Preparation of optically active α-hydroxy oxime ether by diastereoselective imino 1,2-Wittig rearrangement of hydroximates and its application to synthesis of (+)-cytoxazone

Article abstract of DOI:10.1016/j.tetlet.2005.04.026

The diastereoselective imino 1,2-Wittig rearrangement of hydroximates provides a novel method for the construction of optically active α-hydroxy oxime ethers. Upon treatment with LDA, allyl p-methoxyphenylhydroximate carrying a chiral auxiliary smoothly u

Full text of DOI:10.1016/j.tetlet.2005.04.026

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4015–4018
Preparation of optically active a-hydroxy oxime ether by
diastereoselective imino 1,2-Wittig rearrangement of
hydroximates and its application to synthesis of (+)-cytoxazone
Okiko Miyata, Jun Hashimoto, Ryuuichi Iba and Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Received 17 March 2005; revised 5 April 2005; accepted 7 April 2005
Available online 21 April 2005
Abstract—The diastereoselective imino 1,2-Wittig rearrangement of hydroximates provides a novel method for the construction of
optically active a-hydroxy oxime ethers. Upon treatment with LDA, allyl p-methoxyphenylhydroximate carrying a chiral auxiliary
smoothly underwent diastereoselective rearrangement to give the (R)-a-hydroxy oxime ether which was effectively converted into
(+)-cytoxazone.
Ó 2005 Elsevier Ltd. All rights reserved.
The a-hydroxy oximes and oxime ethers 1 have recently
received much attention as important precursors and
intermediates for the preparation of a wide variety of
OR3
N
R2
R1
natural products, drugs, and metal-binding ligands.1
Furthermore, they can be easily converted into amino
alcohols and hydroxy ketones which are one of the most
important functional groups.1 Therefore, the develop-
ment of methodologies for the preparation of enantio-
merically pure a-hydroxy oximes and oxime ethers is
of considerable interest. Recently, we found that the imi-
no 1,2-Wittig rearrangement of benzyl and allyl Z-
hydroximates (N-alkoxyimidates) proceeded smoothly
to give the ( )-2-hydroxy oxime ethers.2 This method
is suitable for the preparation of unsymmetrical a-hy-
droxy oxime ethers (R1 5 R2). We now report the first
example of diastereoselective imino 1,2-Wittig rear-
rangement of allyl hydroximates 2 for preparation of
optically active a-hydroxy oxime ethers 3 and applica-
tion of this method to the synthesis of (+)-cytoxazone
4 (Scheme 1). To our knowledge, there are a few papers
published on diastereo- and enantioselective migration
of the sp2 carbon in 1,2-Wittig rearrangement.3
OH
1
R3=H or R
3
3
*
*
OR
OR
O
N
diastereoselective
N
R2
R1
R1
R2
*
imino 1,2-Wittig
rearrangement
OH
3
2
O
O
HN
MeO
OH
We first investigated the diastereoselective 1,2-Wittig
rearrangement of allyl hydroximates 54 carrying a chiral
(+)-Cytoxazone 4
Scheme 1.
Keywords: Imino Wittig rearrangement; Hydroximate; Diastereoselec-
tive reaction; Oxime ether; Cytoxazone.
auxiliary on the oxime ether moiety (Scheme 2,
Table 1). We chose an optically active (S)-(2-hydroxy-
1-phenyl)ethyl group as a chiral auxiliary.5,6 The
*
Corresponding author. Tel.: +81 78 441 7554; fax: +81 78 441
7556; e-mail: taknaito@kobepharma-u.ac.jp
0040-4039/$ - see front matter Ó 2005Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.026

4016
O. Miyata et al. / Tetrahedron Letters 46 (2005) 4015–4018
Ph
Ph
OH
OH
O
O
O
O
8
N
N
R1
R1
Ph
R1 = p-MeOC6H4
a : R1 = Ph
5a-c
b : R1 = p-MeOC6H4
c : R1 = o-MeOC6H4
LDA
THF, -78°C
22 %
Ph
O
4 eq. LDA
THF
Li
O
N
R1
O
Ph
Ph
Ph
Ph
A
OH
OH
O
O
N
N
+
S
R
R1
R1
Ph
Ph
OH
OH
10
OH
OH
O
O
9
N
N
+
R
S
9
:
91
R1
R1
OH
OH
Scheme 3.
7a-c
6a-c
Similarly, benzyl hydroximate 8 was subjected to diaste-
reoselective rearrangement to afford (R)-107 in low yield,
but with high diastereoselectivity (Scheme 3).
Scheme 2.
Table 1. Imino 1,2-Wittig rearrangement of allyl hydroximates 5a–c
Entry
Substrate
Solvent
Temp
(°C)
Yield (%)a
6+7
Ratio
(6:7)
In order to examine the influence of a hydroxyl group on
a chiral auxiliary, we investigated the rearrangement of
hydroximate 11 carrying an (S)-(2-methoxy-1-pheny-
l)ethyl group and found that under the same conditions,
11 afforded two diastereomers 12 with low diastereo-
selectivity (Scheme 4).
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5b
5b
5c
5c
THF
THF
Et2O
Toluene
THF
THF
THF
THF
ꢀ40
ꢀ78
ꢀ40
ꢀ78
ꢀ40
ꢀ78
ꢀ40
ꢀ78
65(6)
25:75
24:76
25:75
25(60)
25(46)
22 (42)
55 (14)
63 (29)
61 (9)
26:74
31:69
10:90
33:67
27:73
From the above result, we propose a possible reaction
pathway in the rearrangement of 5a–c and 8 (Scheme
5). Low diastereoselectivity in the rearrangement of 11
having the methoxy group suggests that the formation
of the lithium alkoxide is crucial for promoting the dia-
stereoseletive rearrangement of 5 and 8. Intermediates
13A and 13B, which have a bicyclic chelated structure,
are formed by the treatment of 5 and 8 with LDA. Inter-
mediate 13B is more stable than 13A because steric
repulsion between the Ar and R groups exists in inter-
mediate 13A. Therefore, the rearrangement of 5 and 8
proceeds via intermediates 13B and 13C to afford (R)-
7 and 10 as a major product.
23 (49)
a Yields in parentheses are for recovered starting materials.
diastereoselective reaction of 5 would proceed smoothly
under the basic conditions because the conformation of
the chiral auxiliary part could be easily fixed even in the
absence of Lewis acid as shown in intermediate A. The
results are summarized in Table 1. The chiral allyl phen-
ylhydroximate 5a was treated with 4 equiv of LDA in
THF at ꢀ40 °C. The imino 1,2-Wittig rearrangement
proceeded smoothly to give a mixture of (S)-6a7 and
(R)-7a7 with a ratio of 25:75 (entry 1). In order to
improve diastereoselectivity, the reaction was carried
out at ꢀ78 °C. However, 6a and 7a were obtained in
low yield with almost the same selectivity (entry 2).
When Et2O and toluene were used as the solvent, no in-
creased selectivity was observed (entries 3 and 4). Previ-
ously, we found that an electron-donating group on the
benzene ring accelerated the rearrangement.2d There-
fore, we next examined the rearrangement of hydroxi-
mates 5b and 5c having p- and o-methoxyphenyl
groups (entries 5–8). As shown in entry 6, the rearrange-
ment of hydroximate 5b with a p-methoxylphenyl group
proceeded smoothly even at ꢀ78 °C to give (R)-7b7 with
high diastereoselectivity which was readily isolated by
column chromatography.
With (R)-a-hydroxy oxime ether 7b in hand, we next
investigated its conversion into (+)-Cytoxazone
(Scheme 6). Cytoxazone has shown cytokine-modulat-
4
Ph
Ph
OMe
OMe
LDA, THF
–78°C
48%
O
O
O
N
N
R1
R1
OH
12
11
R1 = p-MeOC6H4
(diastereomeric ratio = 61/39)
Scheme 4.

O. Miyata et al. / Tetrahedron Letters 46 (2005) 4015–4018
4017
have synthesized (ꢀ)-cytoxazone from racemic ( )-a-hy-
droxy oxime ether via optical resolution. According to
the reported method,2d we examined the conversion of
7b into oxazolidinone 15 via reduction with LiAlH4
and subsequent acylation with (Boc)2O. However, an
undesired diastereomer (4R,5R)-15 was obtained in
low yield and the desired (4S,5R)-15 was not isolated.
The reduction of the oxime ether part with other reduc-
ing agents was reexamined. As a result, the diastereo-
selective reduction of 7b with NaBH3CN proceeded
smoothly to give the desired (aR,bS)-alkoxyamino alco-
hol 14 in 78% yield, in addition to 15% yield of a diaste-
reomer. The reductive cleavage of the N–O bond
followed by acylation of the resulting amino alcohol
gave (4S,5R)-oxazolidinone 15. Treatment of 15 with
TFA gave the desired oxazolidinone 16 in 67% yield,
which was smoothly converted into (+)-cytoxazone 410
via oxidation of 16 with O3 and subsequent reduction
of the ozonide with NaBH4. The physical and spectral
data of the synthetic (+)-cytoxazone 4 were identical
with those of the authentic sample.
Ph
Li
LDA
O
Li
5a-c, 8
O
O
N
Ar
R
13
H
H
O
O
N
Ph
Ph
N
Li
O
Li
Li
O
Ar
Ar
O
O
Li
R
H
R
H
13A
13B
Ph
R
OLi
Li
O
O
N
Ar
7a-c, 10
In conclusion, we have now developed a new strategy
for preparation of optically active a-hydroxy oxime
ethers via diastereoselective imino 1,2-Wittig rearrange-
ment of allyl hydroximates. Furthermore, this method
has been successfully applied to the asymmetric synthe-
sis of (+)-cytoxazone.
H
13C
Scheme 5.
Ph
Ph
Acknowledgements
OH
OH
O
O
a)
N
HN
We acknowledge Grants-in Aid for Scientific Research
(B) (T.N.) and Scientific Research (C) (O.M.) from the
Japan Society for the Promotion of Science. Our thanks
are also directed to the Science Research Promotion
Fund of the Japan Private School Promotion Founda-
tion for a research grant.
αR
R1
βS
R1
78%
OH
7b
R1 = p-MeOC6H4
OH
14
O
O
References and notes
BocN
b)
c)
4
R1
5
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55%
(4S,5R)-15
O
O
O
HN
HN
d)
O
R1
50%
MeO
(+)-Cytoxazone 4
OH
(4S,5R)-16
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4018
O. Miyata et al. / Tetrahedron Letters 46 (2005) 4015–4018
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absolute configurations of 6a,c, 9 and 7a,c, 10 were
deduced from comparison of the 1H NMR spectra with
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7a–c, 9, and 10 were deduced as follows. It is established
that the imino 1,2-Wittig rearrangement of Z-hydroxi-
mates gave stereoselectively Z-a-hydroxy oxime ethers
with complete retention of the configuration.2a,d Since the
oxime ethers 6a–c, 7a–c, 9, and 10 were derived from Z-
hydroximates 5a–c and 8, 6a–c, 7a–c, 9, and 10 are
deduced to be Z-oxime ethers.
10. (+)-Cytoxazone 4: 1H NMR (DMSO-d6, 500 MHz) d: 8.00
(1H, br s), 7.11 (2H, br d, J = 9 Hz), 6.89 (2H, br d,
J = 9 Hz), 4.87 (1H, d, J = 8.5Hz), 4.76 (1H, t, J = 5Hz),
4.66 (1H, br td, J = 8.5, 5 Hz), 3.71 (3H, s), 2.93 (2H, m).
13C NMR (DMSO-d6, 125MHz) d: 159.0, 158.7, 129.3,
128.0, 113.7, 80.0, 61.0, 56.2, 55.1. HRMS m/z: Calcd for
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30
C11H13NO4 (M+) 223.0844. Found: 223.0846. ½aꢁD +74.4
29
(c 0.86, MeOH). [lit.2d ½aꢁD +75.0 (c 0.51, MeOH)].