A concise synthesis of (-)-cytoxazone and its stereoisomers via imino 1,2-Wittig rearrangement

Article abstract of DOI:10.1055/s-1999-2992

A concise synthesis of (-)-cytoxazone (1) and its stereoisomers has been achieved via the route involving the imino 1,2-Wittig rearrangement of hydroximate.

Full text of DOI:10.1055/s-1999-2992

LETTER
1915
A Concise Synthesis of (-)-Cytoxazone and its Stereoisomers via Imino 1,2-
Wittig Rearrangement
Okiko Miyata, Hiroshi Asai, Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Fax +8178 441 7556; E-mail: taknaito@kobepharma-u.ac.jp
Received 16 September 1999
Abstract: A concise synthesis of (-)-cytoxazone (1) and its stereoi-
somers has been achieved via the route involving the imino 1,2-Wit-
tig rearrangement of hydroximate.
O
2
3
HN
4
O1
5
H O
Key words: hydroximate, Wittig rearrangement, 2-hydroxy oxime
ether, oxazolidinone, cytokine modulator
7
6
H
H
MeO
(-)-cytoxazone 1
Cytoxazone (1)1,2 containing a 4,5-disubstituted 2-oxazo-
lidinone ring was recently isolated from Streptomyces sp.
and the absolute configuration was unambiguously estab-
lished by the first total asymmetric synthesis reported very
recently by Nakata’s group.3 Compound 1 has shown a
cytokine-modulating activity by inhibiting the signaling
pathway of Th2 cells. Inhibitors of Th2-dependent
cytokine production would be potent chemotherapeutic
agents in the field of immunotherapy. Therefore, cy-
toxazone and its analogs have been a new subject of
synthetic studies for the development of a cytokine
modulator. Here, we describe a second example of the to-
tal synthesis of cytoxazone via a novel route involving the
imino 1,2-Wittig rearrangement of hydroximate which
has been recently developed as an effective synthetic
route for 2-hydroxyimines.4 The versatile nature of
this method prompted us to examine its applicability to
the synthesis of cytoxazone. Our synthetic method for
cytoxazone and its 4-epimer consist of two crucial steps
involving recently found imino 1,2-Wittig rearrangement
and conventional optical resolution of the diastereomers.
NOMe
O
NOMe
a
OH
MeO
MeO
3
2
b
O
O
O
RN
RN
O
MeO
MeO
trans-5
cis-4
5a: R=Boc
4a: R=Boc
c
c
5b: R=H
4b: R=H
d
d
O
O
O
HN
HN
O
We first investigated the rearrangement of hydroximate 2
which was prepared in 82% yield from p-anisoyl chloride
according to the reported procedure.4 1,2-Wittig rear-
rangement of hydroximate 2 proceeded smoothly under
the conditions involving 2 equiv. of LDA in THF at
-78 °C to afford 2-hydroxy oxime ether 3 as a sole product
in 82% yield. We next investigated the reduction of 2-hy-
droxy oxime ether 3 into amino alcohol according the re-
ported procedure.5 Unfortunately, application of the
reported procedure to our 2-hydroxy oxime ether 3 gave
the desired erythro-amino alcohol with low selectivity.
Reduction of 3 with LiAlH4 followed by acylation6 of the
resulting demethoxylated amino alcohol with 2 equiv. of
Boc2O afforded a mixture of two N-Boc-oxazolidinones
cis-4a and trans-5a in 81% yield with a ratio of 2.1:1. It is
well known6 that treatment of acyclic 2-amino alcohols
with Boc2O gives the corresponding oxazolidinones as a
result of spontaneous cyclization of the intermediate, N-
Boc-amino alcohol. On the other hand, reduction of 3 with
MeO
OH
MeO
OH
6
(±)-cytoxazone 1
e
(-)-cytoxazone 1
(+)-cytoxazone
Reagents and conditions: a) LDA (2 eq.), THF, -78°C, 82%; b) 1)
LiAlH4 (3 eq.), Et2O, 0°C; 2) LiAlH4 (9 eq.), 35°C; 3) Boc2O (2.5
eq.), DMAP (1 eq.), MeCN, r.t., 81% from 3 (cis-4a : trans-5a = 2.1
: 1); c) TFA, CH2Cl2, r.t., 99%; d) 1) O3, CH2Cl2, -78°C; 2) NaBH4
(5 eq.), MeOH, -78 – 0°C, 88% from 4b, 95% from 5b; e) 1) (-)-cam-
phanic chloride; 2) KOH, 99%.
Scheme
Synlett 1999, No. 12, 1915–1916 ISSN 0936-5214 © Thieme Stuttgart · New York

1916
O. Miyata et al.
LETTER
Red-Al at -30 °C gave a 1:2.1 mixture of erythro- and
threo-methoxyamines in high yield as a result of reduction
of carbon-nitrogen double bond. Treatment of cis-4a with
TFA gave the desired oxazolidinone 4b in 99% yield,
which was smoothly converted into (±)-alcohol 1 via oxi-
dation of 4b with O3 and subsequent reduction of the ozo-
nide with NaBH4. Similarly, (±)-4-epi-cytoxazone (6)7
was synthesized from trans-5a by the same reaction se-
quence.
References and Notes
(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.
Tetrahedron Lett. 1999, 40, 4203.
(4) Miyata, O.; Koizumi, T.; Ninomiya, I.; Naito, T. J. Org.
Chem. 1996, 61, 9078.
(5) (a) Shimizu, M.; Tsukamoto, K.; Fujisawa, T. Tetrahedron
Lett. 1997, 38, 5193. (b) Boukhris, S.; Souizi, A. Tetrahedron
Lett. 1999, 40, 1669. (c) Barluenga, J.; Aguilar, E.; Fustero, S.;
Olano, B.; Viado, A. L. J. Org. Chem. 1992, 57, 1291. (d)
Narasaka, K.; Ukaji, Y.; Yamazaki, S. Bull. Chem. Soc. Jpn.
1986, 59, 525.
Optical resolution of racemic cytoxazone was readily ac-
complished via the conventional separation of the corre-
sponding diastereoisomers. Acylation of (±)-cytoxazone
(1) with (-)-camphanic chloride gave a mixture of two
corresponding esters which was easily separated into their
diastereomers in high yield. Hydrolysis of each diastere-
omer gave (-)-alcohol 18 and its (+)-enantiomer,9 respec-
tively. (-)-Alcohol 1 was identical with natural (-)-
cytoxazone (1) upon comparisons of the spectra with
those of the authentic sample.
(6) Knölker, H. J.; Braxmeier, T. Tetrahedron Lett. 1998, 39,
9407.
(7) (±)-4-epi-Cytoxazone (6): Colorless crystals; mp. 161-163 °C
(lit.3 (-)-4-epi-Cytoxazone (6):161.5-162.5 °C). IR nmax/cm-1
(CHCl3): 3688, 3456, and 1760. 1H NMR(CDCl3, 500 MHz)
d:2.44 (1H, br s), 3.71 (1H, br d, J = 13 Hz), 3.82 (3H, s), 3.96
(1H, br d, J = 13 Hz), 4.39 (1H, dt, J = 7.5, 3.5 Hz), 4.83 (1H,
d, J = 7.5 Hz), 5.49 (1H, br s), 6.92 (2H, m), 7.28 (2H, m).
(8) (-)-Cytoxazone (1): Colorless crystals; mp. 120-123 °C (lit.3
122-123 °C). IR nmax/cm-1 (CHCl3): 3585, 3453, and 1761. 1H
NMR(DMSO-d6, 500 MHz) d:2.97 (2H, m), 3.75 (3H, s), 4.69
(1H, ddd, J = 8.0, 7.0, 4.0 Hz), 4.80 (1H, t, J = 7.0 Hz), 4.90
(1H, d, J = 8.0 Hz), 6.93 (2H, m), 7.14 (2H, m), 8.05 (1H, br
s). [a]D29 -73.3 (c 0.51, MeOH) (lit.2 [a]D23 -71.0 (c 0.1,
MeOH), lit.3 [a]D23 -75.7 (c 1.0, MeOH)).
In conclusion, we have accomplished the total synthesis
of (-)-cytoxazone (1) from hydroximate 2. Our procedure
would provide a practical synthetic method for cytox-
azone and its stereoisomers which would be subjected to
the biological evaluations, particularly, as potent chemo-
therapeutic agents in the field of immunotherapy.
(9) (+)-Cytoxazone (1): [a]D29+75.0 (c 0.52, MeOH).
Acknowledgement
We thank Dr. H. Osada (RIKEN) for providing IR, NMR, MASS,
and UV spectra of natural cytoxazone. This work was supported in
part by Grant-in-Aid for Scientific Research (No. 09672293) from
the Ministry of Education, Science, Sports and Culture, Japan and
the Science Research Promotion Fund of the Japan Private School
Promotion Foundation for research grants.
Article Identifier:
1437-2096,E;1999,0,12,1915,1916,ftx,en;Y17899ST.pdf
Synlett 1999, No. 12, 1915–1916 ISSN 0936-5214 © Thieme Stuttgart · New York