Synthesis of both enantiomers of 1-phenylethane-1,2-diol via chirality transfer from bile acid derivatives

Article abstract of DOI:10.1016/S0957-4166(00)00338-4

Both enantiomers of 1-phenylethane-1,2-diol were synthesized with good to excellent enantioselectivities via selective reduction of the phenylglyoxalates derived from bile acids, followed by reductive cleavage. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00338-4

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3463–3466
Synthesis of both enantiomers of 1-phenylethane-1,2-diol via
chirality transfer from bile acid derivatives
A. K. Bandyopadhyaya, N. M. Sangeetha, A. Radha and Uday Maitra*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 19 July 2000; accepted 23 August 2000
Abstract
Both enantiomers of 1-phenylethane-1,2-diol were synthesized with good to excellent enantioselectivities
via selective reduction of the phenylglyoxalates derived from bile acids, followed by reductive cleavage.
© 2000 Elsevier Science Ltd. All rights reserved.
Efficient synthesis of homochiral molecules is one of the important areas of organic synthesis.
Among various methodologies available for the synthesis of chiral compounds, chirality transfer
through a chiral auxiliary has been widely investigated and utilized. Derivatives of natural
products from several classes such as terpenes, alkaloids, carbohydrates, amino acids etc., have
been extensively used as chiral auxiliaries.1 Bile acids have been successfully exploited as chiral
auxiliaries and chiral templates by us2,3 and others.4 We demonstrated the induction of moderate
to good stereoselectivities for Diels–Alder reactions and a-keto ester reductions using a bile
acid-derived chiral auxiliary.2 Herein, the versatility of bile acid-based auxiliaries is further
demonstrated by synthesizing both enantiomers of 1-phenylethane-1,2-diol5 with good to excel-
lent enantioselectivities.
In the previously reported studies on the asymmetric reduction of bile acid derived a-keto
esters, the relatively unhindered 3-OH group was used for attaching the substrate and up to 70%
de was achieved.6 Since the axial 7-OH and 12-OH groups are much more hindered, we planned
to explore these sites for attaching a reactive site. We first synthesized a-keto esters 1 and 2 (Fig.
1 and Scheme 1) in order to establish the chiral influence of the bile acid backbone. These
compounds were reacted with hydrides at low temperatures and the products obtained were
1
analyzed by H NMR and HPLC for estimating the diastereomeric ratio. Selected results are
summarized in Table 1.
* Corresponding author. E-mail: maitra@orgchem.iisc.ernet.in
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00338-4

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A. K. Bandyopadhyaya et al. / Tetrahedron: Asymmetry 11 (2000) 3463–3466
Figure 1.
For compound 1 the highest diastereoselectivity (78%) was obtained with LiBH4 at −78°C in
THF, while NaBH4 reduction in 1:3 MeOH/THF at −78°C gave a de of 63%. On the contrary,
substrate 2 gave a diastereoselectivity of 76% with NaBH4 and 68% with LiBH4 under similar
Scheme 1. Reagents and conditions: (a) MeOAc, TsOH; (b) PhCOCOCl, DMAP, CH2Cl2; (c) NBS, NaHCO3, H2O;
(d) MeOH, AcCl; (e) Ac2O, Et3N, DMAP, D; (f) NaBH4, MeOH–THF; (g) Ac2O, Py, rt; (h) 2-NpCOCl, CaH2,
BnEt3N+Cl−, PhMe, D (Np: naphthyl)
Table 1
Product diastereomer excess upon reduction of bile acid derived a-keto esters with hydride reagents
Substrate
T (°C)
Reagent
Solvent
de HPLC (NMR)
Major stereoisomer
Yield (%)b
1
1
2
2
3
3
−78
−78
−78
−78
−20
−78
NaBH4
LiBH4
NaBH4
LiBH4
NaBH4
LiBH4
MeOH/THFa 63 (64)
THF 78 (77)
MeOH/THFa 76 (75)
R
R
S
S
S
S
96
96
95
94
93
88
THF
MeOH
THF
68 (68)
\99
96
a 1:3 ratio.
b Isolated yields of 1a, 2a and 3a.

A. K. Bandyopadhyaya et al. / Tetrahedron: Asymmetry 11 (2000) 3463–3466
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conditions used for the reduction of 1. The use of additives such as LiBr, HMPA, TMEDA
etc.,7 had no significant effect on the diastereoselectivities. The stereochemistry of the newly
formed stereocentre for 1a was found to be R, while that for 2a was S.8 These results suggested
that the hydride addition took place from the less hindered side of the prochiral keto group of
the keto ester in the predominant anti conformation of the two carbonyl groups (Fig. 2).
Figure 2. Proposed model to explain observed selectivities
We subsequently designed chiral auxiliary 3 with 2-naphthoate as the shielding group at
12-OH to shield one of the faces of the keto group and hence enhance the chiral induction. This
indeed gave a diastereoselectivity of >99% at −20°C with NaBH4, but somewhat reduced de with
LiBH4 (Table 1).
Selective hydrolytic cleavage of the a-hydroxy ester linkage in 1a–3a in the presence of
multiple ester linkages using a variety of reagents was unsuccessful in removing the chiral
auxiliary to yield chiral mandelic acid. However, the chiral auxiliary could be removed by
selective reductive cleavage of the mandelate ester with LiBH4 in dry THF at rt to regenerate the
chiral auxiliary and produce 1-phenylethane-1,2-diol. The enantiomeric excess and the configu-
ration of the product were determined by comparison of the specific rotation values with the
literature value.9 The enantiomeric excesses were in good agreement with the observed
diastereomeric ratios of 1a, 2a and 3a (Table 2).
Table 2
Enantiomeric excesses after reductive cleavage of the a-hydroxy esters
Mandelate ester
Recovered auxiliary
Yield (%)
1-Phenylethane-1,2-diol
Yield (%)
[h]2D4 a
ee Configuration of the major isomer
1a
2a
3a
57
50
52
53
65
44
−30.5 77
+30.0 76
+38.3 97
R
S
S
a Measured in ethanol (see Ref. 9).
In conclusion, we have demonstrated the utility of derivatives of readily available bile acids as
chiral auxiliaries by synthesizing both enantiomers of 1-phenylethane-1,2-diol with good to
excellent enantiomeric excess. Further work to optimize some of the reactions described here are
in progress and these results will be reported elsewhere.

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A. K. Bandyopadhyaya et al. / Tetrahedron: Asymmetry 11 (2000) 3463–3466
Acknowledgements
We thank the Department of Science & Technology, New Delhi (grant c SP/S1/G-08/96) for
financial support. A.K.B. and N.M.S. thank the UGC and the CSIR, respectively, for
fellowships.
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