Chirality control by substituents in the asymmetric addition of Et2Zn to aromatic aldehydes catalyzed by cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid derived 1,3-aminoalcohols

Article abstract of DOI:10.1002/cjoc.201090036

A series of novel optically active 1,3-aminoalcohols based on cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid and trans-(1R,2R)-2-benzamidocyclohexanecarboxylic acid were synthesized and used in the asymmetric diethylzinc addition to aromatic aldehydes.

Full text of DOI:10.1002/cjoc.201090036

FULL PAPER
Chirality Control by Substituents in the Asymmetric Addition of
Et2Zn to Aromatic Aldehydes Catalyzed by cis-(1R,2S)-2-
Benzamidocyclohexanecarboxylic Acid Derived
1,3-Aminoalcohols
Wang, Xiangboa(王祥波)
Kodama, Koichia(小玉康一)
Zhang, Guangyoub(张广友)
Hirose, Takuji*,a(廣瀬卓司)
a School of Science & Engineering, Saitama University, 255 Shimo-ohkubo, Sakura, Saitama 338-8570, Japan
b Department of Chemical Engineering, University of Jinan, Jinan, Shandong 250022, China
A series of novel optically active 1,3-aminoalcohols based on cis-(1R,2S)-2-benzamidocyclohexanecarboxylic
acid and trans-(1R,2R)-2-benzamidocyclohexanecarboxylic acid were synthesized and used in the asymmetric di-
ethylzinc addition to aromatic aldehydes. Not only the enantioselectivity but also the stereochemistry of the product
were controlled by the N-substituents and the substituents on the vicinity carbon to hydroxyl group of the
cis-derivatives.
Keywords chirality control, asymmetric addition, aldehyde, cis-(1R,2S)-2-benzamidocyclohexanecarboxylic acid,
1,3-aminoalcohols
Introduction
ligand, cis-(1R,2S)-2-benzamidocyclohexanecarboxylic
acid (1) and trans-(1R,2R)-2-benzamidocyclohexanecar-
boxylic acid (2) were chosen as the starting materials,
which can be easily converted into appropriately substi-
tuted 1,3-aminoalcohols as follows (Scheme 1).
Since the enantioselective addition of diethylzinc to
aldehydes was first reported by Oguni and Omi in
1984,1 various types of ligands, such as aminothiols,2
sulfonamides,3 aminophenols,4 amides,5 diamines6 and
diols7 were synthesized and successfully applied.8
Therefore, in return, the asymmetric addition of di-
ethylzinc to aldehydes became one of the most common
reactions for testing the effectiveness of newly devel-
oped chiral ligands.
Among the chiral ligands studied, aminoalcohols are
particularly attractive due to their high catalytic activity
and excellent enantioselectivity. In the past twenty years,
a variety of chiral 1,2-aminoalcohols have been devel-
oped and showed excellent enantioselectivity.9 Whereas,
1,3-aminoalcohols have been studied relatively too less
and it is interesting and challenging to examine the
chiral controllability.10 Thus we decided to synthesize
some new enantiopure 1,3-aminoalcohols derived from
2-benzamidocyclohexanecarboxylic acid, and studied
their catalytic ability in the asymmetric addition of di-
ethylzinc to aromatic aldehydes.
First, cis-(1R,2S)-2-benzamidocyclohexanecarboxylic
acid was reduced with LiAlH4 in tetrahydrofuran to give
aminoalcohol 311 in good yield. After debenzylation of
3 by catalytic hydrogenolysis under atmospheric pres-
sure of H2 over 10% Pd/C,12 primary amine 413 was ob-
tained in high yield. Cycloalkylation reaction of 4 with
1,4-dibromobutane afforded 5 in 62.9% yield. In addi-
tion, 3 was treated with iodomethane and NaOH in
methanol, then reduced with LiAlH4 to give tertiary
amine 6 (89.3% yield). Thus, four primary alcohols with
different N-substituents (3— 6) were easily prepared.
In order to introduce bulkiness to the vicinity of hy-
droxyl group, 1 was quantitatively esterified and sub-
jected to Grignard reaction with PhMgBr, and then to
reduction of amide group providing aminoalcohol 8
with two phenyl groups in high yield. Debenzylation of
8 gave the primary amine 9 as a white solid (87.5%
yield) and cyclic tertiary amine 10 was obtained in
31.2% yield after cycloalkylation of 9.14
Results and discussion
On the other hand, 12, the trans-isomer of 8, was
synthesized from 2 following the same procedure ap-
plied to 8 in 53.5% overall yield.
Synthesis of enantiopure 1,3-aminoalcohols
In our synthetic routes, commercially available chiral
*
E-mail: hirose@apc.saitama-u.ac.jp; Tel.: 0081-48-858-3522; Fax: 0081-48-858-3522
Received June 18, 2009; revised August 24, 2009; accepted September 15, 2009.
Project supported by the National Natural Science Foundation of China (No. 20271025), the Natural Science Foundation of Shandong Province (No.
L2003B01) and the State Key Laboratory of Crystal Materials, Shandong University.
Chin. J. Chem. 2010, 28, 61— 68
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Wang et al.
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Scheme 1
Reagents and conditions: (a) conc. H2SO4, MeOH, reflux; (b) 5 equiv. PhMgBr/dry THF, reflux; (c) LiAlH4, dry THF, reflux; (d) 10% Pd/C, H2, EtOH, 70
℃; (e) Br(CH2)4Br, Et3N, DMF, 60 ℃; (f) i) MeI, NaOH, MeOH, r.t.; ii) LiAlH4, dry THF, reflux
Enantioselective addition of diethylzinc to benzalde-
hydes and enantioselecitiviy using chiral 1,3-ami-
noalcohols
10, afforded (S)-isomer (Table 1, Entries 1, 2, and 5—
7).
Table 1 Enantioselective addition of diethylzinc to benzalde-
In order to examine the chiral induction abilities of
chiral 1,3-aminoalcohols (3—6, 8—10, 12), we ex-
plored the enantioselective addition reaction of di-
ethylzinc to benzaldehydes in the presence of 10 mol%
of these ligands and the results are summarized in Table
1. The structural study has revealed that the
enantiomeric excess changed with the number and the
size of N-substituents; that is, secondary amines (3 and 8)
worked as better ligands than primary amines (4 and 9),
respectively, and 8 yielded better chemical yield than
tertiary amines (5 and 6). However tertiary amine with a
cyclic structure, 5, showed the best chiral induction
ability (71.2% ee) in the ligands studied.
On the other hand, increasing the steric bulkiness at
the α-position of hydroxyl group also improved the en-
antioselectivity, that is, when two phenyl groups were
introduced to the vicinity of hydroxyl group (3 vs. 8, 4
vs. 9), the enantiomeric excess increased from 33.0% to
65.5% ee and 9.8% to 58.9% ee (Table 1, Entries 1 vs. 5,
2 vs. 6). However, trans-derivative 12 showed the low-
est enantioselectivity due to its trans-configuration,
which will be discussed later.
hyde catalyzed by various chiral ligandsa
Entry Ligand
Time/h
60
Yieldb/%
11.5
eec/%
33.0
9.8
Config.c
1
2
3
4
5
6
7
8
3
4
S
S
R
R
S
S
S
S
70
13.0
5
40
30.1
71.2
58.1
65.5
58.9
27.2
7.7
6
40
13.2
8
20
68.5
9
60
46.0
10
18
63.6
12
30
46.5
a All reactions were carried out in dry n-hexane-toluene (2∶3,
V/V) at 0 ℃. Aldehyde/Et2Zn/chiral ligand＝1/3/0.1 (molar ratio);
Et2Zn (1 mol•L－ solution in n-hexane). b Isolated yield. See the
1
c
experimental.
The substituent effect and chirality inversion can be
explained by the transition state model proposed by some
researchers for 1,3-aminoalcohols,10b,10g,10h which also
corresponds to that by Noyori et al.15 for
1,2-aminoalcohols (Figures 1 — 4). Supposing the
anti-6/4/4 tricyclic transition state, the cyclohexane ring
plays an important role in primary and secondary amine
ligands. As an example, anti-(Si) and anti-(Re) transi-
The most interesting feature of the present system is
that both (R)- and (S)-1-phenyl-1-propanol were pro-
vided depending on the substituents in spite of the same
chirality of the ligand, (1R,2S), derived from 1: primary
alcohols with tertiary amino groups, 5 and 6, gave
(R)-isomer (Table 1, Entries 3 and 4) while primary and
secondary amines, 3, 4, and 9, and tertiary alcohols, 8—
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Chin. J. Chem. 2010, 28, 61—68

Chirality Control by Substituents in the Asymmetric Addition
tion states for the alkylation using 3 are compared in
Figure 1. In the anti-(Re) form, large steric repulsion
between the cyclohexane ring and the Et group is ex-
pected due to the 1,3-diaxial relationship in the
six-membered Zn-chelate ring while the anti-(Si) form
avoids such repulsion to afford (S)-1-phenyl-1-propanol
(33.0% ee, Table 1, Entry 1).
group also affected the stereochemistry of alkylation.
When tertiary alcohol 8 was used as a chiral ligand, ad-
ditional repulsion between the Ph group and the Et
group on Et2Zn for alkylation further destabilized the
anti-(Re) form (Figure 3). As a result, 8 gave higher
(S)-selectivity (65.5% ee, Table 1, Entry 5) than 3
(33.0% ee).
Figure 1 Proposed transition states for the alkylation using 3.
Figure 3 Proposed transition states for the alkylation using 8.
In addition, it was shown that secondary amines, 3
and 8, provided better ee values than the corresponding
primary amines, 4 and 9, (3 [33.0% ee] vs. 4 [9.8% ee]
and 8 [65.5% ee] vs. 9 [58.9% ee]). The result seems to
suggest one N-substituent favours the pseudo-equatorial
position stabilizing the anti-(Si) form.
More rigid and bulky cyclic tertiary amine 5, how-
ever, should have much larger steric repulsion with the
Et group on Zn in 1,2-relationship of the anti-(Si) form
than that with the cyclohexane ring in 1,3-relationship
of the anti-(Re) (Figure 2). As a result, (R)-1-phenyl-1-
propanol was obtained in a high enantiomeric excess,
71.2% ee (Table 1, Entry 3). Similarly another tertiary
amine 6 gave the same stereoselectivity but more flexi-
ble structure (benzyl methylamine) seemed to lead to
lower enantioselectivity of 58.1% ee (Table 1, Entry 4).
Chirality change by the substitution on the α-carbon
of hydroxyl group of 1,3-aminoalcohols has been re-
ported by Cicchi et al.10e In their system, diphenyl
methanol and 9-hydroxy fluorene moieties caused op-
posite chirality in the product. Although similar substi-
tution effect on the α-carbon of hydroxyl group has been
also observed for chiral 1,2-aminoalcohol ligands,9c
there are only limited systems reported for the chirality
inversion by this kind of substituent-effect. Considering
the diversity of structural modification, chiral
1,3-aminoalcohols would be interesting scaffolds for
asymmetric reactions.4,10e,10f,10i
In the case of 12, the trans-(1R,2R)-configuration
allows much less strained transition states than the
cis-derivatives; that is, the steric repulsion of the sub-
stituents on the six-membered chelate ring is largely
relieved and the cyclohexane ring has little effect on
stereocontrol (Figure 4). Consequently, both anti-(Si)
and anti-(Re) transition states have similar stability
showing the least enantioselectivity (7.7% ee, Table 1
Entry 8).
Figure 2 Proposed transition states for the alkylation using 5.
Similar and interesting chirality inversion by N-sub-
stituent-effect has been observed for 1,3-aminoalcohols
derived from α-pinene by Szakonyi et al.10i Their pri-
mary and tertiary amines gave 1-phenyl-1-propanol of
the same chirality (40% & 62% ee) with those obtained
by 4, 5, and 6 (9.8%—71% ee). On the other hand, their
secondary amine gave the opposite chirality (13% ee) to
that obtained by 3 (33% ee). While the cyclohexyl ring
is the common structural feature, the bridging methylene
might cause the difference due to its effect on the transi-
tion state geometry for the α-pinene derived ligands.10i
On the other hand, the bulkiness of the hydroxyl
Figure 4 Proposed transition states for the alkylation using 12.
Enantioselective addition of diethylzinc to various
aldehydes
In order to optimize the reaction, the solvent, tem-
perature and ligand loading effects were examined and
the results are shown in Table 2. Apparently less-polar
solvents (Entries 1 & 2) gave better chemical yield and
enantiomeric excess than polar ethers (Entries 3 & 4),
Chin. J. Chem. 2010, 28, 61—68
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63

Wang et al.
FULL PAPER
especially in THF (26.8% ee). Many studies have shown
that toluene or n-hexane-toluene mixture is a proper
solvent system to provide higher enantios-
electivity9c-e,9j,9k so that the ratio of this mixed solvent
system was changed in our study as well. Although the
ratio of n-hexane to toluene had less effect on the chiral
control, the yield was observably enhanced when only
n-hexane was used (Entries 5 vs. 7, 9 vs. 10). At the
same time, the effect of the amount of chiral ligand on
the enantioselectivity was investigated by the use of 5.
Although the reaction proceeded with 10 mol% ligand
loading, the enantioselectivity and the yield were gradu-
ally improved by increasing the amount of 5 from 10 to
20 and 30 mol% (Entries 1, 5 & 9).
but lower enantioselectivity was obtained for thio-
phene-2-carboxaldehyde (Entries 9 and 17). The heteroa-
tom might be the cause as commented by Noyori et al.15a
On the other hand, the present system was not effective
for aliphatic aldehydes as complex product mixtures were
obtained for three aliphatic aldehydes examined (Entries
10—12). Comparing 1,2-aminoalcohol ligands, a more
flexible 6/4/4 tricyclic transition state might be the cause
of this limitation. Further control of molecular design is
necessary to the present ligand structure.
Conclusion
We have synthesized a series of novel optically ac-
tive 1,3-aminoalcohols from cis-(1R,2S)-2-benzamido-
cyclohexanecarboxylic acid 1. The structural character-
istics of the chiral ligands were explored in asymmetric
diethylzinc addition to various aldehydes. The results
demonstrated that the cyclohexane ring, N-substituents
and the substituents to the vicinity of hydroxyl group
have crucial effect on chirality control. Providing the
rigid and bulky cyclic tertiary amine 5 showed the best
promoting ability to aromatic aldehydes with
(R)-selectivity (79.4% ee) in the ligands studied in this
article. With two phenyl groups to provide the proper
steric bulkiness, the tertiary alcohol 8 showed the oppo-
site (S)-selectivity (66.0% ee). Further studies on chiral
control and versatility are currently underway by
1,3-aminoalcohol ligands derived from 1.
When the reaction was carried out at different tem-
peratures, we found a large effect on the conversion and
the enantioselectivity. The best result was obtained at 0
℃ and either lower or higher temperature decreased
both the chemical yields and ee values (Table 2, Entries
6—8). Similar results on the temperature effect were
observed by other researchers.4c,5b,7c,16
.
Considering the results shown in Table 2, we inves-
tigated the ligand effect on the chiral induction in the
presence of 20 mol% of 5 and 8 for not only various
aromatic aldehydes having an electron donating or
withdrawing group but also heteroaromatic and aliphatic
aldehydes. The results are summarized in Table 3. The
enantioselectivity observed in Table 1 was confirmed for
all aromatic aldehydes: 5 gave (R)-1-aryl-1-propanol
while 8 afforded (S)-enantiomer in good yields. In addi-
tion, little substituent effect was observed for the meta- or
para-substituted benzaldehydes on both chemical yield
and enantioselectivity. However, the orthosubstituent,
especially an ortho-bromo substituent, decreased the
enantioselectivity. The substituent effect on the sub-
strate needs to be further investigated since the present
result is in accordance with the results reported by Yang
et al.,4a,4b Sun et al.,17a and Jaworska et al.,17b but is op-
posite to the results reported by Joshi et al.9i
Experimental
General
All the asymmetric addition reactions of diethylzinc
to aldehydes were carried out under nitrogen in anhy-
drous solvents. NMR spectra were obtained at 400 MHz
(1H NMR) and 100 MHz (13C NMR) on a Bruker
DPX400 spectrometer (Molecular Analysis and Life
Science Center, Saitama University) using CDCl3 as the
solvent. Optical rotations were measured with a JASCO
Among the heteroaromatic aldehydes, a similar re-
sult was obtained for furan-2-carboxaldehyde (Entry 8)
Table 2 Optimization of the reaction conditionsa
Entry
5/mol%
20
Solvent
Time/h
40
T/℃
Yieldb/%
eec/%
71.0
51.0
30.2
26.8
63.3
33.5
71.2
—
Config.c
1
2
n-Hexane
CH2Cl2
0
69.3
49.2
28.0
19.8
40.8
26.9
30.1
2.5
R
R
R
R
R
R
R
—
R
R
20
40
40
40
40
60
40
25
40
20
0
0
3
20
Et2O
4
20
THF
0
5
10
n-Hexane
H/T,d 2∶3
H/T, 2∶3
H/T, 2∶3
n-Hexane
H/T, 2∶3
0
6
10
r.t.
0
7
10
8
10
－18
9
30
0
72.1
45.5
79.4
76.1
10
30
0
a Aldehyde/Et2Zn＝1∶3 (molar ratio); Et2Zn (1 mol•L－ 1 solution in n-hexane). b Isolated yield. c See the experimental. d The volume ratio
of n-hexane to toluene.
64
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Chin. J. Chem. 2010, 28, 61—68

Chirality Control by Substituents in the Asymmetric Addition
Table 3 Asymmetric addition of diethylzinc to aldehydes in the presence of 5 or 8a
Entry
1
Ligand
Aldehyde
p-ClC6H4CHO
Yieldb/%
62.0
eec/%
65.6
63.6
75.4
75.0
32.6
38.1
53.4
52.0
47.5
—
Config.c
5
5
5
5
5
5
5
5
5
5
5
5
8
8
8
8
8
R
R
R
R
R
R
R
R
R
—
—
—
S
2
p-MeC6H4CHO
56.0
3
m-ClC6H4CHO
72.5
4
m-MeC6H4CHO
68.8
5
o-BrC6H4CHO
58.6
6
o-ClC6H4CHO
51.1
7
o-MeC6H4CHO
64.8
8
Furan-2-carboxaldehyde
Thiophene-2-carboxaldehyde
Isobutyraldehyde
Hexanal
70.4
9
57.1
10
11
12
13
14
15
16
17
Trace
Trace
Trace
77.3
—
Cyclohexanecarbaldehyde
p-ClC6H4CHO
—
60.1
55.8
66.0
61.1
27.3
p-MeC6H4CHO
81.0
S
m-ClC6H4CHO
78.3
S
m-MeC6H4CHO
82.5
S
Thiophene-2-carboxaldehyde
60.6
S
a All reactions were carried out in dry n-hexane at 0 ℃ for 72 h. Aldehyde/Et2Zn/chiral ligand＝1/3/0.2 (molar ratio); Et2Zn (1 mol•L－
1
solution in n-hexane). b Isolated yield. c See the experimental.
DIP-370 polarimeter. Melting points were obtained
using a Mitamura Riken Kogyo MEL-TEMP instrument
and uncorrected. IR spectra were recorded on a JASCO
FT/IR 400. Enantiomeric excess was determined using a
set of JASCO LC 900 series with Chiralcel OB-H or OJ
columns (Daicel Chemical Industries, Ltd.). The starting
material 1 is commercially available while 2 was
prepared according to the literature.18
1203, 1188, 1143, 1105, 1080, 1065, 1033, 966, 914,
－1
899, 864, 8＋40, 805, 748, 696, 628, 607, 475 cm
;
HRMS (ESI ) calcd for C14H21NOH＋ 220.1696, found
220.1615.
Synthesis of (1R,2S)-2-aminocyclohexylmethanol (4)
The mixture of 3 (1.80 g, 8.22 mmol) and 10% Pd/C
(0.18 g) in ethanol (40 mL) was stirred under hydrogen
(1×105 Pa) at 70 ℃ or 24 h. After cooling to room
temperature, Pd/C was filtered off and the solvent was
removed under reduced pressure to afford 4 as a white
solid (1.06 g, 94.4%), which could be used directly in
the next step without further purification. m.p. 60—62
Synthesis
methanol (3)
of
(1R,2S)-2-benzylaminocyclohexyl-
To a suspension of LiAlH4 (1.2 g, 31.62 mmol) in
dry THF (20 mL) was added slowly a solution of 1 (2.49
g, 10.07 mmol) in THF (30 mL). After refluxing for 24
h, the reaction was cautiously quenched with water and
the mixture was further treated with 20% NaOH aq. so-
lution. The precipitate was filtered off and washed with
ethyl acetate. The combined organic layer was dried
over anhydrous Na2SO4 and concentrated to dryness.
After purification by column chromatography (silica gel,
n-hexane/ethyl acetate＝1/1—0/1, V/V), 3 was obtained
as a white solid (2.01 g, 91.0%). m.p. 68—68.5 ℃,
[α]2D5 －24.0 (c 1.0, MeOH); 1H NMR (CDCl3, 400 MHz)
δ: 7.35—7.14 (m, 5H), 6.25—5.65 (br, 1H), 3.94—3.87
(m, 1H), 3.82 (d, J＝8.90 Hz, 2H), 3.73—3.71 (m, 1H),
3.00—2.98 (m, 1H), 1.91—1.90 (m, 2H), 1.65—1.36 (m,
7H); 13C NMR (100 MHz, CDCl3) δ: 149.7, 128.6,
128.3, 127.2, 66.4, 58.7, 51.7, 39.0, 27.8, 25.9, 23.5,
22.6; IR (KBr) ν: 3297, 3198, 3065, 3027, 2925, 2844,
1499, 1483, 1462, 1448, 1370, 1348, 1333, 1251, 1228,
1
℃, [α]1D9 ＋16.9 (c 1.1, CHCl3); H NMR (CDCl3, 400
MHz) δ: 3.81—3.70 (m, 2H), 3.27—3.25 (m, 1H), 3.21—
2.85 (br, 3H), 1.73—1.70 (m, 1H), 1.60—1.44 (m, 7H),
1.36—1.28 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ:
66.3, 51.0, 41.1, 33.0, 24.6, 24.2, 21.3; IR (KBr) ν: 3445,
3335, 2934, 2846, 2175, 1630, 1556, 1489, 1464, 1386,
1355, 1335, 1303, 1256, 1217, 1196, 1140, 1105, 1092,
1059, 1047, 1026, 975, 960, 937, 904, 882, 815, 802,
＋
－1
783, 718, 644, ＋586, 539, 498 cm ; HRMS (ESI ) calcd
for C7H15NOH 130.1226, found 130.1278.
Synthesis of (1R,2S)-2-pyrrolidin-1'-ylcyclohexyl-
methanol (5)
Chiral aminoalcohol 4 (0.49 g, 3.90 mmol), Et3N
(0.79 g, 7.80 mmol) and 1,4-dibromobutane (0.84 g,
3.90 mmol) were dissolved in DMF (5 mL), and stirred
at 60 ℃ for 36 h. After chloroform (30 mL) was added,
Chin. J. Chem. 2010, 28, 61—68
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65

Wang et al.
FULL PAPER
＋
＋
－1
the mixture was washed with water. The organic layer
was dried over anhydrous Na2SO4 and concentrated to
dryness. The crude product was purified by column
chromatography (Al2O3, n-hexane/ethyl acetate＝1/1,
V/V) to afford 5 (0.45 g, 62.9%) as a light yellow liquid.
[α]2D6 ＋21.4 (c 0.39, CHCl3); 1H NMR (CDCl3, 400 MHz)
δ: 4.20—4.10 (m, 1H), 3.48—3.44 (m, 1H), 2.87—2.58
(m, 2H), 2.57—2.39 (m, 2H), 2.38—2.31 (m, 2H), 1.76—
1.59 (m, 7H), 1.49—1.46 (m, 1H), 1.38—1.15 (m, 4H);
13C NMR (CDCl3, 100 MHz) δ: 67.9, 64.0, 52.2, 36.2,
28.1, 25.8, 25.7, 23.0, 20.7; IR (KBr) ν: 3437, 3393,
3318, 2934, 2856, 2778, 2708, －1654, 1445, 140＋8, 1126,
cm ; HRMS (ESI ) calcd for C15H19NO3H 262.1438,
found 262.1057.
Synthesis
of
(1R,2S)-2-benzylaminocyclohexyl-
(diphenyl)methanol (8)
A THF (20 mL) solution of 7 (0.64 g, 16.7 mmol) in
a dropping funnel was slowly added to a THF solution
of phenyl magnesium bromide (90 mmol) at 0 ℃ for
20 min. The reaction mixture was stirred at room tem-
perature for 0.5 h and then heated to reflux for 12 h.
After cooling to room temperature, the reaction was
quenched with saturated NH4Cl aq. solution. The mix-
ture was extracted with ether and the organic layer was
dried over anhydrous Na2SO4. After the solvent was
removed, the crude product was obtained as a light yel-
low solid, which was recrystallized from ethyl acetate to
afford a white crystalline solid (0.49 g, 52.3%) for the
use in the next step.
1
1107, 1036, 953, 915, 888 cm ; HRMS (ESI ) calcd
for C11H21NOH＋ 184.1696, found 184.1673.
Synthesis of (1R,2S)-2-[benzyl(methyl)amino]cyclo-
hexylmethanol (6)
To a methanol solution (15 mL) of 3 (0.58 g, 2.64
mmol), iodomethane (3.75 g, 26.45 mmol) and NaOH
(0.21 mg, 5.29 mmol) were added and the reaction mix-
ture was stirred at room temperature for 48 h. After re-
moval of the solvent, the residue was dissolved in 20
mL of chloroform, washed with water, dried over anhy-
drous Na2SO4, and then concentrated to dryness. Reduc-
tion of the white residue with LiAlH4 followed the pro-
cedure similar to that for 3 gave 6 as a colorless liquid
(0.55 g, 89.3%). [α]1D9 ＋23.0 (c 0.29, CHCl3); 1H NMR
(CDCl3, 400 MHz) δ: 7.33—7.25 (m, 5H), 4.33—4.27
(m, 1H), 3.75 (d, J＝12.58 Hz, 1H), 3.61—3.52 (m, 2H),
2.63—2.56 (m, 2H), 2.15 (s, 3H), 1.97—1.89 (m, 2H),
1.75—1.63 (m, 2H), 1.49—1.44 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ: 138.4, 129.2, 128.5 127.2, 67.1,
64.1, 59.3, 39.0, 35.4, 28.6, 26.2, 24.6, 20.8; IR (KBr) ν:
3399, 2930, 2854, 2786, 1495, 1451, 1421, 1375, 1347,
1323, 1253, 1229, 1121, 1069, 1038, 995, 909, 882, 85＋3,
To a suspension of LiAlH4 (0.12 g, 3.16 mmol) in
dry THF (15 mL) was added slowly a solution of the
alcohol in THF (10 mL). After refluxing for 18 h, the
reaction was cautiously quenched with water and the
mixture was further treated with 20% NaOH aq.
solution. The precipitate was filtered off and washed
with ethyl acetate. The combined organic layer was
dried over anhydrous Na2SO4 and concentrated under
reduced pressure. After purification by column chroma-
tography (silica gel, n-hexane/ethyl acetate＝3/1, V/V),
8 was obtained as a colorless viscous liquid (0.44 g,
1
93.1%). [α]2D6 ＋85.6 (c 2.6, MeOH); H NMR (CDCl3,
400 MHz) δ: 8.54—8.25 (br, 1H), 7.67—7.65 (m, 2H),
7.55—7.52 (m, 2H), 7.34—7.24 (m, 9H), 7.16—7.09 (m,
2H), 3.59 (d, J＝12.21 Hz, 1H), 3.24 (d, J＝12.10 Hz,
1H), 3.15—2.94 (m, 1H), 2.48—2.44 (m, 1H), 1.92—
1.89 (m, 1H), 1.76—1.68 (m, 1H), 1.67—1.46 (m, 4H),
1.44—1.22 (m, 3H); 13C NMR (CDCl3, 100 MHz) δ:
149.1, 146.9, 139.3, 128.6, 128.3, 128.2, 128.0, 127.4,
125.9, 125.8, 125.5, 125.2, 80.6, 54.1, 52.0, 47.3, 28.5,
25.8, 21.6, 20.2; IR (KBr) ν: 3317, 3075, 3060, 3029,
2926, 2852, 1597, 1491, 1468, 1450, 1432, 1381, 1313,
1242, 1210, 1176, 1136, 1067, 1032, 992, 969, 909, 881,
－1
＋
745, 700 cm ; HRMS (ESI ) calcd for C15H23NOH
234.1852, found 234.1352.
Synthesis of methyl (1R,2S)-2-benzamidocyclohex-
anecarboxylate (7)
To a dry methanol solution (10 mL) of 1 (0.99 g, 4
mmol), was added concentrated H2SO4 (32 mg, 0.32
mmol) and the reaction mixture was refluxed for 12 h.
After concentration, the residue was dissolved in chlo-
roform (30 mL), washed with water, and dried over an-
hydrous Na2SO4. Removal of the solvent afforded 7 as a
white solid (1.04 g, 99.1%), which could be used di-
rectly in the next step. m.p. 80—81.5 ℃, [α]2D6 －45.0
＋
－1
768, 747, 698, 648, 633, 552 cm ; HRMS (ESI ) calcd
for C26H29NOH＋ 372.2322, found 372.2896.
Synthesis of (1R,2S)-2-aminocyclohexyl (diphenyl)-
methanol (9)
The mixture of 8 (0.24 g, 0.65 mmol) and 10% Pd/C
(24 mg) in ethanol (20 mL) was stirred under hydrogen
(1×105 Pa) at 60 ℃ for 24 h. After cooling to room
temperature, Pd/C was filtered off and the solvent was
removed under reduced pressure. The crude product was
purified by column chromatography (Al2O3, n-hexane/
ethyl acetate＝2/1, V/V) to afford 9 (0.16 g, 87.5%). m.p.
1
(c 0.7, MeOH); H NMR (CDCl3, 400 MHz) δ: 7.79—
7.79 (m, 2H), 7.51—7.41 (m, 3H), 7.26 (s, 1H), 4.38—
4.31 (m, 1H), 3.54 (s, 3H), 2.93—2.91 (m, 1H), 2.20—
2.17 (m, 1H), 1.85—1.64 (m, 4H),1.58—1.47 (m, 2H),
1.32—1.21 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ:
174.9, 166.3, 134.8, 131.3, 128.5, 126.9, 51.8, 48.3,
44.4, 29.4, 27.5, 24.3, 22.5; IR (KBr) ν: 3321, 3060,
3029, 1727, 1636, 1604 1579, 1534, 1490, 1449, 1396,
1337, 1313, 1277, 1261, 1203, 1132, 1120, 1079, 1028,
1004, 962, 924, 857, 818, 801, 727, 693, 679, 666, 583
1
228—230 ℃, [α]2D5 －6.65 (c 0.41, CHCl3); H NMR
(CDCl3, 400 MHz) δ: 7.63—7.61 (m, 2H), 7.53—7.51 (m,
2H), 7.30—7.24 (m, 4H), 7.15—7.09 (m, 2H), 3.91—
3.00 (br, 2H), 3.15—3.14 (m, 1H), 2.45—2.40 (m, 1H),
1.80—1.70 (m, 1H), 1.64—1.40 (m, 6H), 1.39—1.19 (m,
66
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Chin. J. Chem. 2010, 28, 61— 68

Chirality Control by Substituents in the Asymmetric Addition
2H); 13C NMR (CDCl3, 100 MHz) δ: 149.0, 147.0,
128.1, 128.0, 125.9, 125.8, 125.7, 125.2, 80.5, 47.2,
46.5, 35.4, 26.1, 20.8, 19.5; IR (KBr) ν: 3426, 3374,
3313, 3083, 3014, 3013, 2925, 2862, 1598, 1578, 1490,
1459, 1448, 1430, 1387, 1305, 1265, 1246, 1182, 1135,
1063, 1037, 994, 959, 912, 887, 864, 819, 793, 765, 745,
3257, 3086, 3059, 3029, 2932, 2853, 1600, 1581, 1492,
1445, 1356, 1286, 1211, 1140, 1096, 1052, 1032, 1010,
－1
951, 909, 86＋0, 763, 744, 714, 700, 649, 626, 608 cm ;
HRMS (ESI ) calcd for C26H29NOH＋ 372.2322, found
372.2673.
＋
－1
General procedure for the asymmetric addition of
diethylzinc to aldehydes4a,4b
707, 695, 641, 549 cm ; HRMS (ESI ) calcd for
C19H23NOH＋ 282.1852, found 282.1457.
The chiral 1,3-aminoalcohol (0.03 mmol) was dis-
Synthesis of (1R,2S)-2-pyrrolidin-1'-ylcyclohexyl-
(diphenyl)methanol (10)
solved in n-hexane (0.5 mL) at room temperature －under
1
nitrogen and diethylzinc (0.9 mmol, 1 mol•L
in
Chiral aminoalcohol 10 was prepared by the proce-
dure similar to that for the preparation of 5 as a white
solid (31.2%). m.p. 143—145 ℃, [α]2D7 ＋4.4 (c 0.34,
CHCl3); 1H NMR (400 MHz, CDCl3) δ: 9.31—8.65 (br,
1H), 7.66—7.64 (m, 2H), 7.54—7.52 (m, 2H), 7.30—
7.23 (m, 4H), 7.14—7.08 (m, 2H), 3.19 (s, 1H), 2.92—
2.18 (m, 4H), 1.93—1.83 (m, 2H), 1.69—1.49 (m, 8H),
1.43—1.37 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ:
149.3, 147.1, 128.1, 128.0, 125.8, 125.7, 125.5, 125.0,
80.6, 63.7, 54.1, 51.9, 48.0, 29.7, 26.4, 24.4, 22.6; IR
(KBr) ν: 3426, 3055, 3032, 2952, 2916, 2840, 1596,
1489, 1460, 1447, 1434, 1399, 1343, 1253, 1179, 1143,
1066, 1032, 994, 908, 855, 768, 752, 707, 666, 638, 555
n-hexane) was added to this solution. The mixture was
cooled to 0 ℃ and stirred for 30 min. Aldehyde (0.3
mmol in 1 mL n-hexane) was added to the mixture. After
stirring at 0 ℃ for 18—72 h, the reaction was quenched
with saturated NH4Cl aq. solution. The mixture was ex-
tracted with diethyl ether, dried over anhydrous Na2SO4
and concentrated. The crude product was purified by thin
layer chromatography (silica gel, n-hexane/ethyl acetate,
V/V＝4/1) to give the pure alcohol as a colorless oil. The
absolute configuration and the ee values were determined
by the chiral HPLC analysis4 and the data are as follows:
1-phenyl-1-propanol; Daicel Chiralcel OB-H, V(n-hex-
ane)/V(2-propanol)＝90∶10, 0.5 mL/min, 254 nm, tR1＝
11.9 min (S-isomer), tR2＝13.5 min (R-isomer). 1-(4-
Chlorophenyl)-1-propanol; Daicel Chiralcel OJ,
V(n-hexane)/V(2-propanol)＝97∶3, 0.5 mL/min, 254
nm, tR1 ＝ 32.36 min (S-isomer), tR2 ＝ 35.46 min
(R-isomer). 1-(4-Tolyl)-1-propanol; Daicel Chiralcel OJ,
V(n-hexane)/V(2-propanol)＝97∶3, 0.5 mL/min, 254
nm, tR1 ＝ 32.29 min (S-isomer), tR ＝ 34.33 min
(R-isomer). 1-(3-Chlorophenyl)-1-pro2panol; Daicel
Chiralcel OB-H, V(n-hexane)/V(2-propanol)＝90∶10,
0.5 mL/min, 254 nm, tR1＝12.03 min (S-isomer), tR2＝
13.69 min (R-isomer). 1-(3-Tolyl)-1-propanol; Daicel
Chiralcel OB-H, V(n-hexane)/V(2-propanol)＝95∶5,
0.5 mL/min, 254 nm, tR1＝12.68 min (S-isomer), tR2＝
14.93 min (R-isomer). 1-(2-Bromophenyl)-1-propanol;
Daicel Chiralcel OB-H, V(n-hexane)/V(2-propanol)＝
97∶3, 0.5 mL/min, 254 nm, tR ＝16.34 min (S-isomer),
＋
＋
－1
cm ; HRMS (ESI ) calcd for C23H29NOH 336.2322,
found 336.2583.
Synthesis of methyl (1R,2R)-2-benzamidocyclohex-
anecarboxylate (11)
By the procedure similar to that for the preparation
of 7, 11 was quantitatively prepared as a white solid
(99.0%) and could be used directly in the next step
without further purification. m.p. 151—152.5 ℃, [α]1D9
1
－49.2 (c 0.5, MeOH); H NMR (CDCl3, 400 MHz) δ:
7.72—7.64 (m, 2H), 7.41—7.33 (m, 3H), 6.11 (s, 1H),
4.12—4.07 (m, 1H), 3.57 (s, 3H), 2.38—2.33 (m, 1H),
2.13—2.11 (m, 1H), 1.93—1.90 (m, 1H), 1.73—1.58 (m,
3H), 1.41—1.37 (m, 1H), 1.23—1.19 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ: 174.3, 166.8, 134.8, 131.4,
128.5, 126.9, 51.9, 50.7, 49.9, 32.8, 28.4, 24.7, 24.5; IR
(KBr) ν: 3301, 3060, 2948, 2862, 1721, 1637, 1603
1578, 1542, 1491, 1448, 1433, 1372, 1330, 1284, 1248,
1205, 1194, 1179, 1126, 1075, 1049, 1029, 1012, 963,
tR ＝ 17.97 min (R-isomer)1. 1-(2-Chlorophenyl)-1-
2
propanol; Daicel Chiralcel OB-H, V(n-hexane)/
V(2-propanol)＝98∶2, 0.5 mL/min, 254 nm, tR ＝18.46
min (S-isomer), tR ＝21.00 min (R-isomer). 1-(12-Tolyl)-
1-propanol; Daic2el Chiralcel OB-H, V(n-hexane)/
V(2-propanol)＝98∶2, 0.5 mL/min, 254 nm, tR1＝20.92
min (S-isomer), tR2 ＝ 24.41 min (R-isomer).
1-(2-Thienyl)-1-propanol; Daicel Chiralcel OD,
V(n-hexane)/V(2-propanol)＝99.5∶0.5, 1.5 mL/min,
230 nm, tR1＝24.55 min (R-isomer), tR2＝27.16 min
(S-isomer). 1-(2-Furyl)-1-propanol; Daicel Chiralcel OD,
V(n-hexane)/V(2-propanol)＝99.5∶0.5, 1.5 mL/min,
230 nm, tR1＝20.17 min (R-isomer), tR2＝23.55 min
(S-isomer).
－1
915, 873, 835, 800, 725, 697, 671, 583 cm ; HRMS
(ESI ＋ ) calcd for C15H19NO3H ＋ 262.1438, found
262.1081.
Synthesis
of
(1R,2R)-2-benzylaminocyclohexyl-
(diphenyl)methanol (12)
Chiral aminoalcohol 12 was prepared by the proce-
dure similar to that for the preparation of 8 as a colorless
viscous liquid (54.0%). [α]1D9 －102.8 (c 1.27, CHCl3);
1H NMR (CDCl3, 400 MHz) δ: 9.65—10.35 (br, 1H),
7.57—7.49 (m, 2H), 7.42—7.19 (m, 13H), 3.79 (d, J＝
12.4 Hz, 1H), 3.54 (d, J＝12.4 Hz, 1H), 2.49—2.24 (m,
3H), 1.92—1.62 (m, 3H), 1.35—0.80 (m, 4H); 13C
NMR (CDCl3, 100 MHz) δ: 146.3, 145.1, 139.0, 128.7,
128.2, 128.0, 127.7, 127.5, 127.1, 126.8, 126.5, 82.8,
59.2, 51.4, 51.3, 34.7, 30.0, 26.3, 25.8; IR (KBr) ν: 3426,
References
1
2
Oguni, N.; Omi, T. Tetrahedron Lett. 1984, 25, 2823.
(a) Andersen, J. C.; Harding, M. Chem. Commun. 1998, 393.
Chin. J. Chem. 2010, 28, 61— 68
© 2010 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
67

Wang et al.
FULL PAPER
(b) Gibson, C. L. Tetrahedron: Asymmetry 1999, 10, 1551.
Pericàs, M. A. J. Org. Chem. 2008, 73, 5340.
3
(a) You, J. S.; Shao, M. Y.; Gau, H. M. Tetrahedron:
Asymmetry 2001, 12, 2971.
(k) Parrott II, R. W.; Hitchcock, S. R. Tetrahedron: Asym-
metry 2008, 19, 19.
(b) Grach, G.; Reboul, V.; Metzner, P. Tetrahedron: Asym-
metry 2008, 19, 1744.
(l) Xu, C. L.; Wang, M. C.; Hou, X. H.; Liu, H. M.; Wang,
D. K. Chin. J. Chem. 2005, 23, 1443.
4
(a) Yang, X. F.; Wang, Z. H.; Koshizawa, T.; Yasutake, M.;
Zhang, G. Y.; Hirose, T. Tetrahedron: Asymmetry 2007, 18
1257.
(b) Yang, X. F.; Hirose, T.; Zhang, G. Y. Tetrahedron:
Asymmetry 2008, 19, 1670.
(c) Szatmári, I.; Sillanpää, R.; Fülöp, F. Tetrahedron:
Asymmetry 2008, 19, 612.
(a) Burguete, M. I.; Escorihuela, J.; Luis, S. V.; Ujaque, G.
Tetrahedron 2008, 64, 9717.
(b) Blay, G.; Fernández, I.; Marco-Aleixandre, A.; Pedro, J.
R. Tetrahedron: Asymmetry 2005, 16, 1207.
(a) Asami, M.; Inoue, S. Bull. Chem. Soc. Jpn. 1997, 70,
1687.
10 (a) Muchow, C.; Vannoorenberghe, Y.; Buono, G. Tetrahe-
dron Lett. 1987, 28, 6163.
(b) Oppolzer, W.; Radinov, R. N. Tetrahedron Lett. 1988,
29, 5645.
(c) Cho, B. T.; Kim, N. Tetrahedron Lett. 1994, 35, 4115.
(d) Hulst, R.; Heres, H.; Fitzpatrick, K.; Peper, N. C. M. W.;
Kellogg, R. M. Tetrahedron: Asymmetry 1996, 7, 2755.
(e) Cicchi, S.; Crea, S.; Goti, A.; Brandi, A. Tetrahedron:
Asymmetry 1997, 8, 293.
(f) Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron:
Asymmetry 1997, 8, 1869.
(g) Panda, M.; Phuan, P. W.; Kozlowski, M. C. J. Org.
Chem. 2003, 68, 564.
5
6
(b) Saravanan, P.; Bisai, A.; Baktharaman, S.; Chandrasek-
har, M.; Singh, V. K. Tetrahedron 2002, 58, 4693.
(c) Cheng, Y. Q.; Bian, Z.; Kang, C. Q.; Guo, H. Q.; Gao, L.
X. Tetrahedron: Asymmetry 2008, 19, 1572.
(a) Olsson, C.; Friberg, A.; Frejd, T. Tetrahedron: Asymme-
try 2008, 19, 1476.
(h) de Oliveira, L. F.; Costa, V. E. U. Tetrahedron: Asym-
metry 2004, 15, 2583.
(i) Szakonyi, Z.; Balázs, Á.; Martinek, T. A.; Fülöp, F. Tet-
rahedron: Asymmetry 2006, 17, 199.
7
(j) Martins, J. E. D.; Mehlecke, C. M.; Gamba, M.; Costa, V.
E. U. Tetrahedron: Asymmetry 2006, 17, 1817.
11 Folöp, F.; Bernáth, G.; Argay, G.; Kálmán, A.; Sohár, P.
Tetrahedron 1984, 40, 2053.
(b) Dean, M. A.; Hitchcock, S. R. Tetrahedron: Asymmetry
2008, 19, 2563.
(c) Gou, S.; Judeh, Z. M. A. Tetrahedron Lett. 2009, 50,
281.
12 Viňa, D.; Santana, L.; Uriarte, E.; Quezada, E.; Valencia, L.
Synthesis 2004, 2517.
8
9
(a) Soai, K.; Niwa, S. Chem. Rev. 1992, 92, 833.
(b) Pu, L.; Yu, H. B. Chem. Rev. 2001, 101, 757.
(a) Soai, K.; Ookawa, A.; Ogawa, K. J. Am. Chem. Soc.,
1987, 109, 7111.
(b) Paleo, M. R.; Cabeza, I.; Sardina, F. J. J. Org. Chem.
2000, 65, 2108.
13 (a) Wang, X.; Dong, Y.; Sun, J.; Xu, X.; Li, R.; Hu, Y. J.
Org. Chem. 2005, 70, 1897.
(b) Bailey, P. D.; Beard, M. A.; Dang, H. P. T.; Phillips, T.
R.; Price, R. A.; Whittaker, J. H. Tetrahedron Lett. 2008, 49,
2150.
14 (a) Ali, H. E. S. Catal. Commun. 2007, 8, 855.
(b) Chen, H.; Wang, Y.; Wei, S.; Sun, J. Tetrahedron:
Asymmetry 2007, 18, 1308.
(c) Dai, W. M.; Zhu, H. J.; Hao, X. J. Tetrahedron, Asym-
metry 2000, 11, 2315.
(d) Yun, H.; Wu, Y.; Wu, Y.; Ding, K.; Zhou, Y. Tetrahe-
dron Lett. 2000, 41, 10263.
15 (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. 1991,
30, 49.
(e) Okamoto, K.; Kimachi, T.; Ibuka, T.; Takemoto, Y.
Tetrahedron: Asymmetry 2001, 12, 463.
(b) Yamakawa, M.; Noyori, R. J. Am. Chem. Soc. 1995, 117,
6327.
(f) Rasmussen, T.; Norrby, P. O. J. Am. Chem. Soc. 2001,
123, 2464.
(g) Martínez, A. G.; Vilar, E. T.; Fraile, A. G.; de la Moya
Cerero, S.; Martínez-Ruiz, P.; Villas, P. C. Tetrahedron:
Asymmetry 2002, 13, 1.
(c) Jessop, P. G.; Brown, R. A.; Yamakawa, M.; Xiao, J.;
Ikariya, T.; Kitamura, M.; Tucker, S. C.; Noyori, R. J.
Supercrit. Fluids 2002, 24, 161.
16 Cozzi, P. G.; Papa, A.; Umani-Ronchi, A. Tetrahedron Lett.
1996, 37, 4613.
(h) Bastin, S.; Ginj, M.; Brocard, J.; Pélinski, L.; No-
vogrocki, G. Tetrahedron: Asymmetry 2003, 14, 1701.
(i) Joshi, S. N.; Malhotra, S. V. Tetrahedron: Asymmetry
2003, 14, 1763.
(j) Rodríguez-Escrich, S.; Reddy, K. S.; Jimeno, C.; Colet,
G.; Rodríguez-Escrich, C.; Solá, L.; Vidal-Ferran, A.;
17 (a) Sun, J.; Pan, X.; Dai, Z.; Zhu, C. Tetrahedron: Asymme-
try 2008, 19, 2451.
(b) Jaworska, M.; Łączkowski, K. Z.; Wełniak, M.; Welke,
M.; Wojtczak, A. Appl. Catal. A: General 2009, 357, 150.
18 Nohira, H.; Ehara, K.; Miyashita, A. Bull. Chem. Soc. Jpn.
1970, 43, 2230.
(E0906182 Cheng, F.; Zheng, G.)
68
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Chin. J. Chem. 2010, 28, 61— 68