Synthesis of the first water-soluble C2-symmetric bis(oxazolidinone) as a potential bifunctional chiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(00)00086-0

The first water-soluble C₂-symmetric bis(oxazolidinone) 1, a potential bifunctional chiral auxiliary, has been synthesized via regioselective intramolecular cyclization of a biscarbamate. The sodium enolate derived from N,N'-di(phenylacetyl)bis

Full text of DOI:10.1016/S0957-4166(00)00086-0

Tetrahedron: Asymmetry 11 (2000) 1455±1458
Synthesis of the ®rst water-soluble C2-symmetric
bis(oxazolidinone) as a potential bifunctional
chiral auxiliary
Sang-gi Lee,* Chung Woo Lim, Dong Chan Kim and Jae Kyun Lee
Life Sciences Division, Korea Institute of Science and Technology, PO Box 131, Cheongryang,
Seoul 130-650, South Korea
Received 24 January 2000; accepted 21 February 2000
Abstract
The ®rst water-soluble C2-symmetric bis(oxazolidinone) 1, a potential bifunctional chiral auxiliary, has
been synthesized via regioselective intramolecular cyclization of a biscarbamate. The sodium enolate
derived from N,N0-di(phenylacetyl)bis(oxazolidinone) 7 reacts with methyl iodide with high facial selectivity
(95:5). # 2000 Elsevier Science Ltd. All rights reserved.
It is often observed, as reviewed by Whitesell, that auxiliaries with C2-symmetry elements per-
form in their capacity as stereochemical directors to provide higher levels of absolute stereo-
chemical control compared to those totally lacking in symmetry.1 Therefore, C2-symmetrization
of the non-symmetrical chiral auxiliaries is central in the development of chiral auxiliaries.
Recently, to reduce the e€ective molecular mass (EMM) as far as possible within the limits of
maintaining high stereocontrol, a series of C2-symmetric imidazolidinones2 and a cyclic sulfamide3
have been synthesized. In spite of the high chiral induction abilities of chiral oxazolidin-2-ones
as chiral auxiliaries, no C2-symmetric versions have been reported yet.4 Therefore, we decided
to synthesize C2-symmetric bis(oxazolidinone) 1 as a potential bifunctional chiral auxiliary.
Bis(oxazolidinone) 1 has the following characteristic features: (a) each of the oxazolidinone rings
could exhibit equivalent functions either sterically or stereoelectronically, and should act as an
independent chiral-directing group; (b) C2-symmetry of 1 could reduce the e€ective molecular
mass (EMM=86). Moreover, both enantiomers are available from inexpensive (d)- and (l)-tartaric
acid.
* Corresponding author. E-mail: L3712@kistmail.kist.re.kr
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00086-0

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S. Lee et al. / Tetrahedron: Asymmetry 11 (2000) 1455±1458
Recently, we and others have synthesized C2-symmetric chiral bis(oxazolines),5 bis(oxazines)6
and bis(pyrrolinyl) or fused-bicyclic pyrrolinyl7 via regioselective intramolecular cyclization of
C2-symmetric bis(amide) and bis(amine). It has also been reported that 2,3-epoxy alcohols react
with isocyanates to provide the corresponding oxazolidinones.8 Therefore, for the synthesis of the
bis(oxazolidinone) 1, the regioselective intramolecular cyclization reactions have been extended to
the C2-symmetric bis(carbamate) 4 which was synthesized from readily available dibenzyloxy
dimesylate 25a as shown in Scheme 1. Debenzylation of 2 using Pd(OH)2/H2 a€orded the debenzylated
product 3 almost quantitatively. Subsequent reaction of 3 with benzyl isocyanate in THF a€orded
4 (90%). When the bis(carbamate) 4 was treated with NaH, the ring closure occurred highly
regioselectively to form bis(oxazolidinone) 5 in 90% yield.
Scheme 1.
For the debenzylation, N,N0-dibenzyl bis(oxazolidinone) 5 was subjected to Birch conditions
(Na/NH3). Unfortunately, all attempts to isolate the debenzylated product 1 from the organic
phase failed. Instead, we could only isolate 1,2-diphenylethane 6, which may be formed via intra-
molecular reductive homocoupling of the N-benzyl groups followed by debenzylation. Event-
ually, it was found that the bis(oxazolidinone) 1 is highly soluble in water. Thus, the desired
bis(oxazolidinone) 1 could be isolated from the aqueous phase, i.e. after evaporation of water, the
solid residue was extracted with Soxhlet using acetonitrile to give 1 in 72% yield. All spectral data
including X-ray crystallographic analysis consistent with the structure of 1 (Fig. 1).9 As shown in
X-ray crystal structure of 1, the two oxazolidinone rings formed a concave shape and the two
nitrogen atoms are placed on opposite sides. Worthy of note is that the high water solubility of 1
may provide an additional advantage, i.e. easy separation, as with a solid supported auxiliary.10
As a preliminary application of this novel water-soluble C2-symmetric bifunctional bis(oxazolidin-
one) 1, auxiliary controlled diastereoselective methylation has been examined. The phenylacetyl
units were successfully coupled to the auxiliary 1 according to the procedure reported by Prashad

S. Lee et al. / Tetrahedron: Asymmetry 11 (2000) 1455±1458
1457
Figure 1. ORTEP diagram of compound 1
et al., and a€orded 7 in 90% yield.11 For the diastereoselective methylation of 7, to a solution of 7
in THF (0.1 M in THF) and HMPA (2/1,v/v) was slowly added 2.2 equivalents of NaN(TMS)2 at
^78ꢀC followed by excess methyl iodide (5 equivalent) to give the methylated products in 78%
1
yield. The distribution of the three possible diastereomers 8, 9 and 10 was determined by H
NMR analysis. In 1H NMR spectrum, the methyl proton signal of the major isomer 10 resonated
at 1.52 ppm (d, J=7.0 Hz) and the two sets of methyl proton signals of the minor isomer 9 were
detected at 1.48 and 1.32 ppm (d, J=7.0 Hz). The integration ratio of the major isomer 10 and
minor isomer 9 is 10:1. If it is assumed that both alkylation steps proceeded with the same dia-
stereoselectivity and the selectivity of one of the alkylation steps is X:1, the expected ratio of
8:9:10 should be 1:2X:X2. Calculation from the ratio of 9 and 10 resulted in a selectivity X of 20,
consistent with a facial selectivity of 95:5. Hydrolysis of 10 a€orded (S)-a-methylphenylacetic
acid, and the bifunctional chiral auxiliary 1 can be recovered quantitatively from the aqueous
phase by Soxhlet extraction using acetonitrile.
In conclusion, we have synthesized a novel water-soluble C2-symmetric bis(oxazolidinone) 1
via base induced regioselective intramolecular cyclization of bis(carbamate) 4. The high dia-
stereoselective methylation of 7 clearly indicates that each of the oxazolidinone rings could exhibit
equivalent functions both sterically or stereoelectronically, and acts as an independent chiral-
directing group. Moreover, the high water solubility of 1 allowed its easy separation from the
product after cleavage of the N-acyl group. Studies on the extension of our bis(oxazolidinone)
system to other asymmetric reactions are in progress.

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S. Lee et al. / Tetrahedron: Asymmetry 11 (2000) 1455±1458
Acknowledgements
We are grateful to the Korea Institute of Science and Technology for support of this work. We
are also grateful to Ms. Jae-Gyung Lee for her assistance in X-ray structure determination.
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25
D
9. Data for 1: mp 247±249ꢀC; ‰ꢀŠ ^9.26 (c 1.02, H2O); 1H NMR (300 MHz, DMSO-d6) ꢁ 7.84 (bs, 2H), 4.35
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a=5.638(3), b=5.649(2), c=22.237(5) A, space group=P212121 (no.19), V=708.2(5) A3, Z=4, Dc=1.596 g/cm3,
crystal size=0.2Â0.2Â0.18 mm, F(000)=360, a total of 568 re¯ections in the range of 1.83ꢀꢁꢂꢁ24.94ꢀ measured,
the Áꢃmax and Áꢃmin are 0.288 and 0.265 e A^3, goodness-of-®t=1.133, I/ꢄ(I)ꢂ2.0, R=0.0537.
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