Imino 1,2-Wittig rearrangement of hydroximates and its application to synthesis of cytoxazone

Article abstract of DOI:10.1016/j.tet.2004.02.048

The imino 1,2-Wittig rearrangement of hydroximates provides a novel method for the construction of 2-hydroxyoxime ethers. Upon treatment with LDA, Z-hydroximates smoothly underwent stereoselective rearrangement to give Z-2-hydroxyoxime ethers in good yield, which were converted into amino alcohols. On the other hand, the rearrangement of E-hydroximates gave a mixture of E- and Z-2-hydroxyoxime ethers. This method was successfully applied to a practical synthesis of cytoxazone.

Full text of DOI:10.1016/j.tet.2004.02.048

Tetrahedron 60 (2004) 3893–3914
Imino 1,2-Wittig rearrangement of hydroximates and its
application to synthesis of cytoxazone
*
Okiko Miyata, Tomoko Koizumi, Hiroshi Asai, Ryuichi Iba and Takeaki Naito
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Received 26 January 2004; revised 25 February 2004; accepted 25 February 2004
Abstract—The imino 1,2-Wittig rearrangement of hydroximates provides a novel method for the construction of 2-hydroxyoxime ethers.
Upon treatment with LDA, Z-hydroximates smoothly underwent stereoselective rearrangement to give Z-2-hydroxyoxime ethers in good
yield, which were converted into amino alcohols. On the other hand, the rearrangement of E-hydroximates gave a mixture of E- and Z-2-
hydroxyoxime ethers. This method was successfully applied to a practical synthesis of cytoxazone.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
The 1,2-rearrangement of an ether 1 to its isomeric alcohol 2
which can occur upon metalation with excess organolithium
reagent is well known as the 1,2-Wittig rearrangement
(Scheme 1).1 The synthetic utilization of the 1,2-Wittig
rearrangement remains severely limited because of the rather
low yields and restricted range of substrates. Recently,
Tomooka’s group2 has modified the 1,2-Wittig rearrangement
of ethers and applied this reaction to synthesis of natural
products. There have been several papers published on the
migration of the sp2 carbon such as alkenyl,3 carbonyl,4
thiocarbonyl,5 and iminyl6 groups (3!4). Katritzky’s,6a
Uneyama’s,6b and our groups7 have developed a synthetically
useful imino 1,2-Wittig rearrangement. Katritzky’s group6a
reported that the treatment of imidate 5 with a base gave the
2-aminoketones 6, but in moderate yield (42–46%). On the
other hand, we7 found thatthe imino 1,2-Wittigrearrangement
of benzyl and allyl Z-hydroximates (N-alkoxyimidate) 7
proceededsmoothlyto givethe 2-hydroxyoximeethers8. This
reaction provides a new entry to carbon–carbon bond
formation. Furthermore, Uneyama’s group6b synthesized
biologically active compounds having a trifluoromethyl
group via the imino 1,2-Wittig rearrangement.
We disclose herein the full details of the imino 1,2-Wittig
rearrangement of benzyl and allyl hydroximates which are
indispensable in the synthesis of amino alcohols, and
application of this method to synthesis of cytoxazone 9.7
The amino alcohols are not only found in many biologically
active compounds, but also are known to be important
Keywords: Imino Wittig rearrangement; Hydroximate; Imidate; Oxime
ether; Cytoxazone.
*
Corresponding author. Tel.: þ81-78-441-7554; fax: þ81-78-441-7556;
Scheme 1.
e-mail address: taknaito@kobepharma-u.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.048

3894
O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
intermediates for the synthesis of stereo-defined acyclic and
other natural products.8
According to the known procedure,9 Z-13 was prepared via
two different routes (routes A and B) (Scheme 2). Route A
to Z-13 is accomplished via the alkylation of hydroxamates
12, prepared from the corresponding acid chlorides 10 and
alkoxyamines 11. On the other hand, route B consists of two
processes involving conversion of 12 into imidoyl halide 14
followed by treatment with alcohols 16 in the presence of a
base.
2. Results and discussion
2.1. Preparation and imino 1,2-Wittig rearrangement of
Z-hydroximates 13
We first examined the preparation of Z-13 by route A
(Table 1).
At first, we chose the Z-hydroximates 13 as the substrate of
the imino 1,2-Wittig rearrangement.
Scheme 2.
Table 1. Conversion of 12 into 13 by route A
Entry
Substrate
R1
R3
Alkyl halide
R2
Product 13, 17
Yield (%)
Ratio Z-13:17
15
R4
X
1
2
3
4
5
6
7
8
12a
12a
12a
12a
12a
12a
12a
12b
12c
12d
12e
12f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
15a
15b
15c
15d
15e
15f
15g
15a
15a
15a
15a
15a
15b
Ph
CH2vCH
MeO2C
Me
p-MeOC6H4
p-O2NC6H4
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
Me
H
H
H
H
H
H
Br
Br
Br
Br
Cl
Br
Br
Br
Br
Br
Br
Br
Br
a
b
c
d
e
f
g
h
i
98
94
28
82
74
71
82
89
91
80
40
85
97
1:2.8
1:4.5
1:0.1
1:1.1
1:6.4
1:0
1:2.8
1:2.6
1:7.6
1:4.2
1:2.3
1:3.9
1:8.0
Me
Me
Me
Me
Me
Me
PhCH2
Me
Me
Me
Me
Me
9
p-MeC6H4
PhCHvCH
Et
PhCH2CH2
PhCH2CH2
10
11
12
13
j
k
l
12f
CH2vCH
m

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
3895
Table 2. Conversion of 12 into 13 by route B
Entry
Substrate
R1
PCl5 or PPh3–CBr4
Imidoyl halide
R1
Alcohol
R2
Z-13
Yield (%)
14
X
16
1
2
3
4
5
6
7
12a
12a
12g
12g
12h
12i
Ph
Ph
PCl5
14a
14b
14c
14c
14d
14e
14f
Ph
Ph
Cl
Br
Br
Br
Br
Br
Br
16a
16b
16c
16b
16c
16c
16c
Ph
13a
13n
13p
13o
13q
13r
13s
54
59
82
56
75
52
96
PPh3–CBr4
PPh3–CBr4
PPh3–CBr4
PPh3–CBr4
PPh3–CBr4
PPh3–CBr4
PhCHvCH
CH2vCH
PhCHvCH
CH2vCH
CH2vCH
CH2vCH
p-MeOC6H4
p-MeOC6H4
o-MeOC6H4
p-MeO2CC6H4
p-O2NC6H4
p-MeOC6H4
p-MeOC6H4
o-MeOC6H4
p-MeO2CC6H4
p-O2NC6H4
12j
The alkylation of 12a with benzyl bromide in the presence
of potassium carbonate gave a 1:2.8 mixture of the
Z-hydroximate 13a and the alkoxyamide 17a in 98%
combined yield (entry 1). Similarly, 12b–f gave Z-hydroxi-
mates 13b–m accompanied with the formation of amides
17b–m as shown in entries 2–13.
Table 3. Imino 1,2-Wittig rearrangement of Z-13a
Entry Base (equiv.) Solvent T (8C) Time (h)
Yield (%)
Z-18a 19a,b
1
2
3
4
5
6
7
8
9
LDA (1)
LDA (2)
LDA (2)
LDA (2)
LDA (2)
n-BuLi (2)
t-BuLi (2)
LHMDS (2)
PhLi (2)
THF
THF
THF
Et2O
PhMe
THF
THF
THF
THF
223
223
278
223
223
223
223
223
223
1
0.5
1
0.5
0.5
1
1
2
2
35
89
80
79
62
—
19
—
—
—
—
—
54
23
—
—
According to route B, Z-13a,n–s were prepared from
12a,g–j via imidoyl halides 14a–f (Table 2). The
chlorination of hydroxamate 12a with phosphorus penta-
chloride followed by treatment of the resulting imidoyl
chloride 14a with benzyl alcohol 16a in the presence of
sodium hydride gave the Z-hydroximate 13a as the sole
product in 54% yield (entry 1). Treatment of 12g–j with
triphenylphosphine and carbon tetrabromide followed by
reaction of the resulting imidoyl bromide 14b–f with
sodium alcoholates, prepared from 16b,c, gave the Z-hydro-
ximates 13n–s by the same reaction sequence (entries 2–7).
a
—
—
a
a
The starting material was recovered.
base (n-BuLi or t-BuLi) to Z-13a followed by elimination of
the benzyloxy anion. Treatment of Z-13a with either
LHMDS (lithium hexamethyldisilazide) or phenyllithium
did not give Z-18a, but the recovered Z-hydroximate 13a
(entries 8 and 9). It is clear that the conditions using LDA
(2 equiv.) shown in entry 2 are suitable for the formation of
rearranged product Z-18a.
Next, we investigated the reaction of Z-hydroximate 13a
with various kinds of bases (Scheme 3, Table 3). The
Z-hydroximate 13a was treated with 1 equiv. of LDA in
THF at 223 8C to give Z-2-hydroxyoxime ether 18a, along
with recovered Z-hydroximate 13a (entry 1). When 2 equiv.
of LDA was used, the reaction proceeded smoothly to give
Z-18a in 89% yield (entry 2). Similarly, the reaction also
occurred in either Et2O or toluene to give Z-18a in moderate
yield (entries 4 and 5). On the other hand, use of
nucleophilic n-BuLi as a base gave the oxime ether 19a in
54% yield without formation of the desired Z-2-hydroxy-
oxime ether 18a (entry 6). In the case of t-BuLi, a mixture of
Z-18a and 19b was obtained (entry 7). The oxime ethers
19a,b would be formed by the nucleophilic addition of a
The substituent effect at the R2 position in the Z-oxime ether
was then investigated in order to establish the generality of
the rearrangement (Scheme 4, Table 4). The rearrangement
of substrate Z-13b having a vinyl group at the R2 position
proceeded smoothly at 240 8C to give the Z-2-hydroxy-
oxime ether 18b (entry 2). Similarly, Z-cinnamylhydroximate
Scheme 4.
Table 4. Imino 1,2-Wittig rearrangement of Z-13b–f,n
Entry
Substrate
R2
T (8C)
Time (h)
Yield (%)
1
2
3
4
5
6
7
Z-13b
Z-13b
Z-13n
Z-13c
Z-13d
Z-13e
Z-13f
CH2vCH
CH2vCH
PhCHvCH
CO2Me
Me
p-MeOC6H4
p-O2NC6H4
223
240
1.5
3
0.5
8
1.5
4
3
45
60 (82)a
50
240
250!0
b
—
—
—
c
223
223
c
b
240
—
a
Based on recovery of the starting material.
Many spots were observed on TLC.
The starting material was recovered.
b
c
Scheme 3.

3896
O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
13n underwent rearrangement to give the Z-2-hydroxy-
oxime ether 18n (entry 3). However, when methoxy-
carbonyl, methyl, p-methoxyphenyl, and p-nitrophenyl
groups are present at the R2 position, no desired products
were obtained (entries 4–7). In the case of Z-13d and Z-13e,
the corresponding hydroximates were recovered while
Z-13c and Z-13f gave a complex mixture, respectively.
as the sole isolated product under similar conditions (entries
8–10).
Attempted rearrangement of both the substrate Z-13g
having an active methine proton and Z-O-benzyloxy-
hydroximate 13h was unsuccessful and the substrates
Z-13g and Z-13h were mostly recovered (Fig. 1).
We next investigated the substituent effect at the R1 position
(Scheme 5, Table 5). In the case of a substituted phenyl
group having an electron-donating group, such as methyl
and methoxyl groups, the rearrangement proceeded
smoothly to give the products Z-18i, 18o, 18p, and 18q
(entries 1–4). However, the substrate Z-13r having a
methoxycarbonyl group as an electron-withdrawing group
on the benzene ring gave the desired product Z-18r in low
yield while Z-13s having a nitro group did not give Z-18s
but recovered Z-hydroximate 13s (entries 5 and 6). The
Z-cinnamylhydroximate 13j gave the desired Z-oxime ether
18j in good yield (entry 7). In order to extend the reaction to
more reactive hydroximates which carry two methylene
groups at the a- and a0-positions as shown in compound A,
we next investigated the reaction of Z-hydroximates 13k–m
having an additional active methylene group at the
a-position of the N-methoxyimino group, with LDA.
Although the presence of two active methylene groups in
these substrates Z-13k–m was expected to complicate the
reaction, the rearrangement of the Z-hydroximates 13k–m
proceeded cleanly to give the rearranged products Z-18k–m
Figure 1. Z-Hydroximates 13g and 13h.
2.2. Preparation and imino 1,2-Wittig rearrangement of
E-hydroximates 13
This rearrangement was then applied to the E-hydroximates
13a,b,j,l which were prepared as follows (Scheme 6).
According to the reported procedure,9 the reaction of
hydroxamates 12a,d,f with benzyl or allyl bromide in the
presence of silver nitrate afforded the E-hydroximates
13a,b,j,l as the major product but in low yield (Table 6).
Scheme 6.
Scheme 5.
The E/Z-geometries of hydroximates 13 were determined by
1H NMR analysis (Fig. 2, Table 7). It is known9 that the
hydroximates exhibiting signals for the hydrogen Ha and Hb
at lower field have Z-geometries while the hydroximates
showing signals at higher field have E-geometries. From the
fact that signals due to methoxy and 0allylic hydrogens of a
minor product Z-13a (OMe: d 3.94, 1 -H2: d 5.28) appeared
in down-field compared 0with those of the major product
E-13a (OMe: d 3.83, 1 -H2: d 5.18), we deduced their
stereostructures as shown. Similarly, the stereostructures of
Z-13b,j,l and E-13b,j,l were determined.
Table 5. Imino 1,2-Wittig rearrangement of Z-13i–m,o–s
Entry Substrate
R1
R2
T
(8C)
Time
(h)
Yield
(%)
1
2
3
4
5
6
7
8
9
10
Z-13i
Z-13o
Z-13p
Z-13q
Z-13r
Z-13s
Z-13j
Z-13k
Z-13l
Z-13m
p-MeC6H4
Ph
PhCHvCH 223
223 0.5
2
278 0.5
89
76
82
92
25
p-MeOC6H4
p-MeOC6H4
o-MeOC6H4
CH2vCH
CH2vCH
223
278
1
1
p-MeO2CC6H4 CH2vCH
a
—
p-O2NC6H4
PhCHvCH
Et
PhCH2CH2
PhCH2CH2
CH2vCH
Ph
Ph
Ph
223 1.5
223 1.5
223 2.5
79
64
Next, we investigated the rearrangement of E-hydroximates
13a (Scheme 7, Table 8) which proceeded to give 41%
combined yield of a 3:1 mixture of E-18a and Z-18a with
recovery of the starting material E-13a (entry 1). Since
equilibration between E-18a and Z-18a was not observed
223 2.5 75 (89)b
CH2vCH
240
2
64
a
The starting material was recovered.
Based on recovery of the starting material.
b

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
3897
Table 6. Preparation of E-hydroximates 13a,b,j,l
Entry
Substrate
R1
R2
Products
Yield (%)
Ratio (E-13:Z-13:17)
1
2
3
4
12a
12a
12d
12f
Ph
Ph
Ph
CH2vCH
Ph
Ph
a
b
j
28
42
19
6
1:0.3:0.5
1:0.2:0.1
1:0.2:0.5
1:0:0
PhCHvCH
PhCH2CH2
l
Table 8. Imino 1,2-Wittig rearrangement of E-hydroximates 13a,b,j,l
Entry
Substrate
R1
R2
Yield
E-18
Z-18
E-13
1
2
3
4
E-13a
E-13b
E-13j
E-13l
Ph
Ph
Ph
CH2vCH
Ph
Ph
31
12
31
—
10
7
28
—
20
44
17
41
PhCHvCH
PhCH2CH2
under the reaction conditions, both E-18a and Z-18a would
be the kinetic products. Similarly, rearrangement of
E-hydroximates 13b and 13j gave a mixture of E-18b,j
and Z-18b,j (entries 2 and 3). The E-hydroximate 13l having
two types of active methylene protons did not give the
rearranged products E-18l and Z-18l but gave a complex
mixture with recovery of E-13l (entry 4).
Figure 2. Z/E-Hydroximates 13.
1
Table 7. H NMR data of Z-13a,b,j,l and E-13a,b,j,l
R1
R2
Z-13 d (ppm)
10-CH2
E-13 d (ppm)
The substituent effects on the rearrangement of hydroxi-
mates 13 can be summarized as follows.
OCH3
OCH3
10-CH2
a
b
j
Ph
Ph
Ph
CH2vCH
Ph
Ph
3.94
3.91
3.91
3.80
5.28
4.71
5.29
5.20
3.83
3.80
3.86
3.71
5.18
4.66
5.14
4.96
(i) Stereostructure of oxime ether. In the case of
Z-hydroximates 13, the rearrangement proceeded
stereoselectively to give Z-oxime ethers 18 as the
sole product in good yield. On the other hand, the
E-hydroximates 13 gave a mixture of E- and Z-oxime
ethers 18 with no stereoselectivity.
PhCHvCH
PhCH2CH2
l
(ii) Substituent effects at the R1 position. The Z-hydroxi-
mates 13 having a substituted phenyl group, except for
the nitrophenyl group, underwent the rearrangement.
Particularly, the electron-donating group on the
benzene ring accelerated the rearrangement. The
reaction of Z-hydroximates 13k–m having two types
of active methylene groups also proceeded smoothly.
(iii) Substituent effects at the R2 position. The phenyl,
cinnamyl, and vinyl groups were effective for the
rearrangement while the rearrangement of Z-hydroxi-
mates 13d,e having methyl and p-methoxyphenyl
groups did not proceed. Therefore, the O-methylene
group having a moderately acidic hydrogen is required
for the successful rearrangement.
(iv) Substituent effects at the R3 position of alkoxyamino
moiety. The hydroximate having a methyl group at the
R3 position underwent rearrangement while a benzyl
group was not effective for the rearrangement.
2.3. Stereostructure determination of rearranged
products
The stereostructure of rearranged products was established
as follows (Fig. 3, Table 9). The E/Z-geometries of oxime
ethers 18a were determined by 1H NMR spectroscopy.
Scheme 7.

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O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
Figure 3. Z/E-Hydroxyoxime ethers 18.
Table 9. 1H NMR data of Z/E-2-hydroxyoxime ethers 18
R1 R2
2-H
Z-18 d (ppm)
E-18 d (ppm)
a
b
j
Ph
Ph
Ph
CH2vCH
Ph
6.15
5.47
6.05
5.55
5.04
5.63
PhCHvCH
Karabatso’s group10 reported that the oxime ethers
exhibiting signals for 2-H at lower field have Z-geometries
while the oxime ethers showing signals at higher field have
E-geometries. Signals due to hydrogen at the 2-position of
Z-isomer 18a (d 6.15) appeared in down-field compared
with those of E-isomer 18a (d 5.55). Similarly, the
stereostructures of Z-18b,j and E-18b,j were established
from their spectral data. Furthermore, the treatment of
benzoin with methoxyamine gave a 1:4 mixture of the
authentic Z-oxime ether 18a and E-isomer 18a according to
the literature.11 These spectral data were identical with
those prepared from E-hydroximate 13a.11 Since the
rearranged products Z-18i,k–r were obtained from
Z-hydroximates 13i,k–r, Z-18i,k–r were presumed to
have Z-geometries.
Scheme 8.
2.4. Plausible reaction pathway of the imino 1,2-Wittig
rearrangement
In order to clarify the reaction pathway, we investigated the
cross reaction (Scheme 8). A mixture of Z-13i and Z-13b
was treated with LDA to give only a mixture of two
products Z-18i and Z-18b without the formation of Z-18t
and Z-18a. It suggests that the newly found rearrangement
of hydroximates proceeds via an intramolecular process.
From the above results, we propose two possible reaction
pathways for this rearrangement (Schemes 9 and 10). The
first proposed reaction pathway is that rearrangement
proceeds by an ionic addition–elimination process as
proposed for the related 1,2-rearrangements (Scheme 9).3
Grovenstein’s group3a suggested that in the 1,2-Wittig
rearrangement of benzyl propenyl ether, initial cyclization
of the lithio ether, generated from benzyl propenyl ether,
proceeds by anti-addition to give the epoxide and
subsequent ring-opening of the epoxide occurs via syn-
elimination to give the product with the same configuration
at the disubstituted olefin. According to this mechanism, we
propose a possible reaction pathway of the newly found
imino Wittig rearrangement as follows. Treatment of
13 having Z-oxime ether with LDA gives the lithio ether
C which would be stabilized by chelation with the
methoxyl group. Then intramolecular addition of the
resulting carbanion C to the imino double bond proceeds
Scheme 9.

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
3899
the ethers proceeds not in a concerted fashion but via a
radical dissociation–recombination mechanism.2,12 The
cyclic intermediate C, formed from Z-13, dissociates to
the radical pair of the imidoyl radical F and the oxygen
radical G, of which oxygen radical G isomerizes to carbon
radical H. Recombination of the resulting radical pair of
imidoyl radical F and carbon radical H occurs more rapidly
than inversion of the imidoyl radical center F to geometrical
isomer I, judging from the high degree of retention at the
oxime ether group. On the rearrangement of E-hydroximate
13, it is suggested that the isomerization of the imidoyl
radical center I, formed from intermediate D isomerizes
partially to the isomer F due to steric hindrance between the
R1 group and the methoxyl group in I during the course of
the reaction.
However, we are unable to offer a detailed explanation of
the reaction pathway at present.
2.5. Reduction of 2-hydroxyoxime ether
We next investigated the conversion of 2-hydroxyoxime
ethers into 1,2-amino alcohols which are important and
versatile synthetic intermediates for the preparation of a
wide variety of natural products, drugs, and metal-binding
ligands.8 According to the reported procedure13 for
reduction of imines and oxime ethers, we examined the
reduction of Z-18a using various types of reducing reagents
(Scheme 11, Table 10). The reduction of Z-18a with LiAlH4
proceeded smoothly at 0 8C to give a mixture of threo- and
erythro-methoxyamino alcohols 20 in low yield with a ratio
of 74:26, in addition to recovered starting material Z-18
(entry 1). Further reduction of threo-20 and erythro-20 with
LiAlH4 in THF under reflux gave threo- and erythro-amino
alcohols 21, respectively, whose spectral data were identical
with those reported.13 The reduction of Z-18a with LiAlH4
in boiling THF gave demethoxylated amino alcohols threo-
21 and erythro-21 (entry 2). The reduction of Z-18a with
NaBH4 in the presence of zirconium tetrachloride gave
erythro-21 as a major product (entry 4). It is known14 that
TABH (tetramethylammonium triacetoxyborohydride) is
used for the stereoselective reduction of 2-hydroxy-oxime
ethers and -ketones. However, the reduction of Z-18a with
TABH gave only a complex mixture (entry 5). Z-18a was
Scheme 10.
in anti-fashion to give the epoxide E-1 as shown in
Newman’s projection.
Finally, the epoxide E-1 undergoes ring-opening reaction
in anti-periplanar manner involving the nitrogen lone
pair and C–O bond to afford the rearranged product
Z-18 with retention of configuration at the methoxyimino
group.
On the other hand, rearrangement of E-hydroximate 13
proceeded slowly and non-stereoselectively to give a
mixture of E-18 and Z-18. The treatment of E-13 with
LDA gives the lithio ether D which would not be stabilized
by chelation with the methoxy group and then undergoes
anti-addition to the imino group to give the epoxide E-2.
Newman’s projection shows that in the conformation E-2,
the C–O bond and lone pair are not situated in anti-
periplanar suitable for the E2 type of the final ring-opening
reaction. Therefore, there would be two possible reaction
pathways. One is E1cB type elimination from the
conformation E-2 which gives a mixture of E-18 and Z-18
products. The other is E2 type elimination from the
conformational isomers E-1 and E-3 both of which gave
the rearranged products E-18 and Z-18, respectively.
The alternative is a radical mechanism as follows
(Scheme 10). It is known that 1,2-Wittig rearrangement of
Scheme 11.

3900
O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
Table 10. Reduction of oxime ethers 18a and 22
Entry
Substrate
Reagent
T (8C)
Yield (%)
Ratio (threo-21:erythro-21:threo-20:erythro-20)
1
2
3
4
5
6
7
8
Z-18a
Z-18a
Z-18a
Z-18a
Z-18a
Z-18a
E-18a
E-18a
Z-22
LiAlH4
LiAlH4
NaBH3CN/Hþ
NaBH4/ZrCl4
TABH
SMEAH
LiAlH4
SMEAH
LiAlH4
LiAlH4
0
65
18
69
61
62
—
74
65
—
98
33
0:0:74:26
77:23:0:0
69:31:0:0
34:66:0:0
—
83:17:0:0
36:64:0:0
—
Rt!65
Rt
235
80
65
80
a
9b
10b
0
4:96:0:0
9:91:0:0
E-22
0!rt
a
Many spots were observed on TLC.
Amino alcohols threo-21 and erythro-21 were obtained by reduction followed by treatment with p-TsOH.
b
treated with SMEAH (sodium bis(2-methoxyethoxy)-
aluminum hydride) to give a mixture of threo-21 and
erythro-21 with better selectivity than those in other agents
(entry 6).
In the case of E-2-hydroxyoxime ether 18a, the reduction
with LiAlH4 gave threo-21 and erythro-21 (entry 7) while
the use of SMEAH as reducing reagent gave a complex
mixture (entry 8).
We next investigated the reduction of silylated oxime ethers
Z-22 and E-22, prepared from the alcohol Z-18a and E-18a,
respectively. The reduction of Z-22 with LiAlH4 followed
by treatment of the resulting amine with p-TsOH gave
erythro-21 in good yield and with high diastereoselectivity
(entry 9). Similarly, erythro-21 was obtained diastereo-
selectively from E-22, but in poor yield (entry 10).
The observed stereoselectivity would be explained as
follows (Scheme 12). The treatment of Z-18a with LiAlH4
or SMEAH forms intermediate M or N which is complexed
with the hydroxyl group in Z-18a. N is a conformation
according to the Felkin–Anh model, but there is steric
hindrance between the methoxyl group and the phenyl part
in the conformation N because the oxime ether 18a has
Z-configuration. Therefore, the reduction of Z-18a would
proceed via the conformation M by an intramolecular
process to give threo-21 as a major product. On the
other hand, E-18a would exist preferably in the confor-
mation N which is more stable than the conformation M
because there is no steric hindrance between the methoxyl
group and the phenyl group in the conformation N.
Therefore, E-18a gave erythro-21 as a major product. The
protected 2-hydroxyoxime ethers Z-22 and E-22 would exist
preferably in stable conformation P due to existence of
steric hindrance between two phenyl groups in the
conformation O. The hydride would attack the oxime
ether by an intermolecular process to give erythro-21 with
high stereoselectivity.
2.6. Synthesis of cytoxazone
We then applied this methodology to the synthesis of
cytoxazone 9. Cytoxazone 915 containing a 4,5-disubsti-
tuted 2-oxazolidinone ring was recently isolated from
Streptomyces sp. and the absolute configuration was
unambiguously established by the first total asymmetric
synthesis reported recently by Nakata’s group.16 Cytoxa-
zone 9 has shown a cytokine-modulating activity by
inhibiting the signaling pathway of Th2 cells. Inhibitors of
Th2-dependent cytokine production would be potent
chemotherapeutic agents in the field of immunotherapy.
Therefore, cytoxazone and its analogs have been a new
Scheme 12.

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
Table 12. Demethoxylation of methoxyamines 23
3901
Entry
Substrate
Reagent
Solvent
T (8C)
Yield (%)
24
25
1
2
3
4
threo-23
threo-23
erythro-23
erythro-23
SMEAH
LiAlH4
SMEAH
LiAlH4
THF
Et2O
THF
Et2O
65
35
65
35
52
33
—
68
19
Quant.
16
48
using SMEAH gave 2518 as a side product together with the
desired product threo-24 (entry 1). Similarly, reduction of
erythro-23 with LiAlH4 gave erythro-amino alcohol 24 as a
major product (entry 4).
We next investigated conversion of amino alcohols threo-24
and erythro-24 into trans- and cis-oxazolidinones 26
(Scheme 15, Table 13). The treatment of threo-24 with
(Boc)2O (1.1 equiv.) in the presence of DMAP gave a
mixture of threo-N-Boc-amino alcohol 27, trans-N-Boc-
oxazolidinone 28, and trans-N-nor-oxazolidinone 26 (entry
1). Acylation of threo-24 with 2.2 equiv. of (Boc)2O gave
trans-N-Boc-oxazolidinone 28 as the sole product which
was readily converted into trans-N-nor-26 (entry 2). The
trans-oxazolidinone 26 was also obtained from threo-27 by
the treatment with NaH. Similarly, the erythro-amino
alcohol 24 was converted into cis-oxazolidinone 26 via
cis-N-Boc-28 (entry 3).
Scheme 13.
Table 11. Reduction of Z-2-hydroxyoxime ether 18p
Entry
Reagent
Solvent
T
(8C)
Yield
(%)
Ratio
(erythro-23:threo-23)
1
2
3
SMEAH
LiAlH4
LiAlH4
THF
THF
Et2O
230
0
0
77
68
77
1.0:2.1
1.0:1.2
2.1:1.0
subject of synthetic studies17 for the development of a
cytokine modulator.
The cis/trans-stereostructures of oxazolidinones 26 were
determined by 1H NMR spectroscopy (Fig. 4, Table 14). It is
known19 that the oxazolidinones 29 exhibiting signals for
4-H and 5-H at lower field have cis-structure while
the oxazolidinones 29 showing those at higher field have
trans-structure. Signals due to 4-H and 5-H of cis-isomer 26
(4-H: d 4.94; 5-H: d 5.24) appeared in down-field compared
with those of trans-isomer 26 (4-H: d 4.55; 5-H: d 4.68).
We first investigated the reduction of oxime ether in Z-2-
hydroxyoxime ether 18p which was prepared in 82% yield
by rearrangement of Z-hydroximate 13p as described above
(Scheme 13, Table 11). The reduction of Z-18p with
SMEAH was carried out at 230 8C to give a 1.0:2.1 mixture
of erythro- and threo-methoxyamino alcohols 23 as a result
of reduction of the carbon–nitrogen double bond (entry 1).
On the other hand, the reduction with LiAlH4 in Et2O gave
the desired product erythro-23 as the major isomer, but with
low selectivity (entry 3).
Reductive demethoxylation of threo-23 with LiAlH4 at
higher temperature gave threo-amino alcohol 24 as the sole
product (Scheme 14, Table 12, entry 2) while the reduction
Figure 4. Structures of trans-26, 29 and cis-26, 29.
We next investigated a simple method for conversion of
rearranged product Z-18p into cis-oxazolidinone 28
(Scheme 16, Table 15). The treatment of Z-18p with
LiAlH4 (3 equiv.) gave a crude amino alcohol which was
acylated with (Boc)2O to give a 2:1 mixture of cis- and
trans-oxazolidinones 28 (entry 1). The use of either
SMEAH or B2H6-pyridine brought about formation of
trans-oxazolidinone 28 as a major product (entries 2 and 3).
Attempted reduction of oxime ether 30 having the
TBDMSO group, prepared by the treatment of Z-18p with
TBDMSOTf, was unsuccessful (entry 4).
We next converted cis- and trans-oxazolidinones 26
into (^)-cytoxazone 9 and (^)-4-epi-cytoxazone 31
Scheme 14.

3902
O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
Scheme 15.
Table 13. Acylation of amino alcohols 24 with (Boc)2O
Entry Substrate (Boc)2O
(equiv.)
Yield
(%)
trans-26 threo-27 trans-28 cis-28
1
2
3
threo-24
threo-24
erythro-24 2.2
1.1
2.2
30
—
—
9
—
—
30
82
—
—
—
44
(Scheme 17). The oxidation of cis-26 with ozone followed
by treatment with NaBH4 gave (^)-cytoxazone 9. Similarly,
(^)-4-epi-cytoxazone 31 was obtained from trans-26.
Finally, we examined optical resolution of both (^)-9 and
(^)-31 (Scheme 18). Acylation of (^)-9 with (2)-
camphanic chloride gave (4R,5R(S))-32 and (4S,5S(S))-32.
After separation of the diastereomers, the hydrolysis of
(4R,5R)-oxazolidinone 32 gave (2)-cytoxazone 9.
Similarly, (þ)-cytoxazone
9
was obtained from
Scheme 16.
(4S,5S(S))-32. (2)-9 was identical with natural (2)-
cytoxazone 9 upon comparison of the spectral and physical
data ([a]D29¼273.3 (c 0.79, MeOH; lit.15,16 [a]2D3¼275.5 (c
1.0, MeOH)) with those of authentic sample.15,16 (^)-4-epi-
cytoxazone 31 was converted into (2)-4-epi-cytoxazone 31
(([a]D29¼230.1 (c 0.70, MeOH; lit.16 ([a]2D3¼230.4 (c 1.0,
MeOH)) and (þ)-4-epi-cytoxazone 31 by the same reaction
sequence.
Our procedure would provide a practical synthetic method
for cytoxazone and its stereoisomers which would be
subjected to biological evaluations, particularly, as potent
chemotherapeutic agents in the field of immunotherapy.
Table 14. 1H NMR data of trans-26, 29 and cis-26, 29
R
trans-26, 29 d (ppm)
cis-26, 29 d (ppm)
Compound
4-H
5-H
J4,5
Compound
4-H
5-H
J4,5
PhCH2OCH2
Me2CHCH2
PhCH2
trans-29a
trans-29b
trans-29c
trans-26
3.68
3.58
3.77
4.55
4.68
4.50
4.64
4.68
7
7
6
8
cis-29a
cis-29b
cis-29c
cis-26
4.02
3.94
4.08
4.94
5.08
5.01
5.08
5.24
8
7
7
8
p-MeOC6H5

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
Table 15. Conversion of Z-18p and Z-30 into cis-28 and trans-28
3903
Entry
Substrate
Reagent
Solvent
T (8C)
Yield (%)
Ratio (cis-28:trans-28)
1
2
Z-18p
Z-18p
LiAlH4
Et2O
THF
Et2O
10% HCl–EtOH
Et2O
Et2O
0!35
230
35
Rt
35
81
49
2.1:1.0
1.0:2.1
(1) SMEAH
(2) LiAlH4
(1) BH3–py
(2) LiAlH4
LiAlH4
3
4
Z-18p
Z-30
44
—
1.0:2.3
—
0
Scheme 17.
3. Conclusion
We have developed imino 1,2-Wittig rearrangement of the
hydroximates. The feasibility of this rearrangement is
dependent upon the structure of the substrates. The
rearrangement of Z-hydroximates proceeded smoothly to
give the 2-hydroxyoxime ether in good yield while the
corresponding E-isomer gave a mixture of E- and
Z-hydroxyoxime ethers. This method was successfully
applied to the practical synthesis of cytoxazone.
4. Experimental
4.1. General
1
Melting points are uncorrected. H and 13C NMR spectra
were recorded at 200, 300, or 500 MHz and at 75 MHz,
respectively. IR spectra were recorded using FTIR
apparatus. Mass spectra were obtained by EI method.
Flash column chromatography (FCC) was preformed using
E. Merck Kieselgel 60 (230–400 mesh). Medium-pressure
column chromatography (MCC) was performed using
¨
Lober Grobe B (E. Merck 310-25, Lichroprep Si60).
Short column chromatography (SCC) was undertaken on a
short glass filter using E. Merck Kieselgel 60 (230–400
mesh) under reduced pressure.
Scheme 18.

3904
O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
4.2. General procedure for preparation of the
hydroxamates 12a–j
4.2.8. N,2-Dimethoxybenzamide (12h). A colorless oil; IR
(CHCl3) 3348 (NH), 1667 (CON) cm21 1H NMR
;
(200 MHz, CDCl3) d 3.86 and 3.88 (each 3H, s), 6.97
(1H, br d, J¼7.5 Hz), 7.10 (1H, br t, J¼7.5 Hz), 7.48 (1H,
td, J¼7.5, 2 Hz), 8.20 (1H, dd, J¼7.5, 2 Hz); HRMS
(EI, m/z) calcd for C9H11NO3 (Mþ) 181.0739, found
181.0747.
To
a stirred solution of the corresponding acid
chlorides 10 (36 mmol) in CH2Cl2 (360 mL) was added
N-methoxyamine hydrochloride 11a or N-benzyloxyamine
hydrochloride 11b (40 mmol) under a nitrogen atmosphere
at room temperature. After the solution was stirred at the
same temperature for 15 min, pyridine (84 mmol) was
added dropwise to the reaction mixture at 0 8C. After being
stirred at room temperature for 2 h, the reaction mixture was
diluted with CH2Cl2 and washed with H2O. The organic
phase was dried over Na2SO4 and concentrated at reduced
pressure. Purification of the residue by FCC (hexane/AcOEt
1:1) afforded the hydroxamates 12a–j.
4.2.9. Methyl 4-[(methoxyamino)carbonyl]benzoate
(12i).9b Colorless crystals: mp 144–146 8C (hexane/CHCl3)
(lit.9b mp 142–144 8C); IR (CHCl3) 3400 (NH), 1722
(COO), 1690 (CON) cm21; 1H NMR (200 MHz, CDCl3) d
3.85 and 3.93 (each 3H, s), 7.84 (2H, br d, J¼8 Hz), 8.05
(2H, br d, J¼8 Hz), 8.78 (1H, br s).
4.2.10. N-Methoxy-4-nitrobenzamide (12j).25 Colorless
4.2.1. N-Methoxybenzamide (12a).20 A colorless oil; IR
(CHCl3) 3252 (NH), 1684 (CON) cm21
crystals: mp 176–177 8C (hexane/CHCl3) (lit.25 mp 180–
1
;
1H NMR
181 8C); IR (CHCl3) 3420 (NH), 1670 (CON) cm21; H
(300 MHz, CDCl3) d 3.86 (3H, s), 7.37–7.53 (3H, m),
7.75 (2H, br d, J¼7 Hz); HRMS (EI, m/z) calcd for
C8H9NO2 (Mþ) 151.0633, found 151.0634.
NMR (200 MHz, CDCl3) d 3.92 (3H, s), 7.82 (2H, br d,
J¼8 Hz), 8.30 (2H, br d, J¼8 Hz), 8.83 (1H, br s).
4.3. General procedure for preparation of hydroximates
13 route A (Table 1)
4.2.2. N-(Phenylmethoxy)benzamide (12b).21 Colorless
crystals: mp 104–106 8C (hexane/CHCl3) (lit.21 mp 103–
1
104 8C); IR (CHCl3) 3253 (NH), 1684 (CON) cm21; H
To a solution of 12 (10 mmol) and K2CO3 (10 mmol) in
acetone (50 mL) was added dropwise a solution of alkyl
halides 15a–g (10 mmol) in acetone (5 mL) under a
nitrogen atmosphere at room temperature. After being
stirred at room temperature for 24 h, the reaction mixture
was diluted with H2O and extracted with CH2Cl2. The
organic phase was washed with H2O, dried over Na2SO4,
and concentrated at reduced pressure. Purification of the
residue by MCC (hexane/AcOEt 7:1) afforded the hydroxi-
mates Z-13a–m and the amides 17a–m.
NMR (300 MHz, CDCl3) d 5.04 (2H, s), 7.34–7.70 (10H,
m), 8.53 (1H, br d); HRMS (EI, m/z) calcd for C14H13NO2
(Mþ) 227.0946, found 227.0952.
4.2.3. N-Methoxy-4-methylbenzamide (12c).9b Colorless
crystals: mp 63–65 8C (hexane/CHCl3) (lit.9b mp 70–
;
71 8C); IR (CHCl3) 3223 (NH), 1668 (CON) cm21 1H
NMR (300 MHz, CDCl3) d 2.37 (3H, s), 3.83 (3H, s), 7.18
and 7.67 (each 2H, br d, J¼9 Hz), 9.80 (1H, br s); HRMS
(EI, m/z) calcd for C9H11NO2 (Mþ) 165.0789, found
165.0777.
4.3.1. Phenylmethyl (Z)-N-methoxybenzimidate (13a).
A colorless oil; IR (CHCl3) 1609 (CvN) cm21 1H
;
4.2.4. (E)-N-Methoxy-3-phenyl-2-propenamide (12d).9a
Colorless crystals: mp 93–95 8C (hexane/CHCl3); 1H NMR
(200 MHz, CDCl3) d 3.85 (3H, s), 6.49 (1H, d, J¼16 Hz),
7.60–7.28 (5H, m), 7.76 (1H, d, J¼16 Hz), 8.65 (1H, br s);
HRMS (EI, m/z) calcd for C10H11NO2 (Mþ) 177.0791,
found 177.0766.
NMR (300 MHz, CDCl3) d 3.94 (3H, s), 5.28 (2H, s),
7.29–7.49 (8H, m), 7.66 (2H, br d, J¼10 Hz); HRMS
(EI, m/z) calcd for C15H15NO2 (Mþ) 241.1102, found
241.1130.
4.3.2. N-Methoxy-N-(phenylmethyl)benzamide (17a). A
colorless oil; IR (CHCl3) 1635 (CON) cm21 1H NMR
;
(300 MHz, CDCl3) d 3.47 (3H, s), 4.92 (2H, s), 7.25–7.50
(8H, m), 7.70 (2H, br d, J¼7 Hz); HRMS (EI, m/z) calcd for
C15H15NO2 (Mþ) 241.1102, found 241.1103.
4.2.5. N-Methoxypropanamide (12e).22 A colorless oil; IR
(CHCl3) 3221 (NH), 1676 (CON) cm21
;
1H NMR
(300 MHz, CDCl3) d 1.17 (3H, t, J¼7.5 Hz), 2.14 (2H, br
s), 3.76 (3H, s), 8.83 (1H, br s); HRMS (EI, m/z) calcd for
C4H9NO2 (Mþ) 103.0632, found 103.0623.
4.3.3. 2-Propenyl (Z)-N-methoxybenzimidate (13b). A
1
colorless oil; IR (CHCl3) 1604 (CvN) cm21; H NMR
4.2.6. N-Methoxy-3-phenylpropanamide (12f).23 A color-
(300 MHz, CDCl3) d 3.91 (3H, s), 4.71 (2H, dt, J¼6,
1.5 Hz), 5.24 (1H, dq, J¼10.5, 1.5 Hz), 5.35 (1H, dq, J¼17,
1.5 Hz), 6.00 (1H, ddt, J¼17, 10.5, 6 Hz), 7.30–7.45 (3H,
m), 7.60–7.73 (2H, m); HRMS (EI, m/z) calcd for
C11H13NO2 (Mþ) 191.0946, found 191.0953.
1
less oil; IR (CHCl3) 3241 (NH), 1690 (CON) cm21; H
NMR (300 MHz, CDCl3) d 2.38 and 2.96 (each 2H, t,
J¼7.5 Hz), 3.65 (3H, s), 7.15–7.33 (5H, m), 9.08 (1H, br s);
HRMS (EI, m/z) calcd for C10H13NO2 (Mþ) 179.0946,
found 179.0946.
4.3.4. N-Methoxy-N-(2-propenyl)benzamide (17b). A
colorless oil; IR (CHCl3) 1635 (CON) cm21 1H NMR
;
4.2.7. N,4-Dimethoxybenzamide (12g).9b,24 Colorless
crystals: mp 105–107 8C (hexane/CHCl3) (lit.9b,24 mp
(300 MHz, CDCl3) d 3.34 (3H, s), 4.11 (2H, dt, J¼6 Hz),
5.04 (1H, dq, J¼10, 1.5 Hz), 5.11 (1H, dq, J¼17, 1.5 Hz),
5.74 (1H, ddt, J¼17, 10, 6 Hz), 7.13–7.25 (3H, m), 7.44
(2H, br d, J¼6 Hz).; HRMS (EI, m/z) calcd for C11H13NO2
(Mþ) 191.0946, found 191.0957.
102–103 8C); IR (CHCl3) 3261 (NH), 1680 (CON) cm21
;
1H NMR (200 MHz, CDCl3) d 3.86 and 3.88 (each 3H, s),
6.93 (2H, br d, J¼8 Hz), 7.71 (2H, br d, J¼8 Hz), 8.57 (1H,
br s).

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
3905
4.3.5. Methyl (Z)-2-[1-(methoxyimino)-1-phenyl-
methoxy]acetate (13c). A colorless oil; IR (CHCl3) 1761
(COO), 1613 (CvN) cm21; 1H NMR (300 MHz, CDCl3) d
3.79 and 3.88 (each 3H, s), 4.92 (2H, s), 7.32–7.43 (3H, m),
7.76–7.84 (2H, m); HRMS (EI, m/z) calcd for C11H13NO4
(Mþ) 223.0843, found 223.0829.
date (13h). A colorless oil; IR (CHCl3) 1611 (CvN)
1
cm21; H NMR (300 MHz, CDCl3) d 5.15 and 5.30 (each
2H, s), 7.26–7.45 (13H, m), 7.66 (2H, br d, J¼8 Hz);
HRMS (EI, m/z) calcd for C21H19NO2 (Mþ) 317.1415,
found 317.1416.
4.3.15. N-Phenylmethoxy-N-(phenylmethyl)benzamide9c
(17h). Colorless crystals: mp 67–68 8C (hexane/CHCl3)
4.3.6. Methyl [(benzoyl)(methoxy)amino]acetate (17c).
A colorless oil; IR (CHCl3) 1753 (COO), 1648 (CON)
1
(lit.9c mp 66–67 8C); IR (CHCl3) 1636 (CON) cm21; H
1
cm21; H NMR (300 MHz, CDCl3) d 3.60 and 3.80 (each
3H, s), 4.49 (2H, s), 7.38–7.51 (3H, m), 7.74 (2H, br d,
NMR (300 MHz, CDCl3) d 4.53 and 4.91 (each 2H, s),
6.90–7.70 (15H, m); HRMS (EI, m/z) calcd for C21H19NO2
(Mþ) 317.1415, found 317.1426.
J¼8 Hz).
4.3.7. Ethyl (Z)-N-methoxybenzimidate (13d). A colorless
oil; IR (CHCl3) 1611 (CvN) cm21; H NMR (300 MHz,
CDCl3) d 1.35 (3H, t, J¼7 Hz), 3.91 (3H, s), 4.25 (2H, q,
J¼7 Hz), 7.30–7.70 (5H, m); HRMS (EI, m/z) calcd for
C10H13NO2 (Mþ) 179.0946, found 179.0955.
4.3.16. Phenylmethyl (Z)-N-methoxy-4-methylbenzimi-
1
date (13i). A colorless oil; IR (CHCl3) 1612 (CvN) cm21
;
1H NMR (300 MHz, CDCl3) d 2.35 (3H, s), 3.92 (3H, s),
5.25 (2H, s), 7.10–7.56 (9H, m); HRMS (EI, m/z) calcd for
C16H17NO2 (Mþ) 255.1259, found 255.1251.
4.3.8. N-Ethyl-N-methoxybenzamide (17d). A colorless
1
4.3.17. N-Methoxy-4-methyl-N-(phenylmethyl)benza-
mide (17i). A colorless oil; IR (CHCl3) 1634 (CON)
cm21; 1H NMR (300 MHz, CDCl3) d 2.37 (3H, s), 3.47 (3H,
s), 4.91 (2H, s), 7.16–7.65 (9H, m); HRMS (EI, m/z) calcd
for C16H17NO2 (Mþ) 255.1259, found 255.1275.
oil; IR (CHCl3) 1633 (CON) cm21; H NMR (300 MHz,
CDCl3) d 1.29 (3H, t, J¼7 Hz), 3.57 (3H, s), 3.76 (2H, q,
J¼7 Hz), 7.35–7.48 (3H, m), 7.64 (2H, br d, J¼10 Hz);
HRMS (EI, m/z) calcd for C10H13NO2 (Mþ) 179.0946,
found 179.0956.
4.3.18. Phenylmethyl (Z,E)-N-methoxy-3-phenyl-2-pro-
penimidate (13j). A colorless oil; IR (CHCl3) 1636, 1580
4.3.9. (4-Methoxyphenyl)methyl (Z)-N-methoxybenzimi-
1
date (13e). A colorless oil; IR (CHCl3) 1609 (CvN) cm21
;
(CvN, CvC) cm21; H NMR (300 MHz, CDCl3) d 3.91
1H NMR (300 MHz, CDCl3) d 3.78 and 3.93 (each
3H, s), 5.21 (2H, s), 6.87 (2H, br d, J¼9 Hz), 7.24–7.67
(7H, m).
(3H, s), 5.29 (2H, s), 6.48 (1H, d, J¼16 Hz), 7.05 (1H, d,
J¼16 Hz), 7.22–7.46 (10H, m); HRMS (EI, m/z) calcd for
C17H17NO2 (Mþ) 267.1258, found 267.1286.
4.3.10. N-Methoxy-N-[(4-methoxyphenyl)methyl]benza-
4.3.19. (E)-N-Methoxy-3-phenyl-N-phenylmethyl-2-pro-
penamide (17j). A colorless oil; IR (CHCl3) 1651 (CON),
mide (17e). A colorless oil; IR (CHCl3) 1634 (CON) cm21
;
1H NMR (300 MHz, CDCl3) d 3.45 and 3.80 (each 3H, s),
4.85 (2H, s), 6.89 (2H, br d, J¼9 Hz), 7.28–7.48 (5H, m),
7.68 (2H, br d, J¼9 Hz); HRMS (EI, m/z) calcd for
C16H17NO3þH (Mþþ1) 272.1286, found 272.1275.
1615 (CvC) cm21; H NMR (300 MHz, CDCl3) d 3.71
1
(3H, s), 4.92 (2H, s), 7.06 (1H, d, J¼16 Hz), 7.80 (1H, d,
J¼16 Hz), 7.22–7.60 (10H, m); HRMS (EI, m/z) calcd for
C17H17NO2 (Mþ) 267.1258, found 267.1242.
4.3.11. (4-Nitrophenyl)methyl (Z)-N-methoxybenzimi-
date (13f). Colorless crystals: mp 67–68 8C (hexane/
CHCl3); IR (CHCl3) 1609 (CvN), 1525, 1349 (NO2)
cm21; 1H NMR (200 MHz, CDCl3) d 3.93 (3H, s), 5.39 (2H,
s), 7.32–7.70 (7H, m), 8.24 (2H, br d, J¼9 Hz); HRMS (EI,
m/z) calcd for C15H14N2O4 (Mþ) 286.0953, found 286.0964.
Anal. calcd for C15H14N2O4: C, 62.93; H, 4.93; N, 9.79,
found: C, 63.07; H, 4.64; S, 9.69.
4.3.20. Phenylmethyl (Z)-N-methoxypropanimidate
1
(13k). A colorless oil; IR (CHCl3) 1638 (CvN) cm21; H
NMR (300 MHz, CDCl3) d 1.11 (3H, t, J¼7.5 Hz), 2.23
(2H, q, J¼7.5 Hz), 3.80 (3H, s), 5.19 (2H, s), 7.23–7.40
(5H, m); HRMS (EI, m/z) calcd for C11H15NO2 (Mþ)
193.1103, found 193.1113.
4.3.21. N-Methoxy-N-(phenylmethyl)propanamide
1
(17k). A colorless oil; IR (CHCl3) 1656 (CON) cm21; H
4.3.12. 1-Phenylethyl (Z)-N-methoxybenzimidate (13g).
1
NMR (300 MHz, CDCl3) d 1.16 (3H, t, J¼7.5 Hz), 2.50
(2H, q, J¼7.5 Hz), 3.61 (3H, s), 4.79 (2H, s), 7.23–7.37
(5H, m); HRMS (EI, m/z) calcd for C11H15NO2 (Mþ)
193.1103, found 193.1075.
A colorless oil; IR (CHCl3) 1611 (CvN) cm21; H NMR
(200 MHz, CDCl3) d 1.63 (3H, d, J¼6.5 Hz), 3.87 (3H, s),
5.70 (1H, q, J¼6.5 Hz), 7.20–7.40 (8H, m), 7.59 (2H, br d,
J¼10 Hz); HRMS (EI, m/z) calcd for C16H17NO2 (Mþ)
255.1258, found 255.1237.
4.3.22. Phenylmethyl (Z)-N-methoxy-3-phenylpropani-
midate (13l). A colorless oil; IR (CHCl3) 1634 (CvN)
1
4.3.13. N-Methoxy-N-(1-phenylethyl)benzamide (17g). A
colorless oil; IR (CHCl3) 1634 (CON) cm21
cm21; H NMR (300 MHz, CDCl3) d 2.48 and 2.84 (each
;
1H NMR
2H, m), 3.80 (3H, s), 5.20 (2H, s), 7.13–7.40 (10H, m);
HRMS (EI, m/z) calcd for C17H19NO2 (Mþ) 269.1415,
found 269.1420.
(200 MHz, CDCl3) d 1.70 (3H, d, J¼7 Hz), 3.32 (3H, s,
OMe), 5.65 (1H, q, J¼7 Hz), 7.28–7.67 (10H, m); HRMS
(EI, m/z) calcd for C16H17NO2 (Mþ) 255.1258, found
255.1266.
4.3.23. N-Methoxy-N-(phenylmethyl)-3-phenylpropana-
mide (17l). A colorless oil; IR (CHCl3) 1653 (CON) cm21
;
4.3.14. Phenylmethyl (Z)-N-(phenylmethoxy)benzimi-
1H NMR (300 MHz, CDCl3) d 2.80 and 3.01 (each 2H, m),

3906
O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
3.54 (3H, s), 4.79 (2H, s), 7.15–7.40 (10H, m); HRMS (EI,
m/z) calcd for C17H19NO2 (Mþ) 269.1415, found 269.1420.
temperature. After being stirred at the same temperature for
4 h, the reaction mixture was cooled at 0 8C, diluted with
H2O and extracted with CH2Cl2. The organic phase was
washed with H2O, dried over Na2SO4, and concentrated at
reduced pressure. Purification of the residue by MCC
afforded 13n–s.
4.3.24. 2-Propenyl (Z)-N-methoxy-3-phenylpropanimi-
date (13m). A colorless oil; IR (CHCl3) 1634 (CvN) cm21
;
1H NMR (300 MHz, CDCl3) d 2.51 (2H, m), 2.89 (2H, m),
3.78 (3H, s), 4.63 (2H, dt, J¼5.5, 1.5 Hz), 5.25 (1H,
dq, J¼10.5, 1.5 Hz), 5.33 (1H, dq, J¼17, 1.5 Hz), 5.94
(1H, ddt, J¼17, 10.5, 5.5 Hz), 7.17–7.32 (5H, m); HRMS
(EI, m/z) calcd for C13H17NO2 (Mþ) 219.1258, found
219.1257.
4.5.1. (Z)-N-Methoxybenzenecarboximidoyl bromide
1
(14b).9b A colorless oil; H NMR (200 MHz, CDCl3) d
4.14 (3H, s), 7.40 (3H, m), 7.83 (2H, m).
4.5.2. (Z)-N,4-Dimethoxybenzenecarboximidoyl
bromide (14c).24 A colorless oil; 1H NMR (200 MHz,
CDCl3) d 3.83 and 4.10 (each 3H, s), 6.89 (2H, br d,
J¼8 Hz), 7.77 (2H, br d, J¼8 Hz).
4.3.25. N-Methoxy-N-(2-propenyl)-3-phenylpropana-
mide (17m). A colorless oil; IR (CHCl3) 1638 (CON)
1
cm21; H NMR (300 MHz, CDCl3) d 2.75 (2H, m), 2.97
(2H, m), 3.61 (3H, s), 4.22 (2H, br d, J¼6 Hz), 5.19 (1H,
dq, J¼10, 1.5 Hz), 5.23 (1H, dq, J¼17, 1.5 Hz), 5.82
(1H, ddt, J¼17, 10, 6 Hz), 7.15–7.32 (5H, m); HRMS
(EI, m/z) calcd for C13H17NO2 (Mþ) 219.1258, found
219.1249.
4.5.3. (Z)-N,2-Dimethoxybenzenecarboximidoyl
bromide (14d). A colorless oil; 1H NMR (200 MHz,
CDCl3) d 3.88 and 4.11 (each 3H, s), 6.94 (1H, br d,
J¼7 Hz), 6.96 (1H, td, J¼7, 1 Hz), 7.32 (1H, dd, J¼7,
2 Hz), 7.39 (1H, td, J¼7, 2 Hz).
4.4. Route B
4.5.4. Methyl (Z)-4-[bromo(methoxyimino)methyl]-
benzoate (14e).24 A colorless oil; 1H NMR (200 MHz,
CDCl3) d 3.94 and 4.17 (each 3H, s), 7.89 (2H, br d,
J¼8 Hz), 8.05 (2H, br d, J¼8 Hz).
Table 2, entry 1. To a solution of 12a (0.5 mmol) in benzene
(1 mL) was added phosphorus pentachloride (0.75 mmol)
by small portion under a nitrogen atmosphere at 0 8C. After
being stirred at the same temperature for 2 h, the reaction
mixture was diluted with H2O and extracted with CH2Cl2.
The organic phase was washed with H2O, dried over
Na2SO4, and concentrated at reduced pressure to afford the
crude hydroximoyl chloride 14a. After being characterized
by NMR spectra, 14a was immediately subjected to the
following reaction. To a suspension of NaH (60% oil
suspension) (100 mg, 2.5 mmol) in THF was added benzyl
alcohol 16a (270 mg, 2.5 mmol) under a nitrogen atmo-
sphere at 0 8C. After being stirred at room temperature for
20 min, a solution of the crude hydroximoyl chloride 14a in
THF (5 mL) was added at reflux. The reaction mixture was
heated at reflux for a further 2 h, and then cooled at 0 8C,
diluted with H2O and extracted with CH2Cl2. The organic
phase was washed with H2O, dried over Na2SO4, and
concentrated at reduced pressure. Purification of the residue
by MCC (hexane/AcOEt 7:1) afforded 13a (65 mg, 54%
from 12a).
4.5.5. (Z)-N-Methoxy-4-nitrobenzenecarboximidoyl
bromide (14f).26 A colorless oil; 1H NMR (200 MHz,
CDCl3) d 4.20 (3H, s), 7.90 (2H, br d, J¼8 Hz), 8.25 (2H, br
d, J¼8 Hz).
4.5.6. 3-Phenyl-2-propenyl (Z)-N-methoxybenzimidate
1
(13n). A colorless oil; IR (CHCl3) 1609 (CvN) cm21; H
NMR (300 MHz, CDCl3) d 3.95 (3H, s), 4.87 (2H, dd,
J¼6.5, 1.5 Hz), 6.36 (1H, dt, J¼16, 6.5 Hz), 6.64 (1H, d,
J¼16 Hz), 7.27–7.41 (8H, m), 7.69–7.72 (2H, m); 13C
NMR (75 MHz, CDCl3) d 62.4, 72.1, 124.1, 126.6, 127.2,
128.0, 128.3, 128.5, 130.0, 130.9, 133.9, 136.3, 154.3;
HRMS (EI, m/z) calcd for C17H17NO2 (Mþ) 267.1258,
found 267.1257.
4.5.7. 2-Propenyl (Z)-N,4-dimethoxybenzimidate (13p).
1
A colorless oil; IR (CHCl3) 1609 (CvN) cm21; H NMR
(200 MHz, CDCl3) d 3.82 and 3.90 (each 3H, s), 4.70 (2H,
dt, J¼6, 2 Hz), 5.24 (1H, dq, J¼10, 2 Hz), 5.34 (1H, dq,
J¼17, 2 Hz), 6.00 (1H, ddt, J¼17, 10, 6 Hz), 6.88 (2H, br d,
J¼8 Hz), 7.63 (2H, br d, J¼8 Hz); HRMS (EI, m/z) calcd
for C12H15NO3 (Mþ) 221.1051, found 221.1059.
4.5. Route B
Table 2, entries 2–7. To a solution of 12a–j (12.8 mmol) in
MeCN (100 mL) was added Ph3P (19.2 mmol) under a
nitrogen atmosphere at room temperature. After being
stirred at the same temperature for 10 min, CBr4
(19.2 mmol) was added to the reaction mixture. After
refluxing for 3 h, the resulting solution was concentrated at
reduced pressure. Purification of the residue by FCC
(hexane!hexane/AcOEt 10:1) afforded the hydroximoyl
bromide 14b–f. After being characterized by NMR spectra,
14b–f was immediately subjected to the following reaction.
To a suspension of NaH (60% oil suspension) (32 mmol) in
THF (40 mL) was added a solution of alcohols 16b,c
(48 mmol) in THF (40 mL) under a nitrogen atmosphere at
0 8C. After being stirred at room temperature for 20 min, a
solution of the hydroximoyl bromide 14b–f (16 mmol) in
THF (80 mL) was added to reaction mixture at room
4.5.8. 3-Phenyl-2-propenyl (Z)-N,4-dimethoxybenzimi-
date (13o). A colorless oil; IR (CHCl3) 1608 (CvN)
cm21; 1H NMR (300 MHz, CDCl3) d 3.83 (3H, s), 3.93 (3H,
s), 4.85 (2H, dd, J¼6.5, 1.5 Hz), 6.36 (1H, dt, J¼16,
6.5 Hz), 6.64 (1H, d, J¼16 Hz), 6.89 (2H, br d, J¼9 Hz),
7.28–7.40 (5H, m), 7.64 (2H, br d, J¼9 Hz); 13C NMR
(75 MHz, CDCl3) d 55.3, 62.3, 72.1, 113.8, 123.3,
124.3, 126.7, 128.0, 128.6, 128.8, 133.8, 136.3, 161.1;
HRMS (EI, m/z) calcd for C12H15NO3 (Mþ) 221.1051,
found 221.1059.
4.5.9. 2-Propenyl (Z)-N,2-dimethoxybenzimidate (13q).
1
A colorless oil; IR (CHCl3) 1610 (CvN) cm21; H NMR

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
3907
(200 MHz, CDCl3) d 3.86 and 3.90 (each 3H, s), 4.34
(2H, dt, J¼5.5, 1.5 Hz), 5.16 (1H, dq, J¼10.5, 1.5 Hz),
5.22 (1H, dq, J¼17, 1.5 Hz), 5.90 (1H, ddt, J¼17, 10.5,
5.5 Hz), 6.92 (1H, br d, J¼7 Hz), 6.98 (1H, td, J¼7, 1 Hz),
7.33 (1H, dd, J¼7, 2 Hz), 7.42 (1H, td, J¼7, 2 Hz); HRMS
(EI, m/z) calcd for C12H15NO3 (Mþ) 221.1051, found
221.1027.
for 19a, the treatment of 13a (241 mg, 1 mmol) with t-BuLi
(1.46 M in pentane) (1.37 mL, 2 mmol) gave 19b (44 mg,
23%) as a colorless oil and 18a (46 mg, 19%). 19b:1H NMR
(300 MHz, CDCl3) d 1.24 (9H, s), 3.89 (3H, s), 7.15–7.35
(5H, m). NOE was observed between methoxy group (d
3.89) and t-butyl group (d 1.24) in NOESY spectroscopy.
HRMS (EI, m/z) calcd for C12H17NO (Mþ) 191.1309, found
191.1301.
4.5.10. Methyl (Z)-4-[(methoxyimino)(2-propenyloxy)-
methyl]benzoate (13r). A colorless oil; IR (CHCl3) 1718
(COO), 1613 (CvN) cm21; 1H NMR (200 MHz, CDCl3) d
3.82 and 3.90 (each 3H, s), 4.70 (2H, dt, J¼6, 2 Hz), 5.24
(1H, dq, J¼10, 2 Hz), 5.34 (1H, dq, J¼17, 2 Hz), 6.00 (1H,
ddt, J¼17, 10, 6 Hz), 7.78 (2H, br d, J¼8 Hz), 8.02 (2H, br
d, J¼8 Hz); HRMS (EI, m/z) calcd for C13H15NO4 (Mþ)
249.1000, found 249.1012.
4.6. Wittig rearrangement of Z-hydroximates 13b,i–r
According to the procedure given for 18a, the treatment of
Z-hydroximates 13b,i–r with LDA at the temperature
shown in Tables 4 and 5 gave 18b,i–r.
4.6.1. (Z)-2-Hydroxy-1-phenyl-3-buten-1-one O-methyl-
oxime (18b). Colorless crystals: mp 45–46 8C (hexane/
CHCl3); IR (CHCl3) 3531 (OH) cm21; 1H NMR (300 MHz,
CDCl3) d 3.38 (1H, br d, J¼9 Hz), 3.99 (3H, s), 5.24 (1H, dt,
J¼10.5, 2 Hz), 5.38 (1H, dt, J¼17, 2 Hz), 5.47 (1H, ddt,
J¼9, 5, 2 Hz), 6.13 (1H, ddd, J¼17, 10.5, 5 Hz), 7.30–7.40
(3H, m), 7.53–7.62 (2H, m); HRMS (EI, m/z) calcd for
C11H13NO2 (Mþ) 191.0946, found 191.0951. Anal. calcd
for C11H13 NO2: C, 69.09; H, 6.85; N, 7.33, found: C, 69.15;
H, 6.81; N, 7.29.
4.5.11. 2-Propenyl (Z)-N-methoxy-4-nitrobenzimidate
1
(13s). A colorless oil; IR (CHCl3) 1611 (CvN) cm21; H
NMR (200 MHz, CDCl3) d 3.96 (3H, s), 4.86 (2H, dt, J¼6,
2 Hz), 5.24 (1H, dq, J¼10, 2 Hz), 5.34 (1H, dq, J¼17,
2 Hz,), 6.00 (1H, ddt, J¼17, 10, 6 Hz), 7.93 (2H, br d,
J¼8 Hz), 8.21 (2H, br d, J¼8 Hz); HRMS (EI, m/z) calcd
for C11H12N2O4 (Mþ) 236.0796, found 236.0802.
4.5.12. (Z)-2-Hydroxy-1,2-diphenylethanone O-methyl-
oxime (18a). Table 3, entry 2. A solution of Z-hydroximate
13a (241 mg, 1 mmol) in THF (5 mL) was added with
stirring at 223 8C to a LDA solution, prepared from
diisopropylamine (0.28 mL, 2 mmol) and n-BuLi (1.65 M
in hexane)(1.2 mL, 2 mmol) under nitrogen atmosphere.
After being stirred at the same temperature for 30 min, the
reaction mixture was diluted with saturated aqueous NH4Cl
and extracted with CH2Cl2. The organic phase was washed
with H2O, dried over Na2SO4, and concentrated at reduced
pressure. Purification of the residue by MCC (hexane/
AcOEt 7:1) afforded 18a (214 mg, 89%) as colorless
crystals, mp 76–78 8C (hexane/CHCl3) (lit.11 77–
4.6.2. (Z)-2-Hydroxy-1-(4-methylphenyl)-2-phenyletha-
none O-methyloxime (18i). A colorless oil; IR (CHCl3)
3526 (OH) cm21; 1H NMR (300 MHz, CDCl3) d 2.33 (3H,
s), 3.77 (1H, br d, J¼9.5 Hz), 3.97 (3H, s), 6.12 (1H, d,
J¼9.5 Hz), 7.13 (2H, br d, J¼8 Hz), 7.23–7.45 (7H, m);
HRMS (EI, m/z) calcd for C16H17NO2 (Mþ) 255.1258,
found 255.1254.
4.6.3. (Z,E)-1-Hydroxy-1,4-diphenyl-3-buten-2-one
O-methyloxime (18j). Colorless crystals: mp 98–100 8C
1
(hexane/CHCl3); IR (CHCl3) 3532 (OH) cm21; H NMR
(300 MHz, CDCl3) d 3.63 (1H, br d, J¼8 Hz), 3.93 (3H, s),
6.05 (1H, d, J¼8 Hz), 6.82 (1H, d, J¼16.5 Hz), 7.10 (1H, d,
J¼16.5 Hz), 7.23–7.46 (10H, m); HRMS (EI, m/z) calcd for
C17H17NO2 (Mþ) 267.1258, found 267.1249. Anal. calcd
for C17H17NO2: C, 76.38; H, 6.41; N, 5.24, found: C, 76.34;
H, 6.12; N, 5.28.
77.5 8C). IR (CHCl3) 3532 (OH) cm21
;
1H NMR
(300 MHz, CDCl3) d 3.71 (1H, br d, J¼9 Hz), 3.98 (3H,
s), 6.15 (1H, d, J¼9 Hz), 7.25–7.54 (10H, m); 13C NMR
(75 MHz, CDCl3) d 62.4, 71.1, 116.0, 127.3, 128.4, 129.4,
131.2, 139.9, 157.0; HRMS (EI, m/z) calcd for C15H15NO2
(Mþ) 241.1102, found 241.1112.
4.6.4. (Z)-1-Hydroxy-1-phenyl-2-butanone O-methyl-
oxime (18k). A colorless oil; IR (CHCl3) 3478 (OH)
4.5.13. (Z)-1-Phenyl-1-pentanone O-methyloxime (19a).
A solution of Z-hydroximate 13a (241 mg, 1 mmol) in THF
(5 mL) was added with stirring at 223 8C to a solution of
n-BuLi (1.65 M in hexane)(1.2 mL, 2 mmol) in THF
(30 mL) under nitrogen atmosphere. After being stirred at
the same temperature for 1 h, the reaction mixture was
diluted with saturated aqueous NH4Cl and extracted with
CH2Cl2. The organic phase was washed with H2O, dried
over Na2SO4, and concentrated at reduced pressure.
Purification of the residue by MCC (hexane/AcOEt 7:1)
cm21
;
1H NMR (300 MHz, CDCl3) d 1.06 (3H, t,
J¼7.5 Hz), 2.20 (1H, dq, J¼16, 7.5 Hz), 2.34 (1H, dq,
J¼16, 7.5 Hz), 3.19 (1H, br d, J¼6.5 Hz), 3.87 (3H, s), 5.81
(1H, d, J¼6.5 Hz), 7.25–7.42 (5H, m); HRMS (EI, m/z)
calcd for C11H15NO2 (Mþ) 193.1103, found 193.1085.
4.6.5. (Z)-1-Hydroxy-1,4-diphenyl-2-butanone
O-methyloxime (18l). A colorless oil; IR (CHCl3) 3521
1
(OH) cm21; H NMR (300 MHz, CDCl3) d 2.45 and 2.60
1
afforded 19a (103 mg, 54%) as a colorless oil. H NMR
(each 1H, ddd, J¼15.5, 10, 6 Hz), 2.80 (2H, m), 2.97 (1H, br
d, J¼6 Hz), 3.88 (3H, s), 5.90 (1H, d, J¼6 Hz), 7.10–7.42
(10H, m); HRMS (EI, m/z) calcd for C17H19NO2 (Mþ)
269.1415, found 269.1408.
(200 MHz, CDCl3) d 0.91 (3H, t, J¼7 Hz), 1.59 (4H, m),
2.74 (2H, t, J¼7.5 Hz), 3.97 (3H, s), 7.30–7.66 (5H, m);
HRMS (EI, m/z) calcd for C12H17NO (Mþ) 191.1309, found
191.1294.
4.6.6. (Z)-4-Hydroxy-1-phenyl-5-hexen-3-one O-methyl-
oxime (18m). A colorless oil; IR (CHCl3) 3475 (OH) cm21
;
1H NMR (300 MHz, CDCl3) d 2.53 (2H, m), 2.78 (1H, br d,
4.5.14. (Z)-1-Phenyl-2,2-dimethylpropan-1-one
O-methyloxime (19b). According to the procedure given

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O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
J¼5.5 Hz), 2.86 (2H, t, J¼8 Hz), 3.86 (3H, s), 5.20 (2H, m),
5.34 (1H, dt, J¼17, 1 Hz), 5.97 (1H, ddd, J¼17, 10, 5.5 Hz),
7.15–7.31 (5H, m); HRMS (EI, m/z) calcd for C17H19NO2
(Mþ) 269.1415, found 269.1408.
H2O (2.5 mL) under a nitrogen atmosphere at room
temperature. The precipitated silver salt was separated
from the solution by filtration, washed with acetone, and
dried. To a suspension of the silver salt in Et2O (3 mL) was
added a solution of benzyl bromide or allyl bromide
(6.0 mmol) in Et2O (0.3 mL) under a nitrogen atmosphere
at room temperature. After being stirred at the same
temperature for 24 h, the reaction mixture was filtered to
remove AgBr. The filtrate was concentrated at reduced
pressure and the residue was purified by MCC (hexane/
AcOEt 3:1) to afford E-hydroximates 13a,b,j,l, Z-hydroxi-
mates 13a,b,j, and amides 17a,b,j in the yields as shown in
Table 6.
4.6.7. (Z,E)-2-Hydroxy-1,4-diphenyl-3-buten-1-one
O-methyloxime (18n). A colorless oil; IR (CHCl3) 1609
1
(CvN) cm21; H NMR (300 MHz, CDCl3) d 3.57 (1H, d,
J¼9 Hz), 4.02 (3H, s), 5.62 (1H, ddd, J¼9, 5.5, 1.5 Hz),
6.46 (1H, dd, J¼16, 5.5 Hz), 6.70 (1H, dd, J¼16, 1.5 Hz),
7.25–7.40 (8H, m), 7.59–7.64 (2H, m); 13C NMR (75 MHz,
CDCl3)
d 62.6, 71.0, 126.6, 127.3, 127.4, 127.9,
128.5, 128.5, 129.4, 131.4, 133.5, 136.4, 158.7; HRMS
(EI, m/z) calcd for C17H17NO2 (Mþ) 221.1051, found
221.1059.
4.7.1. Phenylmethyl (E)-N-methoxybenzimidate (13a). A
1
colorless oil; IR (CHCl3) 1623 (CvN) cm21; H NMR
4.6.8. (Z,E)-2-Hydroxy-1-(4-methoxyphenyl)-4-phenyl-
3-buten-1-one (18o). A colorless oil; IR (CHCl3) 3530
(300 MHz, CDCl3) d 3.83 (3H, s), 5.18 (2H, s), 7.28–7.83
(10H, m); HRMS (EI, m/z) calcd for C15H15NO2 (Mþ)
241.1102, found 241.1077.
1
(OH), 1608 (CvN) cm21; H NMR (300 MHz, CDCl3) d
3.60 (1H, d, J¼9 Hz), 3.81 (3H, s), 4.01 (3H, s), 5.59 (1H,
ddd, J¼9, 6, 1.5 Hz), 6.47 (1H, dd, J¼16, 6 Hz), 6.68 (1H,
dd, J¼16, 1.5 Hz), 6.89 (2H, br d, J¼9 Hz), 7.21–7.40 (5H,
m), 7.58 (2H, br d, J¼9 Hz); 13C NMR (75 MHz, CDCl3) d
55.3, 62.5, 71.2, 113.9, 125.9, 126.6, 127.5, 127.8, 128.5,
128.7, 131.4, 136.5, 158.3, 160.6; HRMS (EI, m/z) calcd for
C18H19NO3 (Mþ) 297.1364, found 297.1367.
4.7.2. 2-Propenyl (E)-N-methoxybenzimidate (13b). A
1
colorless oil; IR (CHCl3) 1622 (CvN) cm21; H NMR
(300 MHz, CDCl3) d 3.80 (3H, s), 4.66 (2H, dt, J¼5.5,
1.5 Hz), 5.26 (1H, dq, J¼10.5, 1.5 Hz), 5.40 (1H, dq, J¼17,
1.5 Hz), 6.08 (1H, ddt, J¼17, 10.5, 5.5 Hz), 7.35–7.80 (5H,
m); HRMS (EI, m/z) calcd for C11H13NO2 (Mþ) 191.0946,
found 191.0953.
4.6.9. (Z)-2-Hydroxy-1-(4-methoxyphenyl)-3-buten-1-
one O-methyloxime (18p). Colorless crystals: mp 83–
4.7.3. Phenylmethyl (E,E)-N-methoxy-3-phenyl-2-pro-
penimidate (13j). A colorless oil; IR (CHCl3) 1637
1
85 8C (hexane/CHCl3); IR (CHCl3) 3516 (OH) cm21; H
1
NMR (300 MHz, CDCl3) d 3.43 (1H, br d, J¼9 Hz), 3.81
and 3.98 (each 3H, s), 5.24 (1H, dt, J¼10, 2 Hz), 5.37
(1H, dt, J¼17, 2 Hz), 5.44 (1H, ddt, J¼9, 5, 2 Hz), 6.12
(1H, ddd, J¼17, 10, 5 Hz), 6.88 (2H, br d, J¼8 Hz), 7.53
(2H, br d, J¼8 Hz); HRMS (EI, m/z) calcd for C12H15NO3
(Mþ) 221.1051, found 221.1065. Anal. calcd for
C12H15NO3: C, 65.14; H, 6.83; N, 6.33, found: C, 65.07;
H, 6.71; N, 6.32.
(CvN) cm21; H NMR (300 MHz, CDCl3) d 3.86 (3H,
s), 5.14 (2H, s), 7.12 (1H, d, J¼16 Hz), 7.27 (1H, d,
J¼16 Hz), 7.26–7.53 (10H, m); HRMS (EI, m/z) calcd for
C17H17NO2 (Mþ) 267.1258, found 267.1273.
4.7.4. Phenylmethyl (E)-N-methoxy-3-phenylpropanimi-
date (13l). A colorless oil; IR (CHCl3) 1635 (CvN) cm21
;
1H NMR (300 MHz, CDCl3) d 2.73 and 2.88 (each 2H, m),
3.71 (3H, s), 4.96 (2H, s), 7.15–7.39 (10H, m); HRMS (EI,
m/z) calcd for C17H19NO2 (Mþ) 269.1415, found 269.1405.
4.6.10. (Z)-2-Hydroxy-1-(2-methoxyphenyl)-3-buten-1-
one O-methyloxime (18q). A colorless oil; IR (CHCl3)
3516 (OH) cm21; 1H NMR (300 MHz, CDCl3) d 3.56 (1H,
d, J¼8.5 Hz), 3.86 and 3.98 (each 3H, s), 5.18 (1H, dt,
J¼10.5, 2 Hz), 5.34 (1H, dt, J¼17, 2 Hz), 5.41 (1H, ddt,
J¼8.5, 5, 2 Hz), 6.06 (1H, ddd, J¼17, 10.5, 5 Hz), 6.96 (2H,
br d, J¼8 Hz), 7.34 (2H, br d, J¼8 Hz); HRMS (EI, m/z)
calcd for C12H15NO3 (Mþ) 221.1051, found 221.1063.
4.8. Wittig rearrangement of E-hydroximates 13a,b,j,l
According to the procedure given for Z-18a, the treatment of
E-hydroximates 13a,b,j,l with LDA gave E-18a,b,j and
Z-18a,b,j as shown in Table 8.
4.8.1. (E)-2-hydroxy-1,2-diphenylethanone O-methyl-
oxime (18a). Colorless crystals: mp 66–67 8C (hexane/
CHCl3) (lit.11 66–67 8C); IR (CHCl3) 3474 (OH) cm21; 1H
NMR (300 MHz, CDCl3) d 3.94 (3H, s), 3.97 (1H, d,
J¼5.5 Hz), 5.55 (1H, d, J¼5.5 Hz), 7.08–7.28 (10H, m);
13C NMR (75 MHz, CDCl3) d 62.5, 75.3, 127.0, 127.9,
128.0, 128.3, 129.0, 131.2, 139.9, 157.0; HRMS (EI, m/z)
calcd for C15H15NO2 (Mþ) 241.1102, found 241.1106.
4.6.11. Methyl (Z)-4-[[2-hydroxy-1-(methoxyimino)]-3-
butenyl]benzoate (18r). A colorless oil; IR (CHCl3) 3542
1
(OH) cm21; H NMR (300 MHz, CDCl3) d 3.16 (1H, d,
J¼8.5 Hz), 3.92 and 4.03 (each 3H, s), 5.28 (1H, dt, J¼10,
2 Hz), 5.41 (1H, dt, J¼17, 2 Hz), 5.53 (1H, ddt, J¼8.5, 6,
2 Hz), 6.13 (1H, ddd, J¼17, 10, 6 Hz), 7.78 (2H, br d,
J¼8 Hz), 8.03 (2H, br d, J¼8 Hz); HRMS (EI, m/z) calcd
for C13H15NO4 (Mþ) 249.1000, found 249.0989.
4.8.2. (E)-2-hydroxy-1-phenyl-3-butenone O-methyl-
oxime (18b). A colorless oil; IR (CHCl3) 3482 (OH)
;
cm21 1H NMR (300 MHz, CDCl3) d 3.37 (1H, d,
4.7. General procedure for preparation of
E-hydroximates (13a,b,j,l)
J¼5.5 Hz), 3.90 (3H, s), 5.04 (1H, m), 5.14 (1H, dt,
J¼10, 1.5 Hz), 5.30 (1H, dt, J¼17, 1.5 Hz), 5.78 (1H, ddd,
J¼17, 10, 6 Hz), 7.25–7.58 (5H, m); HRMS (EI, m/z) calcd
for C11H13NO2 (Mþ) 191.0946, found 191.0951.
According to the literature procedure,9c to a solution of
12a,d,f (10 mmol) in 95% EtOH (7.1 mL) and 29% NH3
(0.65 mL) was added a solution of AgNO3 (10 mmol) in

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
3909
4.8.3. (E,E)-1-hydroxy-1,4-diphenyl-3-buten-2-one
O-methyloxime (18j). A colorless oil; IR (CHCl3) 3476
(OH) cm21; 1H NMR (300 MHz, CDCl3) d 3.83 (1H, br s),
4.06 (3H, s), 5.63 (1H, br s), 6.90 (1H, d, J¼17 Hz), 7.11
(1H, d, J¼17 Hz), 7.25–7.48 (10H, m); HRMS (EI, m/z)
calcd for C17H17NO2 (Mþ) 267.1258, found 267.1268.
Anal. calcd for C17H17NO2: C, 76.38; H, 6.41; N, 5.24,
found: C, 76.20; H, 6.26; N, 5.36.
addition of 2 M aqueous KOH, and extracted with Et2O. The
organic phase was washed with H2O, dried over Na2SO4,
and concentrated at reduced pressure. Purification of the
residue by SCC (MeOH/AcOEt 1:10) afforded threo-21
(18 mg, 42%) and erythro-21 (8 mg, 19%).
Table 10, entry 4. A solution of ZrCl4 (61 mg, 0.26 mmol)
and NaBH4 (40 mg, 1.05 mmol) in THF (1 mL) was stirred
under a nitrogen atmosphere at room temperature for 20 h.
A solution of Z-18a (48 mg, 0.2 mmol) in THF (2 mL) was
added to the reaction mixture. After being stirred at room
temperature for 2 days, the reaction mixture was made pH 9
by addition of 29% NH3 and extracted with AcOEt. The
organic phase was washed with H2O, dried over Na2SO4,
and concentrated at reduced pressure. Purification of the
residue by SCC (MeOH/AcOEt 1:10) afforded threo-21
(9 mg, 21%) and erythro-21 (17 mg, 41%).
4.9. Wittig rearrangement of a mixture of Z-hydroxi-
mates 13i and 13b
According to the procedure given for Z-18a, the treatment of
a mixture of Z-hydroximates 13i and 13b with LDA gave a
mixture of Z-18i and Z-18b.
4.9.1. Conversion of Z-2-hydroxyoxime ether 18a into
amino alcohols 20. Table 10, entry 1. To a solution of Z-18a
(48 mg, 0.2 mmol) in THF (5 mL) was added LiAlH4
(304 mg, 8 mmol) with stirring under a nitrogen atmosphere
at 0 8C. After being stirred at the same reaction for 4 h, usual
work-up followed by purification of the crude methoxy-
amino alcohol by MCC (hexane/AcOEt 1:1) afforded
(R p ,R p )-(^)-b-(methoxy)amino-a-phenylbenzeneethanol
(20) (7 mg, 13%) and (R p ,S p )-(^)-b-(methoxy)amino-a-
phenylbenzeneethanol (20) (3 mg, 5%).
Table 10, entry 6. To a solution of Z-18a (48 mg, 0.2 mmol)
in benzene (2 mL) was added SMEAH (70% in toluene)
(404 mg, 2 mmol) under nitrogen atmosphere at room
temperature. After being heated at reflux for 3 h, the
reaction mixture was cooled to room temperature. To the
reaction mixture was added 20% H2SO4 and the solution
was filtered to remove the precipitate. The filtrate was
washed with H2O, dried over Na2SO4, and concentrated at
reduced pressure. Purification of the residue by SCC
(MeOH/AcOEt 1:10) afforded threo-21 (26 mg, 61%) and
erythro-21 (6 mg, 13%).
threo-20 and erythro-20 were immediately subjected to the
following reduction.
threo-20 A colorless oil; 1H NMR (300 MHz, CDCl3) d 3.27
and 6.32 (each 1H, br s), 3.49 (3H, s), 4.13 and 4.84 (each
1H, d, J¼8.5 Hz), 7.15–7.32 (10H, m).
4.9.2. Demethoxylation of threo-20 and erythro-20. The
reduction of threo-20 and erythro-20 (48.5 mg each,
0.2 mmol) with LiAlH4 (304 mg, 8 mmol) under the
conditions shown in Table 10, entry 2 gave threo-21 and
erythro-21 (43 mg each, quant.), respectively.
1
erythro-20. A colorless oil; H NMR (300 MHz, CDCl3) d
2.67 (1H, d, J¼3 Hz), 3.51 (3H, s), 4.21 (1H, d, J¼5 Hz),
5.07 (1H, dd, J¼5, 3 Hz), 5.84 (1H, br s), 7.12–7.30 (10H,
m).
4.9.3. Conversion of E-2-hydroxyoxime ether 18a into
amino alcohols 21. Table 10, entry 7. According to the
procedure given for threo-21 and erythro-21 in Table 10,
entry 2, the reduction of E-18a (48 mg, 0.2 mmol) with
LiAlH4 (304 mg, 8 mmol) gave threo-21 (10 mg, 23%) and
erythro-21 (18 mg, 42%).
Table 10, entry 2. To a solution of Z-18a (48 mg, 0.2 mmol)
in THF (5 mL) was added LiAlH4 (304 mg, 8 mmol) with
stirring under a nitrogen atmosphere at 0 8C. After being
heated at reflux for 6 h, usual work-up followed by
purification of the crude amino alcohol by SCC (AcOEt/
MeOH 10:1) afforded of (R p ,R p )-(^)-b-amino-a-
phenylbenzeneethanol (21) (23 mg, 53%) as colorless
crystals, mp 127–129 8C (EtOH) (lit.13a mp 129–131 8C)
and (R p ,S p )-(^)-b-amino-a-phenylbenzeneethanol (21)
(7 mg, 17%) as colorless crystals, mp 164–165 8C (EtOH)
(lit.13a mp 166.5–168 8C). The spectral data of threo-21 and
erythro-21 are identical with those reported.14a
4.9.4. (Z)-2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1,2-
diphenylethanone O-methyloxime (22). To a solution of
Z-18a (482 mg, 2 mmol) in CH2Cl2 (10 mL) was added 2,6-
lutidine (0.47 mL, 4 mmol) and then added dropwise a
solution of TBDMSOTf (0.69 mL, 3 mmol) in CH2Cl2
(1 mL). After being stirred at room temperature for 1 h, the
reaction mixture was diluted with H2O and extracted with
AcOEt. The organic phase was washed with H2O, dried over
Na2SO4, and concentrated at reduced pressure. Purification
of the residue by MCC (hexane/AcOEt 1:1) afforded Z-22
(710 mg, quant.) as colorless crystals, mp 81–81 8C
(hexane/CHCl3); 1H NMR (300 MHz, CDCl3) d 20.14
and 0.00 (each 3H, s), 0.72 (9H, s), 3.97 (3H, s), 6.58 (1H,
s), 7.03–7.45 (10H, m); HRMS (EI, m/z) calcd for
C21H31NO2Si (Mþ) 355.1966, found 355.1944. Anal.
calcd for C21H31NO2Si: C, 70.94; H, 8.22; N, 3.94, found:
C, 70.79; H, 8.41; S, 3.91.
threo-21. 1H NMR (300 MHz, CDCl3) d 3.99 (1H, d,
J¼6.5 Hz), 4.66 (1H, d, J¼6.5 Hz), 7.10–7.40 (10H, m).
1
erythro-21. H NMR (300 MHz, CDCl3) d 4.18 (1H, d,
J¼6 Hz), 4.76 (1H, d, J¼6 Hz), 7.10–7.40 (10H, m).
Table 10, entry 3. To a solution of Z-18a (48 mg, 0.2 mmol)
in MeOH (1 mL) was added NaBH3CN (10 mg, 0.15 mmol)
and methanolic solution of 2 M HCl with stirring at 0 8C.
The pH of reaction mixture was maintained at approxi-
mately pH 3 at 0 8C for 2 h. After being heated at reflux for
5 h, the reaction mixture was cooled to 0 8C, made pH 9 by
4.9.5. (E)-2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1,2-
diphenylethanone O-methyloxime (22). According to the

3910
O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
procedure given for Z-22, the silylation of E-18a (482 mg,
2 mmol) with TBDMSOTf (0.69 mL, 3 mmol) gave E-22
(710 mg, quant.) as a colorless oil; H NMR (300 MHz,
6.13 (1H, br s), 6.85 (2H, br d, J¼8 Hz), 7.25 (2H, br d,
J¼8 Hz).
1
CDCl3) d 0.07 and 0.14 (each 3H, s), 0.91 (9H, s), 3.87 (3H,
s), 5.67 (1H, s), 7.00–7.32 (10H, m); HRMS (EI, m/z) calcd
for C21H31NO2Si (Mþ) 355.1966, found 355.1962.
Table 11, entry 2. To a solution of Z-18p (22 mg, 0.1 mmol)
in THF (2.5 mL) was added LiAlH4 (11.5 mg, 0.3 mmol)
with stirring under a nitrogen atmosphere at 0 8C. After
being stirred at the same temperature for 2 h, usual work-up
afforded the crude amino alcohol. Purification of the crude
amino alcohol by MCC (hexane/AcOEt 2:1) afforded
erythro-23 (7.3 mg, 31%) and threo-23 (8.8 mg, 37%).
4.9.6. Reduction of Z-22 with LiAlH4. Table 10, entry 9.
To a solution of Z-22 (71 mg, 0.2 mmol) in THF (5 mL) was
added LiAlH4 (304 mg, 8 mmol) with stirring under a
nitrogen atmosphere at 0 8C. After being stirred at the same
temperature for 7 h, usual work-up afforded the crude
amine. To a solution of crude amine in MeOH (5 mL) was
added p-TsOH (3.8 mg, 0.02 mmol). After being stirred at
room temperature for 3 h, the reaction mixture was diluted
with saturated aqueous NaHCO3 and extracted with
CH2Cl2. The organic phase was washed with H2O, dried
over Na2SO4, and concentrated at reduced pressure.
Purification of the residue by SCC (MeOH/AcOEt 1:10)
afforded threo-21 (2 mg, 4%) and erythro-21 (40 mg, 94%)
which were identical with the respective sample prepared by
reduction of Z-18a with LiAlH4 shown in Table 10, entry 2.
Table 11, entry 3. To a solution of Z-18p (100 mg,
0.45 mmol) in Et2O (10 mL) was added LiAlH4 (51.8 mg,
1.35 mmol) with stirring at 0 8C. The reaction mixture was
stirred at the same temperature for 2 h. Work-up afforded
the crude amino alcohols. Purification of the crude amino
alcohols by MCC (hexane/AcOEt 2:1) afforded erythro-23
(53 mg, 52%) and threo-23 (25 mg, 25%).
4.9.9. Demethoxylation of threo-23 and erythro-23.
Table 12, entry 1. To a solution of threo-23 (117 mg,
0.5 mmol) in THF (10 mL) was added SMEAH (65% in
toluene) (1.38 mL, 2.2 mmol) under a nitrogen atmosphere
at room temperature. After being heated at reflux for 2 h, the
reaction mixture was diluted with 10% aqueous NaOH and
extracted with CHCl3. The organic phase was washed with
H2O, dried over Na2SO4, and concentrated at reduced
pressure. Purification of the residue by SCC (hexane/AcOEt
5:1!AcOEt/MeOH 5:1) afforded (R p ,R p )-(^)-b-amino-
a-ethenyl-4-methoxybenzeneethanol (24) (52 mg, 52%) as
a colorless oil and 1-(4-methoxyphenylamino)-3-buten-2-ol
(25) (38 mg, 33%) as a colorless oil.
4.9.7. Reduction of E-22 with LiAlH4. Table 10, entry 10.
To a solution of E-22 (71 mg, 0.2 mmol) in THF (5 mL) was
added LiAlH4 (304 mg, 8 mmol) with stirring under a
nitrogen atmosphere at 0 8C. After being stirred at the same
temperature for 7 h, usual work-up afforded the crude
amine. To a solution of crude amine in MeOH (5 mL) was
added p-TsOH (3.8 mg, 0.02 mmol). After being stirred at
room temperature for 3 h, the reaction mixture was diluted
with saturated aqueous NaHCO3 and extracted with
CH2Cl2. The organic phase was washed with H2O, dried
over Na2SO4, and concentrated at reduced pressure.
Purification of the residue by SCC (MeOH/AcOEt 1:10)
afforded threo-21 (2 mg, 3%) and erythro-21 (13 mg, 30%).
1
threo-24. H NMR (300 MHz, CDCl3) d 2.24 (3H, br s),
3.73 (1H, d, J¼6.5 Hz), 3.80 (3H, s), 4.10 (1H, br dd, J¼6.5,
5 Hz), 5.11 (1H, dt, J¼10, 2 Hz), 5.25 (1H, dt, J¼17, 2 Hz),
5.77 (1H, ddd, J¼17, 10, 5 Hz), 6.86 (2H, br d, J¼8 Hz),
7.24 (2H, br d, J¼8 Hz).
25. 1H NMR (300 MHz, CDCl3) d 2.86 (2H, br s), 3.16 (1H,
dd, J¼14, 7 Hz), 3.26 (1H, dd, J¼14, 4.5 Hz), 3.75 (3H, s),
4.31–4.40 (1H, m), 5.24 (1H, dt, J¼10, 2 Hz), 5.38 (1H,
dt,J¼17, 2 Hz), 5.92 (1H, ddd, J¼17, 10, 2 Hz), 6.63 (2H, br
d, J¼8 Hz), 6.78 (2H, br d, J¼8 Hz); HRMS (EI, m/z) calcd
for C11H15NO2 (Mþ) 193.1102, found 193.1098.
4.9.8. Reduction of Z-2-hydroxyoxime ether 18p.
Table 11, entry 1. To a solution of Z-18p (100 mg,
0.45 mmol) in THF (10 mL) was added SMEAH (65% in
toluene) (0.67 mL, 2 mmol) under a nitrogen atmosphere at
230 8C. After being stirred at the same temperature for
1.5 h, the reaction mixture was diluted with 10% aqueous
NaOH and extracted with CHCl3. The organic phase was
washed with H2O, dried over Na2SO4, and concentrated at
reduced pressure. Purification of the residue by MCC
(hexane/AcOEt 2:1) afforded (R p ,S p )-(^)-a-ethenyl-4-
methoxy-b-methoxy-aminobenzeneethanol (23) (111 mg,
25%) as a colorless oil and (R p ,R p )-(^)-a-ethenyl-4-
methoxy-b-methoxyaminobenzeneethanol (23) (229 mg,
52%) as a colorless oil. erythro-23 and threo-23 were
immediately subjected to the following reduction.
Table 12, entry 2. To a solution of threo-23 (117 mg,
0.5 mmol) in Et2O (10 mL) was added LiAlH4 (38 mg,
5 mmol) with stirring under a nitrogen atmosphere at 0 8C.
After being heated at reflux for 2 h, work-up afforded the
crude amino alcohols. Purification of the crude amino
alcohols by SCC (hexane/AcOEt 5:1!AcOEt/MeOH 5:1)
afforded threo-24 (96 mg, quant.).
1
threo-23. H NMR (300 MHz, CDCl3) d 2.46 (1H, br s),
3.55 and 3.80 (each 3H, s), 4.06 (1H, d, J¼7 Hz), 4.45–4.52
(1H, m), 5.16 (1H, dt, J¼10, 2 Hz), 5.27 (1H, dt, J¼17,
2 Hz), 5.71 (1H, ddd, J¼17, 10, 6 Hz), 5.88 (1H, br s), 6.87
(2H, br d, J¼8 Hz), 7.27 (2H, br d, J¼8 Hz).
Table 12, entries 3 and 4. According to the procedure given
for reduction of threo-23, the reduction of erythro-23 with
either SMEAH or LiAlH4 afforded (R p ,S p )-(^)-b-
aminoa-ethenyl-4-methoxybenzeneethanol (24) as a
colorless oil and 25 in the yield shown in Table 12, entries
3 and 4.
1
erythro-23. H NMR (300 MHz, CDCl3) d 2.94 (1H, br s),
3.46 and 3.79 (each 3H, s), 3.84 (1H, d, J¼7.5 Hz), 4.36
(1H, br dd, J¼7.5, 5.5 Hz), 5.05 (1H, dt, J¼10, 2 Hz),
5.21 (1H, dt, J¼17, 2 Hz), 5.67 (1H, ddd, J¼17, 10, 5.5 Hz),
1
erythro-24. H NMR (300 MHz, CDCl3) d 1.90 (3H, br s),
3.80 (3H,s), 3.96 (1H, br d, J¼5 Hz), 4.22 (1H, br dd, J¼6,

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
3911
5 Hz), 5.21 (1H, dt, J¼10, 1.5 Hz), 5.31 (1H, dt, J¼17,
1.5 Hz), 5.71 (1H, ddd, J¼17, 10, 6 Hz), 6.88 (2H, br d,
J¼8 Hz), 7.26 (2H, br d, J¼8 Hz).
(hexane/CHCl3); IR (CHCl3) 1812 (OCONCOO) cm21; 1H
NMR (300 MHz, CDCl3) d 1.32 (9H, s), 3.81 (3H, s), 5.13
(1H, dd, J¼10, 2 Hz), 5.14–5.29 (4H, m), 6.88 (2H, br d,
J¼8 Hz), 7.07 (2H, br d, J¼8 Hz); HRMS m/z: calcd for
C17H21NO5 (Mþ) 319.1420, found 319.1409. Anal. calcd
for C17H21NO5·1/10H2O: C, 63.58; H, 6.65; N, 4.36, found:
C, 63.54; H, 6.53; N, 4.34.
4.9.10. Acylation of threo-24. Table 13, entry 1. To a
solution of threo-24 (74 mg, 0.38 mmol) in MeCN (6 mL)
was added DMAP (45 mg, 0.38 mmol) and (Boc)2O (91 mg,
0.42 mmol) under a nitrogen atmosphere at room tempera-
ture. After being stirred at the same temperature for 2 h, the
reaction mixture was concentrated at reduced pressure.
Purification of the residue by MCC (hexane/AcOEt 2:1)
afforded trans-5-ethenyl-4-(4-methoxyphenyl)-2-oxazolidi-
none (26) (25 mg, 30%), 1,1-dimethylethyl (R p ,R p )-(^)-
N-[2-hydroxy-N-(4-methoxyphenyl)-3-butenyl]carbamate
(27) (10 mg, 9%), and 1,1-dimethylethyl trans-5-ethenyl-4-
(4-methoxyphenyl)-2-oxo-3-oxazolidinecarboxylate (28)
(36 mg, 30%).
4.9.12. Conversion of threo-27 into trans-26. To a
suspension of NaH (60% in oil) (3.3 mg, 0.08 mmol) in
THF (1 mL) was added a solution of threo-27 (20 mg,
0.068 mmol) in THF (1 mL) under a nitrogen atmosphere at
0 8C. After being stirred at room temperature for 4 h, the
reaction mixture was diluted with saturated aqueous NH4Cl
and extracted with CHCl3. The organic phase was washed
with H2O, dried over Na2SO4, and concentrated at reduced
pressure. Purification of the residue by MCC (hexane/
AcOEt 1:1) afforded trans-26 (10 mg, 77%).
trans-26. Colorless crystals, mp 150–151 8C (hexane/
1
CHCl3); IR (CHCl3) 3451 (NH), 1759 (NCOO) cm21; H
4.9.13. Conversion of trans-28 into trans-26. To a solution
of trans-28 (51 mg, 0.16 mmol) in CH2Cl2 (2 mL) was
added TFA (0.013 mL) under a nitrogen atmosphere at
room temperature. After being stirred at the same
temperature for 3 h, the reaction mixture was diluted with
saturated aqueous NaHCO3, extracted with CHCl3. The
organic phase was washed with H2O, dried over Na2SO4,
and concentrated at reduced pressure. Purification of the
residue by MCC (hexane/AcOEt 1:1) afforded trans-26
(35 mg, quant.).
NMR (500 MHz, CDCl3) d 3.81 (3H, s), 4.55 (1H, d,
J¼8 Hz), 4.68 (1H, ddt, J¼8, 7, 2 Hz), 5.22 (1H, dt, J¼16,
2 Hz), 5.33 (1H, dt, J¼10.5, 2 Hz), 5.96 (1H, ddd, J¼16,
10.5, 7 Hz), 6.10 (1H, br s), 6.91 (2H, br d, J¼8 Hz), 7.25
(2H, br d, J¼8 Hz); HRMS (EI, m/z) calcd for C12H13NO3
(Mþ) 219.0895, found 219.0913. Anal. calcd for
C12H13NO3: C, 65.74; H, 5.98; N, 6.39, found: C, 65.44;
H, 5.92; N, 6.33.
threo-27. A colorless oil; IR (CHCl3) 1707 (NCOO) cm21
;
1H NMR (500 MHz, CDCl3) d 1.40 (9H, br s), 2.32 (1H, br
s), 3.80 (3H, s), 4.30–4.39 (1H, m), 4.58–4.70 (1H, m),
5.20 (1H, dt, J¼10, 1.5 Hz), 5.27 (1H, br d, J¼8 Hz), 5.33
(1H, dt, J¼17, 1.5 Hz), 5.84 (1H, ddd, J¼17, 10, 5 Hz), 6.90
(2H, br d, J¼8 Hz), 7.22 (2H, br d, J¼8 Hz); 13C NMR
(75 MHz, CDCl3) d 28.3, 55.2, 75.7, 79.7, 113.9, 116.5,
127.9, 137.3, 156.1, 158.9.
4.9.14. cis-5-Ethenyl-4-(4-methoxyphenyl)-2-oxazolidi-
none (26). According to the procedure given for trans-26,
the treatment of cis-28 (51 mg, 0.16 mmol) with TFA
(0.02 mL, 0.19 mmol) afforded cis-26 (35 mg, quant.) as
colorless crystals, mp 113–114 8C (hexane/CHCl3); IR
(CHCl3) 3448 (NH), 1760 (NCOO) cm21 1H NMR
;
(300 MHz, CDCl3) d 3.81 (3H, s), 4.94 (1H, d, J¼8 Hz),
5.13 (1H, dd, J¼10, 2 Hz), 5.24 (1H, dd, J¼8, 6.5 Hz), 5.27
(1H, ddd, J¼17, 10, 6.5 Hz), 5.34 (1H, dd, J¼17, 2 Hz),
5.45 (1H, br s), 6.90 (2H, br d, J¼8 Hz), 7.13 (2H, br d,
J¼8 Hz); HRMS (EI, m/z) calcd for C12H13NO3 (Mþ)
219.0895, found 219.0913. Anal. calcd for C12H13NO3: C,
65.74; H, 5.98; N, 6.39, found: C, 65.44; H, 6.03; N, 6.35.
trans-28. Colorless crystals, mp 126–128 8C (hexane/
1
CHCl3); IR (CHCl3) 1811 (OCONCOO) cm21; H NMR
(500 MHz, CDCl3) d 1.30 (9H, s), 3.82 (3H, s), 4.66 (1H, dt,
J¼5.5, 2 Hz), 4.79 (1H, d, J¼5.5 Hz), 5.35 (1H, dt, J¼10,
2 Hz), 5.40 (1H, dt, J¼17, 2 Hz), 5.95 (1H, ddd, J¼17, 10,
6 Hz), 6.93 (2H, br d, J¼8 Hz), 7.24 (2H, br d, J¼8 Hz);
HRMS (EI, m/z) calcd for C17H21NO5 (Mþ) 319.1420,
found 319.1409. Anal. calcd for C17H21NO5·1/10H2O: C,
63.58; H, 6.65; N, 4.36, found: C, 63.58; H, 6.63; N, 4.30.
4.9.15. (Z)-2-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-1-
(4-methoxyphenyl)-3-buten-1-one O-methyloxime (30).
According to the procedure given for Z-22, the silylation of
Z-18p (221 mg, 2 mmol) with TBDMSOTf (0.34 mL,
1.5 mmol) gave Z-30 (384 mg, quant.) as a colorless oil;
1H NMR (300 MHz, CDCl3) d 20.14 and 0.03 (each 3H, s),
0.77 (9H, s), 3.81 and 3.91 (each 3H, s), 5.21 (1H, dt, J¼10,
2 Hz), 5.49 (1H, dt, J¼17, 2 Hz), 5,92 (1H, dt, J¼3.5, 2 Hz),
6.07 (1H, ddd, J¼17, 10, 3.5 Hz), 6.92 (2H, br d, J¼8 Hz),
7.54 (2H, br d, J¼8 Hz); HRMS (EI, m/z) calcd for
C18H29NO3Si (Mþ) 335.1916, found 335.1932.
Table 13, entry 2. To a solution of threo-24 (19.3 mg,
0.1 mmol) in MeCN (1.5 mL) were added DMAP (12 mg,
0.1 mmol) and (Boc)2O (48 mg, 0.22 mmol) under a
nitrogen atmosphere at room temperature. After being
stirred at the same temperature for 2 h, the reaction mixture
was concentrated at reduced pressure. Purification of the
residue by MCC (hexane/AcOEt 3:1) afforded trans-28
(26 mg, 82%).
4.9.16. N-Boc-oxazolidinones cis-28 and trans-28 from
Z-18p. Table 15, entry 1. To a suspension of LiAlH4
(764 mg, 20.1 mmol) in Et2O (30 mL) was added a solution
of Z-18p (1.5 g, 6.7 mmol) in Et2O (30 mL) with stirring
under a nitrogen atmosphere at 0 8C. After being stirred at
the same temperature for 2.5 h, LiAlH4 (2.5 g, 67 mmol)
was added to the reaction mixture. After being heated at
4.9.11. 1,1-Dimethylethyl cis-5-ethenyl-4-(4-methoxy-
phenyl)-2-oxo-3-oxazolidinecarboxylate (36). Table 13,
entry 3. According to the procedure given for trans-28
(Table 13, entry 2), the acylation of erythro-24 (15 mg,
0.075 mmol) with (Boc)2O (33 mg, 0.075 mmol) gave cis-
28 (11 mg, 44%) as colorless crystals, mp 130–132 8C

3912
O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
reflux for 4 h, usual work-up afforded the crude amino
alcohols 24. To a solution of the crude amino alcohols in
MeCN (65 mL) were added DMAP (977 mg, 6.7 mmol) and
(Boc)2O (4.7 g, 20.1 mmol) at room temperature. After
being stirred at the same temperature for 1 h, the reaction
mixture was concentrated at reduced pressure. Purification
of the residue by FCC (hexane/AcOEt 2:1) afforded cis-28
(1.08 g, 55%) and trans-28 (507 mg, 26%).
NH), 1713 (NCOO) cm21; 1H NMR (500 MHz, DMSO-d6)
d 2.97 (2H, m), 3.75 (3H, s), 4.69 (1H, ddd, J¼8, 7, 4 Hz),
4.80 (1H, t, J¼7 Hz), 4.90 (1H, d, J¼7 Hz), 6.93 (2H, br d,
J¼8 Hz), 7.14 (2H, br d, J¼8 Hz), 8.05 (1H, br s); HRMS
(EI, m/z) calcd for C11H13NO4 (Mþ) 223.0844, found
223.0861. The spectral data of synthetic (^)-9 was identical
with those of natural cytoxazone.
4.9.18. (6)-4-epi-Cytoxazone (31). According to the
procedure given for (^)-9, the oxidation of trans-26
(200 mg, 0.91 mmol) with ozone followed by reduction of
the resulting ozonide with NaBH4 (182 mg, 4.55 mmol)
gave (^)-4-epi-cytoxazone 31 (193 mg, 95%) as colorless
crystals, mp 161–163 8C (AcOEt) (lit.16 161.5–162.5 8C
(4S,5R-31)), IR (KBr) 3688 and 3456 (OH, NH), 1760
Table 15, entry 2. To a solution of Z-18p (100 mg,
0.45 mmol) in THF (10 mL) was added SMEAH (65% in
toluene) (0.67 mL, 2 mmol) under a nitrogen atmosphere at
230 8C. After being stirred at the same temperature for 2 h,
the reaction mixture was diluted with 10% aqueous NaOH
and extracted with CHCl3. The organic phase was washed
with H2O, dried over Na2SO4, and concentrated at reduced
pressure to give the crude methoxyamino alcohols. To a
solution of the crude methoxyamino alcohols in Et2O
(10 mL) was added LiAlH4 (171 mg, 4.5 mmol) at 0 8C.
After being heated at reflux for 4 h, work-up afforded the
crude amino alcohols 24. To a solution of the crude amino
alcohols in MeCN (10 mL) were added DMAP (55 mg,
0.45 mmol) and (Boc)2O (98 mg, 0.45 mmol) at room
temperature. After being stirred at the same temperature
for 1 h, the reaction mixture was concentrated at reduced
pressure. Purification of the residue by MCC (hexane/
AcOEt 2:1) afforded cis-28 (23 mg, 16%) and trans-28
(47 mg, 33%).
1
(NCOO) cm21; H NMR (500 MHz, acetone-d6) d 3.71
(1H, ddd, J¼12, 6.5, 4.5 Hz), 3.80 (3H, s), 3.83 (1H, ddd,
J¼12, 5.5, 4 Hz), 4.25 (1H, br dt, J¼6.5, 4.5 Hz), 4.29 (1H,
dd, J¼6.5, 5.5 Hz), 4.78 (1H, d, J¼6.5 Hz), 6.91 (1H, br s),
6.96 (2H, br d, J¼8 Hz), 7.33 (2H, br d, J¼8 Hz); HRMS
(EI, m/z) calcd for C11H13NO4 (Mþ) 223.0844, found
223.0842. The spectral data of (^)-31 was identical with
those reported.16
4.9.19. Acylation of (6)-9 with (2)-camphanic chloride.
To a solution of (^)-9 (85 mg, 0.38 mmol) in CH2Cl2
(4.5 mL) were added Et3N (45 mg, 0.45 mmol), DMAP
(4.6 mg, 0.036 mmol), and (2)-camphanic chloride (87 mg,
0.38 mmol) under a nitrogen atmosphere at 0 8C. After
being stirred at the same temperature for 3 h, the reaction
mixture was diluted with H2O and extracted with CHCl3.
The organic phase was washed with H2O, dried over
Na2SO4, and concentrated at reduced pressure. Purification
of the residue by MCC (hexane/AcOEt 2:1) afforded
(4R,5R(S))-32 (67 mg, 44%) as a colorless oil and
(4S,5S(S))-32 (69 mg, 45%) as a colorless oil.
Table 15, entry 3. To a solution of Z-18p (23 mg, 0.1 mmol)
in EtOH (3 mL) were added BH3 –pyridine (0.1 mL,
0.33 mmol) and an ethanolic solution of HCl (10%,
0.5 mL) under a nitrogen atmosphere at room temperature.
After being stirred at the same temperature for 2 h, the
reaction mixture was diluted with saturated aqueous
NaHCO3 and extracted with CHCl3. The organic phase
was washed with H2O, dried over Na2SO4, and concentrated
at reduced pressure to give the crude methoxyamino
alcohols. To a solution of the crude methoxyamino alcohols
in Et2O (3 mL) was added LiAlH4 (38 mg, 1 mmol) at 0 8C.
After being heated at reflux for 4 h, usual work-up afforded
the crude amino alcohols 24. To a solution of the crude
amino alcohols in MeCN (2 mL) were added DMAP
(24 mg, 0.1 mmol) and (Boc)2O (48 mg, 0.2 mmol) at
room temperature. After being stirred at the same
temperature for 1 h, the reaction mixture was concentrated
at reduced pressure. Purification of the residue by MCC
(hexane/AcOEt 2:1) afforded cis-28 (4.2 mg, 13%) and
trans-28 (9.8 mg, 31%).
[4-(4-Methoxyphenyl)-2-oxo-oxazolidin-5-yl]methyl [1S-
[1a(4R p ,5R p ),4b]-4,7,7-trimethyl-3-oxo-2-oxabicyclo-
[2.2.1]heptane-1-carboxylate ((4R,5R(S))-32): IR (CHCl3)
3450 (NH), 1768 (NCOO, COO) cm21; 1H NMR (300 MHz,
CDCl3) d:0.92 and 1.03 and 1.11 (each 3H, s), 1.68 (1H, ddd,
J¼13, 9, 5 Hz), 1.91 (1H, ddd, J¼12, 11, 5 Hz), 2.05 (1H, ddd,
J¼12, 9, 5 Hz), 2.35 (1H, ddd, J¼13, 11, 5 Hz), 3.80 (3H, s),
3.88–4.02 (2H, m), 5.01–5.10 (2H, m), 5.38 (1H, br s), 6.93
(2H, br d, J¼8 Hz), 7.24 (2H, br d, J¼8 Hz); HRMS (EI, m/z)
calcd for C21H25NO7 (Mþ) 403.1629, found 403.1620.
[4-(4-Methoxyphenyl)-2-oxo-oxazolidin-5-yl]methyl [1S-
[1a(4S p ,5S p ),4b]-4,7,7-trimethyl-3-oxo-2-oxabicyclo-
[2.2.1]heptane-1-carboxylate ((4S,5S(S))-32): IR (CHCl3)
4.9.17. (6)-Cytoxazone (9). Ozone was bubbled into a
solution of cis-26 (147 mg, 0.67 mmol) in CH2Cl2 (20 mL)
with stirring under a nitrogen atmosphere at 278 8C. After
being stirred at the same temperature for 1.5 h, MeOH
(10 mL) and NaBH4 (134 mg, 3.35 mmol) were added to the
reaction mixture. After being stirred at room temperature for
2 h, the reaction mixture was diluted with H2O and
extracted with CHCl3. The organic phase was washed
with H2O, dried over Na2SO4, and concentrated at reduced
pressure to give the crude cytoxazone which was
recrystallized from AcOEt to afforded (^)-cytoxazone 9
(131 mg, 88%) as colorless crystals, mp 120–123 8C (lit.15,
3436 (NH), 1764 (NCOO, COO) cm21
;
1H NMR
(300 MHz, CDCl3) d:0.90, 1.03 and 1.10 (each 3H, s),
1.68 (1H, ddd, J¼13, 8, 4 Hz), 1.91 (1H, ddd, J¼12, 10,
4 Hz), 2.00 (1H, ddd, J¼12, 8, 4 Hz), 2.37 (1H, ddd, J¼13,
10, 4 Hz), 3.80 (3H, s), 3.86 (1H, dd, J¼11, 3 Hz), 3.98 (1H,
dd, J¼11, 8 Hz), 5.01–5.10 (2H, m), 5.38 (1H, br s), 6.93
(2H, br d, J¼8 Hz), 7.24 (2H, br d, J¼8 Hz); HRMS (EI,
m/z) calcd for C21H25NO7 (Mþ) 403.1629, found 403.1622.
4.9.20. (2)-Cytoxazone (9). To a solution of (4R,5R(S))-
ester 32 (12 mg, 0.03 mmol) in MeOH (0.8 mL) was added
1 M methanolic KOH (0.34 mL) at room temperature. After
16
122–123 8C (4R,5R-9)), IR (KBr) 3475 and 3250 (OH,

O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
3913
being stirred at room temperature for 30 min, the reaction
mixture was diluted with H2O and extracted with CHCl3.
The organic phase was washed with H2O, dried over
Na2SO4, and concentrated at reduced pressure. Purification
of the residue by MCC (hexane/AcOEt 1:2) afforded (2)-9
(7 mg, 99%) as colorless crystals, mp 121–123 8C (AcOEt),
[a]D29¼273.3 (c 0.51, MeOH) (lit.15,16 275.7 (c 1.0,
MeOH).
extracted with CHCl3. The organic phase was washed with
H2O, dried over Na2SO4, and concentrated at reduced
pressure. Purification of the residue by MCC (hexane/
AcOEt 1:2) afforded (þ)-31 (10 mg, 99%) as colorless
crystals, mp 121–123 8C (AcOEt), [a]2D8¼þ30.0 (c 0.87,
MeOH).
4.9.24. (2)-4-epi-Cytoxazone (31). According to the
procedure given for (2)-9, the hydrolysis of (4R,5S(S))-
ester 32 (18 mg, 0.045 mmol) with KOH gave (2)-31
(7 mg, 99%) as colorless crystals, mp 121–123 8C (AcOEt),
[a]2D9¼230.1 (c 0.70, MeOH) (lit.16 230.4 (c 1.0, MeOH).
The spectral and physical data of (2)-9 are identical with
those reported.15,16
4.9.21. (1)-Cytoxazone (9). According to the procedure
given for (2)-9, the hydrolysis of (4S,5S(S))-ester 32
(12 mg, 0.03 mmol) with KOH gave (þ)-9 (7 mg, 99%) as
colorless crystals, mp 121–123 8C (AcOEt), [a]2D9¼þ75.0
(c 0.51, MeOH).
The spectral and physical data of (2)-9 are identical with
those reported.16
Acknowledgements
4.9.22. Acylation of (6)-31 with (2)-camphanic chloride.
To a solution of (^)-31 (81 mg, 0.36 mmol) in CH2Cl2
(4 mL) were added Et3N (43 mg, 0.43 mmol), DMAP
(4.4 mg, 0.036 mmol), and (2)-camphanic chloride
(82 mg, 0.38 mmol) under a nitrogen atmosphere at 0 8C.
After being stirred at the same temperature for 3 h, the
reaction mixture was diluted with H2O and extracted
with CHCl3. The organic phase was washed with H2O,
dried over Na2SO4, and concentrated at reduced
pressure. Purification of the residue by MCC (hexane/
AcOEt 2:1) afforded (4S,5R(S))-32 (64 mg, 44%) as a
colorless oil and (4R,5S(S))-32 (65 mg, 45%) as a colorless
oil.
We thank Dr. H. Osada (RIKEN) for providing IR, NMR,
MASS, and UV spectra of natural cytoxazone. This work
was supported in part by Grant-in Aids for Scientific
Research on Priority Areas (A) from the Ministry of
Education, Culture, Sports, Science and Technology (T.N.)
and for Scientific Research (C) from Japan Society for the
Promotion of Science (O.M.). Our thanks are also directed
to the Science Research Promotion Fund of the Japan
Private School Promotion Foundation for research grant.
References and notes
[4-(4-Methoxyphenyl)-2-oxo-oxazolidin-5-yl]methyl [1S-
[1a(4S p ,5R p ),4b]-4,7,7-Trimethyl-3-oxo-2-oxabicyclo-
[2.2.1]heptane-1-carboxylate ((4S,5R(S))-32): IR (CHCl3)
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3460 (NH), 1769 (NCOO, COO) cm21
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1H NMR
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3914
O. Miyata et al. / Tetrahedron 60 (2004) 3893–3914
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