Resolution of C2-symmetric 2,3-diphenylbutane-1,4-diol and purification of diastereomeric 1,4-diphenylbutane-1,4-diol using (S)-proline and boric acid

Article abstract of DOI:10.1016/S0957-4166(01)00329-9

Racemic 2,3-diphenylbutane-1,4-diol (±)-1 is resolved to obtain the corresponding (R,R)-isomer in 98% e.e. through reaction with (S)-proline and boric acid. Partially resolved (R,R)-(-)-1 and (S,S)-(+)-1 have been enriched to obtain samples of 95 and 97% e.e. through reaction with (S)-proline and boric acid. Diastereomeric 1,4-diphenylbutane-1,4-diol 2 has been purified to obtain the (R,R)-isomer in 98% e.e. using (S)-proline and boric acid.

Full text of DOI:10.1016/S0957-4166(01)00329-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 1887–1890
Resolution of C2-symmetric 2,3-diphenylbutane-1,4-diol and
purification of diastereomeric 1,4-diphenylbutane-1,4-diol using
(S)-proline and boric acid
Mariappan Periasamy,* Vutukuri Dharma Rao and Muthu Seenivasaperumal
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 16 June 2001; accepted 23 July 2001
Abstract—Racemic 2,3-diphenylbutane-1,4-diol ( )-1 is resolved to obtain the corresponding (R,R)-isomer in 98% e.e. through
reaction with (S)-proline and boric acid. Partially resolved (R,R)-(−)-1 and (S,S)-(+)-1 have been enriched to obtain samples of
95 and 97% e.e. through reaction with (S)-proline and boric acid. Diastereomeric 1,4-diphenylbutane-1,4-diol 2 has been purified
to obtain the (R,R)-isomer in 98% e.e. using (S)-proline and boric acid. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
followed by reduction using NaBH4/I2.5,7,8 We have
observed that the diol 1 can be resolved through the
chiral borate of the type 4 derived from (S)-proline and
boric acid following a convenient protocol (Scheme 1).
It was found that the sample of (2R,3R)-1 with 98% e.e.
and the partially resolved (2S,3S)-1 enantiomer can be
readily isolated from the precipitate and filtrate frac-
tions obtained by heating the racemic diol ( )-1 with
(S)-proline and boric acid in refluxing toluene or ben-
zene (Scheme 1).
Chiral auxiliaries derived from chiral diols, dicarboxylic
acids, amines, diamines, amino acids and amino alco-
hols have proven synthetic applications in asymmetric
synthesis.1 These derivatives can be obtained either by
resolution or by asymmetric synthesis.2 Recently, we
and others have reported the use of (S)-proline for the
resolution of certain racemic diols through preparation
of the corresponding diastereomeric borate complexes.3
These results prompted us to examine the use of (S)-
proline and boric acid for the resolution of C2-symmet-
ric 2,3-diphenylbutane-1,4-diol5a and 1,4-diphenyl-
butane-1,4-diol6g which have proven applications as
starting materials for the synthesis of certain useful
C2-symmetric chiral ligands.5a,6
After filtration and decomposition of the precipitated
complex with a mixture of THF/H2O (1:1), (2R,3R)-1
was isolated (37% yield, 98% e.e.). From the filtrate, the
enantiomeric (2S,3S)-1 was isolated (58% yield, 57%
e.e., entry 1). It is of interest to note that the non-
O
O
B
O
C
O
Ph
Ph
OH
Ph
OH
HN
COOH
N
H
Ph
HOH2C
CH2OH
3
2
4
1
2. Results and discussion
racemic samples of (2S,3S)-1 (57% e.e.) and (2R,3R)-1
(48% e.e.) were also further enriched to obtain samples
of 97% e.e. (entry 2) and 95% e.e. (entry 3) following
the same procedure. We have also examined the resolu-
tion of the racemic diol 1 using n-butyl borate in the
place of boric acid. In this case, only partially resolved
diols were obtained (entry 4, Table 1).
The racemic diol 1 was readily prepared through oxida-
tive coupling of ethyl phenylacetate using TiCl4/Et3N
* Corresponding author.
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00329-9

1888
M. Periasamy et al. / Tetrahedron: Asymmetry 12 (2001) 1887–1890
THF/H2O
Precipitate
(2R, 3R)-1
Ph Ph
B(OH)3
HOH2C CH2OH
COOH
N
H
C6H6 or C6H5CH3
reflux, 12h
C6H6 or C6H5CH3
reflux, 12h
THF/H2O
Filtrate
(2S, 3S)-1
Scheme 1.
Table 1. Resolution of racemic diol 1 and purification of the diastereomeric diol 2 using (S)-proline and boric acid
S. No.
Substrate, % e.e.
Solvent
Diols 1 and 2 obtained fromc
Precipitate
Yield (%)b
Filtrate
% e.e.a (conf.)
% e.e.a (conf.)
Yield (%)b
1
2
1, 00
Benzene
Benzene
Benzene
Benzene
Toluene
Benzene
Benzene
Toluene
98 (2R,3R)
97 (2S,3S)
95 (2R,3R)
53 (2R,3R)
92 (2R,3R)
98 (1R,4R)
98 (1R,4R)
98 (1R,4R)
37
63
53
24
25
84
40
75
57 (2S,3S)
10 (2S,3S)
30 (2S,3S)
15 (2S,3S)
50 (2S,3S)
0
53
23
34
60
60
8
(2S,3S)-1, 57
(2R,3R)-1, 48
1, 00
3
4d
5
1, 00
6
7
8
(1R,4R)-2, 84e
(1R,4R)-2, 45e
(1R,4R)-2, 84e
17 (1R,4R)e
10 (1R,4R)e
45
10
a All e.e. values reported here are based on the reported maximum [h]2D1=−48.2 (c 0.249, CHCl3) for (1R,2R)-(−)-1,10 [h]D21=+48.2 (c 0.249,
CHCl3) for (2S,3S)-(+)-1,10 and [h]D21=−58.5 (c 1.01, CHCl3, >98% e.e.) for (1S,2S)-(−)-2.6g (For entries 6–8 the 13C NMR spectrum of the
(1R,4R)-2 diol obtained from the precipitate fraction indicated the absence of the corresponding meso isomer.)
b The yields are of the recovered products, based on the total amount of the starting isomeric mixture used (e.g. entry 1, total yield 95%).
c For entries 1–3 and 5–8, the experiments were carried out using the following procedure: (S)-proline (1.1 equiv.) and boric acid (1.1 equiv.) were
dissolved in dry solvent (8 mL) and heated under reflux for 12 h. The corresponding diol (1 equiv.), dissolved in dry solvent (8 mL), was added
and heated under reflux for a further 12 h (Dean–Stark set-up).
d (S)-Proline (5.5 mmol), n-butyl borate (5.5 mmol) and the ( )-1 diol (5 mmol) were taken in dry benzene (80 mL) and heated under reflux for
24 h.
e Diastereomeric mixture with the (1R,4R)-isomer present in excess over the sum of racemic and meso compounds.
Efforts were also undertaken to characterize the com-
plex formed through analyses of the precipitate
We have also examined the purification of the syntheti-
cally useful C2-symmetric 1,4-diphenylbutane-1,4-diol 2
through synthesis of the corresponding borate complex
with (S)-proline. Previously, the diol 2 has been pre-
pared in enantiomerically pure form by the asymmetric
reduction of 1,4-diphenylbutanedione using Ipc2BCl6h
or B-methoxy oxazaborolidine/BH3·SMe2.6g We have
found that the reduction of 1,4-diphenylbutanedione by
B-methoxy oxazaborolidine (10 mol%)/NaBH4–TMSCl
system gives diol 2 in 84% e.e. and 70% yield (Scheme
2). Also, the diol 2 (84% e.e.) obtained in this way can
be readily purified to obtain a sample of 98% e.e. (entry
6 and 8, Table 1).
1
obtained (Scheme 1 and entry 5, Table 1) using IR, H,
13C NMR, elemental analysis. The data are in accor-
dance with the formation of the complex of the type 4.
Previously similar cyclic borate ester complexes were
reported by Shan et al.4
To examine whether the resolution can be carried out in
a more acceptable solvent, we examined the use of tolu-
ene (entry 5, Table 1). In this run, the diol (2R,3R)-1
was isolated (25% yield, 92% e.e.) from the precipitate
fraction and the (2S,3S)-1 isomer was isolated with
(60% yield, 50% e.e.) from the filtrate fraction (entry 5,
Table 1). The present method has an advantage over
previously reported procedures that require resolution
of racemic dicarboxylic acids followed by reduc-
tion.3f,9,10 In the present procedure, the resolution is car-
ried out after the reduction and hence there is no
wastage of chiral product after the resolution. Accord-
ingly, the present method would serve as a simple alter-
native procedure for the preparation of the chiral diol 1.
3. Conclusion
In conclusion, the new methods of resolution of the
racemic diol 1 and enrichment of optical purity of the
diastereomeric diol 2 described here would stimulate
further studies on the application of these procedures
involving inexpensive reagents for the resolution of

M. Periasamy et al. / Tetrahedron: Asymmetry 12 (2001) 1887–1890
1889
Ph
Ph
(0.1 equiv)
N
H
HO
OH
O
B(OMe)
3(0.1 equiv)
Ph
OH
Ph
Ph
Ph
NaBH4/TMSCl (1.0 equiv)
THF, rt, 1h
O
70% yield, 84% ee
Scheme 2.
racemic diols. Also, since the chiral diols 1 and 2 have
proven synthetic applications, the methods described
here should be useful for further synthetic exploitation
of these useful C2-symmetric chiral compounds.
4.2. Reduction of 1,4-diphenylbutane-1,4-dione
Freshly distilled chlorotrimethylsilane (3.12 g, 28.8
mmol) was added to a suspension of NaBH4 (1.08 g,
28.8 mmol) in dry THF (120 mL). The mixture was
heated at 70°C for 1 h and then cooled to rt. A solution
of B-methoxy oxazaborolidine6g [prepared using a,a-
diphenyl-2-pyrrolidine methanol (2.4 mmol) and
trimethyl borate (3 mmol) in THF (15 mL)] was added.
A solution of 1,4-diphenylbutane-1,4-dione (2.8 g, 12
mmol) in THF (25 mL) was added slowly with a
pressure equalizer over a 2 h period at 10°C. After
stirring at rt for a further 1 h, the reaction mixture was
hydrolyzed with aqueous HCl (5N, 60 mL) and
extracted with ether (3×25 mL). The combined organic
extract was washed successively with H2O, brine and
dried over MgSO4, filtered and concentrated. Purifica-
tion on a silica gel column using hexane:ethyl acetate
(3:1) as eluent gave diol 2 as a gummy liquid which
solidified on standing at rt (1.99 g, 70% yield, 84% e.e.);
[h]D25=+50.1 (c 0.454, CHCl3), lit.6g [h]2D1=−58.5 (c 1.01,
CHCl3, >98% e.e.) for (1S,2S)-(−)-2; mp 62–64°C; IR
(KBr): 3339, 3025, 1207, 990 cm−1; 1H NMR (200
MHz, CDCl3): l (ppm) 1.8–2.0 (m, 4H), 2.6–2.8 (br s,
2H), 4.7 (m, 2H), 7.3–7.2 (m, 10H); 13C NMR (50
MHz, CDCl3): l (ppm) 35.0, 36.0, 73.9, 74.3, 126.0,
127.3, 128.4, 144.8.
4. Experimental
4.1. Resolution of racemic diol 1 using (S)-proline and
boric acid (entry 5, Table 1)
(S)-Proline (0.64 g, 5.5 mmol) and boric acid (0.34 g,
5.5 mmol) were stirred under reflux in dry toluene (40
mL) for 12 h. The water produced was removed using
Dean–Stark apparatus. Diol-( )-1 (1.21 g, 5 mmol)
dissolved in toluene (40 mL) was added to the reaction
mixture under nitrogen pressure through a cannula.
The slurry becomes homogeneous and precipitation
starts after 3 h. The contents were stirred under reflux
for a further 9 h. The precipitate was filtered in hot
condition and the solution was concentrated. The
residue obtained was decomposed using a 1:1 mixture
of THF and water (30 mL). Aqueous HCl (3N, 15 mL)
was added and stirred at rt for 2 h. It was extracted
with ethyl acetate (2×25 mL). The combined organic
extract was washed successively with water, brine and
dried over anhydrous MgSO4, filtered and concen-
trated. Purification by column chromatography on sil-
ica gel using hexane:ethyl acetate (3:1) as eluent,
4.3. Purification of the non-racemic diol 2 using (S)-
proline and boric acid
afforded (2S,3S)-(+)-2,3-diphenylbutane-1,4-diol
1
(S)-Proline (0.26 g, 2.2 mmol) and boric acid (0.13 g,
2.2 mmol) were dissolved in dry toluene (16 mL) and
refluxed for 12 h. Water produced was removed using a
Dean–Stark apparatus. The non-racemic 2 (0.48 g, 2
mmol, 84% e.e.), dissolved in dry toluene (16 mL), was
added to the reaction mixture under, nitrogen atmo-
sphere through a cannula. The slurry became homoge-
neous and precipitation started after 3 h. The contents
were refluxed for a further 9 h. The precipitate was
filtered hot and the solution was concentrated. The
precipitate obtained was decomposed using a 1:1 mix-
ture of THF and water (20 mL) and HCl (3N, 10 mL)
was added and stirred at rt for 5 h. The precipate was
then extracted with ethyl acetate (2×25 mL). The com-
bined organic extracts were washed successively with
water, brine and dried over anhydrous MgSO4. After
evaporation of the solvent and purification by column
chromatography on silica gel using hexane:ethyl acetate
(3:1) as eluent; the (1R,4R)-diphenylbutane-1,4-diol was
obtained as a gummy liquid which solidified on stand-
(0.726 g, 60% yield, 50% e.e.); [h]2D5=+24.1 (c 0.41,
CHCl3), lit.10 [h]D21=+48.2 (c 0.249, CHCl3). The com-
plex obtained from the precipitate fraction (Scheme 1)
was characterized by CHN, IR, 1H and 13C NMR
analysis. Mp 273°C; IR (KBr): 3200, 3088, 3030, 1747,
1602, 1494, 1450, 1385, 1315, 1296, 1269, 1163, 1136,
1101, 1057, 912, 831, 756, 700 cm−1; 1H NMR (200
MHz, CDCl3): l (ppm) 1.5–2.5 (m, 6H), 3.0–4.4 (m,
9H), 6.9–7.3 (m, 10H); 13C NMR (50 MHz, CD3CN+
CDCl3): l (ppm) 24.2 28.0, 46.6, 53.1, 53.3, 62.2, 66.8,
67.1, 125.3, 127.0, 127.2, 127.3, 141.1, 141.5, 172.3.
Anal. calcd for C21H24BNO4: C, 69.03; H, 6.623; N,
3.83; Found: C, 68.77; H, 6.21; N, 3.65). The precipi-
tate obtained was decomposed using THF/water/dil.
HCl. After work-up, the (2R,3R)-(−)-2,3-diphenylbu-
tane-1,4-diol 1 was isolated, (0.3 g, 25% yield, 92% e.e.);
[h]2D5=−44.3 (c 0.324, CHCl3), lit.10 [h]2D1=−48.2 (c
0.249, CHCl3). After recrystallization from hexane, the
(2R,3R)-1 diol was obtained in 98% e.e.

1890
M. Periasamy et al. / Tetrahedron: Asymmetry 12 (2001) 1887–1890
ing at rt (0.36 g, 75% yield, 98% e.e.); [h]2D5=+58 (c
0.42, CHCl3), lit.6g [h]D21=−58.5 (c 1.01, CHCl3, >98%
e.e.) for (1S,2S)-(−)-2; mp 68–70°C; IR (KBr): 3339,
M.; Prasad, A. S. B.; Kanth, J. V. B.; Reddy, C. K.
Tetrahedron: Asymmetry 1995, 6, 341; (c) Venkatraman,
L.; Periasamy, M. Tetrahedron: Asymmetry 1996, 7, 2471;
(d) Periasamy, M.; Venkatraman, L.; Thomas, K. R. J. J.
Org. Chem. 1997, 62, 4302; (e) Periasamy, M.;
Ramanathan, C. R.; Prasad, A. S. B.; Kanth, J. V. B.
Enantiomer 1998, 3, 3; (f) Ramanathan, C. R.; Periasamy,
M. Tetrahedron: Asymmetry 1998, 9, 2651; (g) Periasamy,
M.; Venkatraman, L.; Sivakumar, S.; Kumar, N. S.;
Ramanathan, C. R. J. Org. Chem. 1999, 64, 7643–7645
(for related work by D. Zhao et al., see Ref. 4 and
references cited therein).
1
3025, 1207, 990 cm−1; H NMR (200 MHz, CDCl3): l
(ppm) 1.8–2.0 (m, 4H), 2.6–2.8 (br s, 2H), 4.7 (m, 2H),
7.3–7.2 (m, 10H); 13C NMR (50 MHz, CDCl3): l (ppm)
35.9, 74.4, 125.9, 127.3, 128.4, 144.7. The filtrate was
evaporated and decomposed using THF/water mixture.
After work-up, the diol 2 was isolated, (0.03 g, 10%
yield, 10% e.e.); [h]2D5=+5.9 (c 0.25, CHCl3), lit.6g
[h]2D1=−58.5 (c 1.01, CHCl3, >98% e.e.) for (1S,2S)-(−)-
2.
4. Shan, Z.; Xiong, Y.; Li, W.; Zhao, D. Tetrahedron:
Asymmetry 1998, 9, 3985.
Acknowledgements
5. dl-1 was prepared following a reported procedure. See:
(a) Dharma Rao, V.; Periasamy, M. Synthesis 2000, 5,
703–706; (b) Matsumura, Y.; Nishimura, M.; Hiu, H.;
Watanabe, M.; Kise, N. J. Org. Chem. 1996, 61, 2809.
6. (a) Tomioka, K.; Nakajima, M.; Koga, K. J. Am. Chem.
Soc. 1987, 109, 6213; (b) Tomioka, K.; Nakajima, M.;
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Tomioka, K.; Nakajima, M.; Koga, K. Tetrahedron Lett.
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Nakajima, M.; Tomioka, K.; Koga, K. Tetrahedron 1993,
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We are thankful to the UGC, New Delhi for support
under the Special Assistance Programme. V.D.R and
M.S.P. also thank CSIR, New Delhi for financial
support.
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