Stereoselective homocoupling of chiral 1-aroylacetyl-2-imidazolidinones by oxidation with Br2

Article abstract of DOI:10.1016/S0957-4166(02)00488-3

The oxidative coupling of sodium enolates of (4R,5S)-1-aroylacetyl-3,4-dimethyl-5-phenyl-2-imidazolidinones with Br₂ as the oxidant affords the R,R-dimers stereoselectively. The R,R-selectivity can be explained by a radical coupling mechanism.

Full text of DOI:10.1016/S0957-4166(02)00488-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1845–1847
Stereoselective homocoupling of chiral
1-aroylacetyl-2-imidazolidinones by oxidation with Br2
Naoki Kise,* Azumi Fujimoto and Nasuo Ueda
Department of Biotechnology, Faculty of Engineering, Tottori University, Koyama, Tottori 680-8552, Japan
Received 31 July 2002; revised 21 August 2002; accepted 22 August 2002
Abstract—The oxidative coupling of sodium enolates of (4R,5S)-1-aroylacetyl-3,4-dimethyl-5-phenyl-2-imidazolidinones with Br2
as the oxidant affords the R,R-dimers stereoselectively. The R,R-selectivity can be explained by a radical coupling mechanism.
© 2002 Elsevier Science Ltd. All rights reserved.
Oxidative homocoupling of b-keto esters has been
of
(4R,5S)-1-acetyl-3,4-dimethyl-5-phenyl-2-imidazo-
1
2
achieved with I2 or K2S2O8 as the oxidant. However,
the diastereoselectivity of this type of reaction was
generally low. On the other hand, we have reported
that the oxidative homocoupling of chiral arylacetic
acid3 and 3-arylpropanoic acid derivatives4 gave opti-
cally active dimers stereoselectively. In continuation
with these studies, we planned to realize the oxidative
homocoupling of chiral aroylacetic acid derivatives,
since the optically active dimers formed by such a
process are useful precursors for the asymmetric synthe-
sis of furofuran lignans, such as Sesamin5 and
Eudesmin.6 Herein, we wish to report that the oxidative
homocoupling of chiral aroylacetic acid derivatives pro-
ceeds stereoselectively when (4R,5S)-3,4-dimethyl-5-
phenyl-2-imidazolidinone is used as a chiral auxiliary
and Br2 is the oxidant.
lidinone with aroyl chlorides (Scheme 1). The oxidation
of sodium salts of 1 was carried out in THF using
several oxidants, such as I2, Br2, CuCl2, CuBr2, TiCl4
and PhI(OAc)2. Only Br2 produced the corresponding
dimers 2 in satisfactory yields (Scheme 2). The dimers 2
were obtained as mixtures of two diastereomers. 1H and
13C NMR spectra clearly showed that the major iso-
mers of 2 were C2-symmetric (R,R or S,S) and the
minor ones were C1-symmetric (R,S). The major iso-
mers were confirmed to have R,R-configuration by
their conversion to known compounds (vide infra) and
S,S-isomers could not be detected.
The reaction of the sodium salts of 1 with bromides 3
(derived from 1 by bromination) also gave the dimers 2
in satisfactory yields (Scheme 3). It is notable that the
diastereoselectivities were similar to those in Scheme 2
although the bromides 3 were 6:4 mixtures of two
diastereomers. This result suggests that the dimerization
proceeds through a radical coupling mechanism.
The
starting
(4R,5S)-1-aroylacetyl-3,4-dimethyl-5-
phenyl-2-imidazolidinones 1 were prepared by acylation
We next tried mixed-coupling reactions as shown in
Scheme 4. The reaction of 1a (1b) with 3b (3a) yields
mixed-coupling product 4 together with homocoupling
products 2 in substantially statistical ratios. These
results also support radical coupling mechanism for this
type of reaction.
The results described above suggest that the dimers 2
(4) are formed by radical coupling reaction. To explain
the R,R-selectivity, the reaction mechanism illustrated
in Scheme 5 can be postulated. Namely, the anti-Z type
enolate anion A generated from 1 with NaH is oxidized
to the radical intermediate B by Br2 or bromide 3,
Scheme 1.
* Corresponding author. Fax: +81-857-31-5636; e-mail: kise@
bio.tottori-u.ac.jp
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00488-3

1846
N. Kise et al. / Tetrahedron: Asymmetry 13 (2002) 1845–1847
Scheme 2.
Scheme 5.
Scheme 3.
Scheme 6.
In summary, the oxidation of (4R,5S)-1-aroylacetyl-
3,4-dimethyl-5-phenyl-2-imidazolidinones with NaH–
Br2 gave the corresponding R,R-dimers stereoselectively
(70–72% de). To our knowledge, this report is the first
example of stereoselective dimerization of chiral b-keto
acid derivatives. Other chiral auxiliaries for this type of
reaction and transformation of the dimers to furofuran
lignans are now being investigated.
The general procedure for the oxidative coupling with
NaH–Br2 is as follows: To a suspension of NaH (1.2
mmol) in THF (5 mL) was added a solution of 1 (1.0
mmol) in THF (5 mL) at room temperature under N2.
After the mixture was stirred for 30 min, Br2 (88 mg,
0.55 mmol) was added. The mixture was stirred for 12
h, diluted with 1M HCl (10 mL), and then extracted
with Et2O. The two isomers of 2 were separated by
column chromatography on silica gel (hexane/ethyl ace-
tate). Each isomer of 2 could be further purified by
recrystallization from ethyl acetate. All coupling prod-
ucts gave satisfactory spectroscopic data and elemental
analyses. (R,R)-2a: mp 244–246°C; [h]2D0 −174 (c 1.08,
CHCl3). (R,S)-2a: mp 226–227°C; [h]2D0 +236 (c 1.02,
CHCl3). (R,R)-2b: mp 228–230°C; [h]2D5 −175 (c 1.04,
CHCl3). (R,S)-2b: mp 145–146°C; [h]2D0 +179 (c 1.06,
CHCl3). (R,R)-4: mp 163–165°C; [h]2D0 −142 (c 1.05,
CHCl3).
Scheme 4.
which is simultaneously reduced to B. The anti-Z type
radicals B couple with each other at the less hindered a
side (Re face) to give R,R-isomer of 2 (4) stereoselec-
tively. It was confirmed that the dimers 2 (4) did not
isomerize under the reaction conditions (NaH/THF, rt).
The major isomers of 2a and 2b were transformed to
(−)-Sesamin 57 and (−)-Eudesmin 6,8 respectively, by
reduction with LiBH4 in THF and subsequent treat-
ment with HCl in methanol (Scheme 6). Therefore, the
R,R-configuration of the major isomers of 2 was
assigned. The yields of 5 and 6 were low probably due
to retro-aldol reaction in the reduction step, since tetra-
hydrofurans 7 and 8 were also formed.

N. Kise et al. / Tetrahedron: Asymmetry 13 (2002) 1845–1847
1847
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