Stereoselective synthesis of (-)-cytoxazone

Article abstract of DOI:10.1016/S0957-4166(02)00227-6

The stereoselective synthesis of the cytokine modulator (-)-cytoxazone in enantiopure form is described. Key steps of the process are a syn-stereoselective aldol addition of a chiral ketone mediated by chlorodicyclohexylborane, and a Curtius rearrangement

Full text of DOI:10.1016/S0957-4166(02)00227-6

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1005–1010
Stereoselective synthesis of (−)-cytoxazone
Miguel Carda,a,* Florenci Gonza´lez,a Richard Sa´ncheza and J. Alberto Marcob,*
aDepartamento de Qu´ımica Inorga´nica y Orga´nica, Univ. Jaume I, E-12080 Castello´n, Spain
bDepartamento de Qu´ımica Orga´nica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
Received 30 April 2002; accepted 7 May 2002
Abstract—The stereoselective synthesis of the cytokine modulator (−)-cytoxazone in enantiopure form is described. Key steps of
the process are a syn-stereoselective aldol addition of a chiral ketone mediated by chlorodicyclohexylborane, and a Curtius
rearrangement. © 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
During screening for chemical immunomodulators
from microbial sources, the novel cytokine modulator
cytoxazone (−)-1 has been recently isolated from cul-
tures of a Streptomyces species.1 It was found to inhibit
the signaling pathway of Th2 cells but not that of Th1
cells. Because of these biological properties, several
total syntheses of (−)-1 and of its trans-diastereoisomer
(4-epi-cytoxazone) have been published in the last three
years. Three of these syntheses relied on asymmetric
dihydroxylations as the source of chirality2 whereas
another made use of a precursor from the chiral pool.3
Two further syntheses led to racemic cytoxazone, which
was then resolved via chemical4 or enzymatic5 proce-
dures. Herein, we present our synthetic approach to
(−)-1, based on our recently developed, stereoselective
aldol methodology.6 The retrosynthetic scheme is
shown below and includes the Curtius degradation of
acid 2, the oxidative cleavage of the acetal ring6 in 3
and the syn-stereoselective boron aldol addition of
chiral ketone 4 to a suitably protected glycolic aldehyde
5.
The homochiral ketone 6 [ꢀ4, R,R=(CH2)5] was read-
ily prepared from L-erythrulose cyclohexylidene acetal
77 in 49% overall yield (Scheme 1). Reduction of 7 with
LAH yielded diol 8 as a mixture of diastereoisomers.
The formation of the epoxide ring to give
9
(diastereoisomeric mixture) was best achieved via tin
acetal methodology.8 Epoxide ring opening in 9 was
performed with an organocopper derivative9 prepared
from 4-methoxyphenyl magnesium bromide. This pro-
vided a mixture of diastereoisomeric alcohols 10, which
was finally oxidised to ketone 6 by means of the
Dess–Martin procedure.10 An interesting feature of the
process is that all four carbon atoms of the chiral
precursor,
L-erythrulose, are used (full atom
economy).11
Aldol additions of ketone 6 with three protected deriva-
tives of glycolic aldehyde (hydroxy acetaldehyde) 5
were then investigated (Scheme 2, P=TBS, TPS, Bn).12
All three reactions worked efficiently to furnish the
expected syn–syn aldol adducts 11a–c. Oxidative cleav-
O
OH
O
O
O
OP
OP
HOOC
OH
HN
O
[O]
Curtius
O
O
aldol
5
O
OP
O
OH
R
R
R
R
MeO
OMe
OMe
MeO
2
3
(-)-1
4
* Corresponding authors. Fax: +34-96-3864328; e-mail: mcarda@qio.uji.es; alberto.marco@uv.es
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00227-6

1006
M. Carda et al. / Tetrahedron: Asymmetry 13 (2002) 1005–1010
the two stereogenic centres of the target molecule were
OH
O
O
simultaneously created in the course of an aldol addi-
tion with complete relative as well as absolute stereo-
control by the stereogenic centre resident in the starting
homochiral precursor 6. This stereocentre was later
sacrificed, once his control role had been accomplished.
Ketone 6 and structurally related compounds may
therefore be considered as chiral equivalents of the d1
synthon type depicted in Scheme 2 (R=alkyl, aryl).
They should thus prove very useful for the synthesis of
a
O
O
b
O
OH
O
O
O
OH
8
7
9
O
OH
O
O
d
c
6
many
naturally
occurring,
nitrogen-containing
O
O
molecules, such as amino acids, amino polyols, alka-
loids, etc., in enantiopure form. Efforts in this direction
are underway and will be reported in due course.
OMe
OMe
10
Scheme 1. Preparation of ketone 6 from L-erythrulose cyclo-
3. Experimental
hexylidene acetal 7. Reagents and conditions: (a) LAH, THF,
74%. (b) TsCl, Et3N, cat. Bu2SnO; NaH, THF, 90% overall.
(c) 4-Methoxyphenyl magnesium bromide, CuI, 83%. (d)
Dess–Martin periodinane, 88%.
3.1. General methods
1H NMR spectra (400 or 500 MHz) and 13C NMR
spectra (100 or 125 MHz) were measured at 22°C. The
signals of the deuterated solvent (CDCl3) were taken as
age of the acetonide ring using periodic acid hydrate
(H5IO6)13 proceeded well when P=TPS or Bn but not
when P=TBS, as the latter group proved too sensitive
to the acidic reaction conditions. As previously
observed in related cases,6 oxidative cleavage of the
aldols with H5IO6 gave intermediate b-formyloxy acids,
which were then converted into the corresponding b-
hydroxy acids 12a–b via mild alkaline hydrolysis. Cur-
tius rearrangement of the latter compounds was per-
formed with the aid of diphenyl phosphoryl azide
(DPPA).14 This furnished oxazolidinones 13a–b directly
through in situ intramolecular capture of the isocyanate
group by the free hydroxyl function.15 Cleavage of the
protecting group in 13a–b led finally to cytoxazone
(−)-1.
1
the reference (the singlet at l 7.25 for H NMR and the
triplet centered at 77.00 ppm for 13C NMR data).
Multiplicity assignments of 13C NMR signals were
made with the DEPT pulse sequence. Mass spectra
were run in a VG AutoSpec mass spectrometer using
either the electron impact mode (EIMS, 70 eV) or the
fast atom bombardment mode (FABMS, m-nitrobenzyl
alcohol matrix). Samples for IR spectral measurements
were prepared as oily films on NaCl plates (oils) or KBr
pellets (solids). Optical rotations were measured at
22°C.
Column chromatography (CC) was performed on silica
gel Su¨d-Chemie AG (60–200 mm). Experiments which
required an inert atmosphere were carried out under
dry argon (Ar) in a flame-dried glassware. THF and
Et2O were freshly distilled from sodium/benzophenone
ketyl and were transferred via syringe. Toluene was
Among the previous syntheses of non-racemic cytoxa-
zone, only one involved the formation of a CꢀC bond.3
A characteristic feature of the present synthesis is that
OH
OH
O
O
OP
OP
HOOC
1) Chx2BCl, Et3N
2) POCH2CHO (5)
O
O
1) H5IO6, EtOAc
O
O
2) KHCO3/MeOH
(70-82% overall)
(76-90%)
OMe
OMe
OMe
12a P = Bn
12b P = TPS
11a P = Bn
11b P = TPS
11c P = TBS
6
O
O
HN
OP
DPPA, Et3N
deprotection
H2N
R
d1
(-)-1
toluene, ∆
(66-68%)
OMe
13a P = Bn
13b P = TPS
Scheme 2. Synthesis of (−)-cytoxazone from chiral ketone 6.

M. Carda et al. / Tetrahedron: Asymmetry 13 (2002) 1005–1010
1007
freshly distilled from sodium wire. Methylene chloride
was freshly distilled from CaH2. Tertiary amines were
freshly distilled from KOH. Commercially available
reagents (Aldrich or Fluka) were used as received. If
not detailed otherwise, the work-up of the reactions
was consistently performed in the following manner:
the reaction mixture was poured into brine and
extracted twice with solvent (Et2O, CH2Cl2 or EtOAc),
the organic layer was washed with diluted aq. NH4Cl
and then washed again with brine, the organic layer
was dried over anhydrous MgSO4 or Na2SO4, and the
solvent was eliminated with a rotary evaporator at
aspirator pressure.
residue on silica gel (hexanes–EtOAc 9:1, then 4:1 and
7:3) afforded alcohol 10 as a mixture of diastereoiso-
mers (3.16 g, 83%).
Alcohol 10 (2.92 g, 10 mmol) was dissolved under Ar in
dry CH2Cl2 (100 mL). After cooling in an ice bath,
NaHCO3 (2.52 g, 30 mmol) and Dess–Martin periodi-
nane (12.72 g, 30 mmol) were successively added. The
orange red reaction mixture was then stirred for 16 h at
room temperature, diluted with Et2O (250 mL) and
poured onto satd aq. Na2S2O3. The organic layer was
then stirred for 15 min, separated from the aqueous
layer, washed again with satd aq. NaHCO3, dried and
evaporated under reduced pressure. Column chro-
matography of the residue on silica gel (hexanes–
EtOAc 9:1, then 4:1) afforded ketone 6 as an oil (2.55
g, 88%): [h]2D2 −99.3 (c 0.5, CHCl3), 1H NMR (500
MHz) l 7.15 (2H, d, J=8.5 Hz, aromatic), 6.89 (2H, d,
J=8.5 Hz, aromatic), 4.53 (1H, dd, J=7.5, 5.7 Hz,
3.2. Preparation of ketone 6
Lithium aluminum hydride (1.14 g, 30 mmol) was
suspended under Ar in dry THF (30 mL). After cooling
in an ice bath, a solution of ketone 77 (5 g, ca. 25
mmol) in dry THF (30 mL) was slowly added dropwise
(10 min). When the addition was complete, the ice bath
was removed, and the reaction mixture was stirred at
room temperature for 16 h. After recooling in an ice
bath, water (2 mL) was slowly added dropwise (caution:
evolution of H2!). After this, 1 M aq. NaOH (2 mL) and
again water (10 mL) were added, the cooling bath was
removed, and the mixture was stirred at room tempera-
ture for 3 h. Filtration through Celite was followed by
concentration under reduced pressure and column chro-
matography on silica gel (hexanes–EtOAc 1:1, then 1:2)
to yield diol 8 as a mixture of diastereoisomers (3.74 g,
74%).
CH
(1H, dd, J=8.5, 5.7 Hz, CH2
Hz, ArCH2), 3.83 (1H, d, J=16 Hz, ArCH2
s, OMe), 1.80–1.45 (10H, br m, cyclohexane protons).
13C NMR (125 MHz) l 208.2 (CꢁO), 158.6, 130.6,
125.3, 114.0 (aromatic), 111.6 (acetal carbon), 79.5
6
OR), 4.16 (1H, dd, J=8.5, 7.5 Hz, CH2
OR), 3.96 (1H, d, J=16
), 3.80 (3H,
6 OR), 4.02
6
6
6
(C6 HOR), 66.1 (C6 H2OR), 55.2 (OMe), 44.5 (ArC6 H2),
35.7, 34.5, 25.1, 24.0, 23.8 (cyclohexane carbons). IR
wmax 2935, 2859, 1721, 1611, 1584, 1563, 1515, 1464,
1449, 1369, 1333, 1301, 1249, 1178, 1161, 1096, 1037,
924, 847, 829, 774 cm−1. HR EIMS m/z (% rel. int.)
290.1514 (M+, 32), 141 (92), 121 (100). Calcd for
C17H22O4, 290.1518. Anal. calcd for C17H22O4: C,
70.32; H, 7.64. Found, C, 70.50; H, 7.80%.
Diol 8 (3.03 g, 15 mmol) was dissolved under Ar in dry
CH2Cl2 (30 mL) and treated with nBu2SnO (75 mg, 0.3
mmol), p-toluenesulphonyl chloride (3.15 g, 16.5 mmol)
and triethylamine (2.6 mL, 18 mmol). The mixture was
stirred at room temperature and stirred for 3 h, then
filtered through Celite and evaporated under reduced
pressure. The oily residue was then dissolved in dry
THF (150 mL) and added dropwise to a suspension of
NaH (30 mmol of the base) in dry THF (40 mL). The
reaction mixture was stirred at room temperature for 3
h. Work-up (extraction with CH2Cl2) and column chro-
matography on silica gel (hexanes–EtOAc 4:1) gave
epoxide 9 as a mixture of diastereoisomers (2.49 g,
90%).
3.3. Aldol additions of ketone 6
Chx2BCl (800 mL, ca. 3.6 mmol) and Et3N (560 mL, 4
mmol) were dissolved under Ar in anhydrous Et2O (8
mL) and cooled to −78°C. Ketone 6 (580 mg, ca. 2
mmol) was dissolved in anhydrous ether (6 mL) and
added dropwise via syringe to the reagent solution.
After 10 min, the reaction mixture was warmed to 0°C,
stirred for 1 h at this temperature and then recooled to
−78°C. After 10 min stirring, a solution of aldehyde 5
(10 mmol) in ether (6 mL) was added dropwise. The
stirring was continued for 10 min, the reaction mixture
was then warmed up to 0°C and further stirred for 5 h
(5, P=Bn or TBS) or 7 h (5, P=TPS). For the work-
up, phosphate pH 7 buffer solution (15 mL) and
MeOH (15 mL) were added at 0°C, followed by 30%
aq. H2O2 (8 mL). After stirring for 1 h at room
temperature, the mixture was poured onto brine and
extracted with Et2O. The organic layer was then dried
over anhyd. Na2SO4 and evaporated under reduced
pressure. Column chromatography of the residue on
silica gel (hexanes–EtOAc, 19:1, then 9:1 and 4:1) pro-
vided aldols 11a (670 mg, 76% yield), 11b (1.06 g, 90%)
and 11c (743 mg, 79%).
Copper iodide (4.95 g, 26 mmol) was dried by means of
gentle heating under vacuum. It was then suspended
under Ar in dry Et2O (200 mL). The mixture was
cooled to −10°C and treated with p-methoxyphenyl
magnesium bromide (0.5 M solution in THF, 104 mL,
52 mmol). After stirring at −10°C for 1 h, a solution of
epoxide 9 (2.40 g, ca. 13 mmol) in dry Et2O (30 mL)
was added dropwise to the organocopper reagent solu-
tion. The cooling bath was removed, and the reaction
mixture was stirred at room temperature. for 16 h. Satd
aq. NH4Cl (50 mL) and 30% aq. NH3 (10 mL) were
sequentially added to the reaction mixture. The organic
layer was then poured onto brine, washed once again
with satd aq. NH4Cl, dried and evaporated under
reduced pressure. Column chromatography of the oily
3.3.1.
(2S,4R,5R)-1,2-O-Cyclohexylidene-6-O-benzyl-
1,2,5,6-tetrahydroxy-4-(4-methoxyphenyl)hexan-3-one,
1
11a. Oil: [h]2D2 +83.6 (c 5, CHCl3). H NMR (500 MHz)
l 7.35–7.25 (5H, m, aromatic), 7.25 (2H, d, J=8.5 Hz,

1008
M. Carda et al. / Tetrahedron: Asymmetry 13 (2002) 1005–1010
aromatic), 6.88 (2H, d, J=8.5 Hz, aromatic), 4.56 (1H,
d, J=11.8 Hz, benzyl CH2), 4.52 (1H, d, J=11.8 Hz,
benzyl CH2), 4.50–4.40 (2H, m, CHOR), 4.35 (1H, d,
J=7.1 Hz, ArCH), 4.07 (1H, t, J=8.1 Hz, CH2OR),
3.80 (3H, s, OMe), 3.75 (1H, dd, J=8.1, 6.5 Hz,
CH2OR), 3.53 (1H, dd, J=9.6, 5.1 Hz, CH2OBn), 3.44
407.1890. Anal. calcd for C25H40O6Si: C, 64.62; H, 8.68.
Found, C, 64.77; H, 8.53%.
6
6
6
3.4. Oxidative cleavage of aldols 11a–c with periodic
acid hydrate
6
6
6
6
The aldol 11a (661 mg, 1.5 mmol) was dissolved in an
Et2O–EtOAc 1:1 mixture (30 mL) and treated with
H5IO6 (1.2 g, ca. 5.25 mmol). The mixture was then
stirred at room temperature until consumption of the
starting material (6.5–7 h, TLC monitoring!). Solid
sodium thiosulphate pentahydrate (500 mg, ca. 2 mmol)
was added to the reaction mixture, which was then
stirred for 15 min, filtered through Celite (the Celite
pad was additionally washed with 30 mL of EtOAc)
and evaporated under reduced pressure. The oily
residue was dissolved in MeOH (20 mL) and treated
with KHCO3 (400 mg, ca. 4 mmol). After stirring the
mixture at room temperature for 2 h, satd. aq. NH4Cl
(2 mL) was added, followed by filtration through Celite
(the Celite pad was additionally washed with 30 mL of
MeOH) and evaporation under reduced pressure. The
residue was then subjected to column chromatography
on silica gel (EtOAc:AcOH, 99:1) to yield 12a (389 mg,
82%). Acid 12b was obtained in 70% yield from aldol
11b using the same procedure. Aldol 11c decomposed
under these conditions.
(1H, dd, J=9.6, 5.1 Hz, CH6 2OBn), 2.45 (1H, br s, OH),
1.70–1.40 (10H, br m, cyclohexane protons). 13C NMR
(125 MHz) l 209.1 (CꢁO), 159.2, 137.9, 130.7, 128.3,
127.9, 125.7, 114.2 (aromatic), 111.6 (acetonide C),
79.7, 73.3, 71.5, 71.2, 66.1, 55.2 (C6 -OR), 55.1 (OMe),
35.2, 34.6, 24.9, 23.9, 23.7 (cyclohexane carbons). IR
wmax 3480 (br), 2934, 2861, 1709, 1610, 1511, 1452,
1368, 1250, 1179, 1161, 1099, 1035, 924, 827, 737 cm−1.
HR FAB MS m/z 441.2262 (M+H+). Calcd for
C26H33O6, 441.2277. Anal. calcd for C26H32O6: C,
70.89; H, 7.32. Found, C, 71.00; H, 7.50%.
3.3.2.
(2S,4R,5R)-1,2-O-Cyclohexylidene-6-O-(tert-
butyldiphenylsilyl)-1,2,5,6-tetrahydroxy-4-(4-methoxy-
phenyl)hexan-3-one, 11b. Oil: [h]2D2 +33.2 (c 5.7, CHCl3).
1H NMR (500 MHz) l 7.70 (4H, m, aromatic), 7.50–
7.40 (6H, m, aromatic), 7.26 (2H, d, J=8.5 Hz, aro-
matic), 6.89 (2H, d, J=8.5 Hz, aromatic), 4.52 (1H, d,
J=6.8 Hz, ArCH
CHOR), 4.36 (1H, m, CH
7.5 Hz, CH2OR), 3.81 (3H, s, OMe), 3.70–3.65 (2H, m,
CH2OR, CH2OTPS), 3.60 (1H, dd, J=10.2, 5.7 Hz,
CH2
6
), 4.48 (1H, dd, J=7.6, 6.5 Hz,
6
6
OH), 4.09 (1H, dd, J=8.5,
6
6
6
3.4.1.
(2R,3R)-4-Benzyloxy-3-hydroxy-2-(4-methoxy-
6
OTPS), 2.60 (1H, br s, OH), 1.65–1.40 (10H, br m,
phenyl)butanoic acid, 12a. Oil: [h]2D2 +20 (c 0.5, CHCl3).
1H NMR (500 MHz) l 7.40–7.30 (7H, m, aromatic),
6.90 (2H, d, J=8.5 Hz, aromatic), 4.55 (2H, s, benzyl
cyclohexane protons), 1.13 (9H, s, tBuSi). 13C NMR
(125 MHz) l 209.7 (CꢁO), 159.3, 135.6, 135.5, 133.2,
133.1, 130.9, 130.1, 129.9, 129.8, 127.8, 127.7, 125.7,
114.1 (aromatic), 111.7 (acetonide C), 79.9, 72.3, 66.4,
CH2
ArCH
Hz, CH2
6
), 4.45 (1H, m, CH
6
6 OH), 3.82 (1H, overl. m,
), 3.81 (3H, s, OMe), 3.53 (1H, dd, J=9.7, 5.9
65.1 (C6 -OR), 55.2 (OMe), 54.6 (ArC6 H), 35.3, 34.7, 25.0,
6
OBn), 3.49 (1H, dd, J=9.7, 4.8 Hz, CH6 2OBn).
23.9, 23.7 (cyclohexane carbons), 26.9, 19.2 (tBuSi). IR
wmax 3430 (br, OH), 3071, 2932, 2857, 1707, 1610, 1511,
1463, 1449, 1428, 1368, 1251, 1179, 1161, 1112, 1038,
924, 824, 740, 703 cm−1. HR FAB MS m/z 589.3001
(M+H+). Calcd for C35H45O6Si, 589.2985. Anal. calcd
for C35H44O6Si: C, 71.39; H, 7.53. Found, C, 71.30; H,
7.59%.
13C NMR (125 MHz) l 177.7 (CꢁO), 159.3, 137.7,
130.4, 130.2, 128.4, 127.8, 127.7, 126.2, 114.1 (aro-
matic), 73.4, 71.4, 70.7 (C
(ArC
6 H2OR), 55.2 (OMe), 52.9
6
H). IR wmax 3430 (br), 2934, 2860, 1726, 1612,
1513, 1452, 1367, 1248, 1179, 1099, 1035, 927, 807, 740
cm−1. HR EIMS m/z (% rel. int.) 316.1308 (M+, 4), 166
(100), 121 (40), 91 (73). Calcd for C18H20O5, 316.1310.
Anal. calcd for C18H20O5: C, 68.34; H, 6.37. Found, C,
68.49; H, 6.50%.
3.3.3.
(2S,4R,5R)-1,2-O-Cyclohexylidene-6-O-(tert-
butyldimethylsilyl)-1,2,5,6-tetrahydroxy-4-(4-methoxy-
phenyl)hexan-3-one, 11c. Oil: [h]2D2 +58.6 (c 7.7, CHCl3);
1H NMR (400 MHz) l 7.20 (2H, d, J=8.5 Hz, aro-
matic), 6.84 (2H, d, J=8.5 Hz, aromatic), 4.49 (1H, dd,
3.4.2. (2R,3R)-4-(tert-Butyldiphenylsilyloxy)-3-hydroxy-
2-(4-methoxyphenyl)butanoic acid, 12b. Oil: [h]2D2 +26.3
(c 4, CHCl3). 1H NMR (500 MHz) l 7.70 (4H, m,
aromatic), 7.50–7.40 (6H, m, aromatic), 7.34 (2H, d,
J=8.5 Hz, aromatic), 6.90 (2H, d, J=8.5 Hz, aro-
J=7.6, 6.5 Hz, CH
ArCH), 4.22 (1H, m, CH
Hz, CH2OR), 3.77 (3H, s, OMe), 3.69 (1H, dd, J=8.4,
6.5 Hz, CH2OR), 3.56 (1H, dd, J=10.1, 5.1 Hz,
CH2OTBS), 3.49 (1H, dd, J=10.1, 5.3 Hz, CH2OTBS),
6
OR), 4.31 (1H, d, J=7.1 Hz,
6
6
OH), 4.07 (1H, dd, J=8.4, 7.6
6
matic), 4.39 (1H, dT, J=6.6, 5.5 Hz, CH6 OH), 3.90 (1H,
6
d, J=6.6 Hz, ArCH
J=10.4, 5.5 Hz, CH2
Hz, CH2
6
), 3.81 (3H, s, OMe), 3.71 (1H, dd,
6
6
6
OTPS), 3.65 (1H, dd, J=10.4, 5.5
6
OTPS), 1.10 (9H, s, tBuSi). 13C NMR (125
MHz) l 177.9 (CꢁO), 159.2, 135.8, 133.2, 130.7, 130.1,
2.50 (1H, br s, OH), 1.60–1.30 (10H, br m, cyclohexane
protons), 0.90 (9H, s, tBuSi), 0.05 (3H, s, Me2Si), 0.04
(3H, s, Me2Si). 13C NMR (100 MHz) l 209.5 (CꢁO),
159.2, 130.8, 125.8, 114.1 (aromatic), 111.7 (acetonide
130.0, 128.1, 128.0, 126.8, 114.3 (aromatic), 72.0, 65.1
(C6 -OR), 55.2 (OMe), 52.7 (ArC6 H), 26.8, 19.2 (tBuSi).
C), 79.9, 72.5, 66.3, 64.4 (C
6 -OR), 55.2 (OMe), 54.9
IR wmax 3430–2800 (br, COOH), 3071, 2932, 2858, 1706
(br, CꢁO), 1610, 1588, 1512, 1463, 1441, 1428, 1252,
1179, 1106, 1064, 1036, 825, 740, 703 cm−1. HR EIMS
m/z (% rel. int.) 407.1334 (M+−tBu, 13), 361 (35), 328
(50), 241 (41), 198 (100), 121 (72). Calcd for
C27H32O5Si-tBu, 407.1315. Anal. calcd for C27H32O5Si:
C, 69.80; H, 6.94. Found, C, 69.60; H, 6.79%.
(ArCH), 35.3, 34.7, 25.0, 23.9, 23.8 (cyclohexane car-
6
bons), 25.9, 18.3 (tBuSi), −5.3 (Me2Si), −5.4 (Me2Si).
IR wmax 3580 (br), 2936, 2859, 1708, 1610, 1511, 1464,
1369, 1253, 1179, 1161, 1113, 1037, 909, 837, 779 cm−1.
HR EIMS m/z (% rel. int.) 407.1890 (M+−tBu, 16), 290
(72), 141 (100), 117 (89). Calcd for C25H40O6Si-tBu,

M. Carda et al. / Tetrahedron: Asymmetry 13 (2002) 1005–1010
1009
3.5. Curtius rearrangement of acids 12a–b with DPPA
[the Celite pad was additionally washed with EtOH (10
mL)] and removal of volatiles under reduced pressure,
the oily residue was chromatographed on silica gel
(EtOAc) to yield (−)-1 (87 mg, 78%).
A solution of acid 12a (316 mg, 1 mmol) and triethyl-
amine (175 mL, 1.25 mmol) in dry toluene (10 mL)
,
containing activated 4 A molecular sieves was treated
under Ar with DPPA (240 mL, ca. 1.1 mmol) and
heated overnight under reflux. After cooling to room
temperature, the mixture was poured into a glass sepa-
ration funnel containing water (40 mL) and CH2Cl2 (40
mL). The organic layer was separated, dried over
anhyd. Na2SO4 and evaporated under reduced pressure.
Column chromatography of the residue on silica gel
(hexanes–EtOAc, 1:3) afforded oxazolidinone 13a (213
mg, 68%) as a yellowish oil. Compound 13b was simi-
larly obtained from acid 12b in 66% yield.
By desilylation: oxazolidinone 13b was desilylated with
TBAF as reported previously2b to yield (−)-1.
3.6.1. (4R,5R)-5-Hydroxymethyl-4-(4-methoxyphenyl)-
oxazolidin-2-one, (−)-cytoxazone, (−)-1. White solid, mp
122–124°C, lit.1 mp 118–121°C, lit.5 mp 122–123°C;
[h]D −74.6 (c 1.1; MeOH), lit.1 [h]D −71 (c 0.1; MeOH),
lit.2b [h]D −75.7 (c 1; MeOH); 1H NMR (500 MHz,
CD3COCD3) l 7.25 (2H, d, J=8.8 Hz, aromatic), 6.93
(2H, d, J=8.8 Hz, aromatic), 6.90 (1H, br s, NH), 5.02
(1H, d, J=8 Hz, H-4), 4.81 (1H, dt, J=8, 4 Hz, H-5),
3.79 (3H, s, OMe), 3.78 (1H, m, OH), 3.22 (1H, ddd,
3.5.1. (4R,5R)-5-Benzyloxymethyl-4-(4-methoxyphenyl)-
oxazolidin-2-one, 13a. Oil: [h]2D2 −44.8 (c 0.8, CHCl3). 1H
NMR (500 MHz) l 7.30 (5H, m, aromatic), 7.20 (2H,
d, J=8.5 Hz, aromatic), 6.90 (2H, d, J=8.5 Hz, aro-
matic), 6.00 (1H, br s, NH), 4.96 (2H, m, H-4, H-5),
J=12, 8, 5 Hz, CH2
6 OH), 3.27 (1H, dd, J=12, 6.3, 4
Hz, CH2
6
OH); 13C NMR (125 MHz, CD3COCD3) l
160.7 (CꢁO), 159.5, 130.2, 129.0, 114.6 (aromatic), 81.5
(C-5), 62.6 (C
6
H2OH), 57.8 (C-4), 55.6 (OMe).
4.33 (1H, d, J=11.8 Hz, benzyl CH2
J=11.8 Hz, benzyl CH2), 3.83 (3H, s, OMe), 3.36 (1H,
dd, J=10.5, 6.2 Hz, CH2OBn), 3.15 (1H, dd, J=10.5,
5.2 Hz, CH2
OBn). 13C NMR (125 MHz) l 160.0 (CꢁO),
159.3, 138.2, 137.4, 128.4, 128.3, 127.8, 127.7, 127.6,
114.1 (aromatic), 79.0, 73.4, 68.7, 57.8 (C-OR), 55.3
6 ), 4.23 (1H, d,
6
6
Acknowledgements
6
6
The authors acknowledge financial support by the
DGICYT (project PB98-1438) and by BANCAJA (pro-
ject P1B99-18). They further thank Dr. H. Ro¨per,
Eridania Be´ghin-Say, Vilvoorde, Belgium, for a gener-
(OMe). IR wmax 3300 (br, NH), 3051, 2928, 2853, 1746
(CꢁO), 1606, 1514, 1453, 1404, 1252, 1178, 1080, 1010,
845, 736, 701 cm−1. HR EIMS m/z (% rel. int.)
313.1314 (M+, 20), 207 (100), 162 (62), 135 (84), 91 (93).
Calcd for C18H19NO4, 313.1314. Anal. calcd for
C18H19NO4: C, 68.99; H, 6.11. Found, C, 68.79; H,
6.20%.
ous supply of L-erythrulose.
References
3.5.2. (4R,5R)-5-(tert-Butyldiphenylsilyloxymethyl)-4-(4-
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aromatic), 7.45–7.30 (8H, m, aromatic), 7.18 (2H, d,
J=8.5 Hz, aromatic), 6.88 (2H, d, J=8.5 Hz, aro-
matic), 6.35 (1H, br s, NH), 4.99 (1H, d, J=8.2 Hz,
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