Synthesis of 2-oxazolidinones from β-lactams: Stereospecific total synthesis of (-)-cytoxazone and all of its stereoisomers

Article abstract of DOI:10.1021/ol062752p

The synthetic correlation between two different antibiotic frameworks, the β-lactams and 2-oxazolidinones, is described for the first time. In this approach, 2-oxazolidinones are prepared in stereomerically pure form from 3-hydroxy β-lactams by a ring-ope

Full text of DOI:10.1021/ol062752p

ORGANIC
LETTERS
2007
Vol. 9, No. 4
575-578
Synthesis of 2-Oxazolidinones from
-Lactams: Stereospecific Total
Synthesis of ( )-Cytoxazone and All of
â
−
Its Stereoisomers
Rajesh Kumar Mishra, Cristina M. Coates, Kevin D. Revell, and Edward Turos*
Center for Molecular DiVersity in Drug Design, DiscoVery, and DeliVery,
Department of Chemistry, UniVersity of South Florida, 4202 East Fowler AVenue,
Tampa, Florida 33620
eturos@shell.cas.usf.edu
Received November 11, 2006
ABSTRACT
The synthetic correlation between two different antibiotic frameworks, the
this approach, 2-oxazolidinones are prepared in stereomerically pure form from 3-hydroxy
process. Application of this methodology to the total synthesis of the cytokine modulator, (
â
-lactams and 2-oxazolidinones, is described for the first time. In
-lactams by a ring-opening cyclization isomerization
)-cytoxazone, and its three stereoisomers is
â
−
−
demonstrated.
The â-lactam antibiotics have been the most important
therapeutic agents in the 20th century, an era which began
with the discovery of penicillin (Figure 1) by Alexander
Fleming in 1928.1 The key feature of penicillin and its well-
known relatives, the cephalosporins, penems, carbapenems,
clavulanic acids, and monobactams, is the â-lactam nucleus.
Over the last 50-60 years, bacteria have been able to develop
resistance to the â-lactam drugs by producing extracellular
enzymes that hydrolyze the â-lactam moiety to inactive ring-
opened amino acids. This resistance has spawned a renewed
interest in identifying new families of antibiotics. One such
class of compounds are the 2-oxazolidinones, which were
discovered by researchers at Dupont in the 1980s to exert
potent antibacterial properties through a unique mechanism
of action.2 Linezolid (Figure 1) was the first oxazolidinone
antibiotic to be introduced into clinical trials by Pharmacia3
and was approved in 2000 by the Food and Drug Admin-
istration for use in the treatment of infections caused by
gram-positive bacteria.
Figure 1. Structures of the penicillins and linezolid (above) and
the synthetic correlation of â-lactams with 2-oxazolidinones
(below).
(1) Fleming, A. Br. J. Exp. Pathol. 1929, 10, 226-236.
(2) Slee, A. M.; Wuonola, M. A.; McRipley, R. J.; Zajac, I.; Zawada,
M. J.; Bartholomew, P. T.; Gregory, W. A.; Forbes, M. Antimicrob. Agents
Chemother. 1987, 31, 1791.
10.1021/ol062752p CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/20/2007

Scheme 1. Synthesis of 2-Oxazolidinones from 3-Hydroxy â-Lactam 1
Our laboratory recently reported N-thiolated â-lactams
the alcohol 5 in 92% yield. Exchange of the hydroxyl group
for an azide proceeded through mesylate 6, which gave azide
7 in 72% yield after treatment with sodium azide in DMF.
Catalytic hydrogenation of the azide and subsequent acetyl-
ation afforded the acetamide 8 in 75% yield for the final
one-pot conversion. Oxazolidinones 4-8 were each con-
verted to their N-thiolated derivatives for biological evalu-
ation, and these compounds were found to be generally quite
active as antibacterials against MRSA.5
We were interested in adapting this sequence to the
asymmetric total synthesis of (4R,5R)-(-)-cytoxazone (9).
A microbial metabolite isolated from Streptomyces, cytox-
azone is a selective modulator of TH2 cytokine secretion.7
Because of its potent biological activity, a number of research
laboratories have pursued the development of efficient
asymmetric routes to cytoxazone and its stereoisomers
(Figure 2).8 A sequence adapted from the one shown in
Scheme 1 would provide a most convenient means to access
cytoxazone and its three stereoisomers. We first set out to
which possess potent antibacterial activity against methicillin-
resistant Staphylococcus aureus (MRSA).4 One of the inter-
esting features of these compounds is that the â-lactam
nucleus is not required for anti-MRSA activity, which led
us to the discovery of N-thiolated 2-oxazolidinones as a new
family of antibacterial agents.5 During the course of our stud-
ies, it occurred to us that the N-thiolated â-lactams and 2-
oxazolidinones could perhaps both be derived from the same
intermediate, 3-hydroxy â-lactam,5 as shown in Figure 1.
Accordingly, we first developed a strategy shown in
Scheme 1 to prepare a selection of racemic oxazolidinone
compounds 4-8, which we utilized to prepare antibacterially
active N-methylthio-2-oxazolidinones.5 Each of these com-
pounds was accessed from cis-hydroxy â-lactam 1. To begin
the synthesis, lactam4c 1 was hydrolyzed with Me3SiCl in
refluxing methanol to afford the syn-aminol 2 in 95% yield.
Upon treatment of 2 with triphosgene and Hunig’s base in
dichloromethane, oxazolidinone 3 was obtained in 80% yield.
The N-methoxyphenyl moiety on the oxazolidinone ring was
then cleaved with ceric ammonium nitrate in acetonitrile and
water6 to yield the N-protio oxazolidinone 4 in 70% yield.
The ester functionality of oxazolidinone 4 was selectively
reduced with sodium borohydride in aqueous THF to furnish
(3) Ford, C. W.; Zurenko, G. E.; Barbachyn, M. R. Curr. Drug.
Targets: Infect. Disord. 2001, 1, 181-199.
(4) (a) Heldreth, B.; Long, T. E.; Jang, S.; Reddy, G. S. K.; Turos, E.;
Dickey, S.; Lim, D. V. Bioorg. Med. Chem. 2006, 14, 3775-3784. (b) Turos,
E.; Long, T. E.; Heldreth, B.; Leslie, J. M.; Reddy, G. S. K.; Wang, Y.;
Coates, C.; Konaklieva, M.; Dickey, S.; Lim, D. V.; Alonso, E.; Gonzalez,
J. Bioorg. Med. Chem. Lett. 2006, 16, 2084-2090. (c) Turos, E.; Coates,
C.; Shim, J. Y.; Wang, Y.; Leslie, J. M.; Long, T. E.; Reddy, G. S. K.;
Ortiz, A.; Culberth, M.; Dickey, S.; Lim, D. V.; Alonso, E.; Gonzalez, J.
Bioorg. Med. Chem. 2005, 13, 6289-6308. (d) Long, T. E.; Turos, E.;
Konaklieva, M. I.; Blum, A. L.; Amry, A.; Baker, E. A.; Suwandi, L. S.;
McCain, M. D.; Rahman, M. F.; Dickey, S.; Lim, D. V. Bioorg. Med. Chem.
2003, 11, 1859-1863. (e) Coates, C.; Long, T. E.; Turos, E.; Dickey, S.;
Lim, D. V. Bioorg. Med. Chem. 2003, 11, 193-196. (f) Turos, E.; Long,
T. E.; Konaklieva, M. I.; Coates, C.; Shim, J. Y.; Dickey, S.; Lim, D. V.;
Cannons, A. Bioorg. Med. Chem. Lett. 2002, 12, 2229-2231.
(5) Mishra, R. K.; Revell, K. D.; Coates, C. M.; Turos, E.; Dickey, S.;
Lim, D. V. Bioorg. Med. Chem. Lett. 2006, 16, 2081-2083.
Figure 2. (-)-Cytoxazone and its stereoisomers.
(6) Kronenthal, D. R.; Han, C. Y.; Taylor, M. K. J. Org. Chem. 1982,
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576
Org. Lett., Vol. 9, No. 4, 2007

Scheme 2. Stereospecific Total Synthesis of (-)-Cytoxazone (9)
prepare the naturally occurring form, (4R,5R)-cytoxazone (9),
methanol to chemoselectively cleave the R-methyl-(4-meth-
oxybenzyl) moiety. The resultant amine was protected as its
tert-butyl carbamate derivative 15 using di-tert-butyl carbon-
ate and NaHCO3 in MeOH under sonication. The hydroxyl
group was inverted under Mitsunobu conditions to afford
from optically pure hydroxy lactam 13, as shown in Scheme
2.9 Methanolysis of 13 with Me3SiCl in refluxing methanol
yielded a 92% yield of syn-amino alcohol 14, which was
subjected to hydrogenation with Pearlman’s catalyst in
(7) Kakeya, H.; Morishita, M.; Koshino, H.; Morita, T.; Kobayashi, K.;
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Scheme 3. Stereospecific Synthesis of (-)-epi-Cytoxazone (10)
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7852. (h) Kim, J. D.; Kim, I. S.; Cheng, H.; Zee, O. P.; Jung, Y. H. Org.
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Org. Lett., Vol. 9, No. 4, 2007
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the anti-amino alcohol 16. Borohydride reduction and base-
promoted cyclization of the diol 17 completed the synthesis
of (-)-cytoxazone (9). NMR spectral data and optical
rotation values confirmed a match to the natural product.8
Our next task was to complete a stereospecific synthesis
of (-)-epi-cytoxazone, which we carried out by first
intercepting amino alcohol 14 with triphosgene and Hunig’s
base to form the trans-disubstituted oxazolidinone 18 (Scheme
3). The R-methyl-(4-methoxybenzyl) moiety was chemo-
selectively cleaved with ceric ammonium nitrate to furnish
the N-protio oxazolidinone 19 in 65% yield. The ester was
reduced with NaBH4 in MeOH to afford (-)-epi-cytoxazone,
whose spectral and physical properties matched those
reported.8
stereoisomer of hydroxy lactam 13. Thus, this protocol
afforded access to all four stereoisomers of the oxazolidinone.
In summary, we have demonstrated the value of â-lactams
as building blocks for the stereospecific synthesis of sub-
stituted 2-oxazolidinones, compounds which are of broad
interest both as synthetic intermediates and as commercial
pharmaceutical products. We believe that this methodology
provides unique flexibility and opportunities to the synthesis
of stereochemically pure oxazolidinones that are needed for
biological studies and drug development.
Acknowledgment. This research was generously sup-
ported by the National Institutes of Health (R01 AI51351).
In a similar fashion, (+)-cytoxazone (11) and (+)-epi-
cytoxazone (12) were synthesized from the enantiomeric
Supporting Information Available: Complete experi-
mental procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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Lawrence, N. J.; Pritchard, R. G.; McGown, A. T. Tetrahedron Lett. 1998,
39, 3559-3562. (c) Bourzat, J. D.; Commercon, A.; Tetrahedron Lett. 1993,
34, 6049-6052. (d) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y.
H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992, 48, 6985-7012.
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