Stereoselective synthesis of (-)-cytoxazone and (+)-5-epi-cytoxazone

Article abstract of DOI:10.1081/SCC-120022181

A novel, stereo selective synthesis of (-)-cytoxazone 1a and stereoselective synthesis of (+)-5-epi-cytoxazone 1b were achieved via stereoselective Grignard addition of vinylmagnesium bromide on N-Boc aldehyde obtained from p-hydroxy-D-phenylglycine 2 followed by cyclization of N-Boc alcohol 6, ozonolysis and reduction to get (+)-5-epi-cytoxazone. Compound 6 underwent mitsunobu conditions, deprotection of ester followed by cyclization of N-Boc alcohol to get (-)-cytoxazone.

Full text of DOI:10.1081/SCC-120022181

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Stereoselective Synthesis of (-)-Cytoxazone and (+)-5-
Epi-cytoxazone
A. Ravi Kumar a , G. Bhaskar a , A. Madhan a & B. Venkateswara Rao a
a Division of Organic Chemistry , Indian Institute of Chemical Technology , Hyderabad, India
Published online: 19 Aug 2006.
To cite this article: A. Ravi Kumar , G. Bhaskar , A. Madhan & B. Venkateswara Rao (2003) Stereoselective Synthesis of (-)-
Cytoxazone and (+)-5-Epi-cytoxazone, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:16, 2907-2916, DOI: 10.1081/SCC-120022181
To link to this article: http://dx.doi.org/10.1081/SCC-120022181
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 16, pp. 2907–2916, 2003
Stereoselective Synthesis of (R)-Cytoxazone
and (Q)-5-Epi-cytoxazone#
A. Ravi Kumar, G. Bhaskar, A. Madhan,
*
and B. Venkateswara Rao
Division of Organic Chemistry, Indian Institute of
Chemical Technology, Hyderabad, India
ABSTRACT
A novel, stereo selective synthesis of (ꢀ)-cytoxazone 1a and stereo-
selective synthesis of (þ)-5-epi-cytoxazone 1b were achieved via
stereoselective Grignard addition of vinylmagnesium bromide on
N-Boc aldehyde obtained from p-hydroxy-D-phenylglycine 2 fol-
lowed by cyclizationof N-Boc alcohol 6, ozonolysis and reduction
to get (þ)-5-epi-cytoxazone. Compound 6 underwent mitsunobu
conditions, deprotection of ester followed by cyclization of N-Boc
alcohol to get (ꢀ)-cytoxazone.
#IICT Communication Number: 020616.
*Correspondence: B. Venkateswara Rao, Division of Organic Chemistry,
Indian Institute of Chemical Technology, Hyderabad 500 007, India;
Fax: þ91-40-716051; E-mail: venky@iict.ap.nic.in.
2907
DOI: 10.1081/SCC-120022181
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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2908
Ravi Kumar et al.
Enantiomerically pure substituted 2-oxazolidinones are important
target molecules in organic synthesis. Some of them act as antibiotics
against highly resistant gram positive bacteria.[1] In1998 Osada et al.,
isolated[2] a novel cytokine modulator[3] from streptomyces species. This
new 4,5-disubstituted oxazolidinone was named as (ꢀ)-cytoxazone 1a. It
interferes with cytokine IL4; IL10 and IgG production by selective inhi-
bition of signaling pathway of Th2 cells, but not Th1 cells. Inhibition of
Th2 dependent cytokine products would be potent chemotherapeutic
agents in the field of immunotherapy.
Cytoxazone 1a is different from known immunomodulators such as
FK 506 and rapamycin in respect of structure and biological activity.
Therefore 1a and its analogues have been a new subject of synthetic
studies for the development of a cytokine modulators. Due to its
potent biological activity, several syntheses of 1a [5b–e] and its isomers[5b–e]
have beendescribed inthe literature. Very recently we reported a stereo-
selective synthesis[5e] of 1a via stereoselective Grignard addition of
p-methoxyphenylmagnesium bromide to N-benzylimine derived from
(S )-2,3-o-isopropylidine glyceraldehyde followed by a single step conver-
sionof N-Boc amine diol to oxazolidinone. Herein we report a short and
stereoselective synthesis of (ꢀ)-cytoxazone 1a and (þ)-5-epi-cytoxazone
1b, a C-5-epimer of cytoxazone.
The commercially available p-hydroxy-D-phenylglycine
2 was
converted to N-Boc methyl ester 3. Treatment of 3 with methyl iodide,
potassium carbonate in DMF gave 4.[7] The next step in the sequence is to
convert the ester to aldehyde followed by stereoselective addition of
vinylmagnesium bromide to get syn N-Boc amino alcohol based on the
well established protocol.[6] Thus the ester 4 was reduced to alcohol 5
under LiBH4 conditions.[7] Swernoxidationof 5 followed by in-situ reac-
tion of the resulting aldehyde with vinylmagnesium bromide based on
above said protocol[6] yielded the syn 1,2-amino alcohol 6. Intramolecular
cyclization[5e,8] of compound 6 inpresence of NaH inTHF yielded the
OMe
OMe
H
H
H
H
HO
5
4
HO
55
4
O
NH
O
NH
O
O
1a
1b

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(R)-Cytoxazone and (Q)-5-Epi-cytoxazone
2909
oxazolidinone 7. Oxidative cleavage of the double bond with ozone
followed by immediate reduction[5c] afford the (þ)-5-epi-cytoxazone 1b
1
whose H, 13C NMR spectral data are inagreement with the assigned
structure.
The synthesis of (ꢀ)-cytoxazone 1a from 6 was achieved as follows:
Oxidative cleavage of 6 followed by reductiongave diol 8. Primary
hydroxyl in 9 was protected as TBS ether. Whencompound 9 was sub-
jected to mitsunobu condition gave 10 as p-nitrobenzoic ester with
inverted configuration. Hydrolysis of ester and TBS ether in one pot
yielded 11 whose NMR and rotational values are in agreement with
the reported compound.[5e] Treatment of compound 11 with NaH in
THF gave (ꢀ)-cytoxazone 1a whose spectral data was inagreement
with the reported compound.[5e]
Some compounds contain oxazolidinone unit shows antibacterial
activity against gram positive and gram negative bacteria. Keeping this
criterion in view antibacterial testing was done for both compounds.
Interestingly we observed that (þ)-5-Epi-cytoxazone and (ꢀ)-cytoxazone
shows some antibiotic activity against gram positive (Gþve) Bacillus sub-
tilis and gram negative (Grꢀve) Escherichia coli by paper disc method.[4]
The activity has beencompared with stadnard streptomycindisc
(10 Mcg). (þ)-5-Epiicytoxazone shows somewhat more antibacterial
activity compared to the (ꢀ)-cytoxazone against gram positive and
gram negative bacteria.
Diameter of inhibition zone
S. no.
Samples
Basillus subtilis Escherichia coli
1
2
3
(ꢀ)-Cytoxazone (100 Mcg)
(þ)-5-Epiicytoxazone (100 Mcg)
Streptomycin(10 Mcg)
12
16
18
14
20
22
In conclusion we developed a short efficient and a common approach
for the synthesis of 5-epi-cytoxazone 1b and (ꢀ)-cytoxazone 1a which
involves stereoselective addition of vinylmagnesium bromide to N-Boc
aldehyde followed by intramolecular cyclization of N-Boc syn-amino
alcohol 6 to oxazolidinone 7. Compound 6 was converted to 1a by
using mitsunobu conditions followed by deprotection and cyclization.
Inthis approach the Boc protectionwas utilized to get required stereo-

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2910
Ravi Kumar et al.
NHBoc
OCH3
NH2
COOH
NHBoc
OCH3
b
c
O
a
O
HO
HO
MeO
3
4
2
O
NHBoc
OH
NHBoc
HN
O
e
d
f
OH
MeO
MeO
MeO
5
6
7
O
HN
O
OH
1b
MeO
Scheme 1. (a) AcCl/MeOH (Boc)2O/TEA/THF, 98.2%; (b) CH3I/K2CO3/
DMF, 99%; (c) LiCl/NaBH4/EtOH/THF, 83.9%; (d) DMSO/(COCl)2/CH2CL2
thenCH ¼CH-MgBr/THF, 60.2%; (e) NAH/THF, 97.3%; (f ) O3/CH2Cl2 then
2
NaBH4/MeOH, 76.1%.
NHBoc
OH
NHBoc
OH
NHBoc
OH
b
c
a
OTBS
OH
MeO
MeO
MeO
9
6
8
O
NHBoc
O
NHBoc
HO
H
N
O
OH
d
OTBS
e
MeO
O
OH
MeO
MeO
1a
10
11
NO2
Scheme 2. (a) O3, CH2Cl2, NaBH4, MeOH, ꢀ78ꢁC to r.t.; 72.37%; (b) TBSCl,
imidazole, CH2Cl2; 83%; (c) TPP, DIAD, PNBA, THF, 63.5%; (d) LiOH, THF–
H2O, TBAF, CH2Cl2; 88.79%; (e) NaH, THF, 94.2%.
selectivity during Grignard reaction and also it was converted to a part
structure of the molecule. Our procedure is very useful to make more
analogues of 1a and 1b for getting chemotherapeutic agents in the field of
immunotherapy and antibacterial.

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(R)-Cytoxazone and (Q)-5-Epi-cytoxazone
EXPERIMENTAL
TLC was performed onMerck Kieselgel 60, F
2911
plates (layer thick-
254
ness 0.25 mm). Column chromatography was performed on silica gel
(60–120 mesh) using ethyl acetate and hexane mixture as eluent.
Melting points were determined on a Fisher John’s melting point appa-
ratus and are uncorrected. IR spectra were recorded on Perkin-Elmer
RX-1FT-IR system as KBr pellets. Inthe case of syrups and liquids IR
spectra was recorded by adding a drop of solution of compound in
chloroform onKBr pellet.
1H NMR (200 MHz) and 13C NMR
(50 MHz) spectra were recorded onVarianGemini-200 MHz spectrom-
eter. NMR (400 MHz) spectra were recorded onVarianUnity-400 MHz
spectrometer. Optical rotations were measured with Jasco-Dip-360
digital polarimeter. The mass spectra were recorded on(VG
MICROMASS-7070H) at 70 eV using a direct inlet system. The LSIMS
(FAB) spectra were recorded onVG AUTOSPEC instrument at the
structure (M þ H) at m/z.
Methyl(2R )-2-(tert-butoxycarbonyl)amino-2-(4-hydroxyphenyl)acetate
3. Acetyl chloride (3.4 mL, 47.86 mmol) was added slowly to anice-cold
solutionof p-hydroxy-D-phenylglycine 2 (4 g, 23.93 mmol) inmethanol
(30 mL). The mixture was slowly heated to reflux and refluxing continued
for 3 h, the reaction mixture was cooled and the solvent removed in vacuo
to give the crude methyl ester hydrochloride as a white solid, which was
used as such for the next reaction, the methyl ester hydrochloride was
suspended in THF (20 mL), to it Et3N (8.4 mL, 60.26 mmol) was added at
0ꢁC followed by a solutionof (Boc) O (5.4 mL, 23.50 mmol) drop wise
2
over 10 min. The mixture was allowed to warm to room temperature and
stirred for 8 h. The white solid was filtered off, solvent was removed in
vacuum and the residue partitioned between ethyl acetate and water. The
aqueous layer was again extracted with ethyl acetate and the combined
organic phases washed with saturated NH4Cl solution and brine. The
organic layer was drying (Na2SO4) and removal of solvents in vacuo
followed by columnchromatography usign 25% ethyl acetate adn
hexane afforded the pure compound 3 (6.6 g, 98.2%) as white solid.
25
M.p.: 83–84ꢁC; ½ꢀꢂD ¼ ꢀ11.54 (c ¼ 1.03, CHCl3); IR: 3388, 1750, 1692,
1
1508, 1285, 1161 cmꢀ1; H NMR (200 MHz, CDCl3): ꢁ 1.42 (s, 9H), 3.65
(s, 3H), 5.18 (d, 1H, J ¼ 6.4 Hz), 5.52 (d, 1H, J ¼ 6.4 Hz), 6.12 (br s, 1H),
6.7 (d, 2H, J ¼ 9.0 Hz), 7.13 (d, 2H, J ¼ 9.0 Hz).
Methyl(2R)-2-(tert-butoxycarbonyl)amino-2-(4-methoxyphenyl) acetate 4.
To a solutionof pheonl
3 (6 g, 21.35 mmol) inDMF (15 mL) was
added potassium carbonate (5.9 g, 42.70 mmol) and methyl iodide
(1.4 mL, 22.47 mmol). The reactionwas allowed to stir for 7 h at

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2912
Ravi Kumar et al.
room temperature. The reactionmixture was partitioend between
water and ethyl acetate. Aqueous phase was further extracted with
ethyl acetate and combined organic extracts were washed with brine.
Drying (Na2SO4) and removal of solvent under reduced pressure
followed by column chromatography using ethyl acetate:hexane (1:9)
afforded the pure compound 4 (6.23 g, 99%) as a white solid. M.p.:
25
27
66–67ꢁC; ½ꢀꢂD ¼ ꢀ95.3 (c ¼ 1.2, CHCl3) (Lit.[7] ½ꢀꢂ Dꢀ97.4 (c 0.57,
CHCl3); IR: 3388, 1741, 1688, 1518, 1297, 1244, 1169 cmꢀ1; H NMR
1
(200 MHz, CDCl3): ꢁ1.42 (s, 9H), 3.70 (s, 3H), 3.79 (s, 3H), 5.19 (br d,
1H, J ¼ 6.4 Hz), 5.40 (br s,1H), 6.84 (d, 2H, J ¼ 9.0 Hz), 7.24 (d, 2H,
J ¼ 9.0 Hz).
1,1-Dimethylethyl(R)-N-[2-hydroxy-1-(4-methoxyphenyl)-ethyl]car-
bamate 5. Anice-cooled solutionof NaBH 4 (1.47 g, 38.98 mmol) and LiCl
(1.65 g, 38.98 mmol) inEtOH (30 mL), stirred for 15 min, to it a solution
of ester 4 (4.6 g, 15.59 mmol) inTHF (35 mL) was added over 30 min. The
reactionmixture was stirred at room temperature for 16 h, filtered and
ꢁ
the filtrate treated with saturated NH4Cl solutionat 0 C, and extracted
with ethylacetate. Combined organic extracts were washed with water,
brine and dried (Na2SO4). Removal of the solvent under vacuum fol-
lowed by columnchromatography (ethyl acetate:hexane 1:2) gave the
alcohol 5 (3.49 g, 83.9%) as a white solid. M.p.: 130–131ꢁC (Lit.[7] m.p.
25
26
130–132ꢁC); ½ꢀꢂD ¼ ꢀ43.59 (c ¼ 1.09, CHCl3) (Lit.[7]½ꢀꢂ Dꢀ38.1 (c 1.31,
CHCl3); IR: 3376, 1685, 1519, 1249, 1171, 1032 cmꢀ1
;
1H NMR
(400 MHz, CDCl3): ꢁ 1.42 (s, 9H), 2.45 (br s, 1H), 3.75–3.85 (m, 2H),
3.82 (s, 3H), 4.78 (br s, 1H), 5.12 (br s, 1H), 6.86 (d, 2H, J ¼ 9.0 Hz), 7.22
(d, 2H, J ¼ 9.0 Hz); FABMS (m/z): 268 (Mþþ1).
1,1-Dimethylethyl(1R,2R)-N-[2-hydroxy-1-(4-methoxyphenyl)-3-bute-
nyl]carbamate 6. To a stirred solutionof oxalyl chloride (0.24 mL,
2.81mmol) inCH Cl2 (20 mL) at ꢀ78ꢁC under nitrogen atmosphere was
2
added DMSO (0.21 mL, 2.96mmol) drop wise. After being stirred for
30minat ꢀ78ꢁC, a solutionof alcohol 5 (0.5 g, 1.87mmol) inCH Cl2
2
(15 mL) was added over 10min. Then the reaction mixture was stirred
for 1 h at ꢀ78ꢁC, allowed to warm to ꢀ35ꢁC, and stirred for 1 h at this
temperature followed by additionof N,N-diisopropylethyl amine (1.94mL,
11.24 mmol) over 10min. The reaction mixture was than warmed to 0ꢁC in
10min and transfer through a canula to a room temperature solution of
vinylmagnesium bromide [prepared from Mg (0.59 g, 24.31 mmol) and
vinylbromide (1.3g, 12.15 mmol) in THF at 0ꢁC] over 20min. After
being stirred for overnight, the mixture was treated with ethanol (3 mL)
and saturated aq. NH4Cl (8 mL). CH2Cl2 and aqueous HCl were then
added and organic layer was washed with brine and dried (Na2SO4).
The solvents were removed under reduced pressure to give the crude pro-

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(R)-Cytoxazone and (Q)-5-Epi-cytoxazone
2913
duct. Chromatography of this material onsilica gel with 20% ethyl acetate
inhexane gave pure compound 6 (0.33 g, 60.2%) as a white solid. M.p.:
25
103–104ꢁC; ½ꢀꢂD ¼ ꢀ13.74 (c ¼ 1.035, CHCl3); IR: 3466, 3383, 1673,
1
1519, 1364, 1247, 1172, 1031cmꢀ1; H NMR (400MHz,CDCl3): ꢁ 1.40
(s, 9H), 2.32 (br s, 1H), 3.80 (s, 3H), 4.30 (br s, 1H), 4.60 (br s, 1H),
5.15–5.30 (m, 2H), 5.35 (d, 1H, J ¼ 17.0 Hz), 5.83 (m, 1H), 6.85 (d, 2H,
J ¼ 9.0 Hz), 7.2 (d, 2H, J ¼ 9.0 Hz); 13C NMR (CDCl3, 50MHz): ꢁ 159.03,
156.05, 137.34, 132.02, 127.98, 116.53, 114.04, 79.74, 75.78, 58.69, 55.25,
28.32.
(4R,5R)-5-(Ethenyl)-4-(4-methoxyphenyl)-2-oxazolidinone 7. To a
solutionof alcohol 6 (0.15 g, 0.512 mmol) indry THF (5 mL) was
added sodium hydride (0.024 g (60% w/w inwax), 0.614 mmol) at
room temperature and the mixture stirred under nitrogen atmosphere
for 2 h. The reactionmixture was concentrated, dichloromethane was
added, washed with NH4Cl (saturated), the organic layer separated,
dried (Na2SO4), concentrated and purified through column chromatogra-
phy using ethylacetate:hexane (6:4) to give the pure compound 7 (0.109 g,
25
97.3%) as a white solid. M.p.: 124–125ꢁC; ½ꢀꢂD ¼ þ23.09 (c for 2 h at
0ꢁC. Reactionmixture was quenched with saturated NH 4Cl solutionand
solvents were removed in vacuum. Crude compound was partitioned
betweenCH 2Cl2 and H2O. Aqueous layer was washed with CH2Cl2.
Combined organic layers were dried (Na2SO4). Removal of the solvent
under reduced pressure followed by column chromatography using ethyl
acetate:hexane (6:4) afforded the pure compound 8 (0.22 g, 72.37%) as a
25
white solid. M.p.: 108–109ꢁC; ½ꢀꢂD ¼ ꢀ27.673 (c ¼ 0.17, CHCl3) IR:
3376, 2925, 1688, 1511, 1367, 1247, 1169, 1035, 833 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): ꢁ 1.42 (s, 9H), 2.68 (br s, 1H), 2.84 (br s, 1H),
3.39–3.54 (m, 2H), 3.8 (s, 3H), 3.82 (m, 1H), 5.20 (br d, 1H), 6.84 (d,
2H), 7.21 (d, 2H); FABMS (m/z): (Mþ þ 1) 298.
3R-(tert-Butoxycarbonyl)-amino-3-(4-methoxyphenyl)-2S-propane-1-
(tert-butyl dimethylsiloxy)-2-ol 9. To a stirred solutionof compound
8
(0.2 g, 0.673 mmol) indry CH 2Cl2 were added imidazole (55 mg,
0.808 mmol) and TBSCl (0.102 g, 0.673 mmol). After being stirred for
2 h, CH2Cl2 was added to the reactionmixture, washed with water and
saturated brine, dried over Na2SO4, an d CHCl2 was concentrated in
2
vacuo. The residue was purified by silicagel columnchromatography
(60–120 mesh) using hexane:EtOAc 22:3 to give compound 9 (0.229 g,
25
83%) as a colorless oil. ½ꢀꢂD ¼ ꢀ20.911 (c ¼ 0.13, CHCl3) IR: 3422,
2926, 2855, 1696, 1511, 1366, 1249, 1170, 1115, 838, 778 cmꢀ1
;
1H NMR (300 MHz, CDCl3): ꢁ 0.06 (s, 6H), 0.92 (s, 9H), 1.38 (s, 9H),
2.42 (br s, 1H), 3.49 (dd, 1H), 3.62 (dd, 1H), 3.79 (br s, 4H), 4.56 (br, 1H),
5.36 (br d, 1H), 6.82 (d, 2H), 7.22 (d, 2H); FABMS (m/z): (Mþ þ 1) 412.

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2914
Ravi Kumar et al.
2R-Amino-1-(tert-butyldimethyl)-siloxymethyl-2-(4-methoxyphenyl)-
(1R)-ethyl-3-nitrobenzoate 10. To a stirred solutionof compoudn
9
(0.18 g, 0.438 mmol) in dry THF (10 mL) were added triphenyl phosphine
(0.287 g, 1.094 mmol), p-nitro benzoic acid (0.183 g, 1.094 mmol) and
diisopropyl aza dicarboxylate in5 mL THF (0.22 mL, 1.094 mmol).
Reactionmixture was allowed to stir at room temperature for 24 h,
under nitrogen atmosphere. THF was removed under in vacuo and
crude compound was added ethyl acetate and water. Organic layer was
washed with brine, dried over Na2SO4 and concentrated under vacuum.
The residue was purified over silicagel columnchromatography (60–120
mesh) using hexane:EtOAc 93:7 to give compound 10 as a yellow color
25
syrup (0.16 g, 63.5%). ½ꢀꢂD ¼ 0.9 (c ¼ 1, CHCl3) IR: 2933, 2360, 1723,
1
1610, 1529, 1348, 1273, 1171, 1104, 1035, 837, 780, 720 cmꢀ1; H NMR
(300 MHz, CDCl3): ꢁ 0.06 (s, 6H), 0.92 (s, 9H), 1.41 (s, 9H), 3.80 (br s,
5H), 5.10–5.19 (m, 2H), 6.21 (br d, 1H), 6.84 (d, 2H), 7.24 (d, 2H), 8.18
(d, 2H), 8.24 (d, 2H).
(2R,3R)-3-tert-Butoxycarbonylamino-3-(4-methoxyphenyl)-1,2-propa-
nediol 11. To a compound 10 (0.093 g, 0.161 mmol) inTHF (2.5 mL) and
water (7.5 mL) was added LiOH (0.024 g, 0.565 mmol) at 0ꢁC. Reaction
mixture was allowed to stir at room temperature for 2 h after that THF
was removed invacuum, aqueous layer was added ethyl acetate. Aqueous
layer was again washed with ethyl acetate and combined organic layer
was extracted with brine, dried over Na2SO4 and concentrated under
vacuum. The residue was purified over silicagel columnchromatography
(60–120 mesh) hexane:EtOAc 22:3 to give compound 11 as a colorless oil
(0.061 g, 92%).
To anice-cooled solutionof the above hydroxy compound (0.053 g,
0.129 mmol) indry THF (5 mL) was added 1M solutionof TBAF
(0.26 mL, 0.257 mmol) and stirred for 2 h at room temperature. Water
was added to the reaction mixture and THF was removed under vacuum.
Then aqueous layer was extracted with EtOAc and organic layer was
washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4
and concentrated in vacuo. The residue was purified by silicagel column
chromatography (60–120 mesh) using hexane:EtOAc: 4:6 to give com-
pound 11 as white solid (0.034 g, 88.79%). M.p.: 115–116ꢁC (Lit.[5e] m.p.
25
25
118ꢁC); ½ꢀꢂD ¼ ꢀ53.2 (c ¼ 0.45, CHCl3) (Lit.[5e] ½ꢀꢂ Dꢀ51.2 (c 1 CHCl3);
IR: 3333, 2976, 1688, 1511, 1247, 1169, 1035, 772 cmꢀ1 1H NMR
;
(200 MHz, CDCl3): ꢁ 1.44 (s, 9H), 2.32 (br s, 1H), 2.95 (br s, 1H),
3.60–3.72 (m, 2H), 3.72–3.80 (m, 1H), 3.82 (s, 3H), 4.58 (ddd, 1H),
5.02 (br s, 1H), 6.88 (d, 2H, J ¼ 8.8 Hz), 7.26 (d, 2H, J ¼ 8.8 Hz).
(4R,5R)-5-Hydroxymethyl-4-(4-methoxyphenyl)-2-oxazolidinone 1a.
To a solutionof compoudn
11 (0.028 g, 0.094 mmol) indry THF

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(R)-Cytoxazone and (Q)-5-Epi-cytoxazone
2915
(5 mL) was added sodium hydride (0.0045 g, 0.188 mmol (60% w/w in
wax) at room temperature and the mixture was stirred under a nitrogen
atmosphere for 2 h. The reaction mixture was concentrated, CH2Cl2 was
added, washed with NH4Cl (saturated), brine and dried over Na2SO4.
The organic layer was concentrated under vacuum and the residue was
purified over silicagel columnchromatography (60–120 mesh) usign
hexane:EtOAc 7:3 to give compound 1a (0.0198 g, 94.2%) as a white
25
solid. M.p.: 119–121ꢁC (Lit.[5e] m.p. 118–120ꢁC); ½ꢀꢂD ¼ ꢀ70.46
25
(c ¼ 0.4, MeOH) (Lit.[5e] ½ꢀꢂ Dꢀ69.7 (c 0.5 inMeOH); IR: 3745, 3325,
2975, 1739, 1514, 1400, 1250, 1181, 1050 cmꢀ1 1H NMR (200 MHz,
;
Acetone-d6): ꢁ 3.12–3.38 (m, 2H), 3.83 (S, 3H), 3.86 (m, 1H), 4.84
(ddd, 1H, J ¼ 4.4, 7.3, 8.1 Hz), 5.05 (d, 1H, J ¼ 8.1), 6.94–6.99 (m, 3H),
7.26 (d, 3H); 13C NMR ( Acetone-d6, 75 MHz): ꢁ 159.83, 158.61, 129.44,
128.15, 113.77, 80.59, 61.70, 57.05, 54.71. FABMS (m/z): (Mþ þ 1) 224.
ACKNOWLEDGMENTS
Authors thank Dr. J. S. Yadav, IICT, and Dr. G. V. M. Sharma,
IICT for their support and Annapurna Jetty, IICT for Biological testing
of samples. Authors A R K, G B, A M thanks CSIR, New Delhi, for a
research fellowship (SRF).
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©2003 Marcel Dekker, Inc. All rights reserved. This material may not be used or reproduced in any form without the express written permission of Marcel Dekker, Inc.
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Received inthe UK October 25, 2002