1H NMR determination of absolute configuration of 1- or 2-aryl-substituted alcohols and amines by means of their diastereomers: Novel separation technique of diastereomeric derivatives of pyridyl alcohols by extraction

Article abstract of DOI:10.1002/1521-3765(20021216)8:24<5551::AID-CHEM5551>3.0.CO;2-V

Abstract: A convenient method to determine the absolute configuration of trans-2-aryl cyclohexanols, 1-aryl alcohols and amines was achieved. This method takes advantage of the ¹H NMR spectroscopic observations of the remarkable high-field shift of C18-CH₃ protons caused by the aromatic shielding effect. It is based on a discrimination of the difference of the environments in two diastereomers derived from 3β-acetoxy-5-etienic acid. Furthermore, it was observed that the corresponding diastereomeric derivatives of the pyridyl alcohols were simply separated by extraction based on the difference in their basicity.

Full text of DOI:10.1002/1521-3765(20021216)8:24<5551::AID-CHEM5551>3.0.CO;2-V

FULL PAPER
1H NMR Determination of Absolute Configuration of 1- or
2-Aryl-Substituted Alcohols and Amines by Means of Their Diastereomers:
Novel Separation Technique of Diastereomeric Derivatives of Pyridyl
Alcohols by Extraction
Masato Matsugi,[c] Kinuyo Itoh,[c] Masatomo Nojima,[b]
Yuri Hagimoto,[a] and Yasuyuki Kita*[a]
Abstract: A convenient method to determine the absolute configuration of trans-2-
aryl cyclohexanols, 1-aryl alcohols and amines was achieved. This method takes
1
advantage of the H NMR spectroscopic observations of the remarkable high-field
shift of C18-CH3 protons caused by the aromatic shielding effect. It is based on a
discrimination of the difference of the environments in two diastereomers derived
from 3b-acetoxy-5-etienic acid. Furthermore, it was observed that the corresponding
diastereomeric derivatives of the pyridyl alcohols were simply separated by
extraction based on the difference in their basicity.
Keywords: CH pi interaction
¥
¥
configuration
determination
diastereomer extraction
spectroscopy
¥
NMR
of an X-ray crystallographic analysis is the necessity to obtain
high-quality single crystals of the target molecule; this is
sometimes associated with difficulties. Although the modified
Mosher method is an excellent method to determine the
absolute configuration, with some exceptions,[4] it requires the
preparation of both corresponding diastereomeric esters with
a-methoxy-a-trifluoromethylphenylacetic acid. Because of
Introduction
Determination of the absolute configuration of chiral alco-
hols, amines and their analogues is one of the important
subjects in organic chemistry,[1] since many biologically active
compounds are associated with a chiral sense dependence on
the activities.[2] X-ray crystallographic analysis or H NM R
1
spectroscopic analysis, represented by the modified Mosher
method,[3] have been frequently used methods to determine
the absolute configuration in this field. The serious drawback
these circumstances, we have described a convenient
1H NMR spectroscopic method to determine the absolute
configuration of some aryl-substituted alcohols and amines[5]
that is based on the observations of the remarkable shielding
effect which discriminates between the environments in two
diastereomers[6] in the optically active molecules. We also
described the distinguishing difference in the pKa values of
the diastereomeric derivatives of trans-2-pyridylcyclohexa-
nols, which allows a simple separation by extraction.[7] This
skillful technique is the first example of the separation of
diastereomers by extraction with achiral media. We now
describe the full account of these studies, in which a
connection for the chiral discrimination between the CH
moiety and the p moiety is described.[8]
[a] Prof. Y. Kita, Y. Hagimoto
Graduate School of Pharmaceutical Sciences
Osaka University, 1-6, Yamada-oka
Suita, Osaka 565-0871 (Japan)
Fax: (81)6-6879-7930
E-mail: kita@phs.osaka-u.ac.jp
[b] Prof. M. Nojima
Department of Materials Chemistry & Frontier Research Center
Graduate School of Engineering, Osaka University, 2-1
Yamada-oka, Suita, Osaka 565-0871 (Japan)
Fax: (81)6-6879-7928
E-mail: nojima@chem.eng.osaka-u.ac.jp
[c] Dr. M. Matsugi, K. Itoh
Department of Materials Chemistry
Graduate School of Engineering, Osaka University
2-1, Yamada-oka, Suita, Osaka 565-0871 (Japan)
Fax: (81)6-6879-7930
Results and Discussion
E-mail: matsugi@chem.eng.osaka-u.ac.jp
Our first interest was to explore the possibility of discrim-
inating the environments in two diastereomers by an intra-
molecular CH p interaction in a chiral environment. The
CH p interaction,[9] which was proposed by Nishio et al. in
Supporting information for this article is available on the WWW under
http://www.chemeurj.org/ or from the author, and includes 1H NM R
spectra of 3a and 4a at various temperatures, and the NOESY
spectrum of 3a.
Chem. Eur. J. 2002, 8, No. 24
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5551

Y. Kita et al.
FULL PAPER
1977,[10] is an attractive force between a soft acid and a soft
base, and it provided an important contribution to the
understanding of weak intramolecular forces and their
potential value to the physical, chemical and biochemical
1
sciences.[9e] First of all, we planned an H NMR analysis of
compounds 3 and 4, which both bear a CH moiety, derived
from the optically active 3b-acetoxy-5-etienic acid,[11] and a p
moiety, derived from the (Æ)-trans-2-arylcyclohexanol deriv-
ative,[12] in the same molecule (Scheme 1).
In this system, we expected an effective intramolecular
attractive force based on a CH p interaction between the
Figure 1. Calculated conformation of (1S, 2R) isomer 3a showing CH
interaction.
p
(d ˆ 0.039; Figure 3). There-
fore, it is reasonable to consider
that that the unusual high-field
COCl
Ar
Ar
CO2
CO2
OH
Ar
2
AcO
+
(S)
(R)
shift is derived from a CH
p
pyridyne
or
Et3N in CH2Cl2
AcO
AcO
interaction. In addition, 3a
showed a red shift of the E1
absorption relative to that of
4a in the UV spectrum in
(±)-1
3a-m
4a-m
Scheme 1. Diastereomeric derivatives (3 and 4) derived from 3b-acetoxy-5-etienic acid and (Æ)-trans-2-
arylcyclohexanols (acylation of (Æ)-1 with steroid compound 2).
acetonitrile (lmax
:
192 and
aromatic ring moiety of the
racemic alcohols and the b-
methyl moiety at the 18-posi-
tion (C18-CH3) of the optically
active steroid ring that exists
only in the (1S, 2R) isomer
3a.[13] A molecular orbital anal-
ysis of the compounds 3a and
4a by MO calculation (PM3)[14]
suggested this possibility, as
depicted in Figure 1.
With the above postulation in
mind, we prepared a mixture of
the two diastereomeric esters,
3a and 4a, from (Æ)-trans-2-
phenyl-1-cyclohexanol.
As
shown in Figure 2, the 1H NM R
spectrum of the mixture indi-
cated that the chemical shift
(d ˆ 0.039) of the b-methyl at
the 18-position (C18-CH3) of
one isomer is quite different
from that of the other isomer
(d ˆ 0.449). This suggests that
the two methyl groups are in
quite different environments.
To determine which isomer
shows the remarkable high-
field shift, the stereo-defined
compound 3a was prepared
from the enantiomerically pure
(1S, 2R)-alcohol 1a. Consistent
with the prediction from the
MO calculations, the b-methyl
protons at the 18-position ap-
peared at an unusually high
1
Figure 2. Partial H NMR spectrum (600 MHz) of a mixture of diastereomeric isomers 3a and 4a in CDCl3 at
258C.
1
1
field in the H NMR spectrum
Figure 3. Partial H NMR spectrum (600 MHz) of (1S,2R) isomer 3a in CDCl3 at 258C.
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Diastereomeric Separation
5551 5564
187 nm, respectively),[15] which supports the consideration of
the unusual high-field shift (d ˆ 0.039) derived from an
affinity, such as a CH p interaction.[16]
the molecule to the more stable CH p conformation as the
molecular momentum decreased with decreasing temperature
(Table 2).
Interestingly, these remarkable high-field shifts of C18-CH3
in the (1S, 2R) isomer were also observed when other
deuterium solvents, such as [D4]methanol and [D6]benzene,
were used. The absolute values of the difference in the
chemical shifts of C18-CH3 between the S isomer and R
isomer obtained from each deuterium solvent is an indication
that CDCl3 was the most effective medium for the phenom-
enon (Table 1).
Table 2. Chemical shifts of b-CH3 at various temperatures.
Compound
Position
d in CDCl3
À 308C
238C
08C
À 608C
3a
4a
C18-CH3
C19-CH3
C18-CH3
0.043
0.946
0.450
0.005
0.943
0.443
À 0.040
À 0.077
0.942
0.946
0.438
0.438
On the other hand, almost no change was observed in the
same variable temperature range in the 1H NM R of4a
derived from the (1R, 2S)-alcohol regarding the chemical shift
value of C18-CH3. The X-ray crystallographic analysis of
Table 1. Chemical shifts of C18-CH3 of 3a and 4a in various deuterated
solvents at 258C.
Solvent
dH 3a
dH 4a
DdH
compound 4c showed the absence of a similar CH
interaction in this molecule (Figure 5).
p
CDCl3
CD3OD
C6D6
0.039
0.045
0.305
0.449
0.430
0.601
0.410
0.385
0.296
More clear-cut evidence for the CH p interaction was
obtained by an X-ray crystallographic analysis of the (1S, 2R)
isomer 3c (Figure 4).[17] The b-methyl at the 18-position was
found to be placed in close proximity to the p face of the
anisyl group.[18] The closest interatomic distance between the
CH moiety and the aromatic p plane was shorter (2.92 ä)
than the sum of the van der Waals radii.[19] We assume that the
trigger of this interaction may fix the conformation to the ap
plane of the chiral esters,[20] and hence the interaction function
is superior to the steric effect between the CH and p moieties.
The NOESY spectrum in CDCl3 also supported the close
proximity between the CH moiety and p moiety.[21] Hence, it
seems that the structure in the solid state is retained in
solution.
Figure 5. ORTEP drawing of (1R, 2S)-4c.
These findings led us to assume that a molecule for which
such an interaction is observed in the 1H NMR spectrum must
always have the (1S, 2R) configuration, since an intramolec-
ular CH p interaction requires a highly ordered conforma-
tion. To verify our hypothesis, we performed, as a further
example, an X-ray crystallographic analysis to determine the
absolute configuration of the resolved chiral alcohol 1 f of the
1
Furthermore, the H NMR spectra of the variable temper-
ature conditions showed that the value of the chemical shift of
C18-CH3 moved to a higher field as the temperature was
lowered (d ˆ À0.077 at À608C versus d ˆ 0.043 at 238C). This
phenomenon appears to be the result of the transformation of
corresponding diastereomer 3 f, which showed a CH
p
interaction in the NMR spectrum, bearing the (1S, 2R)
configuration (Table 3, entry 6). From the results, the deter-
mination of the configurations by means of the CH
p
interaction also seems to hold for other 2-arylcyclohexa-
nols.[22] This method has the advantage that it can easily
predict the absolute configuration with only one diastereom-
er, since the degree of high-field shift is abnormal.
Further examples are given in Table 3.[20] Note that the
alcohols bearing the various aromatic moieties, such as
naphthyl and heteroaryl functions, showed remarkable higher
field shifts (Table 3, entries 5 13). These results seem to
suggest that the high electron density of the aromatic moiety
and/or the spreadability of the p plane lead to a significant
CH p interaction.[23]
.
It is worth noting that the LAH reduction of the individual
diastereomer (3 or 4) gave the corresponding optically pure
alcohol[24] in an almost quantitative yield, suggesting that the
Figure 4. ORTEP drawing of (1S, 2R)-3c.
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5553

Y. Kita et al.
FULL PAPER
Table 3. 1H NMR spectroscopic determination of the absolute configu-
ration by means of the intramolecular CH p interaction.
3 (Figure 6). For instance, the red shift of the linked ester
carbonyl moiety of the diastereomers 3a in the IR spectra
supports the possibility of such a successive stereoelectronic
effect (n ˆ 1727 cmÀ1 in 3a versus 1734 cmÀ1 in 4a). Although
recent reports concerning the calculations of the simple
intermolecular CH p interaction suggest that the origin of
the interaction is the dispersion force rather than charge-
transfer force[25] and the stabilising energy is less than
1 kcalmolÀ1, we guess that the CH p interaction we observed
is a special case based on the contribution of the effective
stereoelectronic effect.
If an interaction, such as charge transfer from the p moiety
to the CH(s*) moiety (Figure 6), is present,[23] the electron
density of the p moiety in the compound, which shows a
shielding effect, will be lower than that of the other
diastereomeric isomer. Thus, for the nitrogen-containing
heteroaromatics, it is possible to observe a differing basicity
between the diastereomers.
In fact, we observed a more interesting phenomenon than
that expected: each pair of corresponding diastereomers (3g
and 4g) derived from (Æ)-trans-2-pyridylcyclohexanol (1g)
could be effectively separated by extraction with achiral
organic media and aqueous acid. That is, partitioning between
an organic solvent, such as diethyl ether, and aqueous HCl
effectively allowed the separation of the diastereomers
(Scheme 3).
Entry Ar
Yield dH of C18-CH3 Predicted
[%][a] in 3 or 4[b]
configuration
of resolved 1
1
2
Ph
3a 85
4a
3b 74
4b
3c 77
4c
3d 66
4d
3e 59
4e
3f 33
4f
3g 92
4g
0.039
0.449
0.068
0.481
0.006
0.490
0.116
0.486
À 0.214
0.322
À 0.246
0.426
0.115
0.463
0.128
0.443
0.098
0.464
0.136
0.490
0.073
0.463
0.128
0.479
À 0.226
0.421
S[c]
R
S
R
S[d]
R
S
R
S
R
S[d]
R
S
R
S
R
S[d]
R
S
R
S
R
S
p-tolyl
3
4-methoxyphenyl
4-chlorophenyl
1-naphthyl
2-naphthyl
2-pyridyl
4
5
6
7
8
2-(3'-methylpyridyl) 3h 73
4h
9
2-(4'-methylpyridyl) 3i
87
4i
10
11
12
13
2-(5'-methylpyridyl) 3j 84
4j
2-(6'-methylpyridyl) 3k 82
4k
2-(4'-chloropyridyl) 3l
96
4l
3m 91
R
S
R
2-quinolyl
4m
It is noteworthy that a pair of diastereomers could be
separated by simple extraction with achiral organic media and
aqueous acid. Only ether-type nonpolar organic media could
be effectively used as the extraction media (Table 4); the
[a] Isolated yields of a mixture of diastereomers by column chromatog-
raphy. [b] 258C in CDCl3. [c] The configuration was confirmed by use of an
enantiomerically pure substrate with known absolute configuration.
[d] The configuration was confirmed by X-ray crystallographic analysis.
enantiomerically pure 1[9b] could be obtained by the removal
of the steroid moiety after recrystallisation, which could cause
a diastereomeric excess (de; Scheme 2). An example is shown
in Figure 6.
COCl
2
AcO
(±)
Et3N (1.2 eq.)
92%
OH
1
Ar
N
2
CO2
OH
LiAlH4
THF
Ar
1g
99%ee
AcO
3c
(1S, 2R)-1c: 14% (from (±)-1c)
N
Ar
shielding effect
OH
Ar
CO2
CO2
LiAlH4
THF
18
organic phase
(1S, 2R)-rich
99%ee
extraction
41%de (73% recovery)
AcO
4c
(1R, 2S)-1c: 9% (from (±)-1c)
AcO
Ar = 4-methoxyphenyl
Scheme 2. Removal of steroid moiety.
aq. 3% HCl
with Et2O
(1S, 2R)-3g
N
aqueous phase
+
CO2
(1R, 2S)-rich
93%de (25% recovery)
H
18
H
AcO
H
O
20
13
(1R, 2S)-4g
O
17
14
Scheme 3. The separation of the diastereomers by extraction. [a] The
kinetic resolution of (Æ)-1 was observed in the acylation process when the
reaction stopped under the situation remaining unreacted 1. [b] The
indication of ™(1S, 2R)∫is depicted by the numbering position of 2-pyr-
idylcyclohexanols before acylation. [c] The ratio used was as follows:
Figure 6. Speculation: contribution of stereoelectronic effect.
We assume that the stereoelectronic effect and/or the
rigidity of the configuration induced by the adjacent carbonyl
group also exerts such a strong CH p interaction in the esters
a
mixture of diastereomers
3 and 4/aqueous HCl/diethyl ether
ˆ 0.3 g:20 mL:50 mL.
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Chem. Eur. J. 2002, 8, No. 24

Diastereomeric Separation
5551 5564
Table 4. Effect of the organic medium versus the extraction ability.
ent (pKa of 3.81 and 4.15 for 3a and 4a, respectively), and the
isomer with the aryl-induced shift has a lower pKa value.
These values were determined by the measurement of the
dissociation constant by means of the ultraviolet absorption
spectrophotometric method at 22 Æ 28C in aqueous methanol.
The measured data are shown in Tables 7 and 8.[26] Equa-
tion (1) was used for the calculation of the pKa value from the
absorptiometric curve (261 nm).
Organic medium
Organic phase
yield[%]
Aqueous phase
yield[%]
de[%][a]
de[%][a]
diethyl ether
diisopropyl ether
MTBE
ethyl acetate
toluene
73
61
78
quant.
quant.
quant.
41 (3g)
64 (3g)
33 (3g)
7 (3g)
0
25
36
19
0
0
0
93 (4g)
88 (4g)
89 (4g)
methylene chloride
0
1
[a] The de value was determined by H NMR (300 MHz).
dB À d
d À dA
pKa ˆ pH ‡ log
(1)
suitable amount of ether was ꢀ40 50 mL for 300 mg of the
crude diastereomer mixture (Table 5). It was likely that
aqueous HCl was the most suitable aqueous acid in terms of
practicality (Table 6 and Scheme 4).
In Equation (1) d is the absorbance at pH ꢀ 3 5, dA is the
absorbance below pH2 and dB is the absorbance above pH 7.
Additionally, the X-ray crystallographic analysis of the pure
(1S, 2R) isomer 3i confirmed the presence of an effective
affinity between the C18-CH3 and p moieties even for the
nitrogen-containing heteroaromatics (Figure 7). The C18-
Table 5. Effect of the amount of diethyl ether versus the extraction ability.
Et2O[mL]
Organic phase
yield[%]
Aqueous phase
yield[%]
de[%][a]
de[%][a]
20
40
50
60
57
71
73
84
65 (3g)
46 (3g)
41 (3g)
22 (3g)
44
29
25
13
76 (4g)
89 (4g)
93 (4g)
94 (4g)
1
[a] The de value was determined by H NMR (300 MHz).
Table 6. Effect of acid type versus the extraction ability.
Acid[wt%]
Organic phase
yield[%]
Aqueous phase
yield[%]
de[%][a]
de[%][a]
Figure 7. ORTEP drawing of 3i. ;total energy : 74.32 kcalmolÀ1
.
1.0% HCl
2.5% HCl
3.0% HCl
5.0% HCl
50% AcOH
3.0% HBr
quant.
88
73
49
quant.
70
2 (3g)
15 (3g)
41 (3g)
74 (3g)
0
0
9
25
50
0
95 (4g)
93 (4g)
57 (4g)
CH3 group was found to be in close proximity to the p face
of the pyridyl group; this is consistent with the remarkable
high-field shift of the C18-CH3 in the 1H NMR spectrum
(Table 3, entry 9).
44 (3g)
29
96 (4g)
1
[a] The de value was determined by H NMR (300 MHz).
On the other hand, the (1R, 2S) isomer 4i, which did not
1
show an effective aryl-induced H NMR shift, was preferen-
tially obtained from the aqueous acid phase. The chemical
shift of the C18-CH3 of the major isomer from the aqueous
acid phase showed the lower value of d ˆ 0.46. Further
examples of the separation of the diastereomers derived from
various (Æ)-pyridyl alcohols are shown in Table 9.
N
N
organic phase
CO2
CO2
(1S, 2R)-rich
+
a), b), or c)
extraction
AcO
AcO
(1S, 2R)-3g
(1R, 2S)-4g
The distribution ability was influenced by the concentration
of the aqueous acid used, and the optimum concentration of
the aqueous HCl was dependent on the structure of mixtures
of the diastereomers. In the case of 3g and 4g, a 93%de of 4g
was obtained in 25% yield by concentration of the 3.0 wt%
aqueous HCl (pH ꢀ 0.02), while 41%de of 3g was obtained in
73% yield from the organic layer (Table 9, entry 2). Further
extraction of the organic phase (41%de) with 7.0 wt%
aqueous HCl improved the de of 3a to 80%de (70% yield;
Scheme 5).
aqueous phase
1 ~ 4%de[a]
crude (300mg)
(1R, 2S)-rich
Scheme 4. a) The separation of the diastereomers by extraction using
various organic media (50 mL) and aqueous HCl (3%). b) The separation
of the diastereomers by extraction with diethyl ether and aqueous HCl
(3%). c) The separation of the diastereomers by extraction with various
acids (20 mL) and diethyl ether (50 mL). [a] The kinetic resolution of (Æ)-
1g was observed in the acylation process when the reaction stopped under
the situation remaining unreacted 1g.
Although we can not provide a clear explanation for this
phenomenon at the moment, it can be assumed that the
intramolecular CH p interaction would reduce the electron
density of the nitrogen atom on the pyridine ring, as a result of
charge-transfer character[23] to CH(s*) from HOMO of the p
It is quite interesting to note that the isomer with the aryl-
induced H NMR signal mostly existed in the organic phase
upon extraction (e.g., 3g: d ˆ 0.12). We measured each pKa
value of the pyridinium chloride of the corresponding
diastereomers and found that these values were quite differ-
1
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Y. Kita et al.
FULL PAPER
Table 7. Measured data and calculated results for the pKa value of 3g.
Measured pH value[a]
Absorbance (d)
dA, dB
dB À d
d À dA
log(dB À d)/(d À dA)
pKa
[b]
1.31
3.25
3.53
3.80
4.01
4.23
8.09
0.3595
0.3185
0.2939
0.2679
0.2456
0.2233
0.1730
0.3595
À 0.1455
À 0.1209
À 0.0949
À 0.0726
À 0.0503
À 0.0410
À 0.0656
À 0.0916
À 0.1139
À 0.1362
0.550
0.2655
0.015
3.80
3.80
3.82
3.81
3.80
À 0.196
À 0.433
0.1730
[a] Measuring apparatus: microbalance: BP-210D (Sartorius AG); pH meter: F-21 (Horiba, Ltd.); spectrophotometer: UV-2400 (Shimadzu Corp.).
[b] Average pKa ˆ 3.81; standard deviation ˆ 0.01.
Table 8. Measured data and calculated results for the pKa value of 4g.
[b]
Measured pH value[a]
Absorbance (d)
dA, dB
dB À d
d À dA
log(dB À d)/(d À dA)
pKa
1.37
3.52
3.79
4.03
4.25
4.46
8.05
0.3898
0.3458
0.3242
0.2987
0.2743
0.2529
0.1775
0.3898
À 0.1683
À 0.1467
À 0.1212
À 0.0968
À 0.0754
À 0.0440
À 0.0656
À 0.0911
À 0.1155
À 0.1369
0.583
0.3495
0.124
4.10
4.14
4.15
4.17
4.20
À 0.077
À 0.259
0.1775
[a] The same instruments were used as in Table 7. [b] Average pKa ˆ 4.15; standard deviation ˆ 0.04.
Table 9. The simple separation of diastereomers (3 and 4) by extraction
Table 10. Removal of steroid moiety from the diastereomer (3 or 4).
technique.
Diastereomer de of starting Method of
diastereomer reduction[b]
3 or 4[%][a]
Yield[%] ee of
product[%][c]
Entry
R
Concentra-
tion of aqueous yield de
HCl[wt%]
Organic phase Aqueous phase
yield de
[%]
[%]
[%][a]
[%][a]
R ˆ H (3g)
R ˆ H (4g)
R ˆ M e (3i)
R ˆ M e (4i)
R ˆ Cl (3l)
R ˆ Cl (3l)
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)
1
2
H (3g ‡ 4g)[b]
2.5
3.0
5.0
88
73
49
67
44
31
81
56
33
97
61
80
59
97
82
42
15 (3g)
9
95 (4g)
93 (4g)
57 (4g)
75 (4h)
73 (4h)
42 (4h)
88 (4i)
82 (4i)
37 (4i)
68 (4j)
95 (4j)
93 (4k)
83 (4k)
41 (3g) 25
74 (3g) 50
29 (3h) 27
78 (3h) 44
75 (3h) 62
19 (3i) 16
67 (3i) 44
73 (3i) 63
3
4
5
3-Me (3h ‡ 4h)[c] 1.0
2.0
3.0
B
6
7
8
9
10
11
12
13
14
15
16
[a] The de value was determined by 1H NMR (300 MHz). [b] Method A:
LiAlH4 (10 equiv), THF, RT, 2.0 h; Method B: DIBAL-H (5 equiv), THF,
À788C, 2.0 h. [c] The ee value was determined by HPLC (CHIRALCE-
L OD, hexane/iPrOH ˆ 95:5).
4-Me (3i ‡ 4i)[d]
5-Me (3j ‡ 4j)[e]
1.0
2.0
3.0
2.0
3.0
0
2
60 (3j) 37
24 (3k)
59 (3k) 31
6-Me (3k ‡ 4k)[f] 2.0
9
found that the (1S, 2R) isomer 3 of the diastereomers with an
3.0
1
4-Cl (3l ‡ 4l)[g]
7.0
10.0
15.0
0
0
aryl-induced H NMR shift has a lower pKa value and was
11 (3l) 12
82 (3l) 56
55 (4l)
54 (4l)
found to exist in the organic phase upon extraction, this
provides a simple and useful method of optically resolving
(Æ)-trans-2-pyridylcyclohexanols accompanied by the deter-
mination of the absolute configuration (Scheme 6).
As has been noted, these studies have focused on the cyclic
aryl alcohols, such as the (Æ)-trans-2-arylcyclohexanols.
However, we examined the other cases by the use of the
acyclic-type alcohols and found that the remarkable 1H NM R
shifts were also observed in more loosely arranged acyclic aryl
alcohols.[27]
[a] The de value was determined by 1H NMR (300 MHz). [b] dH of C18-Me; 3g:
0.115, 4g: 0.463. [c] dH of C18-Me; 3h: 0.128, 4h: 0.443. [d] dH of C18-Me; 3i:
0.098, 4i: 0.464. [e] dH of C18-Me; 3j: 0.136, 4j: 0.490. [f] dH of C18-Me; 3k:
0.073, 4k: 0.463. [g] dH of C18-Me; 3l: 0.128, 4l: 0.479.
moiety, and lead to a decrease in the basicity of the
compounds (3g l) as we previously assumed. This interaction
has been known as the attractive force which functions even in
water.[9e] An alternative possibility is the significant difference
in the steric bulkiness around the nitrogen atom in the
diastereomers. In any event, these results lead us to the
assumption that the difference in the conformation between
The diastereomers (6 and 7) were easily obtained from the
same reaction of various acyclic (Æ)-aryl alcohols 5 and acid
chloride 2 (Scheme 7).[11] In these cases, the values of the
1
chemical shift in the H NMR spectrum of C18-CH3 on the
steroid ring were also apparently different for the diastereo-
mers (Table 11, entries 2 7). One always appeared near d ˆ
0.5, while the other always appeared near d ˆ 0.7. We then
used compound 5a, which has a known absolute configura-
the diastereomers on the basis of the intramolecular CH
interaction is an important factor for this phenomenon.
The removal of the steroid moiety gave the optically active
pyridyl alcohols in moderate yields (Table 10). Since we have
p
5556
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Chem. Eur. J. 2002, 8, No. 24

Diastereomeric Separation
5551 5564
1-alkylamines regarding the ab-
solute configuration and chem-
1
ical shift value in the H NM R
spectra. We also found that the
diastereomer with the shielding
effect was derived from amines
bearing the S configuration (Ta-
ble 12, entry 1). Although the
yields shown here are isolated
yields after column chromatog-
raphy, it is possible to deter-
mine the absolute configura-
tions by the use of crude prod-
ucts without purification, which
were obtained in almost quan-
titative yields (Scheme 8).
Scheme 5. The separation of the diastereomers of 2-pyridylcyclohexanols (3 and 4) by extraction. [a] The kinetic
resolution of (Æ)-1 was observed in the acylation process when the reaction stopped under the situation remaining
unreacted 1. [b] The indication of ™(1S, 2R)∫ is depicted by the numbering position of 2-pyridylcyclohexanols
before acylation. [c] The ratio used was as follows : a mixture of diastereomers 3 and 4/aqueous HCl/diethyl
etherˆ 0.3 g:20 mL:50 mL.
Table 11. 1H NMR spectroscopic determination of the absolute configuration
of 1-aryl alcohols by means of the CH p shielding effect
R
N
Entry Ar
R
Yield dH of C18-CH3 Predicted
[%][b] in 6 or 7[a]
configuration
R
N
CO2
reduction
of resolved 5
OH
1
2
3
4
5
6
7
8
Ph
M
6a e6,4
0.51
0.71
0.52
0.71
0.49
0.70
0.51
0.70
0.52
0.71
0. 48
0.71
0.59
0.73
0.48
0.63
S[c]
R
S
R
S
R
S
R
S
R
S
R
S
R
S
R
(1S, 2R)-3
organic phase
AcO
Me, 7a
Me, 6b 74
Me, 7b
(1S, 2R)-1
p-tolyl
extraction[a]
(1S, 2R)-3
R
+
4-methoxyphenyl Me, 6c 77
Me, 7c
aq. HCl
with Et2O
(1R, 2S)-4
N
R
OH
CO2
4-chlorophenyl
2-naphthyl
Ph
Me, 6d 66
Me, 7d
Me, 6e 59
Me, 7e
Et, 6 f
Et, 7 f
Me, 6g 95
Me, 7g
reduction
N
(1R, 2S)-4[b]
aqueous phase
AcO
(1R, 2S)-1
33
Scheme 6. Reduction of the diastereomers to 2-pyridylcyclohexanols.
[a] The following ratio was used: a mixture of diastereomers/aqueous
HCl/diethyl etherˆ 0.3 g:20 mL:50 mL. [b] These products were obtained
by neutralizing the aqueous phase with NaHCO3 (pH 8).
2-pyridyl
Bn
M
Me, 7h
6h e8,1
[a] 258C in CDCl3. [b] Isolated yields of a mixture of diastereomers by column
chromatography. [c] The configuration was confirmed by the use of an
enantiomerically pure substrate with known absolute configuration.
COCl
(S)
(R)
Ar
O
O
O
18
O
18
Ar
Ar
R
R
R
2
AcO
+
OH
Et3N in CH2Cl2
AcO
AcO
(±)-5
6
7
Table 12. 1H NMR spectroscopic determination of the absolute configuration
Scheme 7. Acylation of (Æ)-5 with steroid compound 2.
of 1-aryl amines by means of the CH p shielding effect.
Entry Ar
R
Yield dH of C18-CH3 Predicted
[%][b] in 9 or 10[a]
configuration
tion, to clarify which diastereomer showed the shielding effect
by the aromatic ring, and found that the diastereomer showing
the shielding effect was derived from the S alcohol. It is
noteworthy that there is almost no exception regarding the
chemical shift values in the case of the 1-aryl-1-alkyl alcohols,
in spite of the use of various kinds of aromatic moieties
(Table 11, entries 1 6). This suggests that this methodology
would be a very general method for the determination of the
absolute configuration of various analogues. In addition, a
similar high-field shift is also observed for the 2-pyridyl
alcohols and homoaryl-type alcohols, such as 1-phenylpropan-
2-ol (Table 11, entries 7 8).
of resolved 5
1
2
3
4
5
Ph
M
9a e,71
0.61
0.73
0.62
0.72
0.58
0.71
0.52
0.71
0.54
0.73
S[c]
R
S
R
S
Me, 10a
Me, 9b
Me, 10b
p-tolyl
69
4-bromophenyl Me, 9c
Me, 10c
2-naphthyl
78
R
Me, 9d
Me, 10d 71[c]
Et, 9e
Et, 10e
68[c]
S[d]
R[d]
S
Ph
68
R
[a] 258C in CDCl3. [b] Isolated yields of a mixture of diastereomers by column
chromatography. [c] The enantiomerically pure S and R substrates were used
because the racemic substrate is not commercially available. [d] The config-
uration was confirmed by the use of an enantiomerically pure substrate with
known absolute configuration.
Similarly, it is probable that the absolute configuration of
the 1-aryl-1-alkylamines could be easily determined by this
method. Almost the same trends were observed for the 1-aryl-
Chem. Eur. J. 2002, 8, No. 24
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5557

Y. Kita et al.
FULL PAPER
easily handled, even when the amount of the target molecule
is low. Needless to say, this methodology can be applied to the
determination of the optical purity of various 1-aryl alcohols
and amines in a similar manner to the strategy in which chiral
shift reagents are used.[29, 30]
COCl
(S)
Ar
(R)
Ar
H
H
O
O
N
N
18
18
R
R
Ar
R
2
AcO
+
NH2
Et3N in CH2Cl2
AcO
AcO
(±)-8
9
10
In addition, we have shown a novel technique for the
optical resolution of (Æ)-trans-pyridyl alcohols by a simple
extraction method that employs an achiral organic solvent
and an acid solution and makes use of the distribution
technique based on a difference in the pKa values of the
diastereomers. We believe that this technique will be able to
play an important role in large-scale syntheses and will thus
have a high practical value.
Scheme 8. Acylation of (Æ)-8 with steroid compound 2.
However, in contrast to the 2-arylcyclohexanols, these
shielding effects are not very effective from the viewpoint of
the extent of the high-field shift in the 1H NMR spectra. The
MM calculations[28] of the S isomers of 6a and 7a suggested
the absence of a particularly effective CH p interaction by
the deviation between the p plane and CH moiety, as shown in
Figure 8. In addition the R isomer 7a did not completely show
the CH p interaction in the MM calculation.
We presume that this shielding effect was also responsible
for the conformational restriction and the attraction of the
intramolecular van der Waals force between the CH and p
moieties.
Experimental Section
General: Melting points are uncorrected. Infrared (IR) absorption spectra
were recorded as a KBr or a NaCl pellet. 1H NMR spectra were measured
on 270, 300, 500 or 600 MHz spectrometers with SiMe4 as the internal
standard. Specific rotations were measured with a JASCO P-1020 polar-
imeter. Merck silica gel 60 (70 230 mesh ASTM) and Fuji Silysia
Chemical silica gel BW-300 were used for column chromatography and
flash column chromatography, respectively. (Æ)-trans-2-Arylcyclohexa-
nols[12, 22] (1b m), and acid chloride[11] (2) were essentially prepared by
the reported method.
In conclusion, the chiral CH p interaction, which discrim-
inates the environments in two diastereomers in the chiral
molecule studied, was found to be a facile tool for the
(Æ)-trans-2-(4-Methylphenyl)cyclohexanol (1b):[12b] Colourless crystals;
m.p. 62 62.58C (AcOEt/hexane); 1H NMR (270 MHz, CDCl3): d ˆ 7.48
(d, J ˆ 8.3 Hz, 1H), 7.15 (m, 3H), 3.65 (m, 1H), 2.33 (s, 3H), 2.13 (m, 2H),
1.34 1.87 (m, 7H).
(Æ)-trans-2-(4-Methoxyphenyl)cyclohexanol (1c):[12b] Colourless crystals;
m.p. 66.5 678C (AcOEt/hexane); 1H NMR (270 MHz, CDCl3): d ˆ 7.18 (d,
J ˆ 6.9 Hz, 2H), 6.88 (d, J ˆ 6.9 Hz, 2H), 3.80 (s, 3H), 3.67 (m, 1H), 2.43
(m, 1H), 2.13 (m, 2H), 1.23 1.89 (m, 6H).
(Æ)-trans-2-(4-Chlorophenyl)cyclohexanol (1d):[12c] Colourless crystals;
m.p. 73 73.58C (AcOEt/hexane); 1H NMR (270 MHz, CDCl3): d ˆ 7.31
(d, J ˆ 6.6 Hz, 2H), 7.19 (d, J ˆ 6.6 Hz, 2H), 3.62 (m, 1H), 2.47 (m, 1H),
2.13 (m, 2H), 1.21 1.87 (m, 6H).
(Æ)-trans-2-(1-Naphthyl)cyclohexanol (1e):[12b] Colourless crystals; m.p.
127 127.58C (AcOEt/hexane); 1H NMR (270 MHz, CDCl3): d ˆ 8.20 (d,
J ˆ 7.9 Hz, 1H), 7.87 (d, J ˆ 2.6 Hz, 1H), 7.76 (d, J ˆ 5.6 Hz, 1H), 7.45 7.55
(m, 4H), 3.98 (m, 1H), 3.39 (m, 1H), 2.24 (m, 2H), 1.25 1.90 (m, 6H).
(Æ)-trans-2-(2-Naphthyl)cyclohexanol (1 f):[12d] Colourless crystals; m.p.
82 838C (AcOEt/hexane); 1H NMR (270 MHz, CDCl3): d ˆ 7.85 7.89 (m,
3H), 7.71 (s, 1H), 7.39 7.50 (m, 3H), 3.78 (m, 1H), 2.62 (m, 1H), 2.17 (m,
2H), 1.36 1.96 (m, 6H).
Synthesis of 2-(2-pyridyl)cyclohexanones: 2-(2-Pyridyl)cyclohexanones
substituted on aromatic ring, which are the precursors of (Æ)-2-(2-
pyridyl)cyclohexanols, were essentially prepared by the reported meth-
Figure 8. Top: Calculated conformation of S isomer 6a. Total energy:
74.32 kcalmolÀ1. Bottom: Calculated conformation of R isomer 7a. Total
c]
od.[19a
energy: 75.43 kcalmolÀ1
.
1
2-Pyridin-2-ylcyclohexanone:[22a] Yellow oil; H NMR (300 MHz, CDCl3):
d ˆ 8.56 (dd, J ˆ 5.3, 1.9 Hz, 0.25H of keto tautomer), 8.32 (d, J ˆ 4.6 Hz,
0.75H of enol tautomer), 7.67 (td, J ˆ 7.8, 1.8 Hz, 0.75H of enol tautomer),
7.66 (td, J ˆ 7.7, 1.9 Hz, 0.25H of keto tautomer), 7.19 7.15 (m, 0.5H of keto
tautomer), 7.11 (d, J ˆ 7.8 Hz, 0.75H of enol tautomer), 7.00 (ddd, J ˆ 7.8,
4.6, 0.8 Hz, 0.75H of enol tautomer), 3.84 (dd, J ˆ 11.2, 5.9 Hz, 0.25H of
keto tautomer), 2.38 2.35 (m, 4H), 1.78 1.74 (m, 4H), OH of enol
determination of the absolute configuration of various
2-arylcyclohexanols. This strategy is applicable to other
acyclic aryl alcohols and amines with high reliability, although
in the case of amines, the participation of the intramolecular
CH p interaction remains to be elucidated. The following
points are the highlights of this method: 1) a remarkable
difference in the shielding effect is observed between the
diastereomeric derivatives, 2) the structure of the aryl moiety
has no significant influence on the chemical shift value in each
series of target molecules and 3) the diastereomeric deriva-
tives have relatively high molecular weight, and can thus be
tautomer was not observed; IR (KBr): nÄ ˆ 1713 cmÀ1
.
2-(3-Methylpyridin-2-yl)cyclohexanone: Orange solid; m.p. 56.0 57.08C;
1H NMR (300 MHz, CDCl3): d ˆ 8.43 (dd, J ˆ 4.8, 0.9 Hz, 1H), 7.44 (dd, J ˆ
7.5, 0.9 Hz, 1H), 7.09 (dd, J ˆ 7.5, 4.8 Hz, 1H), 3.91 (dd, J ˆ 11.7, 5.8 Hz,
1H), 2.66 1.72 (m, 8H), 2.21 (s, 3H); IR (KBr): nÄ ˆ 1713 cmÀ1; MS EI(‡);
‡
m/z (%): 189 (5) [M] , 120 (100); HRMS calcd for C12H15NO: 189.1154
‡
[M] ; found: 189.1150.
2-(4-Methylpyridin-2-yl)cyclohexanone:[22b] Yellow oil; 1H NM
(300 MHz, CDCl3): d ˆ 8.41 (d, J ˆ 5.0 Hz, 0.5H), 8.17 (d, J ˆ 5.2 Hz,
R
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Chem. Eur. J. 2002, 8, No. 24

Diastereomeric Separation
5551 5564
‡
0.5H), 6.99 (d, J ˆ 5.0 Hz, 0.5H), 6.98 (s, 0.5H), 6.92 (s, 0.5H), 6.83 (d, J ˆ
5.2 Hz, 0.5H), 3.81 (dd, J ˆ 11.4, 5.9 Hz, 0.5H), 2.75 1.75 (m, 8H), 2.35 (s,
1.5H), 2.34 (s, 1.5H), OH of enol tautomer was not observed; IR (KBr):
MS EI(‡); m/z (%): 191 (5) [M] , 120 (100); HRMS calcd for C12H17NO:
‡
191.1310 [M] ; found: 191.1310.
(Æ)-trans-2-(5-Methylpyridin-2-yl)cyclohexanol (1j): Colourless crystals;
m.p. 63.5 65.08C (AcOEt/hexane); 1H NMR (300 MHz, CDCl3): d ˆ 8.35
(dd, J ˆ 1.7, 0.6 Hz, 1H), 7.47 (dd, J ˆ 8.0, 1.7 Hz, 1H), 7.13 (d, J ˆ 8.0 Hz,
1H), 4.29 (br, 1H), 3.86 (td, J ˆ 9.9, 4.4 Hz, 1H), 2.62 (td, J ˆ 9.5, 3.1 Hz,
1H), 2.31 (s, 3H), 2.13 (m, 1H), 2.03 (m, 1H), 1.85 1.78 (m, 2H), 1.51 1.34
nÄ ˆ 1715 cmÀ1
.
2-(5-Methylpyridin-2-yl)cyclohexanone: Yellow oil; 1H NMR (300 MHz,
CDCl3): d ˆ 8.38 (dd, J ˆ 1.5 and 0.7 Hz, 0.5H), 8.16 (dd, J ˆ 1.5 and 0.7 Hz,
0.5H), 7.48 (m, 1H), 7.06 (d, J ˆ 8.1 Hz, 0.5H), 7.02 (d, J ˆ 8.4 Hz, 0.5H),
3.81 (dd, J ˆ 11.7, 5.8 Hz, 0.5H), 2.59 1.73 (m, 8H), 2.31 (s, 1.5H), 2.30 (s,
1.5H), OH of enol tautomer was not observed; IR (KBr): nÄ ˆ 2930,
(m, 4H); IR (KBr): nÄ ˆ 3281 cmÀ1; MS EI(‡); m/z (%): 191 (8) [M] , 120
‡
(100); elemental analysis calcd (%) for C12H17NO (191.3): C 75.35, H 8.96,
N 7.32; found: C 75.18, H 8.84, N 7.21.
‡
‡
1717 cmÀ1; MS EI(‡); m/z (%): 190 (13)[M‡H] , 189 (53) [M] , 120 (100);
‡
HRMS calcd for C12H15NO: 189.1154 [M] ; found: 189.1164.
(Æ)-trans-2-(6-Methylpyridin-2-yl)cyclohexanol (1k): Colourless solid;
m.p. 53.5 55.08C; 1H NMR (300 MHz, CDCl3): d ˆ 7.55 (t, J ˆ 8.0 Hz,
1H), 7.04 (d, J ˆ 8.0 Hz, 1H), 7.01 (d, J ˆ 8.0 Hz, 1H), 5.15 (br, 1H), 3.82
(td, J ˆ 10.5, 4.2 Hz, 1H), 2.62 (ddd, J ˆ 10.5, 3.8, 2.0 Hz, 1H), 2.52 (s, 3H),
2.14 2.06 (m, 2H), 1.84 1.80 (m, 2H), 1.54 1.36 (m, 4H); IR (KBr): nÄ ˆ
2-(6-Methylpyridin-2-yl)cyclohexanone:[22b] Yellow oil; 1H NM
(300 MHz, CDCl3): d ˆ 7.56 (t, J ˆ 7.8 Hz, 0.7H of enol tautomer), 7.54 (t,
J ˆ 7.7 Hz, 0.3H of keto tautomer), 7.02 (d, J ˆ 7.7 Hz, 0.3H of keto
tautomer), 6.97 (d, J ˆ 7.7 Hz, 0.3H of keto tautomer), 6.91 (d, J ˆ 7.8 Hz,
0.7H of enol tautomer), 6.84 (d, J ˆ 7.8 Hz, 0.7H of enol tautomer), 3.83
(dd, J ˆ 11.9, 5.5 Hz, 0.3H of keto tautomer), 2.52 (s, 0.9H of keto
tautomer), 2.50 (s, 2.1H of enol tautomer), 2.39 2.32 (m, 3H), 2.15 1.73
(m, 5H), OH of enol tautomer (0.7H) was not observed; IR (KBr): nÄ ˆ
R
3322 cmÀ1
.
(Æ)-trans-2-(4-Chloropyridin-2-yl)cyclohexanol (1l):[22e] Colourless crys-
tals; m.p. 79.0 80.08C (Et2O/hexane); 1H NMR (300 MHz, CDCl3): d ˆ
8.42 (d, J ˆ 5.3 Hz, 1H), 7.25 (s, 1H), 7.18 (dd, J ˆ 5.3, 1.8 Hz, 1H), 3.89 (td,
J ˆ 10.0, 4.4 Hz, 1H), 3.80 (br, 1H), 2.64 (ddd, J ˆ 12.0, 9.6, 3.6 Hz, 1H),
2.13 (m, 1H), 2.01 (m, 1H), 1.86 1.79 (m, 2H), 1.57 1.34 (m, 4H); IR
2934, 1713 cmÀ1
.
2-(4-Chloropyridin-2-yl)cyclohexanone:[22c] Yellow oil; 1H NM
(300 MHz, CDCl3): d ˆ 8.45 (d, J ˆ 6.1 Hz, 0.38H of keto tautomer), 8.22
(d, J ˆ 5.6 Hz, 0.62H of enol tautomer), 7.20 7.19 (m, 0.75H of keto
tautomer), 7.10 (d, J ˆ 1.8 Hz, 0.62H of enol tautomer), 7.00 (dd, J ˆ 5.6 and
1.8 Hz, 0.62H of enol tautomer), 3.82 (dd, J ˆ 11.8 and 5.4 Hz, 0.38H of
keto tautomer), 2.59 2.31 (m, 4H), 2.17 1.74 (m, 4H), OH of enol
R
(KBr): nÄ ˆ 3341 cmÀ1
.
(Æ)-trans-2-Quinolin-2-ylcyclohexanol (1m):[22c] Yellowish solid; m.p.
129.0 130.08C; 1H NMR (300 MHz, CDCl3): d ˆ 8.13 (d, J ˆ 8.6 Hz,
1H), 8.03 (d, J ˆ 8.4 Hz, 1H), 7.79 (d, J ˆ 8.1 Hz, 1H), 7.70 (td, J ˆ 7.6,
1.2 Hz, 1H), 7.51 (t, J ˆ 7.6 Hz, 1H), 7.38 (d, J ˆ 8.4 Hz, 1H), 4.57 (br, 1H),
4.15 (td, J ˆ 10.0, 4.1 Hz, 1H), 2.86 (td, J ˆ 10.6, 3.0 Hz, 1H), 2.20 2.17 (m,
tautomer was not observed; IR (KBr): nÄ ˆ 1715 cmÀ1
.
2H), 1.89 1.86 (m, 2H), 1.58 1.45 (m, 4H); IR (KBr): nÄ ˆ 3329 cmÀ1
.
2-Quinolin-2-ylcyclohexanone:[22a] Orange crystals; m.p. 114.5 116.08C
(MeOH); 1H NMR (300 MHz, CDCl3): d ˆ 8.13 (d, J ˆ 8.4 Hz, 0.11H of
keto tautomer), 8.03 (d, J ˆ 8.8 Hz, 0.11H of keto tautomer), 7.91 (d, J ˆ
8.3 Hz, 0.89H of enol tautomer), 7.80 (d, J ˆ 7.2 Hz, 0.11H of keto
tautomer), 7.71 7.49 (m, 0.33H of keto tautomer), 7.65 (d, J ˆ 8.6 Hz,
0.89H of enol tautomer), 7.62 (d, J ˆ 8.1 Hz, 0.89H of enol tautomer), 7.58
(ddd, J ˆ 8.3, 6.8, 1.5 Hz, 0.89H of enol tautomer), 7.32 (ddd, J ˆ 8.1, 6.8 and
1.3 Hz, 0.89H of enol tautomer), 7.16 (d, J ˆ 8.6 Hz, 0.89H of enol
tautomer), 4.06 (dd, J ˆ 11.3 and 6.0 Hz, 0.11H of keto tautomer), 2.48
2.44 (m, 4H), 1.91 1.78 (m, 4H), OH of enol tautomer (0.89H) was not
(Æ)-2-Pyridylethanol (5g):[22g] Yellow oil; 1H NMR (300 MHz, CDCl3): d ˆ
8.54 (dd, J ˆ 5.0, 1.8 Hz, 1H), 7.69 (td, J ˆ 7.7, 1.8 Hz, 1H), 7.28 (ddd, J ˆ 7.9,
0.6, 0.2 Hz, 1H), 7.20 (ddd, J ˆ 7.5, 5.0, 0.6 Hz, 1H), 4.90 (q, J ˆ 6.6 Hz, 1H),
4.24 (br, 1H), 1.51 (d, J ˆ 6.6 Hz, 3H); IR (KBr): nÄ ˆ 3250 cmÀ1
.
Compound 2:[11] Colourless solid; m.p. 193 1958C (decomp.); IR: nÄ ˆ
1784 cmÀ1
;
1H NMR (270 MHz, CDCl3): d ˆ 5.43 (m, 1H), 4.81 (m, 1H),
2.88 (m, 1H), 1.98 (s, 3H), 1.06 (s, 3H), 0.83 2.59 (m, 19H), 0.82 (s, 3H).
General procedure for esterification: 1a (489 mg, 2.77 mmol) at 08C was
added to a stirred solution of 2 (1.58 g, 4.16 mmol) and Et3N (0.46 mL,
3.33 mmol) in CH2Cl2 (20 mL) under a nitrogen atmosphere. After stirring
for 19 h at room temperature, the reaction mixture was washed with water,
dried with Na2SO4 and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (hexane/AcOEt, 10:1) to give 3a and
4a (1.22 g, 85%) as a diastereomeric mixture.
observed; IR (KBr): nÄ ˆ 2932, 1711 cmÀ1
.
General procedure for the preparation of various (Æ)-trans-2-(2-pyridyl)-
cyclohexanols: Small portions of NaBH4 (1.6 g, 43.1 mmol) at 08C were
added to
a stirred solution of 2-(2-pyridyl)cyclohexanone (12.6 g,
71.9 mmol) in EtOH (180 mL). The reaction mixture was refluxed for
2.5 h. The solution was cooled to 08C, and more NaBH4 (1.1 g, 28.8 mmol)
was added. The reaction mixture was refluxed for a further 1.0 h. After the
removal of EtOH under reduced pressure, distilled H2O was added to the
residue at 08C. The aqueous mixture was extracted with four portions of
CHCl3. The organic layer was washed with brine, dried over Na2CO3,
filtered and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/AcOEt ˆ 1:1 ) to give 1g (6.93 g,
55% yield).
Mixture of compounds 3a and 4a:
(1S,2R)-3a: Colourless crystals; m.p. 146 147.08C (AcOEt/hexane);
1H NMR (600 MHz, CDCl3): d ˆ 7.15 7.24 (m, 5H), 5.32 (m, 1H), 5.05
(dt, 1H, J ˆ 4.2, 10.8 Hz), 4.58 (m, 1H), 2.68 (m, 1H), 2.30 (m, 2H), 2.03 (s,
3H), 0.95 (s, 3H), 0.82 2.17 (m, 26H), 0.04 (s, 3H); IR (KBr): nÄ ˆ
1727 cmÀ1; elemental analysis calcd (%) for C34H46O4 (518.7): C 78.72, H
8.94; found: C 78.43, H 8.88.
(1R,2S)-4a: Colourless crystals; m.p. 121 121.58C (decomp., AcOEt/
hexane); 1H NMR (600 MHz, CDCl3): d ˆ 7.16 7.23 (m, 5H). 5.35 (m,
1H), 4.96 (m, 1H), 4.58 (m, 1H), 2.68 (m, 1H), 2.28 (m, 2H), 2.03 (s, 3H),
(Æ)-trans-2-Pyridin-2-ylcyclohexanol (1g):[22d] Light orange solid; m.p.
59.0 60.08C; 1H NMR (300 MHz, CDCl3): d ˆ 8.53 (d, J ˆ 4.9 Hz, 1H),
7.66 (td, J ˆ 7.5, 1.9 Hz, 1H), 7.24 (d, J ˆ 7.5 Hz, 1H), 7.16 (td, J ˆ 7.5, 4.9 Hz,
1H), 4.23 (br, 1H), 3.90 (td, J ˆ 10.0, 4.2 Hz, 1H), 2.69 (ddd, J ˆ 12.2, 9.5,
3.7 Hz, 1H), 2.09 (m, 2H), 1.83 (m, 2H), 1.62 1.25 (m, 4H); IR (KBr): nÄ ˆ
0.99 (s, 3H), 0.82 2.18 (m, 26H), 0.45 (s, 3H); IR (KBr): nÄ ˆ 1734 cmÀ1
;
elemental analysis calcd (%) for C34H46O4 (518.7): C 78.72, H 8.94; found:
C 78.54, H 8.80.
‡
3326 cmÀ1; MS FAB(‡); m/z (%): 178 (76) [M‡H] , 154 (100); HRMS
Mixture of compounds 3b and 4b: Colourless solid; m.p. 124 1258C; IR
‡
calcd for C11H16NO: 178.1220 [M‡H] ; found: 178.1226.
(KBr): nÄ ˆ 1716 cmÀ1; HRMS calcd for C35H48O4: 532.3553 [M] ; found:
‡
532.3556.
(Æ)-trans-2-(3-Methylpyridin-2-yl)cyclohexanol (1h): Colourless crystals;
m.p. 74.5 75.58C (AcOEt/hexane); 1H NMR (300 MHz, CDCl3): d ˆ 8.40
(d, J ˆ 4.6 Hz, 1H), 7.44 (d, J ˆ 7.5 Hz, 1H), 7.05 (dd, J ˆ 7.5, 4.6 Hz, 1H),
4.28 (td, J ˆ 10.0, 4.1 Hz, 1H), 2.85 (td, J ˆ 10.4, 3.4 Hz, 1H), 2.35 (s, 3H),
1.88 1.74 (m, 4H), 1.51 1.36 (m, 4H), 1H of OH was not observed; IR
(1S*,2R*)-3b: 1H NMR (270 MHz, CDCl3): d ˆ 7.07 (m, 4H, overlap with
signals of the other diastereomer), 5.34 (m, 1H, overlap with signals of the
other diastereomer), 4.98 (m, 1H, overlap with signals of the other
diastereomer), 4.58 (m, 1H, overlap with signals of the other diastereo-
mer), 2.68 (m, 1H, overlap with signals of the other diastereomer), 2.33 (s,
3H, overlap with signals of the other diastereomer), 2.31 0.84 (m, 28H,
overlap with signals of the other diastereomer), 2.04 (s, 3H, overlap with
signals of the other diastereomer), 0.95 (s, 3H), 0.07 (s, 3H).
‡
(KBr): nÄ ˆ 3326 cmÀ1; MS EI(‡); m/z (%): 191 (15) [M] , 120 (100);
‡
HRMS calcd for C12H17NO: 191.1310 [M] ; found: 191.1318.
(Æ)-trans-2-(4-Methylpyridin-2-yl)cyclohexanol (1i): Colourless crystals;
m.p. 61.5 62.08C (Et2O/hexane); 1H NMR (300 MHz, CDCl3): d ˆ 8.37 (d,
J ˆ 5.1 Hz, 1H), 7.05 (s, 1H), 6.98 (d, J ˆ 5.1 Hz, 1H), 3.87 (td, J ˆ 10.0,
4.4 Hz, 1H), 2.61 (ddd, J ˆ 11.9, 9.6, 3.5 Hz, 1H), 2.34 (s, 3H), 2.12 (br, 1H),
(1R*,2S*)-4b: 1H NMR (270 MHz, CDCl3): d ˆ 7.07 (m, 4H, overlap with
signals of the other diastereomer), 5.34 (m, 1H, overlap with signals of the
other diastereomer), 4.98 (m, 1H, overlap with signals of the other
2.03 (m, 2H), 1.82 (m, 2H), 1.53 1.58 (m, 4H); IR (KBr): nÄ ˆ 3326 cmÀ1
;
Chem. Eur. J. 2002, 8, No. 24
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0824-5559 $ 20.00+.50/0
5559

Y. Kita et al.
FULL PAPER
diastereomer), 4.58 (m, 1H, overlap with signals of the other diastereo-
mer), 2.68 (m, 1H, overlap with signals of the other diastereomer), 2.33 (s,
3H, m, 1H, overlap with signals of the other diastereomer), 2.31 0.84 (m,
28H, overlap with signals of the other diastereomer), 2.04 (s, 3H, overlap
with signals of the other diastereomer), 1.00 (s, 3H), 0.48 (s, 3H).
80.24, H 8.51; found: C 79.90, H 8.70; X-ray data: see the Supporting
Information.
(1R,2S)-4 f: Colourless crystals; m.p. 180 1818C (Et2O/hexane); 1H NM R
(270 MHz, CDCl3): d ˆ 7.73 7.81 (m, 3H), 7.64 (s, 1H), 7.33 7.44 (m, 3H),
5.34 (m, 1H), 5.09 (m, 1H), 4.55 (m, 1H), 2.86 (m, 1H), 2.27 (m, 2H), 2.03
(s, 3H), 0.98 (s, 3H), 0.66 2.23 (m, 26H), 0.43 (s, 3H); IR (KBr): nÄ ˆ
Mixture of compounds 3c and 4c:
1727 cmÀ1
.
(1S,2R)-3c: Colourless crystals: m.p. 176 176.58C (Et2O/hexane);
1H NMR (270 MHz, CDCl3): d ˆ 7.11 (d, J ˆ 8.6 Hz, 2H), 6.80 (d, J ˆ
8.6 Hz, 2H), 5.34 (m, 1H), 4.98 (m, 1H), 4.60 (m, 1H), 3.76 (s, 3H), 2.64
(m, 1H), 2.30 (m, 2H), 2.03 (s, 3H), 0.95 (s, 3H), 0.85 2.18 (m, 26H), 0.006
(s, 3H); IR (KBr): nÄ ˆ 1715 cmÀ1; elemental analysis calcd (%) for
C35H48O5 (548.8): C 76.61, H 8.82, found: C 76.30, H 8.60; X-ray data:
see the Supporting Information.
Mixture of compounds 3g and 4g:
(1S*,2R*)-3g: Colourless crystals; m.p. 126.0 129.08C (Et2O/hexane);
1
[a]2D8 ˆ ‡22.3 (c ˆ 0.63, CHCl3); H NMR (300 MHz, CDCl3): d ˆ 8.52 (d,
J ˆ 4.5 Hz, 1H), 7.57 (td, J ˆ 7.7, 1.8 Hz, 1H), 7.18 (d, J ˆ 7.7 Hz, 1H), 7.09
(ddd, J ˆ 7.7, 4.5, 0.8 Hz, 1H), 5.33 (d, J ˆ 4.2 Hz, 1H), 5.24 (td, J ˆ 10.8,
4.3 Hz, 1H), 4.58 (m, 1H), 2.91 (td, J ˆ 11.5, 3.5 Hz, 1H), 2.31 0.84 (m,
28H), 2.03 (s, 3H), 0.95 (s, 3H), 0.11 (s, 3H); IR (KBr): nÄ ˆ 1732 cmÀ1; M S
(1R,2S)-4c: Colourless crystals; m.p. 153 1548C (Et2O/hexane); 1H NM R
(270 MHz, CDCl3): d ˆ 7.11 (d, J ˆ 8.6 Hz, 2H), 6.80 (d, J ˆ 8.6 Hz, 2H),
5.38 (m, 1H), 4.87 (m, 1H), 4.60 (m, 1H), 3.77 (s, 3H), 2.61 (m, 1H), 2.32
(m, 2H), 2.03 (s, 3H), 1.00 (s, 3H), 0.97 2.18 (m, 26H), 0.490 (s, 3H); IR
(KBr): nÄ ˆ 1732 cmÀ1; X-ray data: see the Supporting Information.
‡
EI(‡); m/z (%): 519 (3) [M] , 160 (100); HRMS calcd for C33H45NO4:
‡
519.3348 [M] ; found: 519.3367; elemental analysis calcd (%) for
C33H45NO4 (519.7): C 76.26, H 8.73, N 2.70; found: C 76.06, H 8.72, N 2.62.
(1R*,2S*)-4g: Colourless crystals; m.p. 149.5 150.08C (Et2O/hexane);
1
[a]2D8 ˆ À70.7 (c ˆ 0.59, CHCl3); H NMR (300 MHz, CDCl3): d ˆ 8.51 (d,
Mixture of compounds 3d and 4d: Colourless solid; m.p. 59 608C; IR
J ˆ 4.4 Hz, 1H), 7.56 (td, J ˆ 7.7, 1.8 Hz, 1H), 7.13 (d, J ˆ 7.7 Hz, 1H), 7.09
(ddd, J ˆ 7.7, 4.4, 0.9 Hz, 1H), 5.34 (d, J ˆ 4.4 Hz, 1H), 5.13 (td, J ˆ 11.0,
4.2 Hz, 1H), 4.59 (m, 1H), 2.88 (td, J ˆ 11.0, 3.6 Hz, 1H), 2.32 0.88 (m,
28H), 2.03 (s, 3H), 0.99 (s, 3H), 0.46 (s, 3H); IR (KBr): nÄ ˆ 1732 cmÀ1; M S
‡
(KBr): nÄ ˆ 1728 cmÀ1
;
HRMS calcd for C34H45O4Cl: 552.3007 [M] ;
found:552.3014 .
(1S*,2R*)-3d: 1H NMR (270 MHz, CDCl3): d ˆ 7.24 (d, J ˆ 8.6 Hz, 2H,
overlap with signals of the other diastereomer), 7.16 (d, J ˆ 8.6 Hz, 2H,
overlap with signals of the other diastereomer), 5.34 (m, 1H, overlap with
signals of the other diastereomer), 4.98 (m, 1H, overlap with signals of the
other diastereomer), 4.61 (m, 1H, overlap with signals of the other
diastereomer), 2.68 (m, 1H, overlap with signals of the other diastereo-
mer), 2.32 (m, 2H, overlap with signals of the other diastereomer), 2.29
0.81 (m, 26H, overlap with signals of the other diastereomer), 2.04 (s, 3H,
overlap with signals of the other diastereomer), 0.97 (s, 3H), 0.12 (s, 3H).
‡
‡
EI(‡); m/z (%): 520 (1) [M‡H] , 519 (1) [M] , 459 (100); HRMS calcd for
‡
C33H45NO4: 519.3348 [M] ; found: 519.3358; elemental analysis calcd (%)
for C33H45NO4 (519.7): C 76.26, H 8.73, N 2.70; found: C 75.96, H 8.62, N
2.70.
Mixture of compounds 3h and 4h: Colourless solid; m.p. 107.0 112.58C;
‡
IR (KBr): nÄ ˆ 1730 cmÀ1; HRMS calcd for C34H47NO4: 533.3505 [M] ;
found: 533.3529.
(1S*,2R*)-3h: 1H NMR (300 MHz, CDCl3): d ˆ 8.39 (d, J ˆ 4.6 Hz, 1H,
overlap with signals of the other diastereomer), 7.36 (d, J ˆ 7.6 Hz, 1H,
overlap with signals of the other diastereomer), 6.97 (dd, J ˆ 7.6, 4.6 Hz,
1H, overlap with signals of the other diastereomer), 5.43 5.30 (m, 2H),
4.59 (m, 1H, overlap with signals of the other diastereomer), 3.10 (td, J ˆ
10.8, 4.0 Hz, 1H), 2.43 0.75 (m, 28H, overlap with signals of the other
diastereomer), 2.35 (s, 3H), 2.03 (s, 3H, overlap with signals of the other
diastereomer), 0.94 (s, 3H), 0.13 (s, 3H).
(1R*,2S*)-4h: 1H NMR (300 MHz, CDCl3): d ˆ 8.39 (d, J ˆ 4.6 Hz, 1H,
overlap with signals of the other diastereomer), 7.36 (d, J ˆ 7.6 Hz, 1H,
overlap with signals of the other diastereomer), 6.97 (dd, J ˆ 7.6, 4.6 Hz,
1H, overlap with signals of the other diastereomer), 5.33 (d, J ˆ 5.0 Hz,
1H), 5.20 (td, J ˆ 10.5, 4.0 Hz, 1H), 4.59 (m, 1H, overlap with signals of the
other diastereomer), 3.10 (td, J ˆ 10.8, 4.0 Hz, 1H), 2.43 0.75 (m, 28H,
overlap with signals of the other diastereomer), 2.36 (s, 3H), 2.03 (s, 3H,
overlap with signals of the other diastereomer), 0.99 (s, 3H), 0.44 (s, 3H).
(1R*,2S*)-4d: 1H NMR (270 MHz, CDCl3): d ˆ 7.24 (d, J ˆ 8.6 Hz, 2H,
overlap with signals of the other diastereomer), 7.16 (d, J ˆ 8.6 Hz, 2H,
overlap with signals of the other diastereomer), 5.34 (m, 1H, overlap with
signals of the other diastereomer), 4.98 (m, 1H, overlap with signals of the
other diastereomer), 4.61 (m, 1H, overlap with signals of the other
diastereomer), 2.68 (m, 1H, overlap with signals of the other diastereo-
mer), 2.32 (m, 2H), 0.81 2.29 (m, 26H, overlap with signals of the other
diastereomer), 2.04 (s, 3H, overlap with signals of the other diastereomer),
1.00 (s, 3H), 0.49 (s, 3H).
Mixture of compounds 3e and 4e: Colourless solid; m.p. 139 1408C; IR
‡
(KBr): nÄ ˆ 1736 cmÀ1; HRMS calcd for C38H48O4: 568.3553 [M] ; found:
568.3559.
(1S*,2R*)-3e: 1H NMR (270 MHz, CDCl3): d ˆ 8.18 (d, J ˆ 8.6 Hz, 1H,
overlap with signals of the other diastereomer), 7.81 (d, J ˆ 8.2 Hz, 1H,
overlap with signals of the other diastereomer), 7.51 (d, J ˆ 7.9 Hz, 1H),
7.40 7.48 (m, 4H, overlap with signals of the other diastereomer), 5.26
5.30 (m, 1H, overlap with signals of the other diastereomer), 5.18 5.26 (m,
1H, overlap with signals of the other diastereomer), 4.58 (m, 1H, overlap
with signals of the other diastereomer), 3.64 (m, 1H, overlap with signals of
the other diastereomer), 2.27 (m, 2H, overlap with signals of the other
diastereomer), 2.02 (s, 3H), 0.37 1.98 (m, 26H, overlap with signals of the
other diastereomer), 0.83 (s, 3H), À0.21 (s, 3H).
Mixture of compounds 3i and 4i:
(1S,2R)-3i: Colourless crystals; m.p. 199.0 202.08C (AcOEt/hexane);
1
[a]2D9 ˆ ‡19.2 (c ˆ 0.51, CHCl3); H NMR (300 MHz, CDCl3): d ˆ 8.37 (d,
J ˆ 5.0 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J ˆ 5.0 Hz, 1H), 5.33 (d, J ˆ 4.4 Hz,
1H), 5.22 (td, J ˆ 10.7, 4.3 Hz, 1H), 4.58 (m, 1H), 2.86 (td, J ˆ 11.4, 3.4 Hz,
1H), 2.30 0.84 (m, 28H), 2.30 (s, 3H), 2.03 (s, 3H), 0.95 (s, 3H), 0.10 (s,
‡
3H); IR (KBr): nÄ ˆ 1732, 1721 cmÀ1; MS EI(‡); m/z (%): 533 (10) [M] ,
(1R*,2S*)-4e: 1H NMR (270 MHz, CDCl3): d ˆ 8.18 (d, J ˆ 8.6 Hz, 1H,
overlap with signals of the other diastereomer), 7.81 (d, J ˆ 8.2 Hz, 1H,
overlap with signals of the other diastereomer), 7.51 (d, J ˆ 7.9 Hz, 1H),
7.40 7.48 (m, 4H, overlap with signals of the other diastereomer), 5.26
5.30 (m, 1H, overlap with signals of the other diastereomer), 5.18 5.26 (m,
1H, overlap with signals of the other diastereomer), 4.58 (m, 1H, overlap
with signals of the other diastereomer), 3.64 (m, 1H, overlap with signals of
the other diastereomer), 2.27 (m, 2H, overlap with signals of the other
diastereomer), 2.04 (s, 3H), 0.37 1.98 (m, 26H, overlap with signals of the
other diastereomer), 0.97 (s, 3H), 0.32 (s, 3H).
‡
473 (100); HRMS calcd for C34H47NO4: 533.3505 [M] ; found: 533.3499;
elemental analysis calcd (%) for C34H47NO4 (533.8): C 76.51, H 8.88, N 2.62;
found: C 76.33, H 8.74, N 2.62; X-ray data: see the Supporting Information.
(1R,2S)-4i: Colourless crystals; m.p. 149.0 151.08C (AcOEt/hexane);
1H NMR (300 MHz, CDCl3): d ˆ 8.36 (d, J ˆ 4.7 Hz, 1H), 6.94 (s, 1H), 6.90
(d, J ˆ 4.7 Hz, 1H), 5.35 (d, J ˆ 4.8 Hz, 1H), 5.11 (td, J ˆ 10.3, 4.3 Hz, 1H),
4.59 (m, 1H), 2.84 (td, J ˆ 11.4, 3.3 Hz, 1H), 2.30 (s, 3H), 2.21 0.88 (m,
28H), 2.03 (s, 3H), 1.00 (s, 3H), 0.46 (s, 3H); IR (KBr): nÄ ˆ 1732 cmÀ1; M S
‡
EI(‡); m/z (%): 533 (4) [M] , 473 (100); HRMS calcd for C34H47NO4:
‡
533.3505 [M] ; found: 533.3527; elemental analysis calcd (%) for
C34H47NO4 (533.8): C 76.51, H 8.88, N 2.62; found: C 76.33, H 8.87, N 2.58.
Mixture of compounds 3 f and 4 f:
Mixture of compounds 3j and 4j: Colourless solid; m.p. 112.0 118.58C; IR
(1S,2R)-3 f: Colourless crystals; m.p. 198 199.58C (Et2O/hexane);
1H NMR (270 MHz, CDCl3): d ˆ 7.73 7.81 (m, 3H), 7.62 (s, 1H), 7.33
7.44 (m, 3H), 5.26 (m, 1H), 5.09 (m, 1H), 4.55 (m, 1H), 2.86 (m, 1H), 2.27
(m, 2H), 1.97 (s, 3H), 0.66 2.23 (m, 26H), 0.69 (s, 3H), À0.25 (s, 3H); IR
(KBr): nÄ ˆ 1720 cmÀ1; elemental analysis calcd (%) for C38H48O4 (568.8): C
‡
(KBr): nÄ ˆ 1728 cmÀ1; HRMS calcd for C34H47NO4: 533.3505 [M] ; found:
533.3507.
(1S*,2R*)-3j: 1H NMR (300 MHz, CDCl3): d ˆ 8.35 (d, J ˆ 2.2 Hz, 1H),
7.38 (dd, J ˆ 8.1 and 2.2 Hz, 1H), 7.07 (d, J ˆ 8.1 Hz, 1H), 5.33 (d,
5560
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0824-5560 $ 20.00+.50/0
Chem. Eur. J. 2002, 8, No. 24

Diastereomeric Separation
5551 5564
J ˆ 3.7 Hz, 1H), 5.18 (td, J ˆ 10.6, 4.2 Hz, 1H), 4.58 (m, 1H, overlap with
signals of the other diastereomer), 2.88 (td, J ˆ 11.5, 3.7 Hz, 1H), 2.31 0.84
(m, 28H, overlap with signals of the other diastereomer), 2.28 (s, 3H,
overlap with signals of the other diastereomer), 2.03 (s, 3H, overlap with
signals of the other diastereomer), 0.95 (s, 3H), 0.14 (s, 3H).
2.03 (s, 3H, overlap with signals of the other diastereomer), 0.97 (s, 3H),
0.42 (s, 3H).
Mixture of compounds 6a and 7a:
1
(1S)-6a: Colourless crystals; m.p. 94 94.58C (AcOEt/hexane); H NM R
(270 MHz, CDCl3): d ˆ 7.36 (d, J ˆ 6.6 Hz, 2H), 7.28 7.33 (m, 3H), 5.89 (q,
J ˆ 6.6 Hz, 1H), 5.37 (m, 1H), 4.60 (m. 1H), 2.35 (m, 2H), 2.03 (s, 3H), 1.53
(d, J ˆ 6.6 Hz, 3H), (0.86 2.09 (m, 18H), 0.99 (s, 3H), 0.51 (s, 3H); IR
(1R*,2S*)-4j: 1H NMR (300 MHz, CDCl3): d ˆ 8.34 (d, J ˆ 2.4 Hz, 1H),
7.37 (dd, J ˆ 7.8, 2.4 Hz, 1H), 7.02 (d, J ˆ 7.8 Hz, 1H), 5.35 (d, J ˆ 4.4 Hz,
1H), 5.10 (td, J ˆ 10.8, 4.5 Hz, 1H), 4.58 (m, 1H, overlap with signals of the
other diastereomer), 2.85 (td, J ˆ 11.4, 3.3 Hz, 1H), 2.31 0.84 (m, 28H,
overlap with signals of the other diastereomer), 2.28 (s, 3H, overlap with
signals of the other diastereomer), 2.03 (s, 3H, overlap with signals of the
other diastereomer), 1.00 (s, 3H), 0.49 (s, 3H).
‡
(KBr): nÄ ˆ 1726 cmÀ1; HRMS calcd for C30H40O4: 464.2927 [M] ; found:
464.2922.
1
(1R)-7a: Colourless crystals; m.p. 93 93.58C (AcOEt/hexane); H NM R
(270 MHz, CDCl3): d ˆ 7.36 (d, J ˆ 7.9 Hz, 2H), 7.28 7.33 (m, 3H), 5.93 (q,
J ˆ 6.6 Hz, 1H), 5.38 (m, 1H), 4.60 (m. 1H), 2.35 (m, 2H), 2.04 (s, 3H), 1.54
(d, J ˆ 6.6 Hz, 3H), 0.80 2.20 (m, 18H), 1.03 (s, 3H), 0.71 (s, 3H); IR
Mixture of compounds 3k and 4k: Colourless solid; m.p. 71.5 75.08C; IR
(KBr): nÄ ˆ 1736 cmÀ1
.
‡
(KBr): nÄ ˆ 1730 cmÀ1; HRMS calcd for C34H47NO4: 533.3505 [M] ; found:
533.3526.
Mixture of compounds 6b and 7b: Amorphous yellow solid; IR (NaCl):
‡
nÄ ˆ 1732 cmÀ1; HRMS calcd for C31H42O4: 478.3083 [M] ; found: 478.3072.
(1S*,2R*)-3k: 1H NMR (300 MHz, CDCl3): d ˆ 7.46 (t, J ˆ 7.7 Hz, 1H),
6.94 (d, J ˆ 7.7 Hz, 2H), 5.33 (d, J ˆ 3.6 Hz, 1H), 5.21 (td, J ˆ 10.8, 4.2 Hz,
1H), 4.59 (m, 1H, overlap with signals of the other diastereomer), 2.90 (td,
J ˆ 11.6, 3.8 Hz, 1H), 2.50 (s, 3H, overlap with signals of the other
diastereomer), 2.31 0.88 (m, 28H, overlap with signals of the other
diastereomer), 2.03 (s, 3H, overlap with signals of the other diastereomer),
0.95 (s, 3H), 0.07 (s, 3H).
(1S*)-6b: 1H NMR (270 MHz, CDCl3): d ˆ 7.24 (d, J ˆ 7.6 Hz, 2H, overlap
with signals of the other diastereomer), 7.15 (d, J ˆ 7.6 Hz, 2H, overlap with
signals of the other diastereomer), 5.87 (m, 1H, overlap with signals of the
other diastereomer), 5.37 (m, 1H, overlap with signals of the other
diastereomer), 4.60 (m. 1H, overlap with signals of the other diastereo-
mer), 2.34 (s, 3H, overlap with signals of the other diastereomer), 2.03 (s,
3H), 1.51 (d, J ˆ 6.3 Hz, 3H, overlap with signals of the other diaste-
reomer), 0.74 2.40 (m, 20H, overlap with signals of the other diaste-
reomer), 0.99 (s, 3H), 0.52 (s, 3H).
(1R*,2S*)-4k: 1H NMR (300 MHz, CDCl3): d ˆ 7.45 (t, J ˆ 7.7 Hz, 1H),
6.99 (d, J ˆ 7.7 Hz, 1H), 6.95 (d, J ˆ 7.7 Hz, 1H), 5.34 (d, J ˆ 4.4 Hz, 1H),
5.12 (td, J ˆ 10.5, 4.2 Hz, 1H), 4.59 (m, 1H, overlap with signals of the other
diastereomer), 2.88 (td, J ˆ 11.4, 3.9 Hz, 1H), 2.50 (s, 3H, overlap with
signals of the other diastereomer), 2.31 0.88 (m, 28H, overlap with signals
of the other diastereomer), 2.03 (s, 3H, overlap with signals of the other
diastereomer), 1.00 (s, 3H), 0.46 (s, 3H).
(1R*)-7b: 1H NMR (270 MHz, CDCl3): d ˆ 7.24 (d, J ˆ 7.6 Hz, 2H, overlap
with signals of the other diastereomer), 7.15 (d, J ˆ 7.6 Hz, 2H, overlap with
signals of the other diastereomer), 5.87 (m, 1H, overlap with signals of the
other diastereomer), 5.37 (m, 1H, overlap with signals of the other
diastereomer), 4.60 (m. 1H, overlap with signals of the other diastereo-
mer), 2.34 (s, 3H, overlap with signals of the other diastereomer), 2.04 (s,
3H), 1.51 (d, J ˆ 6.3 Hz, 3H, overlap with signals of the other diaste-
reomer), 0.74 2.40 (m, 20H, overlap with signals of the other diaste-
reomer), 1.03 (s, 3H), 0.71 (s, 3H).
Mixture of compounds 3l and 4l: Colourless solid; m.p. 61.0 63.08C; IR
‡
(KBr): nÄ ˆ 1732 cmÀ1; MS EI(‡); m/z (%): 556 (0.2) [M‡2] , 554 (0.6)
‡
‡
[M] , 493 (100); HRMS calcd for C33H44NO4Cl: 553.2968 [M] ; found:
553.2959.
(1S*,2R*)-3l: 1H NMR (300 MHz, CDCl3): d ˆ 8.43 (d, J ˆ 5.3 Hz, 1H),
7.20 (d, J ˆ 2.0 Hz, 1H), 7.12 (dd, J ˆ 5.3, 2.0 Hz, 1H), 5.34 (m, 1H, overlap
with signals of the other diastereomer), 5.19 (td, J ˆ 10.6, 4.2 Hz, 1H), 4.58
(m, 1H, overlap with signals of the other diastereomer), 2.86 (m, 1H,
overlap with signals of the other diastereomer), 2.31 0.84 (m, 28H,
overlap with signals of the other diastereomer), 2.03 (s, 3H, overlap with
signals of the other diastereomer), 0.96 (s, 3H), 0.13 (s, 3H).
Mixture of compounds 6c and 7c: Colourless amorphous solid; IR (KBr):
‡
nÄ ˆ 1728 cmÀ1; HRMS calcd for C31H42O5: 494.3033 [M] ; found: 494.3034.
(1S*)-6c: 1H NMR (270 MHz, CDCl3): d ˆ 7.30 (d, J ˆ 8.6 Hz, 2H, overlap
with signals of the other diastereomer), 6.87 (d, J ˆ 8.6 Hz, 2H, overlap
with signals of the other diastereomer), 5.87 (m, 1 H overlap with signals of
the other diastereomer), 5.37 (m, 1H, overlap with signals of the other
diastereomer), 4.60 (m. 1H, overlap with signals of the other diastereo-
mer), 3.80 (s, 3H), 2.33 (m, 2H, overlap with signals of the other
diastereomer), 2.03 (s, 3H), 1.52 (d, J ˆ 6.6 Hz, 3H, overlap with signals of
the other diastereomer), 0.93 2.10 (m, 18H, overlap with signals of the
other diastereomer), 0.98 (s, 3H), 0.49 (s, 3H).
(1R*)-7c: 1H NMR (270 MHz, CDCl3): d ˆ 7.30 (d, J ˆ 8.6 Hz, 2H, overlap
with signals of the other diastereomer), 6.87 (d, J ˆ 8.6 Hz, 2H, overlap
with signals of the other diastereomer), 5.87 (m, 1H, overlap with signals of
the other diastereomer), 5.37 (m, 1H, overlap with signals of the other
diastereomer), 4.60 (m. 1H, overlap with signals of the other diastereo-
mer), 3.80 (s, 3H), 2.33 (m, 2H, overlap with signals of the other
diastereomer), 2.04 (s, 3H), 1.52 (d, J ˆ 6.6 Hz, 3H, overlap with signals of
the other diastereomer), 0.93 2.10 (m, 18H, overlap with signals of the
other diastereomer), 1.03 (s, 3H), 0.70 (s, 3H).
(1R*,2S*)-4l: 1H NMR (300 MHz, CDCl3): d ˆ 8.42 (d, J ˆ 5.1 Hz, 1H),
7.15 (d, J ˆ 2.1 Hz, 1H), 7.12 (dd, J ˆ 5.1, 2.1 Hz, 1H), 5.34 (m, 1H, overlap
with signals of the other diastereomer), 5.08 (td, J ˆ 10.4, 4.2 Hz, 1H), 4.58
(m, 1H, overlap with signals of the other diastereomer), 2.86 (m, 1H,
overlap with signals of the other diastereomer), 2.31 0.84 (m, 28H,
overlap with signals of the other diastereomer), 2.03 (s, 3H, overlap with
signals of the other diastereomer), 1.00 (s, 3H), 0.48 (s, 3H).
Mixture of compounds 3m and 4m: Colourless solid; m.p. 84.0 88.08C; IR
‡
(KBr): nÄ ˆ 1728 cmÀ1; HRMS calcd for C37H47NO4: 569.3505 [M] ; found:
569.3504.
(1S*,2R*)-3m: 1H NMR (300 MHz, CDCl3): d ˆ 8.08 (d, J ˆ 7.8 Hz, 1H,
overlap with signals of the other diastereomer), 8.03 (d, J ˆ 8.5 Hz, 1H),
7.76 (dd, J ˆ 8.3, 0.9 Hz, 1H, overlap with signals of the other diaster-
eomer), 7.67 (ddd, J ˆ 8.3, 7.0, 1.5 Hz, 1H), 7.48 (ddd, J ˆ 7.8, 7.0, 0.9 Hz,
1H), 7.36 (d, J ˆ 8.5 Hz, 1H), 5.32 (m, 1H, overlap with signals of the other
diastereomer), 5.26 (m, 1H, overlap with signals of the other diastereom-
er), 4.55 (m, 1H, overlap with signals of the other diastereomer), 3.17 (td,
J ˆ 11.6, 3.7 Hz, 1H), 2.31 0.56 (m, 28H, overlap with signals of the other
diastereomer), 2.03 (s, 3H, overlap with signals of the other diastereomer),
0.69 (s, 3H), À0.23 (s, 3H).
Mixture of compounds 6d and 7d: Yellow solid; m.p. 52 538C; IR (KBr):
nÄ ˆ 1736 cmÀ1
.
(1S*)-6d: 1H NMR (270 MHz, CDCl3): d ˆ 7.31 (d, J ˆ 7.2 Hz, 2H, overlap
with signals of the other diastereomer), 7.23 (d, J ˆ 7.2 Hz, 2H, overlap with
signals of the other diastereomer), 5.88 (m, 1H, overlap with signals of the
other diastereomer), 5.38 (m, 1H, overlap with signals of the other
diastereomer), 4.58 (m. 1H, overlap with signals of the other diastereo-
mer), 2.32 (m, 2H, overlap with signals of the other diastereomer), 2.03 (s,
3H), 0.85 2.20 (m, 18H, overlap with signals of the other diastereomer),
1.51 (d, J ˆ 6.6 Hz, 3H, overlap with signals of the other diastereomer), 0.99
(s, 3H), 0.51 (s, 3H).
(1R*,2S*)-4m: 1H NMR (300 MHz, CDCl3): d ˆ 8.08 (d, J ˆ 7.8 Hz, 1H,
overlap with signals of the other diastereomer), 8.03 (d, J ˆ 8.4 Hz, 1H),
7.76 (dd, J ˆ 8.3, 0.9 Hz, 1H, overlap with signals of the other diaster-
eomer), 7.67 (ddd, J ˆ 8.3, 6.9, 1.5 Hz, 1H), 7.48 (ddd, J ˆ 7.8, 6.9, 0.9 Hz,
1H), 7.31 (d, J ˆ 8.4 Hz, 1H), 5.32 (m, 1H, overlap with signals of the other
diastereomer), 5.26 (m, 1H, overlap with signals of the other diastereom-
er), 4.55 (m, 1H, overlap with signals of the other diastereomer), 3.13 (m,
1H), 2.31 0.56 (m, 28H, overlap with signals of the other diastereomer),
(1R*)-7d: 1H NMR (270 MHz, CDCl3): d ˆ 7.31 (d, J ˆ 7.2 Hz, 2H, overlap
with signals of the other diastereomer), 7.23 (d, J ˆ 7.2 Hz, 2H, overlap with
signals of the other diastereomer), 5.88 (m, 1H, overlap with signals of the
other diastereomer), 5.38 (m, 1H, overlap with signals of the other
Chem. Eur. J. 2002, 8, No. 24
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
0947-6539/02/0824-5561 $ 20.00+.50/0
5561

Y. Kita et al.
FULL PAPER
diastereomer), 4.58 (m. 1H, overlap with signals of the other diastereo-
mer), 2.32 (m, 2H, overlap with signals of the other diastereomer), 2.04 (s,
3H), 0.85 2.20 (m, 18H, overlap with signals of the other diastereomer),
1.51 (d, J ˆ 6.6 Hz, 3H, overlap with signals of the other diastereomer), 1.03
(s, 3H), 0.70 (s, 3H).
(1R*)-7h: 1H NMR (300 MHz, CDCl3): d ˆ 7.18 7.37 (m, 5H, overlap with
signals of the other diastereomer), 5.36 (m, 1H, overlap with signals of the
other diastereomer), 5.11 (m, 1H, overlap with signals of the other
diastereomer), 4.58 (m, 1H, overlap with signals of the other diastereo-
mer), 2.92 (m, 2H), 0.98 2.38 (m, 20H, overlap with signals of the other
diastereomer), 2.04 (s, 3H, overlap with signals of the other diastereomer),
1.23 (d, J ˆ 6.3 Hz, 3H), 1.01 (s, 3H), 0.63 (s, 3H).
Mixture of compounds 6e and 7e: Colourless solid; m.p. 165 1668C; IR
‡
(KBr): nÄ ˆ 1728 cmÀ1; HRMS calcd for C34H42O4: 514.3084 [M] ; found:
515.3152.
Mixture of compounds 9a and 10a
(1S*)-6e: 1H NMR (270 MHz, CDCl3): d ˆ 7.80 7.84 (m, 4H, overlap with
signals of the other diastereomer), 7.32 7.48 (m, 3H, overlap with signals of
the other diastereomer), 6.17 (m, 1H, overlap with signals of the other
diastereomer), 5.38 (m, 1H, overlap with signals of the other diastereo-
mer), 4.61 (m. 1H, overlap with signals of the other diastereomer), 2.02 (s,
3H), 0.72 2.41 (m, 20H, overlap with signals of the other diastereomer),
1.63 (d, J ˆ 6.3 Hz, 3H), 0.95 (s, 3H), 0.50 (s, 3H).
(1S)-9a: Colourless solid; m.p. 73.0 73.58C; 1H NMR (270 MHz, CDCl3):
d ˆ 7.28 7.38 (m, 5H), 5.75 (m, 1H), 5.30 (m, 1H), 4.61 (m, 1H), 0.90 2.33
(m, 20H), 2.03 (s, 3H), 1.49 (d, J ˆ 6.6 Hz, 3H), 1.00 (s, 3H), 0.61 (s, 3H);
‡
IR (KBr): nÄ ˆ 1731, 1646 cmÀ1. HRMS calcd for C30H41NO3: 463.3087 [M] ;
found: 463.3088.
(1R)-10a: Colourless solid; m.p. 75.0 75.58C; 1H NMR (270 MHz,
CDCl3): d ˆ 7.24 7.35 (m, 5H), 5.58 (m, 1H), 5.37 (m, 1H), 4.62 (m,
1H), 0.94 2.37 (m, 20H), 2.04 (s, 3H), 1.50 (d, J ˆ 6.6 Hz, 3H), 1.03 (s,
(1R*)-7e: 1H NMR (270 MHz, CDCl3): d ˆ 7.80 7.84 (m, 4H, overlap with
signals of the other diastereomer), 7.32 7.48 (m, 3H, overlap with signals of
the other diastereomer), 6.17 (m, 1H, overlap with signals of the other
diastereomer), 5.38 (m, 1H, overlap with signals of the other diastereo-
mer), 4.61 (m. 1H, overlap with signals of the other diastereomer), 2.03 (s,
3H), 0.72 2.41 (m, 20H, overlap with signals of the other diastereomer),
1.65 (d, J ˆ 6.3 Hz, 3H), 1.02 (s, 3H), 0.73 (s, 3H).
3H), 0.73 (s, 3H); IR (KBr): nÄ ˆ 1732, 1646 cmÀ1
.
Mixture of compounds 9b and 10b: Colourless solid; m.p. 77.0 78.08C; IR
(KBr): nÄ ˆ 1734, 1645 cmÀ1
.
(1S*)-9b: 1H NMR (270 MHz, CDCl3): d ˆ 7.21 (d, J ˆ 7.9 Hz, 2H), 7.14 (d,
J ˆ 7.9 Hz, 2H), 5.50 (d, J ˆ 7.9 Hz, 1H), 5.36 (m, 1H), 5.12 (q, J ˆ 7.3 Hz,
1H), 4.60 (m, 1H), 2.03 (s, 3H), 0.82 2.39 (m, 20H), 1.63 (s, 3H), 1.47 (d,
J ˆ 6.9 Hz, 3H), 1.00 (s, 3H), 0.62 (s, 3H).
Mixture of compounds 6 f and 7 f: Colourless amorphous solid; IR (NaCl):
‡
nÄ ˆ 1747 cmÀ1; HRMS calcd for C31H42O4: 478.3083 [M] ; found: 478.3090.
1
(1R*)-10b: H NMR (270 MHz, CDCl3): d ˆ 7.25 (d, J ˆ 7.9 Hz, 2H), 7.15
(1S*)-6 f: 1H NMR (270 MHz, CDCl3): d ˆ 7.23 7.36 (m, 5H, overlap with
signals of the other diastereomer), 5.66 (m, 1H, overlap with signals of the
other diastereomer), 5.36 (m, 1H, overlap with signals of the other
diastereomer), 4.60 (m. 1H, overlap with signals of the other diastereo-
mer), 2.33 (m, 2H, overlap with signals of the other diastereomer), 2.15 (m,
2H, overlap with signals of the other diastereomer), 2.03 (s, 3H, overlap
with signals of the other diastereomer), 0.81 2.11 (m, 18H, overlap with
signals of the other diastereomer), 0.87 (t, J ˆ 7.3 Hz, 3H, overlap with
signals of the other diastereomer), 0.99 (s, 3H), 0.48 (s, 3H).
(d, J ˆ 7.9 Hz, 2H), 5.51 (m, 1H), 5.36 (m, 1H), 5.39 (m, 1H), 5.16 (m, 1H),
4.63 (m, 1H), 2.03 (s, 3H), 0.85 2.46 (m, 20H), 1.72 (s, 3H), 1.48 (d, J ˆ
6.9 Hz, 3H), 1.03 (s, 3H), 0.72 (s, 3H).
Mixture of compounds 9c and 10c: Colourless solid; m.p. 68.5 69.58C; IR
‡
(KBr): nÄ ˆ 1732, 1648 cmÀ1; HRMS calcd for C30H40NO3Br: 541.2192 [M] ;
found: 541.2193.
(1S*)-9c: 1H NMR (270 MHz, CDCl3): d ˆ 7.44 (d, J ˆ 8.6 Hz, 2H), 7.21 (d,
J ˆ 8.6 Hz, 2H), 5.84 (d, J ˆ 7.6 Hz, 1H), 5.36 (m, 1H), 5.09 (m, 1H), 4.60
(m, 1H), 2.32 (m, 2H), 0.97 2.27 (m, 18H), 2.04 (s, 3H), 1.45 (d, J ˆ 6.9 Hz,
3H), 1.01 (s, 3H), 0.58 (s, 3H).
(1R*)-7 f: 1H NMR (270 MHz, CDCl3): d ˆ 7.23 7.36 (m, 5H, overlap with
signals of the other diastereomer), 5.66 (m, 1H, overlap with signals of the
other diastereomer), 5.36 (m, 1H, overlap with signals of the other
diastereomer), 4.60 (m. 1H, overlap with signals of the other diastereo-
mer), 2.33 (m, 2H, overlap with signals of the other diastereomer), 2.15 (m,
2H, overlap with signals of the other diastereomer), 2.03 (s, 3H, overlap
with signals of the other diastereomer), 0.81 2.11 (m, 18H, overlap with
signals of the other diastereomer), 0.87 (t, J ˆ 7.3 Hz, 3H, overlap with
signals of the other diastereomer), 1.03 (s, 3H), 0.71 (s, 3H).
1
(1R*)-10c: H NMR (270 MHz, CDCl3): d ˆ 7.44 (d, J ˆ 8.6 Hz, 2H), 7.21
(d, J ˆ 8.6 Hz, 2H), 5.49 (m, 1H), 5.40 (m, 1H), 5.17 (m, 1H), 4.60 (m, 1H),
0.97 2.30 (m, 18H), 2.05 (s, 3H), 1.47 (d, J ˆ 6.6 Hz, 3H), 1.03 (s, 3H), 0.71
(s, 3H).
Mixture of compounds 9d and 10d:
(1S)-9d: Colourless solid; m.p. 133.5 134.08C; 1H NMR (270 MHz,
CDCl3): d ˆ 7.80 7.84 (m, 4H), 7.44 7.49 (m, 3H), 5.59 (d, J ˆ 7.9 Hz,
1H), 5.37 (m, 1H), 5.34 (m, 1H), 4.59 (m, 1H), 0.90 2.34 (m, 20H), 2.01 (s,
3H), 1.58 (d, J ˆ 6.9 Hz, 3H), 0.99 (s, 3H), 0.62 (s, 3H); IR (KBr): nÄ ˆ
Mixture of compounds 6g and 7g: Colourless amorphous solid; m.p. 44.5
51.08C; IR (KBr): nÄ ˆ 1732 cmÀ1
.
1728 cmÀ1
.
(1S*)-6g: 1H NMR (300 MHz, CDCl3): d ˆ 8.58 (ddd, J ˆ 4.9, 1.7, 0.9 Hz,
1H), 7.68 (td, J ˆ 7.7, 1.7 Hz, 1H), 7.38 (dd, J ˆ 7.9, 1.2 Hz, 1H), 7.19 (ddd,
J ˆ 7.5, 4.9, 1.2 Hz, 1H), 5.93 (q, J ˆ 6.5 Hz, 1H), 5.37 (m, 1H), 4.60 (m, 1H,
overlap with signals of the other diastereomer), 2.43 (dd, J ˆ 17.8 and
9.0 Hz, 1H, overlap with signals of the other diastereomer), 2.33 1.18 (m,
19H, overlap with signals of the other diastereomer), 2.03 (s, 3H, overlap
with signals of the other diastereomer), 1.60 (d, J ˆ 6.5 Hz, 3H), 1.00 (s,
3H), 0.59 (s, 3H).
(1R)-10d: Colourless solid; m.p. 135.0 135.58C; 1H NMR (270 MHz,
CDCl3): d ˆ 7.76 7.84 (m, 4H), 7.43 7.49 (m, 3H), 5.56 (d, J ˆ 7.9 Hz, 1H),
5.38 (m, 1H), 5.35 (m, 1H), 4.67 (m, 1H), 0.90 2.38 (m, 20H), 2.04 (s, 3H),
1.60 (d, J ˆ 6.9 Hz, 3H), 1.03 (s, 3H), 0.75 (s, 3H); IR (KBr): nÄ ˆ 1736,
1658 cmÀ1
.
Mixture of compounds 9e and 10e: Pale yellow solid; m.p. 78.5 79.58C;
‡
IR (KBr): nÄ ˆ 1736, 1652 cmÀ1; HRMS calcd for C31H43NO3: 477.3243 [M] ;
(1R*)-7g: 1H NMR (300 MHz, CDCl3): d ˆ 8.57 (ddd, J ˆ 4.9, 1.7 0.9 Hz,
1H), 7.67 (td, J ˆ 7.7, 1.7 Hz, 1H), 7.36 (d, J ˆ 7.9 Hz, 1H), 7.19 (ddd, J ˆ 7.5,
4.9, 1.3 Hz, 1H), 5.95 (q, J ˆ 6.7 Hz, 1H), 5.38 (d, J ˆ 4.2 Hz, 1H), 4.60 (m,
1H, overlap with signals of the other diastereomer), 2.43 (dd, J ˆ 17.8,
9.0 Hz, 1H, overlap with signals of the other diastereomer), 2.33 1.18 (m,
19H, overlap with signals of the other diastereomer), 2.03 (s, 3H, overlap
with signals of the other diastereomer), 1.60 (d, J ˆ 6.7 Hz, 3H), 1.03 (s,
3H), 0.73 (s, 3H).
found: 477.3241.
(1S*)-9e: 1H NMR (270 MHz, CDCl3): d ˆ 7.23 7.36 (m, 5H, overlap with
signals of the other diastereomer), 5.54 (m, 1H, overlap with signals of the
other diastereomer), 5.37 (m, 1H, overlap with signals of the other
diastereomer), 4.91 (m, 1H, overlap with signals of the other diastereo-
mer), 4.59 (m, 1H, overlap with signals of the other diastereomer), 0.91
2.32 (m, 20H, overlap with signals of the other diastereomer), 2.05 (s, 3H,
overlap with signals of the other diastereomer), 1.83 (m, 2H, overlap with
signals of the other diastereomer), 0.99 (s, 3H), 0.89 (m, 3H, overlap with
signals of the other diastereomer), 0.54 (s, 3H).
Mixture of compounds 6h and 7h: Colourless amorphous solid; IR (KBr):
‡
nÄ ˆ 1731 cmÀ1; HRMS calcd for C31H42O4: 478.3083 [M] ; found: 478.3063.
(1S*)-6h: 1H NMR (300 MHz, CDCl3): d ˆ 7.18 7.37 (m, 5H, overlap with
signals of the other diastereomer), 5.36 (m, 1H, overlap with signals of the
other diastereomer), 5.11 (m, 1H, overlap with signals of the other
diastereomer), 4.58 (m, 1H, overlap with signals of the other diastereo-
mer), 2.78 (m, 2H), 0.98 2.38 (m, 20H, overlap with signals of the other
diastereomer), 2.04 (s, 3H, overlap with signals of the other diastereomer),
1.22 (d, J ˆ 6.3 Hz, 3H), 1.00 (s, 3H), 0.48 (s, 3H).
(1R*)-10e: 1H NMR (270 MHz, CDCl3): d ˆ 7.23 7.36 (m, 5H, overlap
with signals of the other diastereomer), 5.54 (m, 1H, overlap with signals of
the other diastereomer), 5.37 (m, 1H, overlap with signals of the other
diastereomer), 4.91 (m, 1H, overlap with signals of the other diastereo-
mer), 4.59 (m, 1H, overlap with signals of the other diastereomer), 0.91
2.32 (m, 20H, overlap with signals of the other diastereomer), 2.05 (s, 3H,
overlap with signals of the other diastereomer), 1.83 (m, 2H, overlap with
5562
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Diastereomeric Separation
5551 5564
signals of the other diastereomer), 1.03 (s, 3H), 0.89 (m, 3H, overlap with
signals of the other diastereomer), 0.73 (s, 3H).
[2] See, for example a) E. Juaristi, Introduction to Stereochemistry and
Conformational Analysis, Wiley, New York, 1991; b) E. L. Eliel, S. H.
Wilen, L. N. Mander, Stereochemistry of Organic Compounds, Wiley,
New York, 1994; c) E. Juaristi, An. Quim. Int. Ed. 1997, 93, 135.
[3] a) J. A. Dale, H. S. Mosher, J. Am. Chem. Soc. 1973, 95, 512; b) I.
Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc. 1991,
113, 4092.
General procedure for extraction: Aqueous 3.0 wt% HCl (20 mL, diluted
36% HCl with dist. H2O) was added to a solution of 3g and 4g (300 mg, 1:1
mixture of diastereomers) in diethyl ether (50 mL). After vigorous shaking,
the ethereal solution was separated from the aqueous layer, dried over
Na2CO3 and filtered. The filtrate was concentrated in vacuo to give 3g in
73% yield with 41%de. The aqueous layer was made alkaline with
NaHCO3 (pH 8) to precipitate a white solid. The precipitate was collected
by suction filtration and dried to give 4g in 25% yield with 93%de.
¬
[4] See, for example: a) M. Trujillo, E. Q. Morales, J. T. Vazquez, J. Org.
Chem. 1994, 59, 6637; b) H. Yamase, T. Ooi, T. Kusumi, Tetrahedron
¬
ƒ
¬
Lett. 1998, 39, 8113; c) B. Lopez, E. Quinoa, R. Riguera, J. Am. Chem.
Soc. 1999, 121, 9724.
Procedure for the reduction of ester 3c: To a stirred solution of 3c (112 mg,
0.204 mmol) in dry THF (3 mL) was added LiAlH4 (78 mg, 2.05 mmol) at
room temperature. After 1 h, the reaction mixture was treated by
successive dropwise addition of 78 mL of water, 78 mL of 15% sodium
hydroxide solution, and 234 mL of water. After filtration of the granular
precipitate, the filtrate was concentrated in vacuo. The residue was purified
by column chromatography on silica gel (hexane/AcOEt 2:1) to give
(1S, 2R)-1c (42 mg, 99.8%) as colourless crystals.
(1S,2R)-trans-2-(4-Methoxyphenyl)cyclohexanol[12b] (1c): Colourless sol-
id; m.p. 66 678C; [a]3D0 ˆ ‡26.0 (c ˆ 0.908, CHCl3); 99% ee [The ee was
determined by HPLC analysis (Daicel Chiralcel OJ; hexane/iPrOH ˆ 99:1;
flow rate: 1.0 mLminÀ1; 258C; tR 43.0 min.)]; 1H NMR (270 MHz, CDCl3):
d ˆ 7.18 (m, 2H), 6.88 (m, 2H), 3.80 (s, 3H), 3.61 (m, 1H), 2.29 (m, 1H),
2.11 (m, 1H), 1.26 1.89 (m, 8H).
[5] M. Matsugi, K. Itoh, M. Nojima, Y. Hagimoto, Y. Kita, Tetrahedron
Lett. 2001, 42, 6903.
[6] Some examples of the diastereoface-differentiating reactions that
make use of the CH p interaction: a) K. Nishihata, M. Nishio,
Tetrahedron Lett. 1977, 18, 1041; b) M. Hirota, K. Abe, H. Tashiro, M.
Nishio, Chem. Lett. 1982, 777; c) S. Saito, Y. Morikawa, T. Moriwake, J.
Org. Chem. 1990, 55, 5424.
[7] M. Matsugi, M. Nojima, Y. Hagimoto, Y. Kita, Tetrahedron Lett. 2001,
42, 8039.
[8] Recent examples, see: a) M. Yamakawa, I. Yamada, R. Noyori,
Angew. Chem. 2001, 113, 2900; Angew. Chem. Int. Ed. 2001, 40, 2818;
b) R. Noyori, M. Yamakawa, S. Hashiguchi, J. Org. Chem. 2001, 66,
7931.
[9] For reviews, see: a) M. Oki, Acc Chem. Res. 1990, 23, 351; b) M. C.
Etter, J. Phys. Chem. 1991, 95, 4601; c) M. J. Zaworotko, Chem. Soc.
Rev. 1994, 23, 283; d) M. Nishio, Y. Umezawa, M. Hirota, Y. Takeuchi,
Tetrahedron 1995, 51, 8665; e) M. Nishio, Y. Umezawa, M. Hirota, The
CH p Interaction, Wiley-VCH, New York, 1998.
[10] Y. Kodama, K. Nishihata, M. Nishio, N. Nakagawa, Tetrahedron Lett.
1977, 18, 2105.
[11] The chiral 3b-acetoxy-5-etienic acid can be prepared from a commer-
cially available pregnenolone acetate in two steps. a) J. Staunton, E. J.
Eisenbraun, Org. Synth. 1962, 42, 4; b) C. Djerassi, P. A. Hart, E. J.
Warawa, J. Am. Chem. Soc. 1964, 86, 78.
[12] a) A. Schwartz, P. Madan, J. K. Whitesell, R. M. Lawrence, Org.
Synth. 1990, 69, 1; b) D. Basavaiah, P. D. Rao, Tetrahedron Asymmetry
1994, 5, 223; c) A. C. Huitric, W. G. Clarke, Jr., K. Leigh, D. Staiff, J.
Org. Chem. 1962, 27, 715; d) F. Dumas, B. Mezrhab, J. d×Angelo, C.
Riche, A. Chiaroni, J. Org. Chem. 1996, 61, 2293; e) M. Mizuno, M.
Kanai, A. Iida, K. Tomioka, Tetrahedron 1997, 53, 10699.
[13] The numbering positions on the steroid ring and hexane ring are,
respectively, depicted by the positions of the 3b-acetoxy-5-etienic acid
and 2-arylhexanols before esterification for the simple discussion.
[14] MO calculations were performed with CS ChemDraw Ultra (Ver. 5.0)
using the PM3 Hamiltonian. The conformation of 3a was not obtained
by the usual procedure. The most stable conformation of 3a was
obtained when the calculation was performed on an initial conforma-
tion 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 the same.
[15] E. A. Braude, Determination of Organic Structures by Physical
Methods, Academic Press, New York, 1955, pp. 131 194.
[16] F. A. Bovey, Nuclear Magnetic Resonance Spectroscopy, Academic,
New York, 1969, pp. 64 71.
(1R,2S)-trans-2-(4-Methoxyphenyl)cyclohexanol (1c):[12b] Colourless sol-
id; m.p. 68 698C; 99% ee [The ee was determined by HPLC analysis
(Daicel Chiralcel OJ; hexane/iPrOH ˆ 99:1; flow rate: 1.0 mLminÀ1; 258C;
tR 46.0 min.)]; 1H NMR (270 MHz, CDCl3): d ˆ 7.18 (m, 2H), 6.88 (m, 2H),
3.80 (s, 3H), 3.61 (m, 1H), 2.29 (m, 1H), 2.11 (m, 1H), 1.26 1.89 (m, 8H).
(1S*,2R*)-trans-2-Pyridin-2-ylcyclohexanol (1g): White solid; m.p. 64.0
64.58C; [a]2D8 ˆ ‡20.4 (c ˆ 0.49, CHCl3); 77% ee [The ee was determined by
HPLC analysis (Daicel Chiralcel OD; hexane/iPrOH ˆ 95:5); flow rate:
1.0 mLminÀ1; 258C; tR 9.9 min.]].
(1R*,2S*)-trans-2-Pyridin-2-ylcyclohexanol (1g): White solid; m.p. 64.5
65.58C; [a]2D7 ˆ À23.5 (c ˆ 0.53, CHCl3); 93% ee [The ee was determined by
HPLC analysis (Daicel Chiralcel OD; hexane/iPrOH ˆ 95:5; flow rate:
1.0 mLminÀ1; 258C; tR 13.2 min.)].
(1S,2R)-trans-2-(4-Methylpyridin-2-yl)cyclohexanol (1i): White crystals;
m.p. 65.0 66.08C; [a]2D7 ˆ ‡17.0 (c ˆ 0.53, CHCl3); 64% ee [The ee was
determined by HPLC analysis (Daicel Chiralcel OD; hexane/iPrOH ˆ
95:5; flow rate: 1.0 mLminÀ1; 258C; tR 8.9 min.)].
(1R,2S)-trans-2-(4-Methylpyridin-2-yl)cyclohexanol (1i): White crystals;
m.p. 64.0 65.08C; [a]2D9 ˆ À24.8 (c ˆ 0.56, CHCl3); 80% ee [The ee was
determined by HPLC analysis (Daicel Chiralcel OD; hexane/iPrOH ˆ
95:5; flow rate: 1.0 mLminÀ1; 258C; tR 10.3 min.)].
(1S*,2R*)-trans-2-(4-Chloropyridin-2-yl)cyclohexanol (1l): White solid;
m.p. 75.5 76.58C; [a]2D8 ˆ ‡30.6 (c ˆ 0.92, CHCl3); 79% ee [The ee was
determined by HPLC analysis (Daicel Chiralcel OD; hexane/iPrOH ˆ
95:5; flow rate: 1.0 mLminÀ1; 258C; tR 8.4 min.)].
(1R*,2S*)-trans-2-(4-Chloropyridin-2-yl)cyclohexanol (1l): White solid;
m.p. 77.0 78.08C; [a]2D8 ˆ À20.5 (c ˆ 0.72, CHCl3); 50% ee [The ee was
determined by HPLC analysis (Daicel Chiralcel OD; hexane/iPrOH ˆ
95:5; flow rate: 1.0 mLminÀ1; 258C; tR 9.7 min.)].
[17] Representative study of X-ray crystallographic analysis of CH
p
interaction: a) M. Mizutani, S. Tomosue, H. Kinoshita, K. Jitsukawa,
H. Masuda, H. Einaga, Bull. Chem. Soc. Jap. 1999, 72, 981; b) K.
Yamanari, T. Nozaki, A. Fuyuhiro, Y. Kushi, S. Kaizaki, J. Chem. Soc.
Dalton Trans. 1996, 13, 2851; c) S. K. Chowdhury, V. S. Joshi, A. G.
Samuel, V. G. Puranik, S. S. Tavale, A. Sarkar, Organometallics 1994,
13, 4092; d) K. Jitsukawa, K. Iwai, H. Masuda, H. Ogoshi, H. Einaga,
Chem. Lett. 1994, 303.
Acknowledgements
We thank Dr. Shunji Aoki, Osaka University, for the measurements of the
1H NMR at various temperatures and Mr. Shinji Hirose, Sumika Chemical
Analysis Service, for the pKa value measurements of the HCl salt of 3g and
4g. We also thank Dr. Kinji Hashimoto and Dr. Yasuhisa Kurogi, Otsuka
Pharmaceutical Factory, Inc., for the MM calculations of the 6a and 7a
structures, and Mr. Masahiko Bando, Otsuka Pharmaceutical Co., Ltd., for
the X-ray determination of the 3c, 3 f, 3i and 4c structures.
[18] The spatial-positions of the hydrogen atoms at the 18-position were
optimized by the difference Fourier map method.
[19] a) A. Bondi, J. Phys. Chem. 1964, 68, 443; b) L. Pauling, The Nature of
the Chemical Bond, 3rd ed., Cornell University Press, Ithaca, 1960.
[20] The prediction of the absolute configuration of achiral carboxylic
acids from the observation of the difference in 1H NMR spectra
between the d values (DdRS) of their esters with chiral non-racemic
[1] For a recent report, see S. K. Latypov, N. F. Galiullina, A. V. Aganov,
V. E. Kataev, R. Riguera, Tetrahedron, 2001, 57, 2231 and references
therein.
¬
ƒ
aryl alcohols is reported: M. J. Ferreiro, S. K. Latypov, E. Quinnoa, R.
Riguera, J. Org. Chem. 2000, 65, 2658.
Chem. Eur. J. 2002, 8, No. 24
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5563

Y. Kita et al.
FULL PAPER
[21] The NOESY spectrum is shown in the Supporting Information. It has
already reported that the nuclear overhauser enhancement was shown
[27] M. Matsugi, K. Itoh, M. Nojima, Y. Hagimoto, Y. Kita, Tetrahedron
Lett. 2001, 42, 8019.
to be useful to determine the abundance of the intramolecular CH
p
[28] The two-dimensional structures of diastereomeric compounds 6a and
7a were converted to three-dimensional structures by using the
Converter program in InsightII [(ver. 2000), Accelrys, San Diego,
CA]. The so-obtained three-dimensional structures were subjected to
a systematic conformational search with an algorithm to eliminate the
high-energy conformations due to steric repulsion. In this study, the
potential energy values of every accessible conformation (248832
conformers) for each compound were calculated with a rotation
increment of 308 for all the torsional angles of the benzyl ester moiety
by means of the molecular mechanics methods using the Steepest
Descent algorithm of Discover [(ver. 2.98, CVFF forcefield), Accel-
rys, San Diego, CA]. One hundred lowest energy conformers for each
compound, with potential energies within 10 kcalmolÀ1 from the
current global minimum, were then collected for the validation of the
conformational analysis. The lowest energy conformer, obtained by
using the steepest descent algorithm, was optimized to evaluate the
detailed conformational structure and total energy with the conjugate
gradient algorithm. The calculated structures and total energies are
described in Figure 8.
interaction: H. Suezawa, T. Hashimoto, K. Tsuchinaga, T. Yoshida, T.
Yuzuri, K. Sakakibara, M. Hirota, M. Nishio, J. Chem. Soc. Perkin
Trans. 2 2000, 1243.
[22] a) H. Noda, Chem. Pharm. Bull. 1965, 13, 912; b) M. Hamana, H.
Noda, Chem. Pharm. Bull. 1966, 14, 762; c) M. Hamana, H. Noda,
Chem. Pharm. Bull. 1967, 15, 474; d) A. Funke, E. Rissi, C. R. Acad.
Sci. Ser. IIc 1954, 239, 713; e) O. P. Petrenko, V. P. Krivopalov, V. V.
Lapachev, V. P. Mamaev, Izv. Akad. Nauk SSSR Ser. Khim. 1981, 227;
f) C. A. Otter, D. A. Bardwell, S. M. Couchman, J. C. Jeffery, J. P.
Maher, M. D. Ward, Polyhedron 1997, 17, 211; g) H. Bullitt, J. T.
Maynard, J. Am. Chem. Soc. 1954, 76, 1370.
[23] a) T. Takagi, A. Tanaka, S. Matsuo, H. Maezaki, M. Tani, H. Fujiwara,
Y. Sasaki, J. Chem. Soc. Perkin Trans. 2 1987, 1015; b) H. Suezawa, T.
Hashimoto, K. Tsuchinaga, T. Yoshida, T. Yuzuri, K. Sakakibara, M.
Hirota, M. Nishio, J. Chem. Soc. Perkin Trans. 2 2000, 1243.
[24] The utilities as chiral auxiliaries in synthesis: J. K. Whitesell, Chem.
Rev. 1992, 92, 953.
[25] a) S. Tsuzuki, K. Honda, T. Uchimal, M. Mikami, K. Tanabe, J. Am.
Chem. Soc. 2000, 122, 3746; b) S. Tsuzuki, K. Honda, T. Uchimal, M.
Mikami, K. Tanabe, J. Am. Chem. Soc. 2000, 122, 11450.
[29] For a review, see: D. Perker, Chem. Rev. 1991, 91, 1441.
[30] For recent examples, see: a) D. Monchaud, J. Lacour, C. Coudret, S.
Fraysse, J. Organomet. Chem. 2001, 624, 388; b) M. Watanabe, T.
Hasegawa, H. Miyake, Y. Kojima, Chem. Lett. 2001, 4; c) H. Ratni, J. J.
Jodry, J. Lacour, E. P. Kundig, Organometallics 2000, 19, 3997; d) A.
Inamoto, K. Ogasawara, K. Omata, K. Kabuto, Y. Sasaki, Org. Lett.
2000, 2, 3543.
[26] The pKa values were determined by the measurement of the
dissociation constant using the ultraviolet absorption spectrophoto-
metric method at 22 Æ 28C in aqueous methanol; a) A. Albert, E. P.
Sergeant, Ionization Constants of Acids and Bases, Wiley, New York,
1962; b) K. Y. Tam, M. Hadley, W. Patterson, Talanta 1999, 49, 539;
c) L. Roman, S. Mirel, E. Florean, R. Oprean, J. Pharm. Biomed.
Anal. 1998, 18, 137; d) H. Diehl, N. Horchak-Morris, Talanta 1987, 34,
739; e) F. Garcia Sanchez, C. Cruces Blanco, J. J. Medinilla, Talanta
1986, 33, 847.
Received: June 10, 2002 [F4169]
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