Determination of stereochemistry and separation of diastereomeric derivatives of trans-2-pyridylcyclohexanols by extraction

Article abstract of DOI:10.1016/S0040-4039(01)01710-5

The example of the determination of the stereochemistry and separation of diastereomeric derivatives of trans-2-pyridylcyclohexanols by extraction is shown here. The facile separation of the corresponding diastereomers is based on a difference in the basicity of the diastereomers.

Full text of DOI:10.1016/S0040-4039(01)01710-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8039–8042
Determination of stereochemistry and separation of
diastereomeric derivatives of trans-2-pyridylcyclohexanols
by extraction
Masato Matsugi,a Masatomo Nojima,a Yuri Hagimotob and Yasuyuki Kitab,*
aDepartment of Materials Chemistry, Graduate School of Engineering, Osaka University, 2-1, Yamada-oka, Suita,
Osaka 565-0871, Japan
bGraduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamada-oka, Suita, Osaka 565-0871, Japan
Received 25 June 2001; revised 27 August 2001; accepted 7 September 2001
Abstract—The example of the determination of the stereochemistry and separation of diastereomeric derivatives of trans-2-
pyridylcyclohexanols by extraction is shown here. The facile separation of the corresponding diastereomers is based on a
difference in the basicity of the diastereomers. © 2001 Elsevier Science Ltd. All rights reserved.
Optical resolution using chiral auxiliary has widely been
used as a method to obtain various optically active
molecules,1 although it involves somewhat troublesome
procedures such as recrystallization,2 column chro-
matography,3 etc. We report here the first example of
the prediction of the stereochemistry and a novel opti-
cal resolution method of diastereomeric derivatives of
trans-2-pyridylcyclohexanols by extraction with organic
solvent after treatment with aqueous acid. Previously,4
we reported a simple prediction method of the absolute
configuration of trans-2-arylcyclohexanols using
2). Further extraction of the organic phase (41% de)
with 7.0 wt.% aq. HCl improved the de of 3a to 80%
(70% yield).
The chemical shift of b-methyl proton on 18-position
(C18-CH3)9 of the major isomer in organic phase
1
showed an unusual high field shift in H NMR (for
example, 3a: l 0.115) (see Fig. 1).10
This phenomenon strongly suggested the presence of
the affinity between C18-CH3 and the p moiety, which
had already been reported in the previous paper,4 even
in the case of nitrogen containing heteroaromatics. This
is confirmed by the X-ray crystallographic analysis11 of
pure (1S,2R)-isomer 3b, which is obtained by recrystal-
lization of the corresponding diastereomers. C18-CH3
was found to be in close proximity to the p-face of the
pyridyl group, which was consistent with the remark-
1
intramolecular aryl-induced H NMR shifts probably
caused by intramolecular CH/p interaction.5,6 During
the course of the study, we unexpectedly observed that
diastereomers (3 and 4) derived from 3b-acetoxy-D5-eti-
ocholenic acid chloride7 and ( )-trans-2-pyridylcyclo-
hexanols 1,8 could be separated by extraction with
organic solvent after treatment with aqueous acid
(Table 1). That is, partitioning between organic solvent
such as diethyl ether and aq. HCl effectively made the
separation of the diastereomers.
1
ably high field shift of the C18-CH3 in H NMR (Fig.
2).
On the other hand, the (1R,2S)-isomer 4b, which did
1
The ability of distribution was influenced by the con-
centration of the aqueous acid used and the optimum
concentration of aq. HCl was based on the mixtures of
the obtained diastereomers. Thus, in the case of 3a and
4a, a 93% de of 4a was obtained in 25% yield by
concentration of the 3.0 wt.% aq. HCl and a 41% de of
3a in 73% yields from the organic layer (Table 1, entry
not show the effective aryl-induced H NMR shift was
preferentially obtained from the aqueous acid phase.
The chemical shift of the C18-CH3 of the major isomer
from the aqueous acid phase showed a lower value of l
0.463 (see Fig. 1).
It is quite interesting to note that the isomer showing
aryl-induced 1H NMR mostly existed in the organic
phase on extraction. The pKa value of pyridinium
chloride of the corresponding diastereomers is quite
* Corresponding author. E-mail: kita@phs.osaka-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01710-5

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M. Matsugi et al. / Tetrahedron Letters 42 (2001) 8039–8042
Table 1. The simple separation of diastereomers (3 and 4) by extraction technique
R
N
shielding effect
CO2
18
COCl
organic phase
(1S, 2R)-rich
2
R
N
extractionc
AcO
R
N
AcO
(1S, 2R)b-3
(±)
Et3N (1.2 eq.)
OH
aq. HCl
with Et2O
1
2
~ 97%
+
CO2
aqueous phase
0 - 4% dea
(1R, 2S)-rich
1a: R = H
b: R = Me
c: R = Cl
AcO
(1R, 2S)-4
Entry
R
Concentration of HCl aq. (wt.%)
Organic phase
Aqueous phase
Yield (%)
De (%)d
Yield (%)
De (%)d
1
2
3
4
5
6
7
8
9
H (3a+4a)e
Me (3b+4b)f
Cl (3c+4c)g
2.5
3.0
5.0
1.0
2.0
3.0
7.0
10.0
15.0
88
73
49
81
56
33
97
82
42
15 (3a)
41 (3a)
74 (3a)
19 (3b)
67 (3b)
73 (3b)
0
9
25
50
16
44
63
0
95 (4a)
93 (4a)
57 (4a)
88 (4b)
82 (4b)
37 (4b)
–
11 (3c)
82 (3c)
12
56
55 (4c)
54 (4c)
aThe kinetic resolution of 1 was observed in the acylation process when the reaction stopped under the situation remaining unreacted 1.
bThe indication of ‘(1S,2R)’ is depicted by the numbering position of 2-pyridylcyclohexanols before acylation.
cThe ratio used was as follows: a mixture of diastereomers 3a and 4a/aq. HCl/diethyl ether=0.3 g/20 ml/50 ml.
dThe de value was determined by 1H NMR (300 MHz).
eChemical shift of protons on C18-Me; 3a: 0.115, 4a: 0.463.
fChemical shift of protons on C18-Me; 3b: 0.098, 4b: 0.464.
gChemical shift of protons on C18-Me; 3c: 0.128, 4c: 0.479.
different (pKa of 3a: 3.81 and pKa of 4a: 4.15, respec-
tively),12 and the isomer showing the aryl-induced shift
has lower pKa value. Although we cannot give a clear
account of this phenomenon, it can be assumed that the
intramolecular CH/p interaction would reduce the elec-
tron density of the nitrogen atom on pyridine ring and
lead to a decrease in basicity of compounds 3a13 (Fig.
1
Figure 1. Partial H NMR spectrum (600 MHz) of a mixture
of diastereomeric isomers 3a and 4a (41% de) obtained from
the organic phase in CDCl3 at 25°C.
Figure 2. ORTEP drawing of 3b.

M. Matsugi et al. / Tetrahedron Letters 42 (2001) 8039–8042
8041
1
3). An alternative possibility is a significant difference
of the steric bulkiness around the nitrogen atom in the
diastereomers.
the diastereomers showing aryl-induced H NMR shift
has a lower pKa value and proves to exist in the
organic phase on extraction. These results thus provide
a simple optical resolution method of trans-2-pyridylcy-
clohexanols. Attempts to extend the method to other
substrates are in progress.
Finally, deprotection of the steroid moiety gave the
optically active pyridyl alcohols in good yields (Table
2).
Here we have shown a novel optical resolution tech-
nique by simple extraction using achiral-organic solvent
and acid solution. The facile separation of the corre-
sponding diastereomers takes advantage of the distribu-
tion technique based on a difference in pKa values of
the diastereomers. We find that the (1S,2R)-isomer 3 of
Acknowledgements
We thank Mr. Masahiko Bando, Otsuka Pharmaceuti-
cal Co. Ltd, for the X-ray determination of the struc-
Figure 3. Speculation: charge-transfer interaction via ideal overlap of orbitals.
Table 2. Deprotection of the diastereomers (3 or 4) to pyridylalcohols
R
N
shielding effect
R
N
CO2
reduction
OH
(1S, 2R)-3
AcO
organic phase
(1S, 2R)-1
(1S, 2R)-3
extractiona
R
+
aq. HCl
with Et2O
(1R, 2S)-4
N
R
OH
CO2
reduction
N
(1R, 2S)-4b
AcO
(1R, 2S)-1
aqueous phase
Diastereomer
De of starting diastereomer 3 or 4 (%)c
Method of reductiond
Yield (%)
Ee of product (%)e
R=H (3a)
R=H (4a)
R=Me (3b)
R=Me (4b)
R=Cl (3c)
R=Cl (4c)
81
93
67
82
82
54
A
A
A
A
B
68
90
83
90
70
89
77 (1S,2R)
93 (1R,2S)
64 (1S,2R)
80 (1R,2S)
79 (1S,2R)
50 (1R,2S)
B
aThe ratio used was as follows : a mixture of diastereomers/aq. HCl/diethyl ether=0.3 g/20 ml/50 ml.
bThese products were obtained by neutralizing the aqueous phase with NaHCO3 (pH 8).
cThe de value was determined by 1H NMR (300 MHz).
dMethod A: LiAlH4 (10 equiv.), THF, rt, 2.0 h; method B: DIBAL-H (5 equiv.), THF, −78°C, 2.0 h.
eThe ee value was determined by HPLC (CHIRALCEL OD®, hexane:iPrOH=95:5).

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M. Matsugi et al. / Tetrahedron Letters 42 (2001) 8039–8042
ture of 3b and Mr. Shinji Hirose, Sumika Chemical
Analysis service, for the pKa value measurements of
HCl salt of 3a and 4a.
8. (a) Funke, A.; Rissi, E. Compt. Rend. 1954, 239, 713; (b)
Petrenko, O. P.; Krivopalov, V. P.; Lapachev, V. V.;
Mamaev, V. P. Izv. Akad. Nauk SSSR, Ser. Khim. 1981,
227.
9. The numbering positions on the steroid ring and hexane
ring are, respectively, depicted by the positions of 3b-ace-
toxy-D5-etienic acid and 2-arylhexanols before esterifica-
tion for the simple discussion.
10. Bovey, F. A. Nuclear Magnetic Resonance Spectroscopy;
Academic: New York, 1969; pp. 64–71.
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