Short synthesis of both enantiomers of cytoxazone using the Petasis reaction

Article abstract of DOI:10.1016/j.tetasy.2004.08.004

Both enantiomers of cytoxazone, (-)-1 and (+)-1, were synthesized using the Petasis reaction of dl-glyceraldehyde 2, 4-methoxyphenylboronic acid 3 and (R)-1-(1-naphthyl)ethylamine 7, following formation of an oxazolidin-2-one ring.

Full text of DOI:10.1016/j.tetasy.2004.08.004

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3149–3153
Short synthesis of both enantiomers of cytoxazone using the
Petasis reaction
Shigeo Sugiyama,* Satoshi Arai and Keitaro Ishii*
Department of Medicinal Chemistry, Meiji Pharmaceutical University, 2-522-1, Noshio, Kiyose, Tokyo 204-8588, Japan
Received 14 July 2004; accepted 4 August 2004
Abstract—Both enantiomers of cytoxazone, (ꢀ)-1 and (+)-1, were synthesized using the Petasis reaction of DL-glyceraldehyde 2, 4-
methoxyphenylboronic acid 3 and (R)-1-(1-naphthyl)ethylamine 7, following formation of an oxazolidin-2-one ring.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
tate catalyzed by Penicillium camemberti lipase.3 These
methods require two extra steps: acylation of enantio-
meric mixtures and hydrolysis of the acyl groups after
separation. Several groups have also synthesized (ꢀ)-
cytoxazone (ꢀ)-1 using asymmetric reactions.4 Madhan
et al. developed the total synthesis of (ꢀ)-1, which
involved the stereoselective addition of p-methoxyphen-
ylmagnesium bromide to a benzylimine of (S)-2,3-O-
isopropylidene glyceraldehyde to give the protected 3-
amino-1,2-propanediol derivative, as well as subsequent
regioselective cyclization to give an oxazolidin-2-one
ring.4d A similar 3-amino-1,2-propanediol derivative
( )-4 has been synthesized using the Petasis three-com-
ponent coupling reaction;5,6 DL-glyceraldehyde 2 reacted
with 4-methoxyphenylboronic acid 35 and N-methyl-
benzylamine in ethanol to give a (2RS,3RS)-3-amino-
1,2-propanediol derivative ( )-4 (Scheme 1).
Over the course of screening for chemical immunomod-
ulators that inhibit type 2 cytokine production in Th2
cells, the RIKEN group found (ꢀ)-cytoxazone (ꢀ)-1
(Fig. 1) as a novel cytokine modulator produced by
the Streptomyces species.1 (ꢀ)-Cytoxazone (ꢀ)-1 shows
cytokine-modulating activity by inhibiting the signaling
pathway of Th2 cells but not Th1 cells.
O
O
O
O
NH
NH
HO
HO
OMe
OMe
(_)-1
(+)-1
Figure 1. (ꢀ)-Cytoxazone (ꢀ)-1 and (+)-cytoxazone (+)-1.
(HO)2B
Me
Due to the potent biological activity and the simple
structure, the synthesis of (ꢀ)-1 has been well investi-
gated. The racemic product of cytoxazone ( )-1 has
been synthesized and then separated.2,3 Acylation of
( )-1 with (ꢀ)-camphanic chloride gives a mixture of
two corresponding esters, and both esters can be easily
separated into their diastereomers.2 The kinetic resolu-
tion of ( )-1 is performed by acetylation with vinyl ace-
Bn
N
HO
HO
HO
HO
OMe
3
CHO
MeNHBn
EtOH, rt
24h
2
(+)-4
-
OMe
72 %
(>99 %de)
Scheme 1. An example of the Petasis three-component coupling
reaction.
*
Corresponding authors. Tel.: +81 424 958791/83; fax: +81 424
958783; e-mail addresses: sugiyama@my-pharm.ac.jp; ishiikei@
my-pharm.ac.jp
Several optically active oxazolidin-2-ones possessing
a-methylbenzyl and 1-(1-naphthyl)ethyl groups on the
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.08.004

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S. Sugiyama et al. / Tetrahedron: Asymmetry 15 (2004) 3149–3153
nitrogen have been synthesized,7–11 with the diastereo-
mers of the corresponding 5-bromomethyl-,7 5-phenyl-,8
5-chloromethyl-,7 5-iodomethyl-9 and 5-vinyloxazol-
idin-2-ones10 easily separable on silica gel column
chromatography. Therefore, we expected that the dia-
stereomers of oxazolidin-2-ones 5a, 6a, 5b and 6b (Fig.
2), each of which would be a precursor for the total syn-
thesis of optically active cytoxazones (ꢀ)-1 or (+)-1,
could be separated on silica gel column chromatography.
glyceraldehyde 2 and 4-methoxyphenylboronic acid 3
(Scheme 2). This reaction proceeded very slowly at room
temperature compared to the reaction5 shown in
(Scheme 1). Even in refluxing ethanol, the reaction
required a long reaction time to afford a diastereomeric
mixture (dr, ca. 1:1) of 8 and 9 (reaction time: one day,
28% yield; three days, 50% yield). A reaction using (R)-
a-methylbenzylamine instead of 7 was also slow; how-
ever, it proceeded at room temperature to give a mixture
of the corresponding amino alcohols (dr, ca. 1:1) in 56%
yield (reaction time, three days). Amino alcohols 8 and 9
were silylated to protect the primary hydroxyl groups
selectively to give silyl ethers 10 and 11. After the forma-
tion of oxazolidin-2-ones 12 and 13 using N,N0-succin-
imidyl carbonate (DSC) in acetonitrile, the silyl groups
were removed with tetrabutylammonium fluoride
(TBAF) in THF to give oxazolidin-2-ones 5a and 6a.
The Rf values of 5a and 6a were 0.20 and 0.12 (hex-
ane/AcOEt, 1:1), respectively, and as we had expected,
5a and 6a were easily separated using silica gel column
chromatography. Although a diastereomeric mixture
of 5b and 6b (Fig. 2) was also synthesized from (R)-a-
methylbenzylamine according to the procedure de-
scribed above, the mixture 5b and 6b proved difficult
to separate on silica gel column chromatography.
O
O
N
O
O
N
Ar
Ar
HO
HO
OMe
OMe
5a, Ar = 1-naphthyl
5b, Ar = Ph
6a, Ar = 1-naphthyl
6b, Ar = Ph
Figure 2. Proposed precursors for cytoxazones.
To synthesize cytoxazones from the intermediates
5a, 6a, 5b and 6b, the a-methylbenzyl groups and the
1-(1-naphthyl)ethyl groups must be removed. We have
developed mild reaction conditions to remove N-a-
methylbenzyl and N-1-(1-naphthyl)ethyl groups from
oxazolidin-2-ones using methanesulfonic acid (MsOH)
and anisole.7,8 These reaction conditions do not influ-
ence the 4-phenyloxazolidin-2-one rings,8 which are
cleaved by general debenzylation conditions such as
To simplify this synthetic procedure, we investigated the
one-pot synthesis of 5a and 6a from 8 and 9 as follows
(Scheme 3): (i) after selective protection of the primary
hydroxyl groups in 8 and 9 with TBDMSCl in dichloro-
methane, (ii) the reaction mixture containing silyl ethers
10 and 11 was treated with 1,1-carbonyl bis-1H-imid-
azole (CDI) to afford oxazolidin-2-ones 12 and 13 and
then (iii) was treated with 10% hydrochloric acid for
desilylation to give the desired oxazolidin-2-ones 5a
and 6a. In the one-pot procedure, we used CDI for the
formation of oxazolidin-2-one rings instead of DSC
owing to the low solubility in dichloromethane, and
we used hydrochloric acid for desilylation instead of
TBAF because desilylation of 12 and 13 with TBAF
gave 5a and 6a accompanied by undesired by-products.
12
Li/NH3 and Na/NH3,13 and the yield of removal of
the N-1-(1-naphthyl)ethyl group using MsOH is much
better than that of the N-a-methylbenzyl group.7
On the basis of these findings, we investigated a short
synthesis of (ꢀ)- and (+)-cytoxazones (ꢀ)-1 and (+)-1,
respectively from DL-glyceraldehyde 2, 4-meth-
oxyphenylboronic acid 3 and (R)-1-(1-naphthyl)ethyl-
amine 7b as starting materials.
Absolute configurations of 5a and 6a were deduced by a
comparison of the 1H NMR chemical shift values of the
1-(1-naphthyl)ethyl moieties based on the empirical
rule8 that methyl protons of (4S,aS)-3-(a-methyl-
benzyl)-4-phenyloxazolidin-2-one derivatives 148 absorb
at a higher field (1.16–1.22ppm) than the corresponding
2. Results and discussion
According to the procedure5,6 reported by Petasis et al.,
we synthesized 3-amino-1,2-propanediols 8 and 9 by
reactions of (R)-1-(1-naphthyl)ethylamine 7 with DL-
O
O
N
O
O
N
HN
HO
RO
HO HN
RO
Ar
Ar
Ar
a
Ar
c
RO
RO
+
+
H2N
Ar
7
OMe
OMe
OMe
OMe
Ar = 1-naphthyl
12/13; R = SitBuMe2
5a and 6a; R = H
8/9; R = H
b
d
10/11; R = SitBuMe2
Scheme 2. Stepwise synthesis of the precursors of cytoxazones. Reagents and conditions: (a) 2, 3, EtOH, reflux, three days (50%); (b) TBDMSCl,
Et3N, DMAP, CH2Cl2, rt, 5h; (c) DSC, Et3N, MeCN, rt, 6h (66% from 8 and 9); (d) TBAF, THF, rt, 63h and SiO2 column chromatography (5a;
59%, 6a; 26%).

S. Sugiyama et al. / Tetrahedron: Asymmetry 15 (2004) 3149–3153
3151
achieved using a five-step synthesis via the Petasis reac-
tion to give a mixture of 8 and 9, separation of the dia-
stereomers 5a and 6a using silica gel column
chromatography and the acidic removal of 1-naphthyl-
ethyl groups. The diastereomers of 5a and 6a have been
synthesized from 8 and 9 by a stepwise procedure (5a,
39%; 6a, 17%) or by a one-pot procedure (5a, 29%; 6a,
16%). The overall yields of (ꢀ)-1 and (+)-1 by the
one-pot procedure from the starting material, 4-meth-
oxyphenylboronic acid 3, were 13% and 6.9%, respec-
tively. Considering the one-pot procedure, this is the
shortest route to (ꢀ)-1 from commercially available
starting materials. Some phenylboronic acid derivatives,
including m-methoxy-, p-fluoro-, p-bromo- and p-vinyl-
phenylboronic acids, as well as other heterocyclic boro-
nic acids, are applied for the Petasis reaction.15
Therefore, various cytoxazone derivatives can be pre-
pared using this procedure.
a-(i)
a-(ii)
a-(iii)
8/9
10/11
12/13
5a and 6a
b
b
(_)-1
(+)-1
Scheme 3. One-pot synthesis of the precursors and removal of the 1-
naphthylethyl group. Reagents and conditions: (a) (i) TBDMSCl,
Et3N, DMAP, CH2Cl2, rt, 30h, (ii) CDI, rt, four days, (iii) aq HCl 23h
and SiO2 column chromatography (5a; 29%, 6a; 16 %); (b) MsOH,
anisole, MeNO2, 50ꢁC, 6h [(ꢀ)-1; 90%, (+)-1; 86%].
protons of (4S,aR)-derivatives 158 (1.75–1.84ppm), and
the benzylic proton of 14 absorbs at a lower field (5.27–
5.35ppm) than that of 15 (4.48–4.55ppm) (Fig. 3). We
1
found identical H NMR spectral characters between
the oxazolidin-2-ones 5a and 6a. The C-methyl protons
of 5a absorb at a higher field (1.34ppm) compared to
those of 6a (1.86ppm), and the benzylic-type proton
(NCHMe) of 5a absorbs at a lower field (5.88ppm) com-
pared to that of 6a (5.68ppm). Therefore, we predicted
that the relative configuration of 5a would be identical
to that of 14. After removal of the 1-naphthylethyl
groups of 5a and 6a, we confirmed that this deduction
was correct.
4. Experimental
All commercially available materials were used without
further purification. Melting points were measured with
Yanaco MP-3 apparatus and are uncorrected. Optical
rotations were determined on a JASCO DIP-140 pola-
rimeter. IR spectra were recorded on a Hitachi 215 spec-
trophotometer. NMR spectra were obtained with JEOL
JNM-GSX400 (1H NMR: 400MHz and 13C NMR:
100MHz) and JEOL JMS-DX302 (1H NMR: 300
MHz, for a mixture of 8 and 9) spectrometers using
tetramethylsilane as an internal standard. MS and
high-resolution MS (HR-MS) were taken on a JEOL
JMS-DX302 spectrometer. Column chromatography
was performed with Merck silica gel 60 (230–400 mesh).
Analytical TLC was performed on plates pre-coated
with 0.25mm layer of silica gel 60 F254 (Merck).
Determination of the enantiomeric purities were
performed using CHIRALCEL OD (250 · 4.6mm) in
hexane/2-propanol (3:1) for (ꢀ)-1 and (+)-1, flow rate
0.5mL/min (retention time, (ꢀ)-1: 27.5min, (+)-1:
40.7min).
5.27_5.35 ppm
1.16_1.22 ppm
4.48_4.55 ppm
1.75_1.84 ppm
O
O
Me
Me
H
Ph
H
N
N
O
O
S and R
S
S
Ph
S and R
S
R
Ph
R
Ph
R
14
15
R = H, Ph
5.88 ppm
1.34 ppm
5.68 ppm
1.86 ppm
O
O
Me
Me
H
H
Naph
N
O
O
N
R
R
Naph
S
R
Ar
HO
HO
Ar
5a
6a
4.1. The Petasis reaction giving 8 and 9
Ar = 4-methoxyphenyl
Naph = 1-naphthyl
DL-Glyceraldehyde dimer (652mg, 3.62mmol) was
dissolved in ethanol (16.5mL), and (R)-1-(1-naph-
thyl)ethylamine 7 (1.24g, 7.24mmol) and 4-methoxy-phen-
ylboronic acid 3 (1.00g, 6.58mmol) were added to this
solution. The mixture was refluxed vigorously for three
days (bath temperature: 100ꢁC). After being cooled to
room temperature, the dark brown reaction mixture
was concentrated in vacuo. The residue was diluted with
ethyl acetate, and the mixture washed with saturated
aqueous sodium hydrogen carbonate. The aqueous layer
was then extracted twice with ethyl acetate. The organic
layers were combined, dried over magnesium sulfate and
concentrated in vacuo. The residue was chromato-
graphed on silica gel (chloroform) to give a mixture of
(2R,3R)- and (2S,3S)-3-(4-methoxyphenyl)-3-[(R)-1-(1-
Figure 3. Relationships of shift values on 1H NMR (in CDCl3).
The respective 1-naphthylethyl groups in 5a and 6a were
removed with MsOH and anisole7,8 in nitromethane to
afford (ꢀ)-cytoxazone (ꢀ)-1 and (+)-cytoxazone (+)-1
in good yield (Scheme 3). We used here nitromethane
as a solvent because nitromethane is a good solvent
for cationic reactions.14 The absolute stereochemistry
was determined by a comparison of the reported specific
rotation.1
3. Conclusions
naphthyl)ethylamino]propane-1,2-diols,
respectively (1.16g, 50%, diastereomeric ratio: major/
minor, 53:47). Rf = 0.35 (CHCl3/MeOH, 9:1). This
8
and 9,
In conclusion, the synthesis of (ꢀ)- and (+)-cytoxazones,
(ꢀ)- and (+)-1, respectively, has been conveniently

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S. Sugiyama et al. / Tetrahedron: Asymmetry 15 (2004) 3149–3153
mixture was used in the next reaction without further
separation. Characteristic signals of H NMR spectrum
4.3. Removal of the 1-(1-naphthyl)ethyl groups
1
(300MHz, CDCl3) d (major): 1.52 (3H, d, J = 6.6Hz,
Me), d (minor): 1.43 (3H, d, J = 6.6Hz, Me).
Methanesulfonic acid (257mg, 2.30mmol) and anisole
(129mg, 1.15mmol) were added to a stirred solution
of 5a (86.2mg, 0.23mmol) in nitromethane (2.3mL),
and the mixture stirred for 6h at 50ꢁC. The reaction
mixture was poured into saturated aqueous sodium
hydrogen carbonate and extracted twice with dichloro-
methane. The organic extracts were combined, dried
over magnesium sulfate, and concentrated in vacuo.
The residue (139mg) was purified with silica gel column
chromatography (chloroform) to give a pure (ꢀ)-1
(46.0mg, 90%, >98% ee) as colorless needles.
4.2. One-pot silylation, cyclization and desilylation giving
5a and 6a from 8 and 9
tert-Butyldimethylchlorosilane (115mg, 0.76mmol) was
added to a mixture of 8 and 9 (223mg, 0.64mmol), tri-
ethylamine (96mg, 0.95mmol) and DMAP (7.3mg,
60lmol) in dichloromethane (6.4mL). After the mixture
was stirred at room temperature for 30h, 1,1-carbonyl
bis-1H-imidazole (CDI) (208mg, 1.28mmol) was added
portionwise to the mixture. After being stirred for four
days at room temperature, dichloromethane (15mL)
and 6M hydrochloric acid (20mL) were added to the
mixture, and the resulting mixture stirred for 23h at
room temperature. The reaction mixture was then ex-
tracted three times with dichloromethane. The extracts
were combined, dried over magnesium sulfate and con-
centrated in vacuo. The residue (257mg) was chromato-
graphed on silica gel (hexane/ethyl acetate, 4:1) to give
5a (70.0mg, 29%) and 6a (38.5mg, 16%).
4.3.1. (ꢀ)-Cytoxazone, (4R,5R)-hydroxymethyl-(4-methoxy-
phenyl)oxazolidin-2-one
(ꢀ)-1. Mp
115–116ꢁC.
D
26
D
23
½aꢁ ¼ ꢀ70:9 (c 0.87, MeOH) {Ref. 1 ½aꢁ ¼ ꢀ71 (c
1
0.100, MeOH)}. H NMR (DMSO-d6) d: 8.00 (1H, s,
NH), 7.14 (2H, d, J = 8.4Hz, Ar), 6.92 (2H, d,
J = 8.8Hz, Ar), 4.89 (1H, d, J = 8.4Hz, NCHAr), 4.80
(1H, t, J = 3.2Hz, OH), 4.66–4.71 (1H, m, OCHCH2OH),
3.74 (3H, s, OMe), 2.94–2.97 (2H, m, COCH2). 13C NMR
(DMSO-d6) d: 158.7 (C@O), 158.4 (Ar, C), 129.0 (Ar, C),
127.7 (Ar, CH · 2), 113.4 (Ar, CH · 2), 79.9 (OCH),
61.0 (CH2), 56.1 (NHCH), 55.0 (OMe). MS (FAB) (gly-
cerol) m/z: 224 [(M+1)+]. HRMS (FAB) (glycerol)
calcd for C11H14NO4 (M+1): 224.0923. Found: 224.0915.
4.2.1. (4R,5R)-5-Hydroxymethyl-4-(4-methoxyphenyl)-3-
[(R)-1-(1-naphthyl)ethyl]oxazolidin-2-one 5a. Rf = 0.20
(hexane/ethyl acetate, 1:1). Colorless needles, mp 169–
30
170ꢁC. ½aꢁ ¼ ꢀ104:9 (c 1.7, CHCl3). 1H NMR (CDCl3)
4.3.2. (+)-Cytoxazone, (4S,5S)-hydroxymethyl-(4-meth-
oxyphenyl)oxazolidin-2-one (+)-1. According to the
method described above, (+)-1 (35.4mg, 86%, >98%
ee) was synthesized from 6a (69.4mg, 0.18mmol).
D
d: 8.00 (1H, d, J = 8.1Hz, Ar), 7.88 (1H, d, J = 7.8Hz,
Ar), 7.84 (1H, d, J = 8.1Hz, Ar), 7.49–7.57 (2H, m,
Ar), 7.38 (1H, t, J = 7.6Hz, Ar), 7.30 (1H, br s, Ar),
7.14 (1H, d, J = 6.8Hz, Ar), 6.65–7.00 (2H, br m, Ar),
6.40–6.65 (1H, br s, Ar), 5.88 (1H, q, J = 6.8Hz, ArCH),
4.27–4.32 (1H, m, OCHCH2OH), 3.81 (3H, s, OMe),
3.77 (1H, d, J = 8.4Hz, CHAr), 3.36 (1H, dd, J = 11.9,
8.0Hz, HOCHH), 3.00 (1H, dd, J = 11.9, 4.4Hz,
HOCHH), 1.34 (3H, d, J = 6.8Hz, Me). 13C NMR
(CDCl3) d: 159.7, 157.1, 133.7, 133.6, 131.3, 128.9,
128.8, 127.7, 127.0, 125.9, 124.5, 124.4, 122,6, 113.9,
82.4, 78.7, 61.5, 59.0, 55.2, 49.2, 18.4. IR (CHCl3)
cmꢀ1: 1770, 1610, 1550, 1400, 1250, 1030. MS (FAB)
(glycerol) m/z: 378 [(M+1)+]. HRMS (FAB) (glycerol)
calcd for C23H24NO4 (M+1): 378.1705. Found:
378.1702.
26
D
1
½aꢁ ¼ þ70:9 (c 0.7, CH3OH). H NMR spectrum was
in good agreement with that of (ꢀ)-1.
Acknowledgements
The authors wish to thank the staff of the Analysis Cen-
ter of Meiji Pharmaceutical University for performing
the mass spectra (Ms. T. Koseki).
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