43%) as white amorphous solid. Mp:
56.5–57.5 ꢁC; [a]D25 +28.38 (c 1, CHCl3); IR (CHCl3) nmax
3481, 3020, 2927, 2360, 1639, 1598, 1407, 1303, 1149,
4.9. 1-(4-Methylsulfanylphenyl)-2-propen-1-ol (4b)
To a stirred suspension of Mg (7.1 g, 296 mmol) in THF
(75 mL), vinyl bromide (15.82 g, 147.81 mmol) in THF
(45 mL) was added at 0 ꢁC under nitrogen atmosphere over
a period of 15 min and continued stirring at room tempera-
ture for a further 30 min. The reaction mixture was cooled
to 0 ꢁC and 4-(methylthio)benzaldehyde 3b (7.5 g,
49.26 mmol) dissolved in THF (75 mL) was added over a
period of 10 min. After the addition was completed, the reac-
tion mixture was allowed to return to room temperature
and stirring continued for another 2 h. The reaction mixture
was quenched by the addition of aqueous ammonium chlo-
ride and extracted with ethyl acetate (3ꢂ100 mL). The com-
bined organic fractions were collected and washed with
water and brine solution, then dried over Na2SO4 and con-
centrated under reduced pressure. The crude compound
was purified by column chromatography using petroleum
ether/EtOAc (8:2) to afford compound 4b (8.5 g, 96%) as
a thick syrup; IR (CHCl3) nmax 3398, 3078, 2981, 2920,
1639, 1598, 1492, 1431, 1404, 1219, 1093, 989, 927,
1
1087, 958, 761 cmꢀ1; H NMR (200 MHz, CDCl3) d 7.91
(d, J¼8.5 Hz, 2H), 7.58 (d, J¼8.2 Hz, 2H), 5.99 (m, 1H),
5.23–5.43 (m, 3H), 3.03 (s, 3H), 2.20 (br s, 1H); 13C NMR
(50 MHz, CDCl3) d 149.0, 139.3, 139.1, 127.3, 127.1,
116.2, 74.34, 44.39. Anal. Calcd for C10H12O3S (212.27):
C, 56.58; H, 5.69; S, 15.11. Found: C, 56.55; H, 5.61; S,
15.26%.

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S. George et al. / Tetrahedron 62 (2006) 10202–10207
4.12. (1R,2S)-1-(4-Methylsulfonylphenyl)oxirane-
methanol (7b)
J¼10.1 Hz, 1H), 3.20 (s, 3H); 13C NMR (50 MHz, DMSO-
d6) d 155.7, 146.1, 140.2, 136.9, 127.5, 127.4, 117.0, 74.5,
43.7. Anal. Calcd for C11H13NO4S (255.30): C, 51.75; H,
5.13; N, 5.49; S, 12.56. Found: C, 51.79; H, 5.27; N, 5.40;
S, 12.49%.
Thick syrup. [a]2D5 +47.3 (c 1, CHCl3); 1H NMR (200 MHz,
CDCl3) d 7.91 (d, J¼8.3 Hz, 2H), 7.59 (d, J¼8.3 Hz, 2H),
4.96 (br d, J¼3.0 Hz, 1H), 3.19 (m, 1H), 3.02 (s, 3H), 2.88
(dd, J¼3.0, 5.2 Hz, 1H), 2.73 (dd, J¼3.7, 5.2 Hz, 1H),
2.50 (br s, 1H).
4.15. (5R,6R)-4-(Hydroxymethyl)-5-(4-(methyl-
sulfonyl)phenyl)-2-oxazolidinone (9b)
4.13. Preparation of Mosher’s ester of 1-(S)-(4-methyl-
sulfonylphenyl)-2-propen-1-ol (10b)
A fresh aqueous solution of sodium hydroxide (0.08 M,
0.9 equiv) was prepared. All but a few drops of this were
added in one portion to a stirred solution of the allylic car-
bamate (0.76 g, 3 mmol) in propan-1-ol (30 mL). The solu-
tion was allowed to stir for 5 min, before freshly prepared
tert-butyl hypochlorite (0.4 mL, 3 mmol) was added. The
mixture was again allowed to stir for 5 min. To this was
added diisopropyl ethylamine (5 mol %) in one portion.
The mixture was allowed to stir for a further 5 min before
the final addition of a solution of potassium osmate
(4 mol %) in the remainder of the sodium hydroxide solu-
tion made earlier. The reaction was monitored by TLC
and halted when no further change was detected. The reac-
tion was quenched by the addition of sodium sulfite (1.5 g),
and allowed to stir for 30 min. The mixture was extracted
with ethyl acetate (2ꢂ50 mL). The combined organics
were washed with brine, dried over sodium sulfate and con-
centrated under reduced pressure. The crude material was
purified by flash column chromatography on silica using
petroleum ether/EtOAc (2:8) to give 9b (0.53 g, 65%) as
a pale yellow amorphous solid. Mp: 152 ꢁC; [a]D25 +9.74
(c 1.16, MeOH); IR (neat) nmax 3259, 3020, 2929, 2399,
2360, 1716, 1602, 1407, 1299, 1215, 1149, 1089, 1026,
A two-neck 10 mL flask with septum was charged with
(44 mg, 0.21 mmol) N,N0-dicyclohexylcarbodiimide (DCC),
catalytic amount of 4-dimethylaminopyridine (DMAP) and
CH2Cl2 (2 mL) under argon atmosphere. The flask was
allowed to cool at 0 ꢁC for 10 min and a solution of alcohol
6b (38 mg, 0.179 mmol) in CH2Cl2 (2 mL) was introduced
through a syringe. It was allowed to stir for additional
10 min, followed by dropwise addition of (R)-a-methoxy-
a-trifluoromethylphenyl acetic acid (46 mg, 0.196 mmol)
in CH2Cl2 (2 mL). This reaction mixture was then stirred
at 0 ꢁC for additional 1 h and then at room temperature over-
night. The reaction mixture was diluted with CH2Cl2
(50 mL), washed with saturated sodium bicarbonate solution
(50 mL), dried over Na2SO4 and then concentrated under
reduced pressure to get Mosher’s ester of the alcohol
(53 mg, 70%) as a thick syrup. [a]2D5 +42.5 (c 0.4, MeOH);
IR (CHCl3) nmax 3156, 3069, 2951, 2930, 2851, 2255,
1754, 1644, 1601, 1496, 1452, 1410, 1318, 1243, 1154,
1016, 957, 910, 737, 650 cmꢀ1 1H NMR (200 MHz,
;
CDCl3) d 7.87 (d, J¼8.5 Hz, 2H), 7.35–7.45 (m, 7H), 6.48
(d, J¼6.5 Hz, 1H), 5.89–6.06 (m, 1H), 5.35–5.47 (m,
2H), 3.55 (s, 3H), 3.04 (m, 3H); 13C NMR (100 MHz,
CDCl3) d 165.33, 147.44, 143.67, 140.73, 134.17, 131.99,
129.77, 128.43, 127.78, 127.24, 119.84, 77.31, 55.55,
44.44. Anal. Calcd for C20H19F3O5S (428.42): C, 56.07;
H, 4.47; F, 13.30; S, 7.48. Found: C, 57.24; H, 4.24; F,
13.06; S, 7.71.
1
954, 769 cmꢀ1; H NMR (200 MHz, DMSO-d6) d 7.98 (d,
J¼8.5 Hz, 2H), 7.95 (br s, 1H), 7.62 (d, J¼8.3 Hz, 2H),
5.45 (d, J¼3.9 Hz, 1H), 5.20 (t, J¼5.3 Hz, 1H), 3.46–3.59
(m, 3H), 3.22 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
d 158.1, 146.0, 140.8, 127.8, 126.6, 77.8, 62.6, 61.3, 43.7.
Anal. Calcd for C11H13NO5S (271.30): C, 48.69; H, 4.83;
N, 5.17; S, 11.82. Found: C, 48.62; H, 4.94; N, 5.23; S,
11.76%.
4.14. 1-(S)-(4-(Methylsulfonyl)phenyl)allyl carbamate
(8b)
4.16. (1R,2R)-2-(Dichloroacetamido)-1-[(4-methyl-
sulfonyl)phenyl]-1,3-propanediol (2)
To a stirred solution of alcohol 6b (1 g, 4.7 mmol) in di-
chloromethane (23 mL) at 0 ꢁC was added dropwise trichlo-
roacetyl isocyanate (0.71 mL, 5.64 mmol). The resulting
solution was stirred for 2 h and then concentrated in vacuo.
The residue was diluted with MeOH (25 mL), cooled to
0 ꢁC and a solution of potassium carbonate (1.95 g,
14.1 mmol) in H2O (5 mL) was added. The resulting suspen-
sion was stirred at 0 ꢁC for 2 h, then at room temperature for
16 h. The reaction was concentrated in vacuo, diluted with
H2O (50 mL) and brine (50 mL) and extracted with dichloro-
methane (2ꢂ50 mL). The combined organic extracts were
dried over MgSO4 and concentrated in vacuo. The crude ma-
terial was purified by column chromatography using petro-
leum ether/EtOAc (4:6) to give 8b (0.99 g, 86%) as a white
crystalline solid. Mp: 159 ꢁC; [a]D25 ꢀ10.23 (c 1, MeOH);
IR (neat) nmax 3421, 3265, 2906, 1720, 1608, 1406, 1379,
A solution of 1 N NaOH was made in methanol. The above
solution (10 mL) was added to 9b (0.14 g, 0.4 mmol) and
stirred overnight at room temperature. The reaction mixture
was filtered and the filtrate concentrated in vacuum. The
crude compound was taken in methyl dichloroacetate
(2 mL) and heated at 90 ꢁC for 3 h. The excess ester was re-
moved under reduced pressure and the crude compound was
purified by column chromatography using petroleum ether/
EtOAc (1:9) to give the product 2 (0.11 g, 77%) as a white
amorphous solid. Mp: 164–165 ꢁC [lit.2 164.3–166.3 ꢁC];
[a]D25 +12.5 (c 1, EtOH) [lit.2 [a]2D5 +12.9 (c 1, EtOH)]; IR
(neat) nmax 3481, 3407, 3242, 3082, 3020, 2925, 1699,
1562, 1406, 1282, 1215, 1145, 1033, 906, 806, 767 cmꢀ1
;
1H NMR (200 MHz, acetone-d6) d 7.93 (d, J¼8.5 Hz,
2H), 7.71 (d, J¼8.2 Hz, 2H), 7.70 (d, J¼8.2 Hz, 1H), 6.41
(s, 1H), 5.31 (d, J¼2.4 Hz, 1H), 5.27 (d, J¼3.8 Hz, 1H)
4.28 (t, J¼4.7 Hz, 1H), 4.10–4.20 (m, 1H), 3.77–3.89 (m,
1H), 3.63–3.72 (m, 1H), 3.10 (s, 3H); 13C NMR
(100 MHz, acetone-d6) d 164.42, 149.59, 140.95, 127.85,
1298, 1145, 1041, 947, 769 cmꢀ1 1H NMR (500 MHz,
;
DMSO-d6) d 7.93 (d, J¼7.8 Hz, 2H), 7.58 (d, J¼7.8 Hz,
2H), 6.84 (s, 1H), 6.61 (s, 1H), 6.10 (d, J¼5.5 Hz, 1H),
5.97–6.04 (m, 1H), 5.32 (d, J¼16.9 Hz, 1H), 5.22 (d,

S. George et al. / Tetrahedron 62 (2006) 10202–10207
10207
(g) Corey, E. J.; Choi, S. Tetrahedron Lett. 2000, 41, 2765;
(h) Park, J. N.; Ko, S. Y.; Koh, H. Y. Tetrahedron Lett. 2000,
41, 5553; (i) Loncaric, C.; Wul, W. D. Org. Lett. 2001, 3,
3675; (j) Bhaskar, G.; Kumar, V. S.; Rao, B. V. Tetrahedron:
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127.77, 71.21, 67.51, 62.08, 57.99, 44.34. Anal. Calcd for
C12H15Cl2NO5S (356.23): C, 40.46; H, 4.24; Cl, 19.9; N,
3.93, S, 9.0. Found: C, 40.59; H, 4.38; Cl, 19.85; N, 4.05;
S, 8.96%.
Acknowledgements
S.G. and S.V.N. thank CSIR, New Delhi for the award of
research fellowships. The authors are thankful to Dr. B. D.
Kulkarni, Head, CEPD, for his support and encouragement.
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