Solid-phase synthesis of 1,3-oxazolidine derivatives

Article abstract of DOI:10.1016/S0040-4039(00)00775-9

1,3-Oxazolidines 9 were synthesized by using a solid support. Regioselective ring opening of resin-bound epoxy ether 3 with ammonium chloride followed by nucleophilic substitution with sodium azide gave azido alcohol 7. Reduction of 7 provided 1-amino-2-alkanol 6, which was treated with various aldehydes and acyl chlorides or isocyanates to afford the corresponding 1,3-oxazolidines immobilized on Wang resin. Oxidative cleavage with DDQ from the solid support yielded 1,3-oxazolidines as a mixture of 10 (cis) and 11 (trans). (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00775-9

Tetrahedron Letters 41 (2000) 5069±5072
Solid-phase synthesis of 1,3-oxazolidine derivatives
a,
a
b
c
Heong Sub Oh, * Hoh-Gyu Hahn, Seung Hoon Cheon and Deok-Chan Ha
aLife Science Division, Korea Institute of Science and Technology, Cheongryang PO Box 131,
Seoul 136-791, South Korea
b
Chonnam National University, Kwangju 500-757, South Korea
cKorea University, Seoul 136-701, South Korea
Received 14 February 2000; accepted 12 May 2000
Abstract
,3-Oxazolidines 9 were synthesized by using a solid support. Regioselective ring opening of resin-bound
1
epoxy ether 3 with ammonium chloride followed by nucleophilic substitution with sodium azide gave azido
alcohol 7. Reduction of 7 provided 1-amino-2-alkanol 6, which was treated with various aldehydes and
acyl chlorides or isocyanates to a€ord the corresponding 1,3-oxazolidines immobilized on Wang resin.
Oxidative cleavage with DDQ from the solid support yielded 1,3-oxazolidines as a mixture of 10 (cis) and
11 (trans). # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: 1,3-oxazolidine; solid phase synthesis; oxidative cleavage; diabetes.
Solid-phase reactions play an important role in combinatorial chemistry in the area of medicinal
as well as agrochemical chemistry, where its potential has emerged due to the possibility of
1
automated synthesis. In particular, access to heterocyclic compounds by solid-phase synthesis is
urgently required, since small, substituted heterocycles o€er a high degree of structural diversity
2
and they are proven to be exceptionally useful in many applications. In our study aimed at the
development of therapeutic agents for the treatment of diabetes mellitus, we were interested in the
3
combinatorial synthesis of 1,3-oxazolidine derivatives. The ®rst concern was selection of a readily
4
cleavable linker since 1,3-oxazolidines were labile even under mild acidic conditions. p-Hydroxy-
benzyl alcohol, immobilized with Wang resin in the form of a benzyl ether, was chosen as a linker.
5
We anticipated that the DDQ oxidation would not only cleave the linker from Wang resin but
also generate terminal aldehyde suitable for further functionalization.
Scheme 1 shows an overall synthetic procedure. A nucleophilic displacement of epibromohydrin
with p-hydroxybenzyl alcohol in the presence of sodium hydride in DMF, followed by treat-
1
ment with chlorinated Wang resin gave the epoxy ether 3 immobilized on the solid phase in good
6
7
8
yield (92%). Ring opening of the epoxide 3 to 1-amino-2-alkanol 6 by treating with methanolic
*
Corresponding author. Tel: +82 2 958 5168; fax: +82 2 958 5189; e-mail: oohs@kistmail.kist.re.kr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00775-9

5
070
ꢀ
Scheme 1. Reagents and conditions: (i) p-hydroxybenzyl alcohol, NaH, DMF, 65 C, 19 h, 70%; (ii) chlorinated Wang
ꢀ
6
ꢀ
ꢀ
resin, NaH, DMF, 0 C to rt, 24 h, 92%; (iii) NH Cl, DMSO, 80 C, 24 h, quantitative; (iv) NaN , DMSO, 80 C, 24 h,
3
4
9
R
6%; (v) C
6
H
5
SH, Et
NCS, Et N, THF, rt, 24 h; (viii) DDQ, CH Cl :H O (18:1), rt, 3 h; (ix) 1% TFA, CH CH
3
N, SnCl
2
, THF, rt, 4 h; (vi) R
1
CHO, CH(OCH
3
)
3
2 2
, THF, rt, 12 h; (vii) R COCl, R NCO, or
2
3 2 2 2 2 2
9
ammonia was unsuccessful, presumably due to the poor swelling ability of the resin in this solvent.
ꢀ
Alternatively, the epoxy ether 3 was subjected to ammonium chloride in DMSO at 80 C to give
1
-chloro-2-alkanol 4, which was smoothly transformed to azido alcohol 7 by treatment with
10
sodium azide at room temperature in excellent yield (95%). Direct nucleophilic substitution of
the epoxy ether 3 with sodium azide resulted in a low yield (70%) of the azido alcohol 7.
Subsequent reduction of the azido alcohol 7 to an amine using thiophenol:triethylamine:tin
chloride (4:5:1) as reported by Bartra and co-workers gave the desired 1-amino-2-alkanol 6
immobilized on the Wang resin. The progress of reaction was monitored by FT±IR following the
disappearance of the azide stretch absorption band (2098 cm ). Condensation of 1-amino-2-
alkanol 6 with an aldehyde in the presence of a large excess trimethylorthoformate in THF followed
by treatment with acyl chloride, or isocyanate, or isothiocyanate a€orded the corresponding
polymer-bound 1,3-oxazolidines 8. No increased yields were observed even though the inter-
mediate imine 5 immobilized on the resin was puri®ed by washing before reacting with electro-
philes. The progress of 1,3-oxazolidine formation reaction was monitored by FT±IR following
11
^1
^1
the disappearance of the secondary hydroxyl absorption band (3600±3300 cm ) and appearance
^
1
^1
of the CˆO or CˆS absorption band (1650±1680 cm and 2350±1100 cm , respectively). It was
reported that the 1,3-oxazolidines derived from serine or threonine and benzaldehyde on a Sasrin
linker were relatively stable (less than 10% decomposition) under the 95% TFA/water or 5%
TFA/CH Cl . However, in our case, resin bound 1,3-oxazolidines 8's were decomposed to give
2
aldehyde (R CHO) by the treatment of 1% TFA/CH Cl at room temperature. In fact, 1,3-oxa-
2
4
2
1
2
zolidine 9 prepared through solution-phase synthesis was easily decomposed even in the presence
of a trace amount of acid (TFA) at room temperature. Therefore, other cleavage conditions as a

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071
mild and neutral alternative to TFA were examined. Successful oxidative cleavage from the resin
was achieved by the treatment with DDQ in methylene chloride at room temperature. Subsequent
puri®cation by ¯ash chromatography a€orded the corresponding 1,3-oxazolidines 9 with a new
functional moiety, aldehyde, which would be suitable for further functionalization.
1
which could be separated by ¯ash chromatography. The stereochemistry of the isomers was
,3-Oxazolidines obtained were a mixture of 10 (cis) (major) and 11 (trans) isomers (minor),
1
determined by H NOE. Irradiation to the C-5 proton led the signal of the C-2 proton in 10 (cis)
to a 4.9% enhancement, while no e€ect was observed in 11 (trans) (Fig. 1).
Figure 1. 1H NOE of the isomers: the arrows, which stand for the observed NOE e€ects point from the irradiated to
the observed signal; data of the relative increase in intensity are given in percentages
Table 1
The structures of 1,3-oxazolidines

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072
Table 1 provides structures of the various compounds prepared, the yields, and the ratios of the
1
isomers. The structure and the stereochemistry of the isomers were determined by H NMR
spectroscopy and mass spectrometry. Some 1,3-oxazolidines, having an electron rich substituent
at C-2, could not be prepared by this method. By monitoring their FT±IR spectra, an electron-
donating substituent such as the methoxy or phenoxy group in the C-2 phenyl group (entries 4
and 5) made the 1,3-oxazolidine ring unstable under the reaction conditions. In contrast, 1,3-
oxazolidines (entries 14, 15, 16) derived from the cinnamaldehyde were stable on the solid support,
but they were decomposed during the oxidative cleavage process.
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1
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8
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