A novel stereoselective total synthesis of (+)-5-epi-cytoxazone

Article abstract of DOI:10.1081/CAR-200030048

Stereoselective synthesis of a potent cytokine modulator cytoxazone isomer has been achieved from 2,3-O-isopropylidene D-glyceraldehyde involving Grignard reaction, subsequent formation of an azide followed by reduction to the aminodiol, and finally cyclization of the N-Boc diol. Copyright

Full text of DOI:10.1081/CAR-200030048

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A Novel Stereoselective Total Synthesis
of (+)‐5‐epi‐Cytoxazone
Navath Raghavendra Swamy a , Pendem Krishnaiah a , Natala
Srinivasa Reddy a & Yenamandra Venkateswarlu a
a Natural Products Laboratory, Organic Chemistry Division‐1, Indian
Institute of Chemical Technology, Hyderabad, 500 007, India
Published online: 17 Aug 2006.
To cite this article: Navath Raghavendra Swamy , Pendem Krishnaiah , Natala Srinivasa Reddy &
Yenamandra Venkateswarlu (2004): A Novel Stereoselective Total Synthesis of (+)‐5‐epi‐Cytoxazone,
Journal of Carbohydrate Chemistry, 23:4, 217-222
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 23, No. 4, pp. 217–222, 2004
A Novel Stereoselective Total Synthesis of
(1)-5-epi-Cytoxazone#
Navath Raghavendra Swamy, Pendem Krishnaiah,
Natala Srinivasa Reddy, and Yenamandra Venkateswarlu
*
Natural Products Laboratory, Organic Chemistry Division-1, Indian Institute of
Chemical Technology, Hyderabad, India
CONTENTS
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
II. RESULTS AND DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . 219
III. CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
IV. EXPERIMENTAL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
#IICT Communication no. 021009.
*
Correspondence: Yenamandra Venkateswarlu, Natural Products Laboratory, Organic Chemistry
Division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India; Fax: þ91-40-
27173757; E-mail: luchem@iict.res.in.
217
DOI: 10.1081/CAR-200030048
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

218
Swamy et al.
ABSTRACT
Stereoselective synthesis of a potent cytokine modulator cytoxazone isomer has been
achieved from 2,3-O-isopropylidene D-glyceraldehyde involving Grignard reaction,
subsequent formation of an azide followed by reduction to the aminodiol, and finally
cyclization of the N-Boc diol.
Key Words: 2,3-O-Isopropylidene D-glyceraldehyde; Grignard reaction; (þ)-5-epi-
Cytoxazone.
INTRODUCTION
The synthesis of biologically active natural products from carbohydrate substrates
is an important tool for rapid accesses to the desired constitution and stereochemistry.
This certainly correlated with the discovery of highly chemo- and stereoselective methods
of modern organic synthesis. The subject of total synthesis of biologically active
natural products has been covered in several surveys.[1–3] Cytoxazone (1) containing a
4,5-disubstituted 2-oxazolidinone ring[4,5] was recently isolated from the fermentation
broth of Streptomyces sp. in low yield[4] and its absolute configuration has been deter-
mined by x-ray crystallographic analysis and CD-spectroscopy.
Cytoxazone exhibits cytokine-modulating activity by inhibiting the signaling
pathway of TH2 cells.[6,7] Inhibitors of TH2-dependent cytokine production would be
potent chemotherapeutic agents in the field of immunotherapy. Therefore, the cytoxazone
and its analogs have been a contemporary subject of synthetic studies for the development
of new cytokine modulators. Several stereoselective syntheses have been reported during
the last 2 years.[8–10] The first total asymmetric synthesis was reported by Nakata et al.[8]
employing sharpless asymmetric dihydroxylation of a p-methoxycinnamic derivative, and
later Sunjic et al.[9] obtained the compound from readily available glycidic ester deriva-
tive. Here, we describe the stereoselective synthesis of 5-epi-cytoxazone, Grignard reac-
tion of (R)-2,3-O-isoproplideneglyceraldehyde (4) with p-methoxyphenyl magnesium
bromide to give the corresponding alcohol (5) in 60% enantiomeric excess, and this com-
pound was further elaborated to give (þ)-5-epi-cytoxazone (Sch. 1).

Total Synthesis of (1)-5-epi-Cytoxazone
219
Scheme 1. Reagents and conditions: (i) acetone, ZnCl2, r.t.; (ii) NaIO4/DCM, aqueous NaHCO3;
(iii) p-methoxyphenyl magnesium bromide/dry THF; (iv) MsCl/Et3N, DCM; (v) acetone, NaN3,
reflux; (vi) LAH/dry THF; (vii) Boc2O/Et3N, DCM; (viii) p-toluenesulfonic acid/MeOH, r.t.;
(ix) NaH/DMF.
RESULTS AND DISCUSSION
Our approach for the synthesis of 5-epi-cytoxazone employs inexpensive and readily
available starting material, mannitol diacetonide (3), which on chopping with NaIO4 in
dichloromethane at room temperature afforded (R)-2,3-O-isoproplidene glyceradehyde
(4). This on reaction with p-methoxyphenyl magnesium bromide in dry THF gave
a diastereomeric mixture of alcohols 5 (80%) and 5a (20%). The diastereomers 5 and
5a were separated by silica gel column chromatography. Compound 5 was converted to
corresponding mesylate (6), which on further treatment with sodium azide in acetone
gave azide (7) in excellent yield. Reduction of azide 7 with lithium aluminum hydride
gave the amine (8), which was protected with di-tert-butyldicarbonate in dichloromethane
in presence of triethylamine to give the N-Boc derivative 9 in 82% yield. Compound 9 was
hydrolyzed in the presence of PTSA in MeOH to afford the Boc protected aminodiol (10)
in 78% yield. In the final step, the N-Boc protective group was advantageously utilized for

220
Swamy et al.
the regioselective formation of the oxazolidinone ring using NaH in THF, which avoided
the protection and deprotection of primary hydroxyl group.
CONCLUSION
We have accomplished the stereoselective total synthesis of (þ)-5-epi-cytoxazone (1)
starting from easily available D-mannitol. This method is a valuable alternative route for
the synthesis of this class of compounds.
EXPERIMENTAL
(2R,3S)-3-Hydroxy-1,2-O-isopropylidene-3-p-methoxyphenyl-1,2-propanediol (5).
To a solution of compound 3 (5 g, 21 mmol) in CH2Cl2 (15 mL) were added NaIO4
(8.94 g, 42.01 mmol), saturated aqueous NaHCO3 (0.5 mL), and stirred for 3 hr. After
completion of the reaction, the reaction mixture was extracted into dichloromethane
(3 ꢀ 15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to
give (R)-2,3-O-isoproplidene glyceradehyde (4) in 81% yield (1.59 g, 19.91 mmol). This
was immediately reacted with p-methoxyphenyl magnesium bromide (3.90 g, 18.57 mmol)
in dry THF (20 mL) under nitrogen atmosphere for 3 hr at room temperature. After com-
pletion of the reaction, the reaction was quenched with saturated ammonium chloride solu-
tion (15 mL) and extracted with ethyl acetate (3ꢀ15 mL). The organic layer was dried
over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude diaster-
eomeric mixture of 5 (80%) and 5a (20%). This diastereomeric mixture was separated by
silica gel chromatography eluting with ethyl acetate : hexane (1 : 9) to give 5 (3.09 g,
1
14.43 mmol) in 80% yield. [a]D25 9.27 (c 1, CHCl3), H NMR (CDCl3, 200 MHz), d
1.37 (s, 3H), 1.48 (s, 3H), 3.64 (dd, J ¼ 5.5, 8.5 Hz, 1H, Ha-31), 3.74 (dd, J ¼ 5.5,
8.5 Hz, 1H, Hb-31), 3.80 (s, 3H, OMe), 4.18 (dd, J ¼ 5.5, 8.0 Hz, 1H, H-21), 4.48
(d, J ¼ 6 Hz, 1H, H-11), 6.84 (d, J ¼ 7 Hz, 2H, Ar), 7.3 (d, J ¼ 7 Hz, 2H, Ar).
(2R,3S)-1,2-O-Isopropylidene-3-O-mesyl-3-p-methoxyphenyl-1,2-propanediol (6).
To an ice-cooled solution of compound 5 (2.80 g, 13.08 mmol) in dry dichloromethane
(15 mL) were added triethyl amine (5.46 mL, 39.25 mmol) and methanesulfonyl chloride
(0.9 mL, 14.39 mmol) and stirred at room temperature for 3 hr. After completion of the
reaction, water was added to the reaction, mixture and extraction done with dichloro-
methane (3 ꢀ 20 mL). The combined organic layer was dried over anhydrous Na2SO4
and concentrated under reduced pressure to give mesylate (6) (3.05 g) in 80% yield,
which was used for the next reaction without further purification.
(2S,3R)-3-Azido-1,2-O-isopropylidene-3-p-methoxyphenyl-1,2-propanediol (7).
To a solution of compound 6 (2.7 g, 9.24 mmol) in dry acetone (15 mL) was added
sodium azide (0.66 g, 10.17 mmol) and refluxed for 3 hr. After completion of the reaction,
acetone was removed under reduced pressure, water was added, and the contents extracted
with EtOAc, dried over anhydrous Na2SO4, and concentrated to give a crude product,
which was purified by silica gel column chromatography to afford the pure compound 7
1
(1.85 g, 7.03 mmol) in 84% yield. H NMR (CDCl3, 200 MHz), d 1.39 (s, 3H), 1.5
(s, 3H), 3.58 (dd, J ¼ 5.6, 10.0 Hz, 1H, Ha-31), 3.68 (dd, J ¼ 5.6, 10.0 Hz, 1H, Hb-31),

Total Synthesis of (1)-5-epi-Cytoxazone
221
3.8 (s, 3H, OMe), 3.92 (dd, J ¼ 5.6, 8.5 Hz, 1H, H-21), 4.3 (d, J ¼ 6 Hz, 1H, H-11), 6.88
(d, J ¼ 8 Hz, 2H, Ar), 7.22 (d, J ¼ 8 Hz, 2H, Ar).
(2S,3R)-3-Amino-1,2-O-isopropylidene-3-p-methoxyphenyl-1,2-propanediol (8).
To an ice-cooled solution of compound 7 (1.50 g, 5.70 mmol) in dry THF (15 mL) was
added LAH (0.211 g, 5.7 mmol) and stirred at room temperature. After 3 hr, the reaction
was quenched with ethyl acetate, water was added, extraction done with ethyl acetate,
dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the
crude amino compound, which was purified by silica gel column chromatography
eluting with ethyl acetate : hexane (6 : 4) to give title compound 8 (0.94 g 3.96 mmol) in
1
70% yield. H NMR (CDCl3, 200 MHz), d 1.38 (s, 3H), 1.43 (s, 3H), 3.59 (dd, J ¼ 6,
8 Hz, 1H, Ha-31), 3.68 (dd, J ¼ 6, 8 Hz, 1H, Hb-31), 3.8 (s, 3H, OMe), 3.84 (d, J ¼ 6 Hz,
1H, H-21), 4.1 (dd, J ¼ 6, 8 Hz, IH, H-11), 6.81 (d, J ¼ 7 Hz, 2H, Ar), 7.24 (d, J ¼ 7 Hz,
2H, Ar).
(2S,3R-3-tert-Butoxycarbonylamino-1,2-O-isopropylidene-3-p-methoxyphenyl-
1,2-propanediol (9). To an ice-cooled solution of compound 8 (0.8 g, 3.37 mmol) in dry
dichloromethane (15 mL) were added triethylamine (1.4 mL, 10.12 mmol) and di-tert-
butyl dicarbonate (0.8 g, 3.71 mmol) under nitrogen atmosphere and stirred at room temp-
erature. After 3 hr, water was added, extracted into dichloromethane (3 ꢀ 15 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude
product, which was purified by silica gel column chromatography eluting with ethyl ace-
tate : hexane (2 : 8) to give the title compound 9 (0.93 g) in 82% yield. [a]2D5 2 7.76 (c 1,
1
CHCl3), H NMR (CDCl3, 200 MHz), d 1.31 (s, 3H), 1.39 (s, 9H),1.48 (s, 3H), 3.7 (dd,
J ¼ 5, 8 Hz, 1H, Ha-31),3.78 (s, 3H, OMe), 3.91 (dd, J ¼ 5, 8 Hz, 1H, Hb-31), 4.28
(m, 1H, H-21), 5.17 (d, J ¼ 8 Hz, 1H, H-11), 6.81 (d, J ¼ 8 Hz, 2H, Ar), 7.21
(d, J ¼ 8 Hz, 2H, Ar).
(2S,3R)-3-tert-Butoxycarbonylamino-3-p-methoxyphenyl-1,2-propanediol (10).
To a solution of compound 9 (0.7 g, 2.07 mmol) in methanol (10 mL) was added p-TSA
(0.39 g, 2.07 mmol) and stirred at room temperature for 2 hr. After completion of the reac-
tion, the reaction mixture was neutralized with saturated NaHCO3, extracted with ethyl
acetate, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give
the crude product 10, which was purified by silica gel column chromatography to give
pure diol 10 (0.46 g) in 76% yield. M.p. 125–1288C, [a]2D5 1.09 (c 1, CHCl3), H NMR
1
(CDCl3, 200 MHz), d 1.41 (s, 9H), 3.20 (d, J ¼ 7 Hz, 2H, Ha-31, Hb-31), 3.61 (m, 1H,
H-21), 3.77 (s, 3H, OMe), 3. 8.2–3.89 (m, 1H, H-11), 6.8 (d, J ¼ 8 Hz, 2H, Ar), 7.24
(d, J ¼ 8 Hz, 2H, Ar). FABMS (m/z): 320 (M þ Na)þ.
(4R,5S)-5-Hydroxymethyl-4-(4-methoxyphenyl)-2-oxazolidinone (1). To a solu-
tion of compound 10 (0.1 g, 0.336 mmol) in dry THF (10 mL) was added sodium
hydride (0.016 g, 0.67 mmol) at room temperature, and the mixture was stirred under
N2 atmosphere for 2 hr. After completion of the reaction, the solvent was removed,
water was added, extracted with ethyl acetate, dried over anhydrous Na2SO4, and con-
centrated under reduced pressure to give 5-epi-cytoxazone (1), which was purified by
silica gel column chromatography using ethyl acetate : hexane (4 : 6) to give pure 5-epi-
cytoxazone (1) (0.067 g) in 90% yield as a white solid. (þ)-5-epi-cytoxazone, m.p.
1
155–1588C [a]2D5 70.18C (c, 1.32, MeOH), H NMR (DMSO, 200 MHz), d 3.61 (dd,
J ¼ 5, 8 Hz, 1H, Ha-6), 3.75 (dd, J ¼ 5, 8 Hz, 1H, Hb-6), 3.81 (s, 3H, OMe), 4.21
(m, 1H, H-5), 4.73 (d, J ¼ 7 Hz, 1H, H-4), 6.89 (d, J ¼ 8 Hz, 2H, Ar), 7.28 (d, J ¼ 8 Hz,
2H,Ar), 7.65 (br d, J ¼ 8 Hz, 1H, H-3). 13C NMR (DMSO, 50 MHz), d 55.0, 57.0, 83.75,

222
Swamy et al.
114.0, 128.0, 133.0, 158.0, 159.0. EIMS (m/z): 223 (M þ) [Literature[10] values for (þ)-5-
1
epi-cytoxazone: m.p. 143–1448C, H NMR (acetone-d6), d 3.15–3.26 (m, 3H), 3.80
(s, 3H), 4.82 (ddd, 1H),5.03 (d, 1H, J ¼ 8.0 Hz), 6.94 (d, 2H, J ¼ 8.5 Hz), 6.96 (br s,
1H), 7.24 (d, 2H, J ¼ 8.5 Hz), 13C NMR (acetone-d6), d 54.9, 57.2, 61.9, 113.9, 128.3,
129.6, 158.8, 159.9].
ACKNOWLEDGMENTS
We are thankful to the Director, IICT and the UGC, and the CSIR, New Delhi for pro-
viding a fellowship to P.K., N.R.S., and N.S.R.
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