A concise synthesis of (-)-cytoxazone and (-)-4-epi-cytoxazone using chlorosulfonyl isocyanate

Article abstract of DOI:10.1016/j.tet.2006.07.073

A concise synthesis of (-)-cytoxazone and its stereoisomer (-)-4-epi-cytoxazone, novel cytokine modulators, has been accomplished each in six steps from readily available p-anisaldehyde with good diastereoselectivity. Key steps in the synthesis include th

Full text of DOI:10.1016/j.tet.2006.07.073

Tetrahedron 62 (2006) 9349–9358
A concise synthesis of (L)-cytoxazone and (L)-4-epi-cytoxazone
using chlorosulfonyl isocyanate
*
In Su Kim, Ji Duck Kim, Chae Baek Ryu, Ok Pyo Zee and Young Hoon Jung
College of Pharmacy, Sungkyunkwan University, Suwon 440-746, South Korea
Received 3 July 2006; revised 25 July 2006; accepted 26 July 2006
Available online 14 August 2006
Abstract—A concise synthesis of (ꢀ)-cytoxazone and its stereoisomer (ꢀ)-4-epi-cytoxazone, novel cytokine modulators, has been accom-
plished each in six steps from readily available p-anisaldehyde with good diastereoselectivity. Key steps in the synthesis include the
regioselective and diastereoselective amination of anti- and syn-1,2-dimethyl ethers with chlorosulfonyl isocyanate and the subsequent
regioselective cyclization of the diol to construct the oxazolidin-2-one core. The diastereoselectivity of amination reaction using CSI was
explained by the Cieplak electronic model via SN1 mechanism and neighboring group effect, leading to the retention of the configuration.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
rearrangement,7 the addition of Grignard reagents to pro-
tected imines,8 and the conjugated addition of chiral lithium
amide.9 Moreover, very recently, we reported a stereoselec-
tive synthesis of 1 via the regioselective and diastereoselec-
tive introduction of an N-protected amine group using
chlorosulfonyl isocyanate (CSI) and subsequent regioselec-
tive cyclization to give the oxazolidin-2-one unit.10 In this
paper, we describe a concise synthesis of (ꢀ)-cytoxazone
(1) and its stereoisomer (ꢀ)-4-epi-cytoxazone (2), based
on the regioselective and diastereoselective reaction using
CSI.11
Cytoxazone (1) containing a 4,5-disubstituted oxazolidin-2-
one ring is a novel cytokine modulator that was isolated from
Streptomyces sp., and was found to interfere with the produc-
tions of IL4, IL10, and IgG via the selective inhibition of the
signaling pathway in Th2 cells. The absolute configuration
of 1 was determined to be (4R,5R)-5-hydroxymethyl-4-
p-methoxyphenyl-1,3-oxazolidin-2-one based on NMR, CD,
and X-ray data,1 and was unambiguously confirmed by the
first total asymmetric synthesis reported by Nakata et al.
(Fig. 1).2a
Due to its potent bioactivity, several methods of synthesizing
(ꢀ)-cytoxazone and (ꢀ)-4-epi-cytoxazone have been re-
ported. These include Sharpless asymmetric dihydroxyla-
tion and the introduction of amine,2 Sharpless asymmetric
aminohydroxylation,3 asymmetric epoxidation and the
regioselective introduction of azide,4 the use of Petasis
reaction,5 asymmetric aldol reaction,6 imino-1,2-Wittig
2. Results and discussion
Retrosynthetic analyses of 1 and 2 are shown in Scheme 1.
Key steps for the synthesis of 1 and 2 are the regioselective
and diastereoselective introduction of an N-protected amine
group into anti-1,2-dimethyl ether 4 and syn-1,2-dimethyl
ether 5 to give the protected anti-1,2-amino alcohol 3a and
syn-1,2-amino alcohol 3b, respectively, using CSI and regio-
selective intramolecular cyclization. Compounds 4 and 5 can
be easily prepared from commercially available p-anisalde-
hyde by using the chiral borane reagents.12,13
O
O
HN
O
HN
O
OH
OH
We first investigated the regioselectivity and diastereoselec-
tivity of the reaction between CSI and anti- and syn-1,2-di-
methyl ethers 4 and 5 prior to addressing the total synthesis
of 1 and 2 (Scheme 2).
MeO
MeO
1
2
Figure 1. Structure of (ꢀ)-cytoxazone 1 and (ꢀ)-4-epi-cytoxazone 2.
In initial studies, we examined the diastereoselectivity of
the reaction of anti-1,2-dimethyl ether 4 with CSI. Treat-
ment of 4 with CSI afforded anti-1,2-amino alcohol 3a as
the major product. The ratio of anti-1,2-amino alcohol 3a
Keywords: Chlorosulfonyl isocyanate; Cytoxazone; 4-epi-Cytoxazone;
Amination.
* Corresponding author. Tel.: +82 31 290 7711; fax: +82 31 290 7773;
e-mail: yhjung@skku.ac.kr
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.073

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I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
ꢀ78 ꢁC furnished a 7.0:1 ratio (entries 1 and 2). In particular,
O
O
in toluene at ꢀ78 ꢁC (entry 6), the highest diastereoselectiv-
ity of 27:1 was obtained in 95% yield. Table 1 shows that
anti-stereoisomer of the 1,2-amino alcohol tends to be
formed as the solvent polarity is reduced.
HN
O
HN
O
OH
OH
2
1
MeO
MeO
We also examined the reaction of syn-1,2-dimethyl ether 5
with CSI in various solvents and at different temperatures.
The results are summarized in Table 2. In the case of 5,
syn-1,2-amino alcohol 3b was obtained as the major product.
NHCOOMe
NHCOOMe
OMe
3b
OMe
MeO
MeO
Although the ratio of stereoisomers was reduced versus anti-
1,2-dimethyl ether case, reaction in hexane afforded a high
diastereoselectivity of 1:9.3 in 91% yield.
3a
OMe
OMe
Byreacting anti-andsyn-1,2-dimethyletherswithCSI, itwas
found that the stereochemistry of the major product was the
same as that of the starting material, even though the reaction
between CSI and p-methoxybenzylic methyl ether prog-
resses via a carbocation intermediate and a SN1 mechanism.
OMe
OMe
MeO
MeO
5
4
O
H
The results of these reactions can be explained as follows:
First, regioselective substitution at the p-methoxybenzylic
position is expected. This is because regioselectivity was
controlled by the stability of the carbocation intermediate,
i.e., the p-methoxybenzylic carbocation is more stable than
the allyl carbocation.14 Second, the formation of anti-1,2-
amino alcohol 3a from anti-1,2-dimethyl ether 4 can be
explained by the Cieplak electronic model11c,15 via a SN1
mechanism. In this model, the vinyl group takes up an anti
position to nucleophile attack (Fig. 2).
MeO
Scheme 1. Retrosynthetic analyses of 1 and 2.
to syn-1,2-amino alcohol 3b depended on solvent and
temperature, as shown in Table 1.
The reaction in methylene chloride at 0 ꢁC gave a 5.7:1 in-
separable mixture of diastereoisomers in 94% yield, and at
OMe
OMe
MeO
4
NHCOOMe
NHCOOMe
1) CSI, Na2CO3
+
OMe
OMe
2) Na2SO3, KOH
OMe
MeO
MeO
3a
3b
OMe
MeO
5
Scheme 2. CSI reactions of anti- and syn-1,2-dimethyl ethers 4 and 5 with CSI.
Table 1. Reactions of anti-1,2-dimethyl ether 4 with CSI in various solvents and at different temperatures
NHCOOMe
OMe
NHCOOMe
1) CSI, Na2CO3
2) Na2SO3, KOH
+
OMe
OMe
OMe
MeO
MeO
MeO
4
3a
3b
Solvent
Temperature (ꢁC)
Yield (%)a
Ratio (3a:3b)b
1
2
3
4
5
6
7
8
9
CH2Cl2
0
ꢀ78
0
94
92
89
96
94
95
91
67
91
5.7:1
7.0:1
7.6:1
12:1
16:1
27:1
18:1
13:1
15:1
CHCl3
Et2O
Toluene
0
0
ꢀ78
CCl4
Hexane
0
0
ꢀ78
a
Isolated yield of pure material.
Isomer ratio determined by 1H NMR.
b

I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
9351
Table 2. Reactions of syn-1,2-dimethyl ether 5 with CSI in various solvents and at different temperatures
NHCOOMe
OMe
NHCOOMe
1) CSI, Na2CO3
2) Na2SO3, KOH
+
OMe
OMe
OMe
MeO
MeO
MeO
5
3a
3b
Solvent
Temperature (ꢁC)
Yield (%)a
Ratio (3a:3b)b
1
2
3
4
5
6
7
8
9
CH2Cl2
0
ꢀ78
0
91
92
89
74
84
94
59
81
91
1.1:1
1:1.1
1:1.2
1:1.3
1:1.4
1:2.6
1:1.5
1:4.8
1:9.3
CHCl3
Et2O
Toluene
0
0
ꢀ78
CCl4
Hexane
0
0
ꢀ78
a
Isolated yield of pure material.
Isomer ratio determined by 1H NMR.
b
the neighboring group effect, as shown in Figure 3. This
neighboring group (OMe) can use its electron pair to
interact with the backside of the carbon atom undergoing sub-
stitution, andthennucleophileattackcanonlytakeplacefrom
the front side—thus leading to retention of configuration.16
NHCOOMe
MeO
H
H
O
Me
OMe
MeO
3a
Nu
Nu = CIO2S N COOMe
Initial attack by the oxygen of p-methoxybenzylic methyl
ether on CSI yields a p-methoxybenzylic carbocation. This
attack is following an internal attack by the vicinal OMe to
yield the oxiranium with an inversion of configuration at
the p-methoxybenzylic carbon. This p-methoxybenzylic
carbon atom, in turn, undergoes an ordinary SN2 attack by
ClSO2–Nꢀ–CO2Me, with a second inversion of configura-
tion. In this case, the configuration of the product is the
same as that of the starting material. In case of syn-1,2-
dimethyl ether 5, the formation of syn-stereoisomer 3b
was slightly reduced due to the increasing steric repulsion
Figure 2. Cieplak electronic model of nucleophilic attack on the p-meth-
oxybenzylic carbocation.
However, this mechanism cannot explain the formation of
syn-stereoisomer as a major product in the case of syn-1,2-
dimethyl ether.
Therefore, another mechanism for diastereoselectivity
should be suggested. One plausible mechanism is offered by
ClO2S
N C O
H
H
H
O
COOMe
SO2Cl
and/
or
MeO
MeO
MeO
N
δ+ δ+
SO2Cl
N
OMe
O
(p-OMe)Ph
(p-OMe)Ph
(p-OMe)Ph
H
H
H
Me
anti-1,2-dimethyl ether 4
COOMe
SO2Cl
NHCOOMe
OMe
N
H
O
Ph(p-OMe)
MeO
Me
H
anti-isomer 3a
ClO2S
N C O
COOMe
SO2Cl
H
H
H
O
N
and/
or
MeO
MeO
MeO
δ+
SO2Cl
δ+
OMe
Ph(p-OMe)
N
O
H
H
H
Ph(p-OMe)
Me
(p-OMe)Ph
syn-1,2-dimethyl ether 5
COOMe
SO2Cl
NHCOOMe
OMe
N
H
H
O
MeO
Me
Ph(p-OMe)
syn-isomer 3b
Figure 3. Neighboring group effect of nucleophilic attack on the p-methoxybenzylic carbocation.

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I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
OMe
NHCOOMe
MeO
MeO
NHCOOMe
1) CSI, Na2CO3
6
+
2) Na2SO3, KOH
OMe
MeO
MeO
8a
8b
7
Scheme 3. CSI reactions of b-methyl homoallyl ethers 6 and 7 with CSI.
between the p-methoxyphenyl ring and the vinyl group
oriented in the cis form.
derived from (ꢀ)-B-methoxydiisopinocamphenyl borane
and allyl(diisopropylamino)dimethylsilane, n-butyllithium,
and N,N,N0,N0-tetramethylethylenediamine (TMEDA) in
ether at 0 ꢁC, to provide, upon workup with hydrogen per-
oxide under basic conditions, an optically pure (1R,2S)-
anti-diol 10 with high enantioselectivity (95% ee via the
Mosher ester) and diastereoselectivity (>99% ds) in 52%
yield after recrystallization (toluene). Dimethylation of
compound 10 with sodium hydride and iodomethane in
tetrahydrofuran furnished the anti-1,2-dimethyl ether 4 in
96% yield. The key reaction is the regioselective and dia-
stereoselective introduction of an N-protected amine group
to compound 4 using CSI. The treatment of compound 4
with CSI in the presence of sodium carbonate in anhydrous
toluene at ꢀ78 ꢁC, followed by reduction of an N-chlorosul-
fonyl group with an aqueous solution of 25% sodium sulfite
furnished the desired anti-1,2-amino alcohol 3a with a high
diastereoselectivity of 27:1 in 95% yield. The conversion of
compound 3a into the terminal primary alcohol 11 was
achieved in 94% yield by ozonolysis of the double bond fol-
lowed by sodium borohydride reduction.17 The regioselec-
tive deprotection of the methyl ether of compound 11 with
boron tribromide18 in methylene chloride at 0 ꢁC gave the
desired diol 12 in 80% yield without affecting the p-methoxy
group of the phenyl ring. Finally, the regioselective intra-
molecular cyclization of compound 12 using sodium
hydride7 in tetrahydrofuran at 0 ꢁC, led to formation of
(ꢀ)-cytoxazone (1) in 95% yield. Spectroscopic data and
specific rotation data of 1 were in full agreement with values
reported in the literature.2a
As the polarity of the solvent decreased, the attack of the
vicinal OMe (the neighboring group effect) become more
rapid than nucleophile attack and the diastereoselectivity
of 1,2-amino alcohol increased, and therefore, this reaction
is more efficient in nonpolar solvents.
A methyl moiety instead of a methoxy group was introduced
at the allylic position in order to confirm the neighboring
group effect (Scheme 3).
The treatment of threo-ether 6 with CSI in methylene chlo-
ride furnished an 1:1.8 mixture of threo-stereoisomer 8a and
erythro-carbamate 8b in 91% yield (entry 1). Other results
are summarized in Table 3.
The reaction between CSI and compound 6 in toluene and
hexane afforded a ratio similar to that obtained in methylene
chloride (entries 2 and 3). In addition, in the case of the
erythro-ether 7, the ratio of diastereoisomers was similar to
that obtained for the reaction between CSI and compound 6.
The results shown in Table 3 reveal that the reaction between
the b-methyl homoallyl ether and CSI is not affected by sol-
vent and progresses through a free carbocation intermediate.
Therefore, it is clear that the diastereoselectivity of the reac-
tion between CSI and 1,2-dimethyl ethers 4 and 5 can be
explained by the neighboring group effect and a partial
SN1 mechanism.
The total synthesis of (ꢀ)-4-epi-cytoxazone (2) was accom-
plished from p-anisaldehyde by using a sequence similar
to that described for the synthesis of (ꢀ)-cytoxazone
(Scheme 5).
On the basis of the above results, the total synthesis of
(ꢀ)-cytoxazone (1) was achieved from p-anisaldehyde as
a starting material (Scheme 4).
p-Anisaldehyde was reacted with B-[3-((diisopropyl-
amino)dimethylsilyl)allyl]diisopinocamphenylborane12 (9),
Treatment of p-anisaldehyde with allylmethyl ether, (+)-B-
methoxydiisopinocamphenyl borane,13 and sec-BuLi in
THF at ꢀ78 ꢁC gave alcohol 13 with moderate enantioselec-
tivity (80% ee via the Mosher ester) and high diastereoselec-
tivity (>99% ds) in 63% yield. Alcohol 13 was then
methylated with iodomethane in the presence of sodium
hydride to afford syn-1,2-dimethyl ether 5 in 78% yield, and
treatment of compound 5 with CSI in the presence of sodium
carbonate in anhydrous hexane at ꢀ78 ꢁC, followed by
reduction of an N-chlorosulfonyl group with an aqueous
solution of 25% sodium sulfite furnished the desired syn-
1,2-amino alcohol 3b in high diastereoselectivity of 1:9.3
in 91% yield. Ozonolysis of the double bond of 3b followed
by direct reduction of the resulting ozonide then gave the
Table 3. Reactions of the b-methyl homoallyl ethers 6 and 7 with CSI in
various solvents
Ether
Solvent
Yield (%)a
Ratio (8a:8b)b
1
2
3
4
5
6
6
CH2Cl2
Toluene
Hexane
CH2Cl2
Toluene
Hexane
91
83
81
83
88
75
1:1.8
1:1.7
1:1.6
1:1.2
1:1.7
1:1.8
7
a
Isolated yield of pure material.
Isomer ratio determined from the 1H NMR.
b

I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
9353
OH
O
OMe
1) 9, Et2O, –78°C
MeI, NaH
THF, 0°C
H
2) H2O2, KF, KHCO3
THF/MeOH (1:1)
OH
OMe
MeO
MeO
MeO
96%
4
10
52%
NHCOOMe
O3, –78°C
NHCOOMe
1) CSI, Na2CO3
toluene, –78°C
2) 25% Na2SO3
95%
then NaBH4, 0°C
OH
CH2Cl2/MeOH (1:2)
94%
OMe
OMe
MeO
MeO
3a ds = 27:1
11
NHCOOMe
OH
BBr3
CH2Cl2, 0°C
80%
NaH
THF, 0°C
95%
1
OH
MeO
12
Scheme 4. Total synthesis of (ꢀ)-cytoxazone (1).
OCH3
B2
O
OH
OMe
allylmethyl ether,
.
sec-BuLi, BF3 OEt2
THF, –78°C
73%
MeI, NaH
H
THF/DMF
97%
OMe
OMe
MeO
MeO
MeO
5
13
O3, –78°C
NHCOOMe
NHCOOMe
1) CSI, Na2CO3
hexane, –78°C
then NaBH4, 0°C
OH
2) 25% Na2SO3
91%
CH2Cl2/MeOH (1:2)
86%
OMe
OMe
MeO
MeO
3b
ds = 1 : 9.3
14
NHCOOMe
BBr3
CH2Cl2, 0°C
54%
NaH
2
OH
OH
THF, 0°C
82%
MeO
15
Scheme 5. Total synthesis of (ꢀ)-4-epi-cytoxazone (2).
primary alcohol 14 in 86% yield. The regioselective depro-
tection of the methyl ether of compound 14 with boron
tribromide gave the desired diol 15 in 54% yield. Finally,
the regioselective intramolecular cyclization of compound
15 afforded the (ꢀ)-4-epi-cytoxazone (2) as a crystalline
form, mp 110–112 ꢁC (EtOAc) [lit.7b 121–123 ꢁC], which
also had spectral properties (1H and 13C NMR) that were
in full agreement with values reported in the literature.7b
conditions for the diastereoselective reaction of anti- and
syn-1,2-dimethyl ethers with CSI were identified. Moreover,
the retention of configuration is explained by the neighbor-
ing group effect and a partial SN1 mechanism, and the
described synthetic protocol using CSI can be applied to
the formation of various natural products containing more
complex amines.
4. Experimental
4.1. General
3. Conclusion
In conclusion, we accomplished the total synthesis of
(ꢀ)-cytoxazone (1) and its stereoisomer (ꢀ)-4-epi-cytox-
azone (2), in six linear steps, starting from readily available
p-anisaldehyde via the regioselective and diastereoselective
introduction of an N-protected amine group using the reac-
tion of anti- and syn-1,2-dimethyl ethers with CSI, and
subsequently used regioselective cyclization to construct
the oxazolidin-2-one ring. In addition, the optimum reaction
Commercially available reagents were used without addi-
tional purification, unless otherwise stated. All anhydrous
solvents were distilled over CaH2 or P2O5 or Na/benzophe-
none prior to reaction. All reactions were performed under
an inert atmosphere of nitrogen or argon. Melting points
were measured on a Gallenkamp melting point apparatus
or Electrothermal IA9300 melting point apparatus and

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I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
were not corrected. Nuclear magnetic resonance spectra (1H
and 13C NMR) were recorded on a Varian Unity Inova
500 MHz spectrometer for CDCl3 solutions and chemical
shifts are reported as parts per million (ppm) relative to,
respectively, residual CHCl3 dH (7.26 ppm) and CDCl3 dC
(77.0 ppm) as internal standards. Resonance patterns are
reported with the notations s (singlet), d (doublet), t (triplet),
q (quartet), and m (multiplet). In addition, the notation br is
used to indicate a broad signal. Coupling constants (J) are
reported in hertz (Hz). IR spectra were recorded on a Nicolet
205 Infrared spectrophotometer or Bruker Vector 22 Infrared
spectrophotometer and are reported as cmꢀ1. Optical rota-
tions were measured with a Jasco P1020 polarimeter. Thin
layer chromatography was carried out using plates coated
with Kieselgel 60F254 (Merck). For flash column chromato-
graphy, E. Merck Kieselgel 60 (230–400 mesh) was used.
High-resolution mass spectra (HRMS) were recorded on
a JEOL, JMS-505 or JMS-600 spectrometer using the chem-
ical ionization (CI) method.
concentrated in vacuo. The residue was purified by column
chromatography (hexane/EtOAc 10:1) to afford 1.32 g
(96%) of anti-1,2-dimethyl ether 4 as a colorless oil; Rf
0.40 (hexane/EtOAc 6:1); [a]2D9 ꢀ44.6 (c 0.1, CDCl3); IR
(neat) 2934, 2822, 1612, 1512, 1464, 1302, 1248, 1174,
1
1093, 1035 cmꢀ1; H NMR (500 MHz, CDCl3) d 3.23 (s,
3H), 3.24 (s, 3H), 3.65 (dd, 1H, J¼8.0, 5.0 Hz), 3.81 (s,
3H), 4.80 (d, 1H, J¼5.0 Hz), 5.15 (dd, 1H, J¼17.5,
1.5 Hz), 5.27 (dd, 1H, J¼10.0, 1.5 Hz), 5.74 (ddd, 1H,
J¼17.5, 10.0, 8.0 Hz), 6.88 (dd, 2H, J¼6.5, 2.0 Hz), 7.23
(dd, 2H, J¼6.5, 2.0 Hz); 13C NMR (125 MHz, CDCl3)
d 55.19, 56.80, 56.95, 85.51, 86.33, 113.41, 119.17,
128.99, 130.58, 134.69, 159.14; Anal. Calcd for C13H18O3:
C, 70.24; H, 8.16. Found: C, 70.33; H, 8.04.
4.1.3. (1R,2R)-2-Methoxy-1-p-methoxyphenylbut-3-en-1-
ol (13). To a stirred solution of allylmethyl ether (2.0 g,
27.50 mmol) in anhydrous THF (15 mL) was added sec-
BuLi(19.7 mL, 27.54 mmol,1.4 Mincyclohexane)atꢀ78 ꢁC
under N2. The reaction mixture was treated with (+)-B-
methoxydiisopinocamphenylborane (6.97 g, 22.04 mmol) in
anhydrous THF (19 mL) and stirred at ꢀ78 ꢁC for 1 h. To
this solution were added boron trifluoride etherate (3.71 mL,
29.31 mmol) and a solution of p-anisaldehyde (3.0 g,
22.04 mmol) in anhydrous THF (3 mL). The reaction mixture
was stirred at ꢀ78 ꢁC for 3 h and then slowly warmed to room
temperature. The reaction mixture was concentrated in vacuo.
The residue was washed with pentane and the pentane layer
decanted. The combined pentane layers were cooled at 0 ꢁC
and treated with ethanolamine (2.7 mL). After the reaction
mixture was stirred at 0 ꢁC for 2 h, the white turbid solution
was filtered through Celite pad and concentrated in vacuo.
The residue was purified by column chromatography (hex-
ane/EtOAc 3:1) to afford 3.35 g (73%) of 13 as a colorless
oil; Rf 0.26 (hexane/EtOAc 3:1); [a]2D9 +15.8 (c 0.5, CDCl3);
IR (neat) 3468, 2936, 2834, 1614, 1512, 1464, 1303, 1249,
1175, 1097, 1035 cmꢀ1; 1H NMR (500 MHz, CDCl3) d 3.20
(d, 1H, J¼1.5 Hz), 3.38 (s, 3H), 3.60 (dd, 1H, J¼8.0,
7.5 Hz), 3.80 (s, 3H), 4.44 (dd, 1H, J¼8.0, 3.5 Hz), 5.07
(dd, 1H, J¼17.5, 1.5 Hz), 5.17 (dd, 1H, J¼17.5, 1.5 Hz),
5.51 (ddd, 1H, J¼17.5, 10.5, 7.5 Hz), 6.85 (dd, 2H, J¼7.0,
2.5 Hz), 7.25 (dd, 2H, J¼7.0, 2.5 Hz); 13C NMR (125 MHz,
CDCl3) d 55.21, 56.76, 76.32, 87.60, 113.52, 119.63, 128.55,
131.77, 134.03, 159.28; HRMS (CI) calcd for C12H16O3
[M+H+] 209.1178, found 209.1172.
4.1.1. (1R,2S)-1-p-Methoxyphenylbut-3-ene-1,2-diol (10).
To a stirred solution of allyl(diisopropylamino)dimethyl-
silane (5.10 mL, 20.86 mmol) in anhydrous Et2O (25 mL)
were added TMEDA (3.15 mL, 20.86 mmol) and n-BuLi
(13.04 mL, 20.86 mmol, 1.6 M in hexane) at 0 ꢁC under
N2. The solution was kept at 0 ꢁC for 4 h and cooled to
ꢀ78 ꢁC. The reaction mixture was treated with (ꢀ)-B-
methoxydiisopinocamphenyl borane (7.85 g, 24.83 mmol)
in anhydrous Et2O (5 mL) and stirred at ꢀ78 ꢁC for 2 h. To
this solution were added boron trifluoride etherate (3.43 mL,
27.03 mmol) and a solution of p-anisaldehyde (2.00 g,
14.69 mmol) in anhydrous Et2O (5 mL). The reaction mix-
ture was kept at ꢀ78 ꢁC for 3 h. To this mixture were added
THF (20 mL), MeOH (20 mL), KF (2.43 g, 41.87 mmol),
KHCO3 (4.19 g, 41.87 mmol), and 30% H2O2 (45 mL).
The reaction mixture was stirred at room temperature for
20 h and cooled to 0 ꢁC, and the excess H2O2 was quenched
by the addition of Na2S2O3. The mixture was diluted with
EtOAc (100 mL) and filtered through Celite pad. The Celite
pad was washed with EtOAc and the filtrate was dried over
MgSO4 and concentrated in vacuo. The residue was purified
by column chromatography (hexane/EtOAc 1:1) and recrys-
tallization (toluene) to give 1.48 g (52%) of diol 10 as a color-
less crystal; Rf 0.25 (hexane/EtOAc 1:1); mp 87–89 ꢁC; [a]D29
ꢀ73.2 (c 0.1, CDCl3); IR (CH2Cl2) 3408, 2954, 2837, 1612,
1514, 1463, 1303, 1248, 1176, 1116, 1032 cmꢀ1; 1H NMR
(500 MHz, CDCl3) d 1.93–1.99 (br, 1H), 2.30–2.37 (br,
1H), 3.81 (s, 3H), 4.25–4.33 (br, 1H), 4.66–4.70 (br, 1H),
5.24 (dd, 1H, J¼10.5, 1.5 Hz), 5.31 (dd, 1H, J¼17.0,
1.5 Hz), 5.83 (ddd, 1H, J¼17.0, 10.5, 6.5 Hz), 6.89 (dd,
2H, J¼7.0, 2.0 Hz), 7.29 (dd, 2H, J¼7.0, 2.0 Hz); 13C
NMR (125 MHz, CDCl3) d 55.52, 76.44, 77.53, 114.03,
118.07, 128.19, 132.12, 136.36, 159.59; Anal. Calcd for
C11H14O3: C, 68.02; H, 7.27. Found: C, 68.22; H, 7.29.
4.1.4. (1R,2R)-1,2-Dimethoxy-1-p-methoxyphenylbut-3-
ene (5). To a stirred solution of 13 (3.67 g, 17.62 mmol) in
anhydrous THF (36 mL) and DMF (36 mL) were added
NaH (0.85 g, 21.15 mmol, 60% in mineral oil) and MeI
(1.65 mL, 26.44 mmol) at 0 ꢁC under N2. The reaction
mixture was stirred at room temperature for 1 h and
quenched with H2O (10 mL). The aqueous layer was ex-
tracted with EtOAc (50 mL). The organic layer was washed
with H2O and brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by column chromatography
(hexane/EtOAc 6:1) to afford 3.81 g (97%) of syn-1,2-di-
methyl ether 5 as a colorless oil; Rf 0.28 (hexane/EtOAc
6:1); [a]2D9 +66.8 (c 0.1, CDCl3); IR (neat) 2934, 2822,
1612, 1586, 1512, 1464, 1303, 1247, 1174, 1094,
4.1.2. (1R,2S)-1,2-Dimethoxy-1-p-methoxyphenylbut-3-
ene (4). To a stirred solution of diol 10 (1.20 g, 6.18 mmol)
in anhydrous THF (25 mL) were added NaH (0.54 g,
13.59 mmol, 60% in mineral oil) and MeI (1.15 mL,
18.53 mmol) at 0 ꢁC under N2. The reaction mixture was
stirred at 0 ꢁC for 3 h, H2O (30 mL) was added and the solu-
tion was extracted with EtOAc (50 mL). The organic layer
was washed with H2O and brine, dried over MgSO4, and
1
1035 cmꢀ1; H NMR (500 MHz, CDCl3) d 3.23 (s, 3H),
3.33 (s, 3H), 3.74 (dd, 1H, J¼7.5, 6.5 Hz), 3.81 (s, 3H),
4.10 (d, 1H, J¼6.5 Hz), 5.08 (dd, 1H, J¼17.5, 1.5 Hz),

I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
9355
5.12 (dd, 1H, J¼10.0, 1.5 Hz), 5.49 (ddd, 1H, J¼17.5, 10.0,
7.5 Hz), 6.87 (dd, 2H, J¼6.5, 2.0 Hz), 7.20 (dd, 2H, J¼6.5,
2.0 Hz); 13C NMR (125 MHz, CDCl3) d 55.19, 56.88, 56.98,
85.76, 86.12, 113.51, 118.72, 129.08, 130.49, 134.84,
159.27; HRMS (CI) calcd for C13H18O3 [M+H+]
223.1334, found 223.1326.
using p-anisaldehyde (0.70 g, 5.14 mmol), excess of cis-2-
butene,19 n-BuLi (3.21 mL, 5.14 mmol, 1.6 M in hexane),
KOtBu (0.58 g, 5.14 mmol), (ꢀ)-B-methoxydiisopinocam-
phenyl borane (1.95 g, 6.17 mmol), and boron trifluoride
etherate (0.87 mL, 6.89 mmol), and then treated with 3 N
NaOH (3.76 mL) and 30% H2O2 (1.54 mL), and the mixture
was refluxed for 2 h. The reaction mixture was purified
by column chromatography (hexane/EtOAc 6:1) to give
0.66 g (67%) of (1S,2R)-1-p-methoxyphenyl-2-methylbut-
3-en-1-ol as a colorless oil; Rf 0.40 (hexane/EtOAc 3:1);
IR (neat) 3419, 2963, 2836, 1612, 1513, 1460, 1303, 1248,
4.1.5. (1R,2R)-1-Methoxy-1-p-methoxyphenyl-2-methyl-
but-3-ene (6). To a suspension of potassium tert-butoxide
(0.58 g, 5.14 mmol) in anhydrous THF (5 mL) were
added excess of trans-2-butene19 and n-BuLi (3.21 mL,
5.14 mmol, 1.6 M in hexane) at ꢀ78 ꢁC under N2. The reac-
tion mixturewas stirred at ꢀ45 ꢁC for 10 min and recooled to
ꢀ78 ꢁC. To this mixture was added (+)-B-methoxydi-
isopinocamphenyl borane (1.95 g, 6.17 mmol) in anhydrous
Et2O (3 mL) at ꢀ78 ꢁC and the reaction mixture was stirred
at ꢀ78 ꢁC for 30 min. To this mixture were added boron
trifluoride etherate (0.87 mL, 6.89 mmol) and a solution of
p-anisaldehyde (0.70 g, 5.14 mmol) in anhydrous Et2O
(3 mL). The reaction mixture was stirred at ꢀ78 ꢁC for 3 h,
and then treated with 3 N NaOH (3.76 mL) and 30% H2O2
(1.54 mL), and the mixture was refluxed for 1 h. The organic
layer was separated, washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (hexane/EtOAc 6:1) to give
0.64 g (65%) of (1R,2R)-1-p-methoxyphenyl-2-methylbut-
3-en-1-ol as a colorless oil; Rf 0.40 (hexane/EtOAc 3:1);
[a]2D9 +43.2 (c 0.2, CDCl3); IR (neat) 3432, 2962, 2836,
1612, 1513, 1461, 1303, 1248, 1175, 1035 cmꢀ1; 1H NMR
(500 MHz, CDCl3) d 0.97 (d, 3H, J¼6.5 Hz), 2.06–2.11 (br
d, 1H, J¼2.5 Hz), 2.47 (ddq, 1H, J¼8.0, 8.0, 6.5 Hz), 3.82
(s, 3H), 4.33 (dd, 1H, J¼8.0, 2.5 Hz), 5.19 (dd, 1H,
J¼11.0, 1.5 Hz), 5.23 (dd, 1H, J¼17.0, 1.5 Hz), 5.84 (ddd,
1H, J¼17.0, 11.0, 8.0 Hz), 6.91 (dd, 2H, J¼7.0, 2.0 Hz),
7.26 (dd, 2H, J¼7.0, 2.0 Hz); 13C NMR (125 MHz, CDCl3)
d 16.82, 46.63, 55.49, 77.75, 113.91, 116.89, 128.22,
134.86, 141.19, 159.39; HRMS (CI) calcd for C12H16O2
[M+H+] 193.1228, found 193.1226. To a stirred solution of
(1R,2R)-1-p-methoxyphenyl-2-methylbut-3-en-1-ol (0.50 g,
2.60 mmol) in THF (10 mL) were added NaH (0.11 g,
2.86 mmol, 60% in mineral oil) and MeI (0.24 mL,
3.90 mmol) at 0 ꢁC under N2. The reaction mixture was
stirred at 0 ꢁC for 3 h and quenched with H2O (5 mL). The
aqueous layer was extracted with EtOAc (20 mL). The
organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The reaction mixture
was purified by column chromatography (hexane/EtOAc
30:1) to give 0.51 g (95%) of the homoallyl ether 6 as a
colorless oil; Rf 0.40 (hexane/EtOAc 15:1); [a]2D9 +82.8 (c
0.2, CDCl3); IR (neat) 2976, 2932, 2835, 1612, 1512, 1463,
1
1175, 1098 cmꢀ1; H NMR (500 MHz, CDCl3) d 1.02 (d,
3H, J¼6.5 Hz), 1.83–1.90 (br, 1H), 2.56 (ddq, 1H, J¼7.0,
6.5, 5.5 Hz), 3.81 (s, 3H), 4.54 (d, 1H, J¼5.5 Hz), 5.03
(dd, 1H, J¼16.0, 1.5 Hz), 5.05 (dd, 1H, J¼10.5, 1.5 Hz),
5.72 (ddd, 1H, J¼16.0, 10.5, 7.0 Hz), 6.87 (dd, 2H, J¼6.5,
2.0 Hz), 7.22 (dd, 2H, J¼6.5, 2.0 Hz); 13C NMR
(125 MHz, CDCl3) d 14.64, 44.95, 55.53, 77.81, 113.72,
115.75, 127.97, 135.01, 140.59, 159.13; HRMS (CI) calcd
for C12H16O2 [M+H+] 193.1228, found 193.1225. To
a stirred solution of (1S,2R)-1-p-methoxyphenyl-2-methyl-
but-3-en-1-ol (0.50 g, 2.60 mmol) in THF (10 mL) were
added NaH (0.11 g, 2.86 mmol, 60% in mineral oil) and
MeI (0.24 mL, 3.90 mmol) at 0 ꢁC under N2. The reaction
mixture was purified by column chromatography (hexane/
EtOAc 30:1) to give 0.52 g (97%) of 7 as a colorless oil;
Rf 0.40 (hexane/EtOAc 15:1); IR (neat) 2976, 2932, 2835,
1612, 1512, 1463, 1302, 1249, 1173, 1091 cmꢀ1; 1H NMR
(500 MHz, CDCl3) d 1.07 (d, 3H, J¼6.5 Hz), 2.51 (ddq,
1H, J¼7.0, 7.0, 6.5 Hz), 3.21 (s, 3H), 3.83 (s, 3H), 3.90 (d,
1H, J¼7.0 Hz), 4.90 (dd, 1H, J¼16.0, 1.5 Hz), 4.92 (dd,
1H, J¼10.5, 1.5 Hz), 5.65 (ddd, 1H, J¼16.0, 10.5, 7.0 Hz),
6.88 (dd, 2H, J¼6.5, 2.0 Hz), 7.15 (dd, 2H, J¼6.5,
2.0 Hz); 13C NMR (125 MHz, CDCl3) d 15.87, 44.49,
55.43, 56.99, 87.68, 113.61, 114.61, 128.88, 134.79,
140.83, 159.18; HRMS (CI) calcd for C13H18O2 [M+H+]
207.1385, found 207.1381.
4.2. General procedure for the reaction of p-methoxy-
benzylic ethers with CSI
A stirred solution of Na2CO3 (6.75 mmol) in anhydrous sol-
vent (12 mL) was adjusted to ꢀ78 ꢁC, then CSI (4.50 mmol)
and p-methoxybenzylic ether (3.00 mmol) were added under
N2. The reaction mixture was stirred at ꢀ78 ꢁC, and
quenched with H2O (10 mL) when the reaction was com-
pleted (TLC monitoring), then extracted with EtOAc
(10 mLꢂ2). The organic layer was added to an aqueous
solution of Na2SO3 (25%) and KOH (10%), and the reaction
mixture was stirred at room temperature for overnight. The
organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (hexane/EtOAc).
1302, 1249, 1173, 1091 cmꢀ1
;
1H NMR (500 MHz,
CDCl3) d 0.85 (d, 3H, J¼7.0 Hz), 2.52 (ddq, 1H, J¼8.0,
7.0, 7.0 Hz), 3.19 (s, 3H), 3.84 (s, 3H), 3.88 (d, 1H,
J¼8.0 Hz), 5.04 (dd, 1H, J¼10.5, 1.5 Hz), 5.06 (dd, 1H,
J¼16.5, 1.5 Hz), 5.91 (ddd, 1H, J¼16.5, 10.5, 7.0 Hz),
6.90 (dd, 2H, J¼6.5, 2.0 Hz), 7.19 (dd, 2H, J¼6.5, 2.0 Hz);
13C NMR (125 MHz, CDCl3) d 16.63, 44.58, 55.45, 56.96,
87.99, 113.73, 114.39, 128.85, 132.73, 141.71, 159.29;
HRMS (CI) calcd for C13H18O2 [M+H+] 207.1385, found
207.1387.
4.2.1. (1R,2S)-Methyl N-(2-methoxy-1-p-methoxyphenyl-
but-3-enyl)carbamate (3a). The above general procedure
was followed using anti-1,2-dimethyl ether 4 (0.70 g,
3.15 mmol), Na2CO3 (1.10 g, 10.39 mmol), and CSI
(0.60 mL, 6.93 mmol) in anhydrous toluene (13 mL) at
ꢀ78 ꢁC. The reaction mixture was purified by column
chromatography (hexane/EtOAc 3:1) to give 0.79 g (95%,
anti:syn¼27:1) of anti-1,2-amino alcohol 3a as a white
solid; Rf 0.28 (hexane/EtOAc 3:1); mp 93–95 ꢁC; [a]D29
4.1.6. (1S,2R)-1-Methoxy-1-p-methoxyphenyl-2-methyl-
but-3-ene (7). The similar procedure for 6 was followed

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I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
ꢀ66.0 (c 0.1, CDCl3); IR (CH2Cl2) 3330, 2938, 2836, 1710,
1612, 1514, 1464, 1296, 1246, 1181, 1101, 1034 cmꢀ1; 1H
NMR (500 MHz, CDCl3) d 3.32 (s, 3H), 3.66 (s, 3H), 3.81
(s, 3H), 3.86–3.93 (br, 1H), 4.72–4.80 (br, 1H), 5.26 (dd,
1H, J¼11.0, 2.0 Hz), 5.29 (dd, 1H, J¼17.5, 2.0 Hz), 5.35–
5.42 (m, 1H), 5.50–5.60 (br, 1H), 6.86 (dd, 2H, J¼8.0,
2.0 Hz), 7.23 (dd, 2H, J¼8.0, 2.0 Hz); 13C NMR
(125 MHz, CDCl3) d 52.37, 55.45, 57.08, 57.72, 85.08,
113.77, 119.71, 129.30, 131.17, 135.06, 156.52, 159.10;
Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28.
Found: C, 63.50; H, 7.25; N, 5.33.
4.2.4. (2R,3R)-2-Methoxy-3-methoxycarbonylamino-3-p-
methoxyphenylpropan-1-ol (11). Ozone was bubbled
through a solution of anti-1,2-amino alcohol 3a (0.70 g,
2.64 mmol) in anhydrous CH2Cl2 (10 mL) and MeOH
(20 mL) at ꢀ78 ꢁC until blue color persisted, the excess
was then purged out with N2 until decolorization, and
NaBH4 (1.00 g, 26.38 mmol) was added at ꢀ78 ꢁC. The re-
action mixture was slowly warmed to 0 ꢁC, stirred at 0 ꢁC for
1 h and concentrated in vacuo. The residue was dissolved in
H2O (30 mL) and EtOAc (50 mL), the organic layer was
separated and washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (hexane/EtOAc 1:2) to give
0.67 g (94%) of alcohol 11 as a colorless syrup; Rf 0.21
(hexane/EtOAc 1:2); [a]2D9 ꢀ48.6 (c 0.1, CDCl3); IR
(CH2Cl2) 3390, 2951, 2836, 1704, 1612, 1514, 1463, 1295,
4.2.2. (1R,2R)-Methyl N-(2-methoxy-1-p-methoxy-
phenylbut-3-enyl)carbamate (3b). The above general pro-
cedure was followed using syn-1,2-dimethyl ether 5 (2.96 g,
13.32 mmol), Na2CO3 (6.35 g, 59.93 mmol), and CSI
(3.48 mL, 39.95 mmol) in anhydrous hexane (67 mL) at
ꢀ78 ꢁC. The reaction mixture was purified by column chro-
matography (hexane/EtOAc 3:1) to afford 3.21 g (91%,
syn:anti¼9.3:1) of syn-1,2-amino alcohol 3b as a white
solid; Rf 0.28 (hexane/EtOAc 3:1); [a]2D9 +55.4 (c 0.1,
CDCl3); IR (neat) 3340, 2938, 2852, 1725, 1612, 1514,
1247, 1180, 1115, 1063 cmꢀ1
;
1H NMR (500 MHz,
CDCl3) d 2.20–2.28 (br, 1H), 3.43 (ddd, 1H, J¼7.5, 5.5,
3.5 Hz), 3.46 (s, 3H), 3.50–3.56 (br d, 1H, J¼2.0 Hz), 3.68
(s, 3H), 3.64–3.75 (br, 1H), 3.82 (s, 3H), 4.97–5.03 (br,
1H), 5.82 (br d, 1H, J¼8.5 Hz), 6.89 (dd, 2H, J¼7.0,
2.0 Hz), 7.25 (dd, 2H, J¼7.0, 2.0 Hz); 13C NMR
(125 MHz, CDCl3) d 52.59, 55.24, 55.55, 58.21, 61.19,
82.84, 114.28, 128.42, 131.52, 157.15, 159.24; HRMS (CI)
calcd for C13H19NO5 [M+H+] 270.1341, found 270.1341.
1
1463, 1295, 1246, 1179, 1098 cmꢀ1; H NMR (500 MHz,
CDCl3) d 3.24 (s, 3H), 3.65 (s, 3H), 3.75–3.82 (br, 1H),
3.81 (s, 3H), 4.65–4.72 (br, 1H), 5.28 (dd, 1H, J¼17.0,
1.0 Hz), 5.30 (dd, 1H, J¼10.5, 1.0 Hz), 5.50–5.58 (br, 1H),
5.78 (ddd, 1H, J¼17.0, 10.5, 7.5 Hz), 6.87 (dd, 2H, J¼7.5,
2.0 Hz), 7.26 (dd, 2H, J¼7.5, 2.0 Hz); 13C NMR
(125 MHz, CDCl3) d 52.46, 55.50, 57.11, 58.07, 85.24,
113.93, 119.36, 128.39, 133.05, 135.53, 156.96, 159.08;
Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28.
Found: C, 63.51; H, 7.25; N, 5.23.
4.2.5. (2R,3R)-3-Methoxycarbonylamino-3-p-methoxy-
phenylpropane-1,2-diol (12). To a stirred solution of alco-
hol 11 (0.50 g, 1.86 mmol) in anhydrous CH2Cl2 (20 mL)
was added BBr3 (2.04 mL, 2.04 mmol, 1.0 M in CH2Cl2)
at 0 ꢁC under N2. The reaction mixture was stirred at 0 ꢁC
for 30 min, quenched with saturated NaHCO3 aqueous solu-
tion. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (10 mLꢂ3). The combined
organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (hexane/EtOAc 1:4) to give
0.38 g (80%) of diol 12 as a white solid; Rf 0.31 (CHCl3/
MeOH 6:1); mp 81–84 ꢁC; [a]D29 ꢀ60.0 (c 0.1, CDCl3); IR
(CH2Cl2) 3347, 2953, 2836, 1699, 1612, 1514, 1462,
4.2.3. (1R,2R)-Methyl N-(1-p-methoxyphenyl-2-methyl-
but-3-enyl)carbamate (8a) and (1S,2R)-methyl N-(1-p-
methoxyphenyl-2-methylbut-3-enyl)carbamate (8b).
The above general procedure was followed using 6
(50 mg, 0.24 mmol), Na2CO3 (58 mg, 0.55 mmol), and
CSI (32 mL, 0.36 mmol) in CH2Cl2 (2 mL) at ꢀ78 ꢁC. The
reaction mixture was purified by column chromatography
(hexane/EtOAc 3:1) to give inseparable mixture (55 mg,
91%) of anti-homoallyl ether 8a and syn-homoallyl ether
8b (ratio¼1:1.8) as a white solid; 8a: Rf 0.31 (hexane/EtOAc
3:1); 1H NMR (500 MHz, CDCl3) d 0.98 (d, 3H, J¼7.0 Hz),
6.86 (dd, 2H, J¼8.5, 2.5 Hz), 2.60 (ddq, 1H, J¼8.0, 7.0,
7.0 Hz), 3.66 (s, 3H), 3.82 (s, 3H), 4.58–4.65 (br, 1H),
4.95–5.05 (br, 1H), 5.06 (dd, 1H, J¼10.5, 1.5 Hz), 5.09
(dd, 1H, J¼16.0, 1.5 Hz), 5.60 (ddd, 1H, J¼16.0, 10.5,
8.0 Hz), 6.86 (dd, 2H, J¼8.5, 2.5 Hz), 7.12 (dd, 2H, J¼8.5,
2.5 Hz); 13C NMR (125 MHz, CDCl3) d 17.41, 43.42,
52.38, 55.50, 58.72, 113.85, 116.35, 128.53, 132.68,
139.96, 156.54, 159.01. Compound 8b: IR (CH2Cl2) 3329,
2958, 2857, 1699, 1612, 1514, 1459, 1247, 1179,
1
1296, 1248, 1179, 1101, 1031 cmꢀ1; H NMR (500 MHz,
CDCl3) d 2.42–2.48 (br, 1H), 2.62–2.72 (br, 1H), 3.67 (s,
3H), 3.60–3.75 (br, 2H), 3.80 (s, 3H), 3.84–3.93 (br d, 1H,
J¼13.5 Hz), 4.72 (dd, 1H, J¼8.0, 7.0 Hz), 5.40–5.46 (br,
1H), 6.90 (dd, 2H, J¼9.5, 2.0 Hz), 7.25 (dd, 2H, J¼9.5,
2.0 Hz); 13C NMR (125 MHz, CDCl3) d 52.73, 55.54,
57.04, 63.53, 74.04, 114.48, 128.75, 130.94, 157.48,
159.53; Anal. Calcd for C12H17NO4: C, 56.46; H, 6.71; N,
5.49. Found: C, 56.34; H, 6.73; N, 5.39.
4.2.6. (4R,5R)-5-Hydroxymethyl-4-p-methoxyphenyl-
1,3-oxazolidin-2-one [(L)-cytoxazone] (1). To a stirred
solution of diol 12 (0.30 g, 1.18 mmol) in anhydrous THF
(12 mL) was added NaH (52 mg, 1.29 mmol, 60% in min-
eral oil) at 0 ꢁC under N2. The reaction mixture was stirred
at 0 ꢁC for 2 h and quenched with H2O (10 mL), then
extracted with EtOAc (10 mLꢂ2). The organic layer was
washed with H2O and brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by column chroma-
tography (hexane/EtOAc 1:4) to give 0.25 g (95%) of
(ꢀ)-cytoxazone (1) as a white solid; Rf 0.37 (CHCl3/
MeOH 6:1); mp 118–120 ꢁC; [a]2D4 ꢀ70.9 (c 0.1, MeOH);
1H NMR (500 MHz, DMSO-d6) d 2.94–2.99 (m, 2H), 3.75
1
1034 cmꢀ1; H NMR (500 MHz, CDCl3) d 0.99 (d, 3H,
J¼6.5 Hz), 2.53 (ddq, 1H, J¼8.0, 7.0, 6.5 Hz), 3.64 (s,
3H), 3.81 (s, 3H), 4.42–4.53 (br, 1H), 4.95–5.05 (br, 1H),
5.08 (dd, 1H, J¼10.5, 1.5 Hz), 5.11 (dd, 1H, J¼16.5,
1.5 Hz), 5.74 (ddd, 1H, J¼16.5, 10.5, 8.0 Hz), 6.87 (dd,
2H, J¼8.5, 2.5 Hz), 7.17 (dd, 2H, J¼8.5, 2.5 Hz); 13C
NMR (125 MHz, CDCl3) d 16.79, 43.97, 52.36, 55.51,
59.01, 114.24, 116.47, 128.02, 133.76, 139.98, 156.64,
158.98; HRMS (CI) calcd for C14H19NO3 [M+H+]
250.1443, found 250.1451.

I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
9357
(s, 3H), 4.70 (ddd, 1H, J¼8.5, 7.5, 4.5 Hz), 4.81 (t, 1H,
J¼5.0 Hz), 4.90 (d, 1H, J¼8.5 Hz), 6.93 (dd, 2H, J¼8.5,
3.0 Hz), 7.15 (dd, 2H, J¼8.5, 3.0 Hz), 8.03–8.06 (br, 1H);
13C NMR (125 MHz, DMSO-d6) d 55.81, 56.92, 61.76,
80.77, 114.39, 128.74, 129.99, 159.47, 159.72; HRMS
(CI) calcd for C11H14NO4 [M+H+] 224.0923, found
224.0925.
0 ꢁC for 4 h and quenched with H2O (12 mL), then extracted
with EtOAc (18 mLꢂ2). The organic layer was washed with
H2O and brine, dried over MgSO4, and concentrated
in vacuo. The residue was purified by column chromato-
graphy (hexane/EtOAc 1:4) to give 0.43 g (82%) of (ꢀ)-4-
epi-cytoxazone (2) as a white solid; Rf 0.27 (CH2Cl2/
MeOH 15:1); mp 110–112 ꢁC (EtOAc); [a]D28 ꢀ22.8
(c 0.5, MeOH); IR (neat) 3256, 2962, 1746, 1725, 1614,
1515, 1417, 1305, 1252, 1175, 1102, 1023 cmꢀ1; 1H NMR
(500 MHz, acetone-d6) d 3.73 (ddd, 1H, J¼12.0, 6.0,
4.0 Hz), 3.82 (s, 3H), 3.84 (ddd, 1H, J¼12.0, 6.0, 4.0 Hz),
4.27 (dt, 1H, J¼6.0, 4.0 Hz), 4.79 (d, 1H, J¼6.5 Hz), 6.93
(br s, 1H), 6.98 (d, 1H, J¼8.5 Hz), 7.35 (d, 1H,
J¼8.5 Hz); 13C NMR (125 MHz, acetone-d6) d 54.95,
57.04, 61.84, 84.92, 114.41, 127.75, 133.29, 158.26,
160.01; HRMS (CI) calcd for C11H14NO4 [M+H+]
224.0923, found 224.0923.
4.2.7. (2S,3R)-2-Methoxy-3-methoxycarbonylamino-3-p-
methoxyphenylpropan-1-ol (14). Ozone was bubbled
through a solution of syn-1,2-amino alcohol 3b (2.15 g,
8.10 mmol) in anhydrous CH2Cl2 (20 mL) and MeOH
(40 mL) at ꢀ78 ꢁC until blue color persisted, the excess
was then purged out with N2 until decolorization, and
NaBH4 (0.77 g, 20.25 mmol) was added at ꢀ78 ꢁC. The reac-
tion mixture was slowly warmed to 0 ꢁC, stirred at 0 ꢁC for
2 h and concentrated in vacuo. The residue was dissolved in
H2O (40 mL) and EtOAc (70 mL), the organic layer was sep-
arated and washed with H2O and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by
column chromatography (hexane/EtOAc 1:2) to give 1.88 g
(86%) of alcohol 14 as a colorless syrup; Rf 0.30 (hexane/
EtOAc 1:2); [a]2D9 +64.1 (c 0.1, CDCl3); IR (neat) 3336,
2922, 2856, 2357, 1702, 1608, 1510, 1456, 1373, 1241,
Acknowledgements
This work was supported by the Korea Research Foundation
Grant (KRF-2003-015-E00232), and partially by the Brain
Korea 21 Program.
1180, 1107, 1028 cmꢀ1 1H NMR (500 MHz, CDCl3)
;
d 2.05–2.07 (br, 1H), 3.29 (s, 3H), 3.50 (ddd, 1H, J¼11.5,
7.0, 2.5 Hz), 3.60 (dd, 1H, J¼11.5, 7.0 Hz), 3.60–3.71 (m,
4H), 3.81 (s, 3H), 4.88–4.91 (br, 1H), 5.50 (br d, 1H,
J¼8.0 Hz), 6.89 (dd, 2H, J¼7.5, 2.0 Hz), 7.27 (dd, 2H,
J¼7.5, 2.0 Hz); 13C NMR (125 MHz, CDCl3) d 52.65,
54.39, 55.49, 59.47, 61.39, 84.34, 114.21, 128.03, 132.52,
157.55, 159.17; HRMS (CI) calcd for C13H20NO5 [M+H+]
270.1341, found 270.1342.
References and notes
1. (a) Kakeya, H.; Morishita, M.; Kobinata, K.; Osono, M.;
Ishizuka, M.; Osada, H. J. Antibiot. 1998, 51, 1126; (b)
Kakeya, H.; Morishita, M.; Koshino, H.; Morita, T.;
Kobayashi, K.; Osada, H. J. Org. Chem. 1999, 64, 1052.
2. (a) Sakamoto, Y.; Shiraishi, A.; Seonhee, J.; Nakata, T.
Tetrahedron Lett. 1999, 40, 4203; (b) Seki, M.; Mori, K. Eur.
J. Org. Chem. 1999, 2965.
3. Milicevic, S.; Matovic, R.; Saicic, R. N. Tetrahedron Lett.
2004, 45, 955.
4. Tosaki, S.; Tsuji, R.; Ohshima, T.; Shibasaki, M. J. Am. Chem.
Soc. 2005, 127, 2147.
5. Sugiyama, S.; Arai, S.; Ishii, K. Tetrahedron: Asymmetry 2004,
15, 3149.
6. Carter, P. H.; LaPorte, J. R.; Scherle, P. A.; Decicco, C. P.
Bioorg. Med. Chem. Lett. 2003, 13, 1237.
7. (a) Miyata, O.; Asai, H.; Naito, T. Synlett 1999, 1915; (b)
Miyata, O.; Koizumi, T.; Asai, H.; Iba, R.; Naito, T. Tetra-
hedron 2004, 60, 3893.
8. Madham, A.; Kumar, A. R.; Rao, B. V. Tetrahedron:
Asymmetry 2001, 12, 2009.
9. Davies, S. G.; Hughes, D. G.; Nicholson, R. L.; Smith, A. D.;
Wright, A. J. Org. Biomol. Chem. 2004, 2, 1549.
10. Kim, J. D.; Kim, I. S.; Jin, C. H.; Zee, O. P.; Jung, Y. H. Org.
Lett. 2005, 7, 4025.
11. (a) Kim, J. D.; Lee, M. H.; Lee, M. J.; Jung, Y. H. Tetrahedron
Lett. 2000, 41, 5073; (b) Kim, J. D.; Lee, M. H.; Han, G.; Park,
H.; Zee, O. P.; Jung, Y. H. Tetrahedron 2001, 57, 8257; (c) Kim,
J. D.; Zee, O. P.; Jung, Y. H. J. Org. Chem. 2003, 68, 3721; (d)
Kim, J. D.; Kim, I. S.; Hua, J. C.; Zee, O. P.; Jung, Y. H.
Tetrahedron Lett. 2005, 46, 1079.
4.2.8. (2S,3R)-3-Methoxycarbonylamino-3-p-methoxy-
phenylpropane-1,2-diol (15). To a stirred solution of alco-
hol 14 (1.65 g, 6.13 mmol) in anhydrous CH2Cl2 (61 mL)
was added BBr3 (7.4 mL, 7.36 mmol, 1.0 M in CH2Cl2) at
0 ꢁC under N2. The reaction mixture was stirred at 0 ꢁC
for 4 h, quenched with saturated NaHCO3 aqueous solution.
The organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (15 mLꢂ3). The combined organic
layer was washed with H2O and brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by
column chromatography (hexane/EtOAc 1:4) to give 0.74 g
(54%) of diol 15 as a white solid; Rf 0.28 (CHCl3/MeOH
10:1); mp 110–113 ꢁC; [a]D29 +16.3 (c 1.0, CDCl3); IR
(neat) 3352, 2956, 1690, 1615, 1543, 1517, 1464, 1345,
1300, 1251, 1180, 1095, 1032, 1008 cmꢀ1
;
1H NMR
(500 MHz, CDCl3) d 1.64–1.81 (br, 2H), 3.56 (dd, 1H,
J¼11.0, 6.0 Hz), 3.62 (dd, 1H, J¼11.0, 4.5 Hz), 3.70 (s,
3H), 3.81 (s, 3H), 3.94–3.98 (br, 1H), 4.78–4.81 (br, 1H),
5.41–5.43 (br, 1H), 6.91 (d, 2H, J¼7.5 Hz), 7.26 (d, 2H,
J¼7.5 Hz); 13C NMR (125 MHz, CDCl3) d 52.74, 55.54,
56.31, 64.02, 75.21, 114.50, 128.13, 131.86, 157.81,
159.45; HRMS (CI) calcd for C12H18NO5 [M+H+]
256.1185, found 256.1186.
4.2.9. (4R,5S)-5-Hydroxymethyl-4-p-methoxyphenyl-1,3-
oxazolidin-2-one [(L)-4-epi-cytoxazone] (2). To a stirred
solution of diol 15 (0.60 g, 2.66 mmol) in anhydrous THF
(13 mL) was added NaH (0.13 g, 3.19 mmol, 60% in mineral
oil) at 0 ꢁC under N2. The reaction mixture was stirred at
12. Barrett, A. G. M.; Malecha, J. W. J. Org. Chem. 1991, 56, 5243.
13. Brown, H. C.; Jadhav, P. K.; Bhat, K. S. J. Am. Chem. Soc.
1988, 110, 1535.
14. Kim, J. D.; Han, G.; Jeong, L. S.; Park, H.-J.; Zee, O. P.; Jung,
Y. H. Tetrahedron 2002, 58, 4395.

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I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
15. Cieplak, A. S. J. Am. Chem. Soc. 1981, 103, 4540.
16. (a) Allred, E. L.; Winstein, S. J. Am. Chem. Soc. 1967, 89,
3991; (b) Allred, E. L.; Winstein, S. J. Am. Chem. Soc. 1967,
89, 3998; (c) Krow, G. R.; Yuan, J.; Lin, G.; Sonnet, P. E.
Org. Lett. 2002, 4, 1259; (d) Roberts, D. D. J. Org. Chem.
1997, 62, 1857.
17. Yudina, O. N.; Sherman, A. A.; Nifantiev, N. E. Carbohydr.
Res. 2001, 332, 363.
18. (a) Demuynck, M.; De Clercq, P.; Vandewalle, M. J. Org. Chem.
1979, 44, 4863; (b) Grieco, P. A.; Nishizawa, M.; Oguri, T.;
Burke, S. D.; Marinovic, N. J. Am. Chem. Soc. 1977, 99, 5773.
19. Brown, H. C.; Bhat, K. S. J. Am. Chem. Soc. 1986, 108, 5919.