Stereoselective synthesis of (-)-cytoxazone

Article abstract of DOI:10.1016/S0957-4166(01)00340-8

A novel stereoselective synthesis of (-)-cytoxazone 1 was achieved via addition of p-methoxyphenylmagnesium bromide to the benzylimine derived from (S)-2,3-O-isopropylidene glyceraldehyde followed by one-step regioselective cyclization of N-Boc amino diol

Full text of DOI:10.1016/S0957-4166(01)00340-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 2009–2011
Stereoselective synthesis of (−)-cytoxazone†
A. Madhan, A. Ravi Kumar and B. Venkateswara Rao*
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 2 July 2001; accepted 31 July 2001
Abstract—A novel stereoselective synthesis of (−)-cytoxazone 1 was achieved via addition of p-methoxyphenylmagnesium bromide
to the benzylimine derived from (S)-2,3-O-isopropylidene glyceraldehyde followed by one-step regioselective cyclization of N-Boc
amino diol 7. © 2001 Published by Elsevier Science Ltd.
1. Introduction
also published. Herein, we report a stereoselective syn-
thesis of 1 via stereoselective Grignard addition of
p-methoxyphenylmagnesium bromide to N-benzyl-
imine derived from (S)-2,3-O-isopropylidene glycer-
aldehyde 2, based on an efficient and highly
diastereoselective approach developed by Cativiela et
al.,5b followed by a single step regioselective conver-
sion of the N-BOC amino diol 7 to afford the oxazo-
lidinone (Scheme 1).6
O
HN
O
OH
MeO
(-)-Cytoxazone 1
2. Results and discussion
Cytoxazone 1, a novel 4,5-disubstituted-2-oxazolidi-
none compound isolated1 from Streptomyces species,
has shown cytokine modulating activity.2 It interferes
with cytokine IL4, IL10 and IgG production by selec-
tive inhibition of the signalling pathway of Th2 cells,
but not Th1 cells.
In the approach of Cativiela et al., the benzylimine
derived from (R)-2,3-O-isopropylidine glyceraldehyde
was treated with PhMgBr to give a benzylamine
derivative having erythro configuration (anti product)
with high diastereoselectivity.5b Based on this protocol,
treatment of (S)-2,3-O-isopropylidine glyceraldehyde
27 with benzylamine in ether gave imine 3, which on
addition to p-methoxyphenylmagnesium bromide solu-
tion gave 4. The amine functionality in 4 was pro-
tected as its N-Boc derivative to give 5 (the overall
yield starting from (S)-2,3-O-isopropylidine glyceralde-
hyde is 20%). Hydrolysis of the isopropylidine moiety
yielded 6, which on hydrogenation resulted in the for-
mation of 7. The next step in the sequence is the
formation of oxazolidinone. The N-Boc protective
group was advantageously utilised for the formation
of the oxazolidinone ring, which avoided the protec-
tion and deprotection of the primary hydroxyl group
unlike other syntheses.3,4b Thus, compound 7 on expo-
sure to NaH/THF cyclised regioselectively to cytoxa-
zone 1, whose NMR spectral data was in agreement
with reported values.3,4
Inhibitors of Th2-dependent cytokine production have
potential as potent chemotherapeutic agents in the
field of immunotherapy. Cytoxazone 1 is different
from known immunomodulators such as FK 506 and
rapamycin in respect of structure and biological activ-
ity. As such, 1 should be a useful tool for understand-
ing signalling pathways in Th2 cells. Therefore, the
synthesis of cytoxazone is of interest for the develop-
ment of new cytokine modulators. Nakata et al.3
established the absolute configuration of the molecule
by its total synthesis. Two more syntheses4 of 1 were
* Corresponding author. Fax: +91-40-7170512; e-mail: venky@
iict.ap.nic.in
† IICT Communication Number: 4832.
0957-4166/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0957-4166(01)00340-8

2010
A. Madhan et al. / Tetrahedron: Asymmetry 12 (2001) 2009–2011
3. Conclusion
glyceraldehyde 2 (1.4 g, 10.7 mmol) in dry ether (10
mL) at 0°C, and the mixture was stirred at room
temperature for 2 h. The reaction mixture was carried
to the next step without further purification.
In conclusion, we have developed a short and efficient
synthesis of (−)-cytoxazone 1 which involves the
stereoselective addition of p-methoxyphenylmagnesium
bromide to the benzylimine of (S)-2,3-O-isopropylidine
glyceraldehyde 2 and the subsequent regioselective
cyclization of N-Boc amino diol 7 to give the oxazolidi-
none unit of 1.
To a suspension of magnesium (0.78 g, 32.1 mmol) in
dry ether (25 mL) was added dibromoethane (0.1 mL)
followed by slow addition of p-bromoanisole (1.8 mL,
14.4 mmol) at 0°C and stirred for 45 min. To the
reaction mixture was added slowly the imine 3 in dry
ether and stirred at room temperature overnight. The
mixture was poured into a saturated ammonium chlo-
ride solution and extracted with ether (80 mL). The
combined organic layers were dried (Na2SO4), concen-
trated in the rotavapor and the residue was passed
through a silica gel column using 3% ethyl acetate in
hexane to give 4 as a thick syrup (1 g).8 [h]D25=−42.4
(c=1, CHCl3); IR: 2984, 1611, 1511, 1455, 1370, 1246,
4. Experimental
TLC was performed on Merck Kiesel gel 60, F254 plates
(layer thickness 0.25 mm). Column chromatography
was performed on silica gel (60–120 mesh) using ethyl
acetate and hexane mixtures as eluents. Melting points
were determined on a Fisher John’s melting point
apparatus and are uncorrected. IR spectra were
recorded on a Perkin–Elmer RX-1 FT-IR system. In
the case of syrups and liquids, IR spectra were recorded
by adding a drop of solution of compound in chloro-
1
1177, 1036 cm−1; H NMR (200 MHz, CDCl3): l 1.30
(s, 3H), 1.38 (s, 3H), 3.50 (d, 1H, J=14 Hz), 3.72–3.78
(m, 2H), 3.80 (s, 3H), 3.85 (d, 1H, J=4 Hz), 4.00 (dd,
1H, J=8 Hz), 4.15–4.25 (m, 1H), 6.85 (d, 2H, J=8
Hz), 7.15–7.35 (m, 7H); FABMS (m/z): 328 (M+H)+,
270, 240, 226; FAB-HRMS: calcd for (M++1)
C20H26O3N: 328.191269, found: 328.192409.
1
form on a KBr pellet. H NMR (200 MHz) and 13C
NMR (50 MHz) spectra were recorded on Varian Gem-
ini-200 MHz spectrometer. Optical rotations were mea-
sured with a Jasco-Dip-360 digital polarimeter. The
mass spectra were recorded on a VG MICROMASS-
7070H at 70 eV using a direct inlet system. FABMS
were recorded on a VG AUTOSPEC at 70 eV using a
direct inlet system.
4.2. (2R,3R)-3-Benzylamino-N-tert-butoxycarbonyl-1,2-
O-isopropylidene-3-(4-methoxyphenyl)-1,2-propanediol 5
To a solution of compound 4 (0.6 g, 1.8 mmol) in
ethanol (20 mL) were added di-tert-butyl dicarbonate
(1.20 g, 5.5 mmol) and triethylamine (0.76 mL, 3.0
mmol) and the mixture was stirred for 24 h. The
reaction mixture was concentrated on a rotavapor and
purified by silica gel chromatography using ethyl acet-
ate and hexane (2:98) to give 5 as a syrup (0.55 g,
4.1. (2R,3R)-3-Benzylamino-1,2-O-isopropylidene-3-
(4-methoxyphenyl)-1,2-propanediol 4
To a solution of benzylamine (1.8 mL, 16.4 mmol) in
dry ether (10 mL) was added (S)-2,3-O-isopropylidene
O
NHCH2Ph
O
O
O
O
O
b
c
a
NCH2Ph
CHO
4
2
5
3
OMe
HO
Ph
NBOC
Ph
NHBOC
HO
O
HO
NBOC
HO
e
d
O
6
7
OMe
OMe
OMe
f
1
a) PhCH2NH2, dry ether, 0˚C, b) MeO
MgBr,
dry ether, c) (BOC)2O,Et3N, dry ethanol
d) PTSA (cat), methanol, e) Pd/C (cat), conc.HCl (a drop), ethanol, f) NaH, dry THF
Scheme 1.

A. Madhan et al. / Tetrahedron: Asymmetry 12 (2001) 2009–2011
2011
overall yield for three steps 20.1%). [h]2D5=−37.1 (c=1,
CHCl3); IR: 1693, 1613, 1513, 1397, 1370, 1267, 1219,
1155, 1067 cm−1; 1H NMR (200 MHz, CDCl3): l
1.22–1.28 (2s, 6H), 1.45 (br s, 9H), 3.45–3.78 (br m,
2H), 3.80 (s, 3H), 4.0 (br d, 1H, J=14 Hz), 4.20–4.60
(br m, 2H), 4.85–5.18 (br s, 1H), 6.85 (d, 2H, J=8 Hz),
7.0–7.40 (m, 7H); FABMS (m/z): 428 (M++1); FAB-
HRMS: calcd for (M++1) C25H34O5N: 428.243699,
found: 428.243568.
layer was separated, concentrated and purified through
column chromatography using ethyl acetate:hexane
(6:4) to give 1 as a white solid (0.043 g, 94%); mp
118–120°C (lit.1 mp 118–121°C); [h]2D5=−69.7 (c=0.5 in
MeOH); lit.2 [h]D23 −71.0 (c=0.1, MeOH); IR (KBr):
1
3228, 1711, 1394, 1236, 1041, 766, 450 cm−1; H NMR
(DMSO-d6, 200 MHz): l 2.97 (m, 2H), 3.75 (s, 3H),
4.62–4.78 (m, 1H), 4.84 (t, 1H, J=5 Hz), 4.90 (d, 1H,
J=8 Hz), 6.93 (d, 2H, J=8.6 Hz), 7.15 (d, 2H, J=8.6
Hz), 8.03 (br s, 1H); 13C NMR (acetone-d6+acetone, 50
MHz): l 160.27, 159.22, 129.86, 128.62, 114.23, 81.11,
62.17, 57.48, 55.19; EIMS (m/z): 223 (M)+; FAB-
HRMS: calcd for (M++1) C11O4H14N: 224.092283,
found: 224.091146.
4.3. (2R,3R)-3-Benzylamino-N-tert-butoxycarbonyl-3-
(4-methoxyphenyl)-1,2-propanediol 6
To a solution of compound 5 (0.45 g, 1.05 mmol) in
methanol (10 mL) was added p-toluenesulphonic acid
(0.016 g, 0.08 mmol), and the mixture was stirred for 3
h at room temperature. The reaction mixture was con-
centrated and purified through column chromatogra-
phy using ethyl acetate:hexane (1:1) to give 6 as a
colorless oil (0.33 g, 81%). [h]2D5=−29.3 (c=1, CHCl3);
IR: 3390, 2976, 2933, 1682, 1612, 1514, 1455, 1407,
Acknowledgements
Authors thank Dr. J. S. Yadav, IICT, for fruitful
discussions and support and Dr. G. V. M. Sharma,
IICT for encouragement.
1
1366, 1251, 1163, 1035; H NMR (200 MHz, CDCl3): l
1.44 (s, 9H), 2.70 (br s, 1H), 3.22 (br s, 1H), 3.4–3.6 (br
m, 2H), 3.8 (s, 3H), 3.82–4.0 (m, 2H), 4.30 (br d, 1H,
J=14 Hz), 5.0 (br d, 1H, J=7 Hz), 6.82 (d, 2H, J=8
Hz), 7.0 (m, 2H), 7.18–7.38 (m, 5H); FABMS (m/z);
388 (M+H) FAB-HRMS: calcd for (M++1) C22O5H30N:
388.212398, found: 388.212324.
References
1. Kakeya, H.; Morishita, M.; Kobinata, K.; Osono, M.;
Osada, H. J. Antibiot. 1998, 51, 1126.
2. Kakeya, H.; Morishita, M.; Koshino, H.; Morita, T.;
Kobayashi, K.; Osada, H. J. Org. Chem. 1999, 64, 1052.
3. Sakamoto, Y.; Shiraishi, A.; Seonhee, J.; Nakata, T. Tet-
rahedron Lett. 1999, 40, 4203.
4.4. (2R,3R)-3-tert-Butoxycarbonylamino-3-
(4-methoxyphenyl)-1,2-propanediol 7
To a solution of compound 6 (0.150 g, 0.38 mmol) in
ethanol (5 mL) was added 10% Pd/C (0.028 g) and
conc. HCl (one drop) and hydrogenated at room tem-
perature under stirring. After 15 h the reaction mixture
was concentrated and purified by column chromatogra-
phy using ethyl acetate:hexane (6:4) to give 7 as a white
solid (0.073 g, 63%); mp: 118°C; [h]2D5=−51.2 (c=1 in
CHCl3); IR (KBr): 3384, 2927, 1689, 1511, 1366, 1247,
4. (a) Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915; (b)
Seki, M.; Mori, K. Eur. J. Org. Chem. 1999, 2965.
5. (a) Cativiela, C.; Diaz-de-villegas, M. D.; Galyez, J. A.
Tetrahedron: Asymmetry 1996, 7, 129; (b) Badorrey, R.;
Cativiela, C.; Diaz-de-Villegas, M. D.; Galvez, J. A. Tetra-
hedron 1997, 53, 1411.
6. (a) Kobayashi, Y.; Matsumoto, T.; Takemoto, Y.;
Nakatani, K.; Ito, Y.; Kamijo, T.; Hiromu, H.;
Terashima, S. Chem. Pharm. Bull. 1991, 39, 2550; (b) Kim,
B. M.; Guare, J. P.; Hanifin, C. M.; Arford-Bickerstaff, D.
J.; Vacca, J. P.; Ball, R. G. Tetrahedron Lett. 1994, 5153.
7. Compound 2 was prepared by sodium periodate cleavage
of 1,2-O-isopropylidene-1,2,3,4-tetrol, which in turn was
prepared from ascorbic acid. See the following references
and references cited therein: (a) Jung, M. E.; Shaw, T. J. J.
Am. Chem. Soc. 1980, 102, 6304; (b) Abushnab, E.; Ven-
ishetti, P.; Leiby, R. W.; Singh, H. K.; Mikkilineni, A. B.;
Wu, D.C.-J.; Saibaba, R.; Panzica, P. J. Org. Chem. 1988,
53, 2598.
1
1169, 1033, 772 cm−1; H NMR (CDCl3, 200 MHz): l
1.42 (s, 9H), 2.38 (br s, 1H), 2.95 (br s, 1H), 3.62–3.7
(br m, 2H), 3.70–3.8 (m, 1H), 3.80 (s, 3H), 4.60 (dd,
1H, J=7 Hz), 5.02 (br d, 1H, J=7 Hz), 6.88 (d, 2H,
J=8 Hz), 7.22 (d, 2H, J=8 Hz); FABMS (m/z): 320
(M+Na)+.
4.5. (4R,5R)-5-Hydroxymethyl-4-(4-methoxyphenyl)-2-
oxazolidinone 1
To a solution of 7 (0.061 g, 0.2 mmol) in dry THF (8
mL) was added sodium hydride (0.009 g (60% w/w in
wax), 2.4 mmol) at room temperature and the mixture
was stirred under a nitrogen atmosphere for 2 h. The
reaction mixture was concentrated, dichloromethane
was added, washed with NH4Cl (saturated), the organic
8. TLC indicated a minor impurity having a very close Rf
value to the desired product. Therefore a small portion of
the product was purified by preparative TLC for clear
spectral analysis and the product was used in the next step
‘as is’.