Non-enzymatic kinetic resolution of β-amino alcohols using C-12 higher carbon sugar as a chiral auxiliary

Article abstract of DOI:10.1016/j.tetasy.2008.01.039

An efficient non-enzymatic kinetic resolution strategy capable of accessing optically active β-adrenergic antagonists intermediates is reported. The C-12 higher carbon sugar derived from naturally occurring sucrose was employed to probe the kinetic resolution. Excellent enantiomeric excesses (ee >99%) and high yields were obtained under very mild conditions. The chiral auxiliary could be recovered in a high reclaimed ratio (>95%) and reusable form without any decrease of the resolving ability.

Full text of DOI:10.1016/j.tetasy.2008.01.039

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 512–517
Non-enzymatic kinetic resolution of b-amino alcohols using C-12
higher carbon sugar as a chiral auxiliary
a,c
Jing-Yu Zhang,a,b Hong-Min Liu,a,c, Hai-Wei Xu and Li-Hong Shana,b,c
*
aNew Drug Research and Development Center, Zhengzhou University, Zhengzhou 450052, PR China
bDepartment of Chemistry, Zhengzhou University, Zhengzhou 450052, PR China
cSchool of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, PR China
Received 17 December 2007; accepted 29 January 2008
Abstract—An efficient non-enzymatic kinetic resolution strategy capable of accessing optically active b-adrenergic antagonists interme-
diates is reported. The C-12 higher carbon sugar derived from naturally occurring sucrose was employed to probe the kinetic resolution.
Excellent enantiomeric excesses (ee >99%) and high yields were obtained under very mild conditions. The chiral auxiliary could be recov-
ered in a high reclaimed ratio (>95%) and reusable form without any decrease of the resolving ability.
Ó 2008 Published by Elsevier Ltd.
1. Introduction
the last decade,9 non-enzymatic kinetic resolution methods
designed for amino alcohols are rarely reported. In recent
years, some effort has therefore been made to design non-
enzymatic alternatives and substantial progress has been
made.10 However, most methods suffer from the multistep
synthesis of chiral auxiliaries and often provide only mod-
erate enantioselectivities.
Chiral b-amino alcohols are important structural elements
in chiral ligands for asymmetric catalysis1 as well as in bio-
logically active compounds (e.g., b-adrenergic receptor
blockers, which have a diverse range of clinical applications
in the treatment of cardiovascular disorders such as hyper-
tension, cardiac arrhythmia, angina pectoris, and open
angle glaucoma).2 The preparation of optically active b-
amino alcohols has received considerable attention due to
their different pharmacokinetic characteristics or the phar-
macological activities of each enantiomer in a racemic
drug3–6 and their extensive use as chiral auxiliaries, resolv-
ing reagents, and intermediates in the synthesis of biologi-
cally important molecules.
2. Results and discussion
In our previous work, we reported a novel C-12 higher car-
bon sugar (denoted as HCS)11 containing eight stereogenic
centres and a two ‘back to back’ V-shaped molecule frame-
work (Fig. 1). With a view to the stereochemistry of HCS,
further investigations were carried out. Herein, we report
the high enantioselective non-enzymatic kinetic resolution
of b-amino alcohols through the formation of oxazolidine
derivatives of HCS. To the best of our knowledge, no work
Enantiopure b-amino alcohols can be produced by the
reduction of optically active b-amino acids.7 The kinetic
resolution of b-amino alcohols through enzyme-catalyzed
acylation or deacylation is also one of the most efficient
methods for the synthesis of chiral b-amino alcohols.8
Non-enzymatic kinetic resolution (NKR) is an alternative
for the enzymatic process, which is considered to be a chal-
lenging issue in organic synthesis. In contrast to the large
variety of enzymes and metallic catalysts reported for the
kinetic resolution (KR) of racemic amino alcohols over
HO
H
OH
O
H
O
O
O
H
O
H
HO
HCS
Figure 1. The structure of a higher carbon sugar (HCS).
H
*
Corresponding author. Tel./fax: +86 37167767200; e-mail: liuhm@
zzu.edu.cn
0957-4166/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2008.01.039

J.-Y. Zhang et al. / Tetrahedron: Asymmetry 19 (2008) 512–517
513
HO
H
OH
O
H
O
OH
O
H
ii, iii
O
NH2
H
O
O
H
HO
NH
O
R
4 R = H
HO
R
H
5 R = CH2CH2OH
OH
OH
6 R = CH2CH2OCH3
O
H
O
NH2
O
i
+
O
OH
H
O
R
H
HO
O
NH2
1 R = H
2 R = CH2CH2OH
3 R = CH2CH2OCH3
H
O
R
Scheme 1. Kinetic resolution of b-amino alcohols 1, 2, and 3. Reagents and conditions: (i) TsOH, CH3OH, rt; (ii) 4% hydrochloric acid, rt; (iii) 5% KOH, rt.
has been reported on the NKR of b-amino alcohols using
higher carbon sugars, which were generally focused on
their biological activity.12 This procedure could be applied
to the enantioselective synthesis of different intermediates
of b-adrenergic receptor blockers, which are important pre-
cursors for biologically active compounds,13 for example,
betaxolol and metoprolol.
of 4 and 5 are shown in Figure 2. The configurations of
b-carbon in 4 and 5 are (R) as shown in Scheme 1. The con-
figuration of b-carbon in oxazolidine 6 was confirmed to be
(R) by comparison with 4 and 5. Therefore, the absolute
configuration of the corresponding amino alcohols 1, 2,
and 3 were deduced to be (R), while the isomers 1, 2, and
3 which remained in solution were accordingly deduced
to be (S). Noticeably, for the specific rotations of 114 we
obtained results that were consistent with the results
reported by Ulrich and Manfred,15 but opposite to those
reported by Zhang et al.16
The reaction of racemic b-amino alcohols 1, 2, and 3 with
HCS was performed in the presence of p-TsOH in various
organic solvents such as ethanol, methanol, and isopropa-
nol at room temperature, respectively. The carbonyl group
of HCS showed an excellent reactivity and stereoselectivity
toward (R)-isomers formed to give the corresponding oxaz-
olidines 4, 5, and 6, which were then crystallized from
organic solvents. The crystallized oxazolidines 4, 5, and 6
obtained by filtration were then acidified to yield (R)-iso-
mers. The solvent of the filtrate was evaporated under
reduced pressure to afford (S)-isomers (Scheme 1).
To improve the yield and enantiomeric purity of the amino
alcohols, we tested possible factors which could influence
the process, such as molar ratios of racemic amino alcohol
to HCS and temperature. It was found that the enantio-
meric purity of the amino alcohols was highly dependent
on the ratio of the racemic amino alcohol to HCS (Table
1). When the ratio of racemic amino alcohol to HCS was
no less than 1:0.49, the corresponding oxazolidines 4, 5,
and 6 were obtained in good yields. Anything less than this
ratio led to a decrease in the enantiomeric purities of the
The single crystals of oxazolidines 4 and 5 were obtained
by recrystallization from methanol. The ORTEP drawing
4
5
Figure 2. ORTEP diagram showing the X-ray structures of compounds 4 and 5.

514
J.-Y. Zhang et al. / Tetrahedron: Asymmetry 19 (2008) 512–517
Table 1. Effect of the molar ratio of b-amino alcohols/HCS in the NKR of b-amino alcoholsa
OH
OH
OH
O
NH2
O
NH2
O
NH2
kinetic resolution
HCS
+
R
R
R
1 R = H, 2 R = CH2CH2OH, 3 R = CH2CH2OCH3
Entry
Ab
Mol ratio (A/HCS)
(R)
(S)
Yieldc (%)
eed (%)
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
1
1
1
1
1
2
2
2
2
2
3
3
3
3
3
1:0.45
1:0.49
1:0.50
1:0.51
1:0.55
1:0.45
1:0.49
1:0.50
1:0.51
1:0.55
1:0.45
1:0.49
1:0.50
1:0.51
1:0.55
38.0
40.5
45.0
42.0
46.5
38.5
39.5
43.5
40.5
45.5
42.0
39.0
40.0
39.0
43.4
>99
>99
95
87
82
>99
>99
86
90
80
>99
>99
94
89
86
47.0
42.5
47.5
40.1
37.5
46.2
38.5
43.0
39.5
36.6
45.0
37.5
41.0
38.5
40.0
78
89
92
>99
>99
75
83
93
>99
>99
78
86
90
>99
>99
a At 25 °C.
b b-Aminoalcohols.
c Isolated yield based on the amount of racemates.
d Determined by HPLC using a Chiralcel OD-H columns.
(R)-isomers dissociated from the corresponding oxazo-
lidines. When the ratio of racemic amino alcohol to HCS
was no more than 1:0.51, the enantiomerically pure
(S)-isomers, which were left in the solution after removing
compounds 4, 5, and 6 were obtained. The lower enantio-
meric purities were obtained when the ratio of racemic
amino alcohol to HCS was above 1:0.51.
drastically increased when the temperature was changed
from 50 °C to 25 °C. Below 25 °C, the isolated yield and
enantiomeric excesses of amino alcohols were increased
with a decrease of the temperature. At the same time, the
reaction time was prolonged with the decrease of the tem-
perature. At the optimized temperature (5 °C), treatment of
1, 2, and 3 (1 equiv) with HCS (0.51 equiv) in methanol in
the presence of p-TsOH gave compounds 4, 5, and 6,
respectively, in good yields and the (S)-isomers of the
amino alcohols with excellent enantiomeric excesses.
For the sake of comparison, the reaction of amino alcohols
with HCS was performed in a ratio of 1:0.51 to test the
effects of temperature on the resolution. As shown in
Table 2, the enantiomeric excesses of amino alcohols were
The investigation indicated that the reactive temperature
and the molar ratios of racemic amino alcohols to HCS
played an important role in the KR of b-amino alcohols,
especially the latter. Using the optimized reaction condi-
tions for each particular racemic amino alcohol, b-amino
alcohols 1, 2, and 3 were resolved with very excellent
enantioselectivities. It is worth noting that the chiral auxil-
iary could be efficiently recovered in a reusable form by
Table 2. Effect of on the NKR of b-amino alcoholsa
Entry
Ab
Temperature
(°C)
Time
(h)
Yieldsc
(%)
eed
(%)
Conf.
1
2
3
4
5
6
7
8
9
1
1
1
1
2
2
2
2
3
3
3
3
0
0
25
50
0
40
20
6
45.5
44.1
40.1
38.1
44.4
45.0
39.5
35.1
44.2
43.6
38.5
37.5
96
>99
>99
55
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
Table 3. Resolving effect of 1 using reclaimed HCSa
3
46
30
9
96
Entry
R-Tb
Yieldsc (%)
R-Pd (%)
eee (%)
Conf.
5
>99
>99
39
25
50
0
5
25
50
1
2
3
4
5
0
1
2
3
4
42.5
41.7
40.1
43.0
40.8
98.2
97.5
96.4
95.7
95.4
>99
>99
>99
>99
>99
(R)
(R)
(R)
(R)
(R)
5
48
35
10
5
94
10
11
12
>99
>99
43
a At 5 °C; molar ratio of amino alcohol/HCS = 1:0.49.
a Molar ratio of amino alcohol/HCS = 1:0.51.
b b-Amino alcohols.
b Reclaimed times.
c Isolated yield based on the amount of racemates.
d Reclaim proportion of HCS.
c Isolated yield based on the amount of racemates.
d Determined by HPLC using a Chiralcel OD-H columns.
e Determined by HPLC using a Chiralcel OD-H columns.

J.-Y. Zhang et al. / Tetrahedron: Asymmetry 19 (2008) 512–517
515
hydrolytic decomposition of the corresponding oxazoli-
dines with a high yield (>95.0%) without any decrease of
the resolving ability. The results of an investigation on
the resolving effect of b-amino alcohol 1 using reclaimed
HCS are displayed in Table 3.
K2CO3 (0.2 mol) in acetone (100 ml) with stirring. The
mixture was heated and kept at reflux for 6–10 h followed
by filtration and then concentration under vacuum pres-
sure to dryness. The residue was then mixed with superflu-
ous 25–28% NH3 aq and the reaction mixture was further
stirred for 10–15 h at 0–10 °C. Water and excess NH3 were
then removed under vacuum. The residue was dissolved
with ethanol after which water was added, subsequently,
a lot of white deposition appears. The mixture was filtered
and then pure racemic amino alcohols were obtained by
recrystallization from ethyl acetate or ethanol in 72–80%
yields.
3. Conclusions
In conclusion, the novel C-12 higher carbon sugar derived
from naturally occurring sucrose was employed to probe
the non-enzymatic kinetic resolution reaction of a series
of b-amino alcohols. This protocol was carried out under
very mild conditions and the results were excellent (ee
>99%). More importantly, the chiral auxiliary could be effi-
ciently recovered in a reusable form, without any decrease
in the resolving ability. Owing to its high efficiency and
convenience, this method will lead to many new applica-
tions in the synthesis of chiral drugs. Further investigations
to broaden the scope and synthetic application of this new
enantioselective NKR are under progress.
4.3. Characterization of amino alcohols
4.3.1. 1-Amino-3-(4-(2-hydroxyethyl)phenoxy)propan-2-ol
2. Mp 102–103 °C IR (KBr): 3325, 3041, 2938, 2881,
1
1610, 1512, 1425, 1046 cmꢀ1; H NMR (400 MHz, D2O):
d 7.18 (d, 2H, J = 8.6 Hz, H-3 and H-5, Ph), d 6.92 (d,
2H, J = 8.6 Hz, H-2 and H-6, Ph), 4.21 (m, 1H,
NH2CH2CHCH2), 4.08 (dd, 1H, J = 3.9, 10.3 Hz, CHaHb-
O–Ph), 4.03 (dd, 1H, J = 5.5, 10.2 Hz, CHaHbO–Ph), 3.73
(t, 2H, J = 6.6 Hz, HOCH2CH2Ph), 3.23 (dd, 1H, J = 3.8,
13.2 Hz, NH2CHaHbCH), 3.11 (dd, 1H, J = 8.3, 13.2 Hz,
NH2CHaHbCH), 2.74 (t, J = 6.6 Hz, HOCH2CH2Ph) 13C
NMR (100.6 MHz, D2O): d 156.8 (C-1 Ph), 132.6 (C-4
Ph), 130.6 (C-3,5 Ph), 115.2 (C-2,6 Ph), 70.1 (CH2O–Ph),
66.6 (NH2CH2CHCH2), 63.0 (HOCH2CH2Ph), 42.2
(CHCH2NH), 37.3 (HOCH2CH2Ph); HRMS: calcd for
C11H17NO3: 211.1208. Found: 212.1265 [M+H]+.
4. Experimental
4.1. General
All chemicals were used as received unless otherwise noted.
Reagent grade solvents were distilled prior to use. All
reported NMR spectra were collected on a Bruker DPX
400 NMR spectrometer with TMS as the internal refer-
ence. Infrared spectra were recorded on Nicolet IR200
instrument using KBr disks in the 400–4000 cmꢀ1 regions.
High resolution mass spectra (HRMS) were obtained on a
Waters Micromass Q-Tof MicroTM instrument using the
ESI technique. Melting points were determined using a
XT5A apparatus and are uncorrected. Optical rotations
were determined on a Perkin Elmer 341 polarimeter at
20 °C in MeOH. Single crystal structure was carried out
on a Rigaku R-AXIS-IV area detector. Enantiomeric
excess was determined by chiral HPLC at room tempera-
ture using Syltech 500 pump equipped with a UV 500
version 4.1 ultra-violet detector with Chiralcel OD-H
(4.6 mm ꢁ 250 mm) column.
4.3.2. 1-Amino-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol
3. Mp 98–99 °C IR (KBr): 3355, 2926, 2871, 1582,
1
1513, 1119 cmꢀ1; H NMR (400 MHz, DMSO-d6): d 7.12
(d, 2H, J = 8.3 Hz, H-3 and H-5, Ph), d 6.84 (d, 2H,
J = 8.4 Hz, H-2 and H-6, Ph), 3.91 (dd, 1H, J = 3.9,
10.3 Hz, CHaHbO–Ph), 3.84 (dd, 1H, J = 5.5, 10.2 Hz,
CHaHbO–Ph), 3.73 (m, 1H, NH2CH2CHCH2), 3.47 (t,
2H, J = 6.9 Hz, HOCH2CH2Ph), 3.23 (s, 1H, CH2OCH3),
3.17 (m 2H, NH2CH2CH), 2.72 (t, J = 6.8 Hz, HOCH2-
CH2Ph) 13C NMR (100.6 MHz, DMSO-d6): d 158.0 (C-1
Ph), 131.7 (C-4 Ph), 130.5 (C-3,5 Ph), 115.1 (C-2,6 Ph),
73.9 (CH2O–Ph), 71.2 (NH2CH2CHCH2), 71.1 (HOCH2-
CH2Ph), 58.6 (CH3OCH2), 45.6 (CHCH2NH), 35.3
(HOCH2CH2Ph); HRMS: calcd for C12H19NO3:
225.1365. Found: 226.2901 [M+H]+.
4.2. Preparation and characterization of b-amino alcohols
4.2.1. General procedure for the preparation of b-amino
alcohols 1, 2, and 3. Racemic amino alcohol 1 was pre-
pared from the reaction of ammonia with glycidphenyl-
ether. Racemic amino alcohols 2 and 3 were prepared from
epichlorohydrin via two steps as shown in Scheme 2. The
corresponding substituted phenol (0.1 mol) was added to
a solution of epichlorohydrin (0.5 mol) in the presence of
4.4. Preparation and characterization of oxazolidine
derivatives 4, 5, and 6
4.4.1. Preparation and characterization of oxazolidine
4. To a solution of HCS (2.82 g, 9.8 mmol) in methanol
(40 ml), racemic amino alcohol 1 (1-amino-3-phenyloxy-
2-propanol) (20.0 mmol) was added (a catalytic amount
OH
O
OH
O
NH2
O
epichlorohydrin
ammonia
0 -10 ºC
2 R=CH2CH2OH
K2CO3
R
R
3 R=CH2CH2OCH3
R
Scheme 2. Preparation of amino alcohols 2 and 3.

516
J.-Y. Zhang et al. / Tetrahedron: Asymmetry 19 (2008) 512–517
of p-TsOH was also added). The mixture was stirred at
5 °C for 20 h, followed by concentration and purification
by crystallization from isopropanol or ethanol, giving com-
2H, J = 8.4 Hz, H-3 and H-5, Ph), 6.88 (d, 2H,
J = 8.5 Hz, H-2 and H-6, Ph), 4.65 (d, 1H, J = 4.2 Hz,
H-9), 4.59 (t, 1H, J = 4.5 Hz, H-4), 4.35 (m, 1H,
HNCH2CHCH2), 4.30 (m, 2H, H-3, H-10), 4.29 (m, 1H,
H-5), 4.15 (m, 1H, H-11), 4.00 (s, 1H, H-7), 3.99 (m, 1H,
CHaHbO–Ph), 3.96 (d, 1H, J = 8.5 Hz, H-1b), 3.95 (m,
1H, H-6b), 3.93 (dd, 1H, J = 4.3, 6.9 Hz, CHaHbO–Ph),
3.91 (d, 1H, J = 8.5 Hz, H-1a), 3.85 (dd, 1H, J = 6.6,
8.4 Hz, H-12b), 3.59 (t, 2H, J = 6.6 Hz, HOCH2CH2Ph),
3.50 (dd, 1H, J = 6.6, 8.4 Hz, H-12b), 3.49 (m, 1H, H-
6a), 3.23 (s, 3H, CH2OCH3), 3.13 (dd, 1H, J = 7.3,
12.3 Hz, HNCHaHbCH), 3.08 (dd, 1H, J = 4.2, 12.3 Hz,
HNCHaHbCH), 2.74 (t, J = 6.5 Hz, HOCH2CH2Ph); 13C
NMR (100 MHz, D2O): d 156.9 (C-1 Ph), 132.3 (C-4 Ph),
130.4 (C-3,5 Ph), 115.2 (C-2,6 Ph), 105.0 (C-8), 86.0
(C-9), 84.1 (C-10), 81.6 (C-3), 81.5 (C-2), 81.3 (C-7), 81.1
(C-4), 75.7 (CHCH2OPh), 75.2 (C-1), 73.5 (CH2OCH3),
72.4 (C-5), 71.7 (C-6), 71.3 (C-12), 71.0 (C-11), 69.6
(–CH2OPh), 58.1 (HOCH2CH2Ph), 46.2 (CHCH2NH),
34.4 (HOCH2CH2Ph); HRMS: calcd for C23H31NO10:
495.5195. Found: 518.2002 [M+Na]+.
pound 4 as white solids in 98.5% yield (determined based
20
on HCS). Mp 121–123 °C, ½aꢂD ¼ þ58:0 (c 1.0, CHCl3);
IR (KBr): 3407, 3285, 2925, 2880, 1632, 1596, 1495 cmꢀ1
;
1H NMR (400 MHz, CDCl3): d 7.29 (m, 2H, H-3 and H-
5, Ph), 6.98 (t, 1H, J = 7.4 Hz, H-4, Ph), 6.92 (d, 2H,
J = 8.4 Hz, H-2 and H-6, Ph), 4.67 (t, 1H, J = 4.4 Hz, H-
10), 4.65 (d, 1H, J = 6.4 Hz, H-3), 4.45 (t, 1H,
J = 6.0 Hz, H-4), 4.39 (m, 1H, CHCH2OPh), 4.31 (dd,
1H, J = 6.0, 11.6 Hz, H-11), 4.26 (d, 1H, J = 4.4 Hz, H-
9), 4.18 (d, 1H, J = 10.6 Hz, H-1a), 4.14 (dd, 1H, J = 5.2,
9.6 Hz, H-5), 4.13 (d, 1H, J = 10.6 Hz, H-1b); 4.08 (dd,
1H, J = 5.6, 9.6 Hz, CHaHbO–Ph), 4.08 (s, 1H, H-7),
4.00 (dd, 1H, J = 6.4, 9.4 Hz, H-12a), 3.98 (dd, 1H,
J = 5.6, 9.6 Hz, CHaHbO–Ph), 3.93 (dd, 1H, J = 4.8,
9.4 Hz, H-6b), 3.85 (dd, 1H, J = 4.8, 9.4 Hz, H-6a), 3.64
(dd, 1H, J = 6.4, 9.4 Hz, H-12b), 3.30 (dd, 1H, J = 7.2,
12.0 Hz, HNCHaHbCH), 3.22 (dd, 1H, J = 4.0, 12.0 Hz,
HNCHaHbCH); 13C NMR (100 MHz, CDCl3): d 158.3
(C-1 Ph), 129.5 (C-3,5 Ph), 121.3 (C-4 Ph), 114.5 (C-2,6
Ph), 105.1 (C-8), 85.3 (C-9), 84.0 (C-3), 82.1 (C-7), 81.6
(C-4), 81.2 (C-10), 79.5 (C-2), 77.2 (C-1), 75.5
(CHCH2OPh), 75.3 (C-12), 73.7 (C-6), 72.7 (C-5), 70.8
(C-11), 68.5 (–CH2OPh), 47.3 (CHCH2NH); HRMS: calcd
for C21H27NO9: 437.1686. Found: 438.1740 [M+H]+.
4.5. Liberation of (R)-isomers of amino alcohols 1, 2, 3 from
compounds 4, 5, and 6
4.5.1. General method. 1 mmol of the crystals of oxazoli-
dine derivatives obtained was dissolved in 20 ml of metha-
nol after which 5.0 mmol c. HCl aq was added. After the
evaporation of methanol, 10 ml of water was added and
the mixture was stirred for 30 min, then HCS was recov-
ered by extracting using toluene or ethyl acetate. Then
2.5 mmol NaOH was added in the water layer (pH 10),
after which the amino alcohols were extracted using tolu-
ene. The toluene solution was dried over Na2SO4 and re-
moved by filtration. The solvent was removed to yield the
resoluted b-amino alcohols recrystallized from ethyl ace-
tate or ethanol.
4.4.2. Preparation and characterization of oxazolidine
5. The same process as for the preparation of 4 was car-
ried out. Compound 5 was obtained as a white solid (yield
20
96.3%). Mp 156–157 °C, ½aꢂD ¼ þ67:3 (c 1.00, CH3OH);
IR (KBr): 3469, 3408, 3287, 2934, 2874, 1614, 1512, 1421,
1235, 1083, 1043 cmꢀ1 1H NMR (400 MHz, D2O): d
;
7.13 (d, 2H, J = 8.5 Hz, H-3 and H-5, Ph), 6.83 (d, 2H,
J = 8.5 Hz, H-2 and H-6, Ph), 4.60 (d, 1H, J = 5.4 Hz,
H-9), 4.54 (t, 1H, J = 4.5 Hz, H-4), 4.35 (m, 1H,
HNCH2CHCH2), 4.26 (m, 2H, H-3, H-10), 4.25 (dd, 1H,
H-5, J = 5.2, 9.3 Hz), 4.11 (m, 1H, H-11), 3.99 (dd, 1H,
J = 3.4, 10.2 Hz, CHaHbO–Ph), 3.97 (s, 1H, H-7), 3.90
(dd, 1H, J = 3.4, 10.2 Hz, CHaHbO–Ph), 3.89 (d, 1H,
J = 8.5 Hz, H-1b), 3.87 (m, 1H, H-6b) 3.84 (d, 1H,
J = 8.5 Hz, H-1a), 3.81 (dd, 1H, J = 6.0, 8.5 Hz, H-12b),
3.65 (t, 2H, J = 6.6 Hz, HOCH2CH2Ph), 3.42 (dd, 1H,
J = 6.0, 8.5 Hz, H-12b), 3.41 (m, 1H, H-6a), 3.09 (dd,
1H, J = 7.4, 12.4 Hz, HNCHaHbCH), 3.03 (dd, 1H,
J = 4.2, 12.4 Hz, HNCHaHbCH), 2.66 (t, J = 6.6 Hz,
HOCH2CH2Ph); 13C NMR (100 MHz, D2O): d 156.3 (C-
1 Ph), 131.9 (C-4 Ph), 130.1 (C-3,5 Ph), 115.0 (C-2,6 Ph),
104.6 (C-8), 85.5 (C-9), 83.6 (C-10), 81.0 (C-3), 80.8 (C-
2), 80.7 (C-7), 80.6 (C-4), 75.3 (CHCH2OPh), 74.6 (C-1),
72.0 (C-5), 71.2 (C-6), 70.8 (C-12), 70.5 (C-11), 69.2 (–
CH2OPh), 62.5 (HOCH2CH2Ph), 45.6 (CHCH2NH), 36.8
(HOCH2CH2Ph); HRMS: calcd for C23H31NO10:
481.1948. Found: 482.2026 [M+H]+.
4.5.2. HPLC conditions of resolved amino alcohols
4.5.2.1. HPLC conditions for amino alcohol 1. n-Hex-
ane/isopropanol/diethylamine = 70:30:0.05, OD-H, 0.3 ml/
min, 254 nm.
25
(S)-1, ½aꢂD ¼ ꢀ3:9 (c 1.0, methanol), >99% ee, tS = 35.7.
25
(R)-1, ½aꢂD ¼ þ3:9 (c 1.0, methanol), >99% ee, tR = 16.2.
4.5.2.2. HPLC conditions for amino alcohol 2 and 3. n-
Hexane/isopropanol/diethylamine = 60:40:0.05,
0.5 ml/min, 254 nm.
OD-H,
25
(S)-2, ½aꢂD ¼ ꢀ4:0 (c 1.0, methanol), >99% ee, tS = 16.7.
25
(R)-2, ½aꢂD ¼ þ4:0 (c 1.0, methanol), >99% ee, tR = 13.3.
25
(S)-3, ½aꢂD ¼ ꢀ6:8 (c 1.0, methanol), >99% ee, tS = 19.1.
25
4.4.3. Preparation and characterization of oxazolidine
6. The same process as for the preparation of 4 was car-
(R)-3, ½aꢂD ¼ þ6:8 (c 1.0, methanol), >99% ee, tR=15.8.
ried out and compound 6 was obtained as a white solid
20
(yield 94.0%). Mp 135–136 °C, ½aꢂD ¼ þ25:6 (c 0.8,
4.5.3. Effect of temperature on the NKR of b-amino alcohols
in a ratio of 1:0.49 of b-amino alcohols and HCS. See
Table 4.
CH3OH); IR (KBr): 3417, 2932, 2878, 1611, 1512, 1243,
1114, 1050 cmꢀ1; H NMR (400 MHz, D2O): d 7.15 (d,
1

J.-Y. Zhang et al. / Tetrahedron: Asymmetry 19 (2008) 512–517
517
Table 4. Effect of temperature on the NKR of b-amino alcoholsa in a ratio
of 1:0.49 of b-amino alcohols and HCS
2005, 65, 787–797; (d) Baran, D.; Horn, E. M.; Hryniewicz,
K.; Katz, S. D. Drugs 2000, 60, 997–1016.
3. See, for example: (a) Ager, D. J.; Prakash, I.; Schaad, D. R.
Chem. Rev. 1996, 96, 835–875; (b) Seyden-Penne, J. Chiral
Auxiliaries and Ligands in Asymmetric Synthesis; Wiley: New
York, 1995, p 306; (c) Zhong, Y. W.; Tian, P.; Lin, G. Q.
Tetrahedron: Asymmetry 2004, 15, 771–776.
4. (a) Atsushi, S.; Kazuhiko, S. Tetrahedron: Asymmetry 1996,
7, 2939–2956; (b) Faber, W. S.; Kok, J.; De, L. B.; Feringa, B.
L. Tetrahedron 1994, 50, 4775–4794; (c) Ishikawa, A.;
Katsuki, T. Tetrahedron Lett. 1991, 32, 3547–3550.
5. Carrillo, L.; Badia, D.; Dominguez, E.; Anakabe, E.; Osante,
I.; Tellitu, I. J. Org. Chem. 1999, 64, 1115–1120.
6. Jamali, F.; Mehvar, R.; Pasutto, F. M. J. Pharm. Sci. 1989,
78, 695–715.
7. McKennon, M. J.; Meyers, A. I. J. Org. Chem. 1993, 58,
3568–3571.
8. Sekar, G.; Kamble, R. M.; Singh, V. K. Tetrahedron:
Asymmetry 1999, 10, 3663–3666.
9. (a) Chayaporn, R.; Darrell, A. P.; Andrew, G. L.; Paul, C. T.;
Jacob, L. I.; Mark, R. P. Chem. Commun. 2007, 3462–3463;
(b) Juan, D.; Vicente, G. J. Org. Chem. 2002, 67, 6816–6819;
(c) Hari, M. R. G.; Deendayal, M.; Philip, D. S.; Max, Y.;
Yong, G. Chem. Commun. 2005, 4432–4434; (d) Oscar, P.;
Jan-E, B. J. Org. Chem. 2001, 66, 4022–4025; (e) Andrei, P.;
Dirk, D. V.; Pierre, J. Chem. Commun. 2005, 5307–5309.
10. (a) Rajender, R. L.; Bhanumathi, N.; Rama, R. K. Chem.
Commun. 2000, 2321–2322; (b) Govindasamy, S.; Hisao, N. J.
Am. Chem. Soc. 2001, 123, 3603–3604; (c) Govindasamy, S.;
Hisao, N. Chem. Commun. 2001, 1314–1315; (d) Wang, Y. J.;
Shen, Z. X.; Li, B.; Zhang, Y.; Zhang, Y. W. Chem. Commun.
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Wang, X. Y.; Hu, Y. F. J. Org. Chem. 2005, 70, 8617–8620;
(f) Tom, G. D.; Jason, R. H.; Woerpel, K. A. J. Am. Chem.
Soc. 2007, 129, 3836–3837.
Entry
Amino
alcohols
T
Time
(h)
Yieldsb
of (R) (%)
eec of
(R) (%)
(°C)
1
2
3
4
5
6
7
8
9
1
1
1
1
2
2
2
2
3
3
3
3
0
5
25
50
0
40
20
6
44.5
44.2
40.5
38.5
46.0
44.3
39.5
35.0
45.0
42.6
39.0
37.8
95
>99
>99
53
3
45
30
9
96
5
>99
>99
42
25
50
0
5
25
50
5
46
35
10
5
93
10
11
12
>99
>99
51
a Molar ratio of amino alcohol/HCS = 1:0.49.
b Isolated yield based on the amount of racemates.
c Determined by HPLC using a Chiralcel OD-H columns.
4.5.4. X-ray crystallographic data of compounds 4 and
5. Crystals of compounds 4 and 5 suitable for X-ray anal-
ysis were obtained by recrystallization from methanol at
room temperature. Crystallographic data (excluding struc-
ture factors) for the structure reported in this paper have
been checked using the CheckCIF utility on the Web at
http://checkcif.iucr.org/ and there were no syntax errors
(Fig. 1).
Crystallographic data for 4 and 5 reported in this paper
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC-
622932 and CCDC-670555. Copies of the data can be ob-
tained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [Fax: +44(0)-1223-
336033 or e-mail: deposit@ccdc.cam.ac.uk].
11. Liu, H. M.; Liu, F. W.; Song, X. P.; Zhang, J. Y.; Yan, L.
Tetrahedron: Asymmetry 2006, 17, 3230–3236.
12. (a) Iwasa, T.; Kusuka, T.; Suetomi, K. J. Antibiot. 1978, 31,
511–518; (b) Harada, S.; Kishi, T. J. Antibiot. 1978, 31, 519–
524; (c) Harada, S.; Mizuta, E.; Kishi, T. Tetrahedron 1981,
37, 1317–1327; (d) Takatsuki, A.; Arima, K.; Tamura, G. J.
Antibiot. 1971, 24, 215–238; (e) Takatsuki, A.; Kawamura,
K.; Okina, M.; Kodama, Y.; Ito, T.; Tamura, G. Agric. Biol.
Chem. 1977, 41, 2307–2309; (f) Wong, C. H.; Halcomb, R. L.;
Ichikawa, Y.; Kajimoto, T. Angew. Chem., Int. Ed. Engl.
1995, 34, 521–546.
Acknowledgment
We acknowledge the National Natural Science Foundation
of the PR China for financial support of this work
(20572103).
13. See, for example: (a) Ostermayer, F.; Zimmermann, M. U.S.
Patent 4,460,580, 1984; (b) Haynes, G. R. U.S. Patent
4,278,687, 1981; (c) Nathanson, J. A. U.S. Patent 5,366,975,
1994; (d) Wang, Z. M.; Zhang, X. L.; Sharpless, K. B.
Tetrahedron Lett. 1993, 34, 2267–2270; (e) Bristow, M. R.;
Hersberger, R. E.; Port, J. D.; Minobe, W.; Rasmussen, R.
Mol. Pharmacol. 1989, 35, 295–303.
References
25
14. Specific rotations we have obtained are (R)-1 ½aꢂD ¼ þ3:9 (c
1. (a) Blasser, H. U. Chem. Rev. 1992, 92, 935–952; (b) Kolb, H.
C.; Van Nieeuwenhze, M. S.; Sharpless, K. B. Chem. Rev.
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25
1.0, methanol), (S)-1: ½aꢂD ¼ ꢀ3:9 (c 1.0 methanol).
15. Ulrich, A.; Manfred, P. S. Tetrahedron: Asymmetry 1992, 3,
25
205–208 (R)-1: ½aꢂD ¼ þ3:7 (c 1.0 methanol).
16. Zhang, G. Y.; Liao, Y.; Wang, Z.; Hiroyuki, N.; Takuji, H.
Tetrahedron: Asymmetry 2003, 14, 3297–3300 (S)-1:
29
½aꢂD ¼ þ2:4 (c 1.0 methanol).