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

Article abstract of DOI:10.1016/j.tetlet.2003.11.096

Optically pure (-)-cytoxazone was synthesized, starting from methyl p-methoxycinnamate, in six steps and in 31% overall yield. The required anti-aminoalcohol configuration was established by combining Sharpless asymmetric aminohydroxylation with the confi

Full text of DOI:10.1016/j.tetlet.2003.11.096

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 955–957
Stereoselective synthesis of ())-cytoxazone and (+)-epi-cytoxazone
Selena Milicevic,a Radomir Matovicb and Radomir N. Saicica,b,
*
aFaculty of Chemistry, University of Belgrade, Studentski trg 16, PO Box 158, 11000 Belgrade, Serbia and Montenegro
bICTM-Centre for chemistry, Njegoseva 12, 11000 Belgrade, Serbia and Montenegro
Received 10 October 2003; revised 8 November 2003; accepted 21 November 2003
Abstract—Optically pure ())-cytoxazone was synthesized, starting from methyl p-methoxycinnamate, in six steps and in 31% overall
yield. The required anti-aminoalcohol configuration was established by combining Sharpless asymmetric aminohydroxylation with
the configurational inversion of the intermediate amidoalcohol via an oxazoline. The synthesis of (+)-epi-cytoxazone is also
described.
Ó 2003 Elsevier Ltd. All rights reserved.
Cytoxazone 1 is a natural product isolated in 1998 from
a fermentation broth of Streptomyces sp.1;2 The strong,
yet selective, immunosuppressive activity of this oxazo-
lidinone derivative (it exerts cytokine modulation
activity through selective inhibition of the Th2 cell sig-
nalling pathway), indicated a possible therapeutic
application and consequently induced the substantial
interest of synthetic organic chemists. Several total
syntheses have been reported, based on asymmetric
synthesis, as well as on the separation of the racemic
product. The enantioselective approaches to biologically
active ())-1 have relied on Sharpless asymmetric
dihydroxylation,3;4 asymmetric aldol reaction with the
internal boron reagent5 and substrate-controlled addi-
tion of organometallics to chiral aldehydes.6;7 The
imino-Wittig rearrangement route,8 as well as the azide
opening of a glycidic ester,9 afforded the racemic com-
pound. The stereoisomer of 1––epi-cytoxazone––2, has
also been synthesized,3;7;9;10 as well as regioisomeric
derivatives required for SAR studies.11
emerged as the most efficient methods for the stereo-
selective synthesis of 1,2-difunctionalized compounds,
where the recently developed Sharpless asymmetric
aminohydroxylation reaction (AA) occupies a promi-
nent place.14;15 However, the AA process does not offer a
universal entry into all types of aminoalcohols, and has
been used more frequently in the synthesis of syn-am-
inoalcohols than for the anti-isomers. This is due to the
fact that AA reactions with Z-alkenes appear to give
products of lower optical purity; in addition, Z-alkenes
are more difficult to obtain than E-alkenes, and some-
times show proclivity towards isomerization. Therefore,
all the syntheses of cytoxazone described so far have
used indirect methods to establish the required vicinal
aminoalcohol functionality.
We endeavoured to develop an efficient enantioselective
synthesis of ())-cytoxazone 1, as well as of (+)-epi-cytox-
azone 2, based on the AA protocol, that would afford
both molecules in the least number of steps, in high yield
and with the highest level of optical purity. Our ap-
proach is delineated in Scheme 1. Retrosynthetic inver-
sion of the configuration at C-5 of the target molecule 1
proceeds via oxazoline 3, and gives amidoalcohol 4, a
common synthetic precursor of both 1 and 2. In turn, 4
should be obtained directly by AA of the easily available
cinnamic ester 5. The epimer 2 does not require the
correction of stereochemistry at C-5, and should be
obtained in a few steps, by routine functional group
manipulations of the AA product 4.
The inevitable synthetic predecessors of cytoxazone (and
epi-cytoxazone) are 1,2-aminoalcohols, which have been
the subject of thorough synthetic studies,12 due to the
frequent presence of this structural subunit in natural
products, biologically active compounds and chiral
ligands for catalytic asymmetric synthesis.13 During the
last few years, asymmetric oxidations of alkenes have
Keywords: Cytoxazone; Asymmetric synthesis; Natural products;
Immunosuppressive compounds; Amino alcohols.
* Corresponding author. Tel.: +381-11-3282537; fax: +381-11-636061;
e-mail: rsaicic@chem.bg.ac.yu
Thus, the synthetic plan for cytoxazone 1 called for a
tactical combination of reactions: AA and inversion of
configuration. Among the many methods that can effect
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.096

956
S. Milicevic et al. / Tetrahedron Letters 45 (2004) 955–957
nitrogen would also have the role as internal nucleo-
O
O
3
phile. The fact that the AA reaction works best with
unencumbered N-haloamides as nitrogen sources16 fur-
ther narrowed the range of isomerization reactions to
those applicable directly to vicinal hydroxy amides of
type 4, pointing to oxazoline 3 as a synthetic inter-
mediate.17 A similar approach was used in stereoselec-
tive transformations of a b-phenyl isoserine derivative.18
HN
HN
2
O
5
1
O
4
OH
OH
MeO
MeO
1 (-)-Cytoxazone
2 (+)-epi-Cytoxazone
The synthesis of 1 proceeded as displayed in Scheme 2.
Sharpless asymmetric aminohydroxylation of 5 with
(DHQD)2PHAL afforded amido alcohol 4 in 72%
yield.19 The next step––oxazoline ring closure––com-
prised a short study aimed towards examining compar-
atively the efficiency of various procedures (Scheme 3).
Thionyl chloride was reported to cyclize anti-amido-
alcohols into oxazolines;20 however, under identical
conditions (CHCl3, 60 °C) the syn-amidoalcohol 4 gave
chloro derivative 9 (the product of an SNi reaction) as
the main product. At higher temperatures the ratio of
products was in favour of the oxazoline, but isomeri-
zation to the trans-oxazoline 10 was also observed.
Surprisingly, triphenylphosphine/diethyl azodicarboxyl-
ate failed to promote any reaction.21 Triphenylphos-
phine/carbon tetrachloride22 effected the desired
transformation in 93% yield (a mixture of 65% of 3 and
28% of 11), but the product was contaminated with 5%
of the trans-oxazoline. We also examined a two-step
N
O
AcNH
CO2R
OR
OH
MeO
MeO
O
4
3
AA
CO2R
MeO
5
Scheme 1. Retrosynthetic analysis of ())-cytoxazone and (+)-epi-cyt-
oxazone.
the latter transformation, we opted for intramolecular
reactions. These were expected to offer at least two
advantages: to facilitate the suppression of unwanted,
bimolecular reactions and to contribute to the atom
economy of the process, as the protective group at
Conditions
+
+
+
+
11
3
9
10
12
4
1) SOCl2, CHCl3, 60 ˚C 10% 51%
2) SOCl2, toluene, 110 ˚C 24% 34%
AcNH
3) SOCl2, xylene, 137 ˚C
4) Ph3P, DEAD, THF
5) Ph3P, CCl4, Et3N,
CH2Cl2, 60 ˚C
0% 36% 25%
CO2Me
CO2Me
i
no reaction
65%
5% 28%
OH
MeO
MeO
MeO
MeO
4
5
6) a) MsCl, Et3N, CH2Cl2,
0 ˚C
70%
35%
ii
b) DIPEA, CHCl3,
60%
80%
45%
60 ˚C, 48 h
7) Tf2O, DMAP (3 eq.),
CH2Cl2, -30 ˚C
8) Tf2O, DMAP (1,5 eq.),
CH2Cl2, -30 ˚C
Me
+
-
2%
45%
N
H3N Cl
CO2H
O
iii
CO2Me
OH
9) Tf2O, DIPEA (3 eq.),
CH2Cl2, -30 ˚C
mixture of unidentified products
6
3
iv
N
O
AcNH
O
O
O
CO2Me
HN
HN
CO2Me
O
Cl
vi
MeO
MeO
10
9
CO2R
OH
MeO
MeO
1
7 R = H
8 R = Me
AcNH
AcNH
v
CO2Me
CO2Me
OMs
MeO
OH
Scheme 2. Total synthesis of ())-cytoxazone. Reagents and conditions:
(i) K2[OsO2(OH)4] (4 mol %), BrNHAc, (DHQD)2PHAL (1 mol %)
LiOHÁH2O, t-BuOH, 4 °C, 20 h, 72%; (ii) Tf2O, DMAP, CH2Cl2, 80%;
(iii) 12% HCl, D, 1.5 h; (iv) ClCO2CCl3, NaOH, H2O, 0 °C; (v) CH2N2,
THF, 72% from 3; (vi) NaBH4, THF, 0 °C, 75%.
MeO
11
12
Scheme 3. Configurational inversion of amidoalcohol 4 under various
conditions.

S. Milicevic et al. / Tetrahedron Letters 45 (2004) 955–957
957
References and notes
O
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Scheme 4. Synthesis of (+)-epi-cytoxazone. Reagents and conditions:
(i) 10% HCl, D, 4 h; (ii) ClCO2CCl3, NaOH, H2O, 0 °C; (iii) CH2N2,
THF, 63% from 4; (iv) NaBH4, THF, 0 °C, 80%.
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procedure including the conversion of alcohol 4 into a
mesylate 12, followed by cyclization.23 The previously
reported procedure proved unsuitable, affording a mix-
ture of isomerized hydroxyester 11 (in low yield) and
unreacted starting compound 4. The use of DIPEA as
base, under anhydrous conditions, improved the yield of
3 (60%), but the reaction time was long and conversion
incomplete (35% recovered 12). The best results were
obtained when the isomerization was performed via the
in situ formed triflate,24 using 3 equiv of DMAP as
base:25 under these conditions oxazoline 3 could be
isolated in 80% yield. Lowering the amount of DMAP,
or using DIPEA instead, proved unsatisfactory. Further
synthetic steps involved acidic hydrolysis of oxazoline 3
to hydroxy amino acid 6, its conversion into cyclic
carbamate 7 by diphosgene, and the esterification to 8
with diazomethane. We found that it was more conve-
nient experimentally not to isolate/purify the interme-
diates 6 and 7, but to proceed directly to the ester 8,
which was isolated in 72% yield (over three steps).
Reduction of 8 with sodium borohydride afforded ())-
cytoxazone 1 (75%) whose physical properties were
identical to those of the natural product.26
16. Bruncko, M.; Schlingloff, G.; Sharpless, B. K. Angew.
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Tetrahedron Lett. 2000, 41, 10071–10074, however, due to
the bulky nature of the t-Boc protecting group, the AA
reaction with N-Boc-N-halocarbamates is not successful,
and the preparation of the N-Boc analogue of 4 would
require additional steps.
epi-Cytoxazone 2 was synthesized from the common
intermediate 4 as delineated in Scheme 4. Submission of
amidoalcohol 4 to the sequence of reactions already
described for cytoxazone (hydrolysis/cyclization/esteri-
fication), gave the methyl ester 13 (63% over three steps),
whose reduction with sodium borohydride furnished the
optically pure epi-cytoxazone 2 (80%).26
18. Lee, S.-H.; Yoon, J.; Nakamura, K. Org. Lett. 2000, 2,
1243–1246.
To summarize, optically pure ())-cytoxazone 1 has been
synthesized in six steps and in 31% overall yield, starting
from readily available methyl p-methoxycinnamate. (+)-
epi-Cytoxazone 2 was also synthesized, starting from the
same precursor, in five steps and 36% overall yield. In
terms of overall yield, number of steps and operational
simplicity, both syntheses compare favorably with those
previously described. The inversion of stereochemistry
of amidoalcohols via oxazolines contributes to the ver-
satility of the well-known Sharpless AA reaction and
allows for its efficient application to the synthesis of
anti-1,2-aminoalcohol derivatives.
19. In addition to the amidoalcohol 4, methyl (2S,3R)-2,3-
dihydroxy-3-(4-methoxyphenyl)-propanoate, the AD
product, was isolated in 13% yield.
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58, 1287–1289.
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Acknowledgements
26. The optical purity of the product, determined by
chiral HPLC as described in Ref. 9, was found to be
>98%.
This work was financially supported by the Ministry of
science, technology and development (Project No. 1719).