Determination of absolute configuration of trans-2-arylcyclohexanols using remarkable aryl-induced 1H NMR shifts in diastereomeric derivatives

Article abstract of DOI:10.1016/S0040-4039(01)01409-5

A facile determination of the absolute configuration of trans-2-arylcyclohexanols was achieved. It takes advantage of the observations of the remarkable aryl-induced ¹H NMR shifts that seems to be ascribable to the discrimination of the diastereo-environment between intermediary optically active diastereomers by intramolecular CH/π interaction.

Full text of DOI:10.1016/S0040-4039(01)01409-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6903–6905
Determination of absolute configuration of
trans-2-arylcyclohexanols using remarkable aryl-induced
1H NMR shifts in diastereomeric derivatives
Masato Matsugi,a Kinuyo Itoh,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; accepted 16 July 2001
Abstract—A facile determination of the absolute configuration of trans-2-arylcyclohexanols was achieved. It takes advantage of
the observations of the remarkable aryl-induced 1H NMR shifts that seems to be ascribable to the discrimination of the
diastereo-environment between intermediary optically active diastereomers by intramolecular CH/p interaction. © 2001 Elsevier
Science Ltd. All rights reserved.
As for the method for the isolation of optically active
secondary alcohols, optical resolution using chiral aux-
iliary has been well used.1 It is, however, generally
difficult to predict the absolute stereochemistry of the
resolved alcohols.2 Therefore X-ray crystallographic
ocholenic acid chloride (2),8 and a p moiety derived
from ( )-trans-2-arylcyclohexanols (1)9 in the same
molecule (see the structure in Table 1). In this system,
we postulate that an effective intramolecular CH/p
interaction between the aromatic ring moiety of the
racemic alcohols and the b-methyl moiety at the 18-
position (C18-CH3) of the optically active steroid ring
exists only in the (1S,2R)-isomer 3a.10 The molecular
orbital analysis of the compounds, 3a and 4a,11 sug-
gested this possibility, as shown in Fig. 1.11
1
analysis or H NMR spectroscopic analysis such as the
modified Mosher’s method3 is used to determine the
absolute configuration. Although X-ray crystallo-
graphic analysis is quite useful to determine the abso-
lute configuration, it is required to obtain good quality
single crystals of the target molecule, which is some-
times difficult. To apply the 1H NMR spectroscopic
analysis such as the modified Mosher’s method, though
with some exception,4 both of the corresponding
With the above data in mind, a mixture of two
diastereomeric esters 3a and 4a from ( )-trans-2-
1
phenylcyclohexanol was prepared. The H NMR spec-
diastereomeric
esters5
with
a-methoxy-a-trifl-
trum of the mixture indicated that the chemical shift (l
0.039) of the C18-CH3 of one isomer is quite different
from that (l 0.449) of the other isomer, suggesting that
the two methyl groups are placed in quite different
environments. To determine which isomer shows the
remarkable high field shift, stereo-defined 3a was pre-
pared from enantiomerically pure (1S,2R)-1a. Consis-
tent with the prediction from MO calculations, the
C18-CH3 appeared at unusually high field in the 1H
NMR spectrum (Table 1, entry 1). In addition, 3a
showed red shift of E1 absorption than 4a in UV
spectrum in acetonitrile (umax: 192 nm; umax: 187 nm,
respectively).12 It is therefore reasonable to consider
that the unusual high field shift (l 0.039) is derived
from an affinity such as the CH/p interaction.13 More
clear-cut evidence for the interaction was obtained by
the X-ray crystallographic analysis of (1S,2R)-isomer
uoromethylphenylacetic acid are required. We now
present a new methodology for the determination of
absolute configuration of trans-2-arylcyclohexanols
1
using H NMR spectroscopic analysis based on a dis-
crimination of the diastereo-environment due to an
intramolecular CH/p interaction.6 The interaction is a
non-bonding interaction6 between the CꢀH bond and
the p system, that was first proposed by Nishio and
co-workers.7
1
First we performed the H NMR analysis of trans-2-
arylcyclohexanol esters 3 and 4 both bearing a CH
moiety, derived from optically active 3b-acetoxy-D5-eti-
* 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)01409-5

6904
M. Matsugi et al. / Tetrahedron Letters 42 (2001) 6903–6905
Table 1. 1H NMR spectroscopic determination of the absolute configuration using remarkable shielding effect
Entry Ar
Chemical shift of protons on Predicted configuration of Actual configuration of Isolated yield of resolved
C18-Me in 3 or 4 [l (ppm)]a resolved 1
resolved 1
1 (%)b
1
2
3
4
5
6
Ph
3a
4a
0.039
0.449
0.006
0.490
−0.246
0.426
0.068
0.481
0.116
0.486
–
–
(1S,2R)c
–
–
(1R,2S)c
p-Methoxyphenyl 3bd
(1S*,2R*)
(1R*,2S*)
(1S*,2R*)
(1R*,2S*)
(1S*,2R*)
(1R*,2S*)
(1S*,2R*)
(1R*,2S*)
(1S*,2R*)
(1R*,2S*)
(1S,2R)e
14
9
27
5f
–
–
–
–
–
4bd
(1R,2S)
2-Naphthyl
p-Tolyl
3cd
4cd
3d
4d
3e
4e
3f
(1S,2R)e
(1R,2S)
–
–
–
–
–
–
p-Chlorophenyl
1-Naphthyl
−0.214
0.322
4f
–
a In CDCl3 at 25°C.
b Isolated yield of resolved 1 was based on a racemic 1.
c A commercially available substrate with known absolute configuration was used.
d Diastereomeric isomer was separated by recrystallization.
e Absolute configuration was determined by X-ray crystallographic analysis of the corresponding 3.
f Optical purity was 65% ee due to the difficulty in separation of the corresponding diastereomers.
which shows remarkable shielding effect to the neigh-
1
borhood of TMS peak in the H NMR spectrum, must
always have (1S,2R) configuration. This is because the
interaction seems to require a highly ordered conforma-
tion. Certainly compound 3c, which showed remarkable
1
shielding effect in H NMR, also has (1S,2R) configu-
ration (Table 1, entry 3).
Thus, the prediction of the configuration using 1H
NMR shifts seems to hold for various aryl cyclohex-
anols. More examples of chiral recognitions are shown
(Table 1, entries 4–6). It was found that this methodol-
ogy could be applied to various aryl functions. Besides,
it is worth noting that the LAH reduction of the
individual diastereomer (3 or 4) gave the corresponding
optically pure alcohol17,18 in almost quantitative yield
(Table 1, entries 2, 3). We assume that the stereoelec-
tronic effect and/or the rigidity of the configuration
induced by the adjacent carbonyl group exerts such a
stout CH/p interaction in the ester 3 (Fig. 4).
Figure 1. Calculated conformation of (1S,2R)-isomer 3a
showing CH/p interaction.
3b (see Fig. 2).5e,14 C18-CH3 was found to be placed in
close proximity to the p-face of the anisyl group. The
shortest inter-atomic distance between the CH moiety
,
and the aromatic p plane was shorter (2.92 A) than the
sum of each van der Waals radius.15 The NOESY
spectrum also supported the close proximity between
the CH moiety and the p moiety.16 Hence, it can be
seen that the structure in crystals is also retained in
solution as the major conformation. On the other hand,
X-ray crystallographic analysis of compound 4b derived
from (1R,2S)-alcohol showed the absence of a similar
interaction in this molecule (Fig. 3).
In conclusion, we have discovered that an intramolecu-
lar CH/p interaction can discriminate the diastereo-
environment between optically active diastereomers in
the crystal structure. This makes it possible to deter-
mine the absolute configuration of various trans-2-aryl-
These findings led us to assume that the molecule,

M. Matsugi et al. / Tetrahedron Letters 42 (2001) 6903–6905
6905
A. N. E.; Rappaport, A. T.; Cuccia, L. A. J. Org. Chem.
1991, 56, 2656.
3. (a) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc. 1973, 95,
512; (b) Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa,
H. J. Am. Chem. Soc. 1991, 113, 4092.
4. Some exceptional examples: (a) Trujillo, M.; Morales, E.
Q.; Va´zquez, J. T. J. Org. Chem. 1994, 59, 6637; (b)
Yamase, H.; Ooi, T.; Kusumi, T. Tetrahedron Lett. 1998,
39, 8113; (c) Lo´pez, B.; Quin˜oa´, E.; Riguera, R. J. Am.
Chem. Soc. 1999, 121, 9724.
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CH/p Interaction; Wiley-VCH: New York, 1998.
6. Recent study using high-level ab initio calculations: (a)
Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.;
Tanabe, K. J. Am. Chem. Soc. 2000, 122, 3746; (b)
Tsuzuki, S.; Honda, K.; Uchimaru, T.; Mikami, M.;
Tanabe, K. J. Am. Chem. Soc. 2000, 122, 11450.
7. Kodama, Y.; Nishihata, K.; Nishio, M.; Nakagawa, N.
Tetrahedron Lett. 1977, 2105.
Figure 2. ORTEP drawing of (1S,2R)-isomer 3b.
8. The use of 3b-acetoxyetienic acid as the chiral auxiliary for
the optical resolution of various alcohols has already been
reported: (a) Staunton, J.; Eisenbraun, E. J. Org. Synth.
1962, 42, 4; (b) Djerassi, C.; Hart, P. A.; Warawa, E. J.
J. Am. Chem. Soc. 1964, 86, 78.
9. Schwartz, A.; Madan, P.; Whitesell, J. K.; Lawrence, R.
Figure 3. ORTEP drawing of (1R,2S)-isomer 4b.
M. Org. Synth. 1990, 69, 1.
10. 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-arylcyclohexanols before ester-
ification for the simple discussion.
11. MO calculations were performed by CS ChemDraw Ultra
(Ver. 5.0) using the PM3 Hamiltonian. This conformation
of 3a was not obtained by usual procedure. The most
stable conformation of 3a was obtained when the calcula-
tion was performed on an initial conformation whose
C18-CH3 was placed in close proximity to the p-face of the
phenyl group. It is likely that the conformation has
minimum energy because the structure obtained by X-ray
analysis is almost same.
12. Braude, E. A. Determination of Organic Structures by
Physical Methods; Academic Press: New York, 1955; pp.
131–194.
13. Bovey, F. A. Nuclear Magnetic Resonance Spectroscopy;
Academic: New York, 1969; pp. 64–71.
Figure 4. Speculation: contribution of the stereoelectronic
effect.
1
cyclohexanols by H NMR analysis. In addition, the
methodology developed in this study would also be
1
applicable to the H NMR spectroscopic measurement
of the optical purity of various trans-2-
arylcyclohexanols.
14. The spatial positions of hydrogen atoms on 18-position
were optimized by Difference Fourier Maps method.
15. (a) Bondi, A. J. Phys. Chem. 1964, 68, 443; (b) Pauling,
L. The Nature of the Chemical Bond, 3rd ed.; Cornell
University Press: Ithaca, 1960.
16. It has already been reported that the nuclear overhauser
enhancement was shown to be useful to determine the
abundance of the intramolecular CH/p interaction:
Suezawa, H.; Hashimoto, T.; Tsuchinaga, K.; Yoshida, T.;
Yuzuri, T.; Sakakibara, K.; Hirota, M.; Nishio, M. J.
Chem. Soc., Perkin Trans. 2 2000, 1243.
Acknowledgements
We thank Mr. Masahiko Bando, Otsuka Pharmaceuti-
cal Co. Ltd, for the X-ray determination of the struc-
tures 3b–c and 4b.
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