Asymmetric synthesis of aryloxypropanolamines via OsO4-catalyzed asymmetric dihydroxylation

Article abstract of DOI:10.1016/j.tet.2005.01.074

A simple and effective procedure for the enantioselective synthesis of several β-adrenergic blocking agents incorporating the first asymmetric synthesis of celiprolol, is described. The key steps are (i) sharpless asymmetric dihydroxylation of aryl allyl ethers to introduce chirality into the molecules and (ii) conversion of cyclic sulfates into the corresponding epoxides using a three-step procedure.

Full text of DOI:10.1016/j.tet.2005.01.074

Tetrahedron 61 (2005) 2831–2838
Asymmetric synthesis of aryloxypropanolamines via
OsO4-catalyzed asymmetric dihydroxylation
Iliyas A. Sayyed, Vinay V. Thakur, Milind D. Nikalje, Gajanan K. Dewkar, S. P. Kotkar
*
and A. Sudalai
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 18 October 2004; revised 4 January 2005; accepted 20 January 2005
Abstract—A simple and effective procedure for the enantioselective synthesis of several b-adrenergic blocking agents incorporating the first
asymmetric synthesis of celiprolol, is described. The key steps are (i) sharpless asymmetric dihydroxylation of aryl allyl ethers to introduce
chirality into the molecules and (ii) conversion of cyclic sulfates into the corresponding epoxides using a three-step procedure.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
activity of the sympathetic nervous system. b-Blockers are
thus used to increase life expectancy after heart attack.
Biological systems, in most cases, recognize the members of
a pair of enantiomers as different substances, and the two
enantiomers will exhibit different responses. It has been
shown for many pharmaceuticals that only one enantiomer
contains all the desired activity, and the other is either
totally inactive or highly toxic. Although (S)-isomers are
known to be much more effective (100–500-fold) than the
(R)-isomer,4 these antihypertensive drugs are presently sold
as racemic mixtures. To avoid unnecessary stress or in some
cases toxicity to an organism caused by the (R)-isomers, the
administration of optically pure (S)-isomer is desirable.
b-Adrenergic blocking agents (b-blockers) are important
drugs widely used for the treatment of hypertension, angina
pectoris, glaucoma, anxiety and obesity. The discovery of
propranolol (1a), the first successful drug having antianginal
and antihypertensive effects, prompted the synthesis of
many thousands of compounds containing an aryloxy-
propanolamine moiety.1 The three fundamental goals of
cardiovascular drugs are: lowering of blood pressure
(antihypertensive), return of the heart to rhythmic beating
(antiarrhythmics) and the general improvement of the heart
muscle tone (cardiotonics).2 Biochemically, the mechanism
of action involves the adrenergic system in which the
hormonal system provides the communication link between
the sympathetic nervous system and involuntary muscle.3
Blocking of the b-receptor system reduces the overall
In the literature, there are several reports available for the
synthesis of b-blockers (1a–g)5 (Fig. 1) which include
classical resolution via diastereomers, chromatographic
Figure 1.
Keywords: Antihypertensive; Asymmetric dihydroxylation; Epoxides; Cyclic sulfates.
* Corresponding author. Tel.: C91 20 25893300; fax: C91 20 25893359; e-mail: sudalai@dalton.ncl.res.in
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.074

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I. A. Sayyed et al. / Tetrahedron 61 (2005) 2831–2838
Figure 2. Retrosynthetic analysis of b-adrenergic blocking agents (A).
separation of enantiomers, enzymatic resolution, kinetic
resolution and asymmetric synthesis via chiral pool strategy.
Furthermore, many of these methods suffer from dis-
advantages such as low overall yields, use of expensive
enzymes and resolving agents, low optical purity, the need
for separation of diastereomers and the use of expensive
chiral catalysts. In order to develop a new general route for
the asymmetric synthesis of b-adrenergic blockers with
good optical purity and yield, we decided to make use of
sharpless asymmetric dihydroxylation (AD) and chemistry
of chiral 1,2- cyclic sulfates.6 Herein, we report catalytic
enantioselective synthesis of seven such b-blockers (1a–g)
from readily available starting materials (Fig. 1).
4-acetamidophenol, 2fZ2,3-dimethylphenol, 2gZ2-
hydroxy, 4-nitro- acetophenone) with allyl bromide gave
allyl ethers 3a–g in O97% yield.
These allylic ethers 3a–g were then subjected for the Os-
catalyzed sharpless asymmetric dihydroxylation (AD) using
(DHQD)2-PHAL (hydroquinidine 1,4-phthalazinediyl
diether) as chiral ligand in the presence of K3Fe(CN)6/
K2CO3 as co-oxidant to give the enantiomerically enriched
diols 4a–g. The diols 4a–g were then treated with freshly
distilled SOCl2, Et3N in CH2Cl2 at 0 8C to afford cyclic
sulfites in 96–99% yield as 1:1 diastereomeric mixture. The
formation of cyclic sulfite was clearly evident from the
1
appearance of multiplets at d 4.00–5.50 in its H NMR
spectrum. The cyclic sulfites of the corresponding diols
were then converted into cyclic sulfates 5a–g in 94–98%
yield using RuCl3-catalyzed oxidation. The 1H NMR
spectrum of cyclic sulfates 5a–g showed the disappearance
of several multiplets at d 4.25–4.32, 4.72–4.86 and at 5.22–
5.26 due to diastereomeric mixtures of cyclic sulfites.
Finally, the cyclic sulfates 5a–g were subjected to
nucleophilic displacement with appropriate amine nucleo-
philes followed by hydrolysis of the resulting salts to afford
the corresponding b-blockers 1(a–g), respectively. How-
ever, these reactions resulted in very low yields of the final
b-blockers (yields were often less than 30%). Hydrolysis of
the salts of cyclic sulfates using various reaction conditions
such as 20% H2SO4 in ether, 50% H2SO4 in ether, concd
HCl, 20% aq NaOH and 50% aq NaOH was conducted but
all of them failed to improve the yields of the final products.
Hence, we decided to convert these cyclic sulfates 5a–g into
the corresponding epoxides 6a–g using a three-step
procedure. Thus, cyclic sulfates 5a–g were first treated
with anhydrous LiBr, followed by treatment with 20% aq
H2SO4 in ether to give the corresponding bromoalcohols.
These were then treated with anhydrous K2CO3 in MeOH at
0 8C to afford the corresponding epoxides 6a–g in high
overall yields (80–85% in three steps).7
2. Results and discussion
Retrosynthetic analysis of these b-adrenergic blocking
agents (A) is shown in Figure 2. There are three possible
disconnections at the a, b and c bonds. Most of the previous
synthetic routes are based on the disconnection of bonds at
either a or b.
The general synthetic scheme we have employed for the
synthesis of (S)-propranolol (1a), (S)-moprolol (1b), (S)-
toliprolol (1c), (S)-bunitrolol (1d), (S)-practolol (1e), (S)-
xibenolol (1f) and (S)-celiprolol (1g) is presented in
Scheme 1.
Allylation of phenols 2a–g (2aZa-naphthol, 2bZ2-meth-
oxyphenol, 2cZ3-methylphenol, 2dZ2-cyanophenol, 2eZ
Finally the epoxides 6a–g were then subjected to regio-
specific nucleophilic opening with the respective amines to
furnish the corresponding b-blockers 1(a–g) in excellent
yields and enantiomeric excess (up to 99%). In case of
celiprolol, the nitro group was hydrogenated at 20 psi H2
pressure with 10% Pd/C as catalyst at room temperature to
get the amine which was condensed with diethyl carbomyl
chloride (DECC) to afford the corrosponding (S)-celiprolol.
Scheme 1. (i) K2CO3, CH2]CHCH2Br, acetone, reflux, 12 h, 97–99%;
(ii) cat. OsO4, (DHQD)2-PHAL, K3Fe(CN)6, K2CO3, t-BuOH/H2O, 0 8C,
12 h, 94–98%, 73–90% ee; (iii) SOCl2, Et3N, CH2Cl2, 0 8C, 40 min. 96–
99%; (iv) cat. RuCl3 3H2O, NaIO4, CH3CN:H2O, 0 8C, 30 min. 94–98%;
(v) LiBr, THF 25 8C, 2–3 h; (vi) 20% H2SO4, Et2O, 25 8C, 10 h;
(vii) K2CO3, MeOH, 0 8C, 2 h, 80–85% overall in three steps; (viii) R-NH2,
H2O (cat.), reflux, 2 h, 99%.

I. A. Sayyed et al. / Tetrahedron 61 (2005) 2831–2838
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3. Conclusion
(100), 80 (30), 77 (95), 65 (25); Analysis: C10H12O2
requires C, 73.15; H, 7.37; found C, 73.28; H, 7.34%.
In conclusion, we have developed a simple and efficient
protocol for the asymmetric synthesis of seven b-blockers
namely (S)-propranolol (1a) (67% overall yield, 90% ee),
(S)-moprolol (1b) (74% overall yield, 68% ee), (S)-
toliprolol (1c) (77% overall yield, 78% ee), (S)-bunitrolol
(1d) (35% overall yield, 60% ee), (S)-practolol (1e) (31%
overall yield, 82% ee), (S)-xibenolol (1f) (35% overall
yield, 67% ee), and (S)-celiprolol (1g) (33% overall yield,
97% ee) in eight steps starting from the corresponding
phenols 2a–g. The asymmetric synthesis of celiprolol has
been achieved for the first time.
4.2.3. Allyl 3-methylphenyl ether (3c). Yield: 1.43 g, 97%;
gum; IR (neat, cmK1): 670, 738, 780, 927, 1020, 1127,
1224, 1260, 1458, 1490, 1510, 1594, 2859, 2945; 1H NMR
(200 MHz, CDCl3): dZ2.36 (3H, s), 4.49–4.55 (2H, m),
5.25–5.48 (2H, m), 5.97–6.21 (1H, m), 6.75–6.79 (3H, m),
7.16 (1H, s); 13C NMR (50 MHz, CDCl3): dZ21.3, 68.5,
111.4, 115.4, 117.2, 121.5, 129.0, 133.4, 139.2, 158.5; MS
m/z (% rel intensity): 148 (MC, 50), 133 (60), 119 (65), 105
(70), 91 (100), 77 (50); Analysis: C10H12O requires C,
81.04; H, 8.16; found C, 81.12; H, 8.21%.
4.2.4. Allyl 2-cyanophenyl ether (3d). Yield: 1.54 g, 97%;
gum; IR (CHCl3, cmK1): 3082, 2925, 2227, 1598, 1579,
1490, 1450, 1425, 1290, 1259, 1234, 1166, 1110, 995, 933,
788, 756, 732; 1H NMR (200 MHz, CDCl3)): dZ4.66 (2H,
d, JZ2.0 Hz), 5.31–5.36 (1H, m), 5.44–5.53 (1H, m), 5.90–
6.20 (1H, m), 6.90–7.10 (2H, m), 7.45–7.65 (2H, m); 13C
NMR (50 MHz, CDCl3): dZ69.1, 101.8, 112.5, 116.0,
117.7, 120.6, 131.6, 133.3, 134.0, 159.9; MS (m/z, RI): 159
(MC, 100), 158 (98), 143 (5), 130 (14), 119 (20), 118 (18),
104 (7), 92 (21), 90 (22), 82 (6), 76 (12), 69 (7), 64 (16), 58
(8); Analysis: C10H9NO requires C, 75.45; H, 5.69; N, 8.79;
found C, 75.41; H, 5.79; N, 8.78%.
4. Experimental
4.1. General information
Solvents were purified and dried by standard procedures
before use; petroleum ether of boiling range 60–80 8C was
used. Melting points are uncorrected. Optical rotations were
measured using sodium D line on a JASCO-181 digital
polarimeter. Infrared spectra were recorded on Shimadzu
FTIR-8400 spectrometer. 1H NMR and 13C NMR were
recorded on Bruker AC-200 and MSL-300 NMR spec-
trometers, respectively. Mass spectra were obtained with a
Finnigan MAT-1020 B-70 eV mass spectrometer. Elemen-
tal analysis was carried out on a Carlo Erba CHNS-O
analyzer. Enantiomeric excess was determined by chiral
HPLC or by using chiral shift reagent Eu-(hfc)3.
4.2.5. Allyl 4-acetamidophenoxy ether (3e). Yield: 1.81 g,
95%; crystalline solid; mp: 100–102 8C (EtOAc and
hexane); IR (CHCl3, cmK1): 3298, 3020, 2962, 1685,
1
1605, 1589, 1514, 1435, 1280, 1217, 1118, 850; H NMR
(200 MHz, CDCl3): dZ2.14 (3H, s), 4.51 (2H, d, JZ
4.0 Hz), 5.20 (1H, d, JZ12.0 Hz), 5.35 (1H, d, JZ16.0 Hz),
5.95–6.20 (1H, m), 6.80 (2H, d, JZ8.0 Hz), 7.30 (2H, d, JZ
8.0 Hz), 7.50 (br s, 1H); 13C NMR (50 MHz, CDCl3): dZ
33.0, 72.3, 79.1, 79.4, 123.7, 130.2, 141.8, 164.1, 177.2;
Mass (m/z, RI): 191 (MC, 18), 190 (6), 150 (12), 149 (5),
109 (11), 108 (100), 95 (3), 80 (12), 65 (4), 57 (5); Analysis:
C11H13NO2 requires C, 69.09; H, 6.85; N, 7.34; found
69.13; H, 6.87; N, 7.32%.
4.2. Preparation of allyl phenyl ethers 3a–g
A mixture of one of the phenols 2a–g (10 mmol),
allylbromide (12 mmol) and anhydrous K2CO3 (15 mmol)
in dry acetone (20 mL) was refluxed under N2 for 20 h
(reactions monitored by TLC). The reaction mixture then
cooled to room temperature, filtered through sintered funnel
to remove solid residue and the filtrate was evaporated to
dryness. The residue was purified by column chromato-
graphy using pet. ether/EtOAc (9:1) as eluent to get pure
allyl phenyl ethers 3a–g in 85–99% yield.
4.2.6. Allyl 2,3-dimethylphenyl ether (3f). Yield: 1.37 g,
85%; gum; IR (CHCl3, cmK1): 2935, 1593, 1503, 1454,
1251, 1224, 1178, 1026, 997, 927, 1593, 1503, 1454, 1251,
1224, 1178, 1026, 997, 927, 742; 1H NMR (200 MHz,
CDCl3): dZ2.17 (3H, s), 2.26 (3H, s), 4.49–4.51 (2H, m),
5.22 (1H, d, JZ10.0 Hz), 5.40 (1H, d, JZ16.0 Hz), 5.99–
6.13 (1H, m), 6.66 (1H, d, JZ8.0 Hz), 6.7(1H, d, JZ
16.0 Hz), 6.98–7.02 (1H, m); 13C NMR (50 MHz, CDCl3):
dZ11.6, 19.9, 68.9, 109.2, 116.6, 122.3, 125.3, 125.6,
133.8, 137.8, 156.5; Mass (m/z, RI): 162 (MC, 32), 147 (35),
119 (54), 103 (22), 91 (100), 77 (88), 65 (15); Analysis:
C11H14O requires C, 81.44; H, 8.70%; found: C, 81.31; H,
8.48%.
4.2.1. Allyl 1-naphthyl ether (3a). Yield: 1.78 g, 97%;
gum; IR (neat, cmK1): 744, 927, 999, 1012, 1028, 1125,
1200, 1260, 1458, 1520, 2829, 2930; H NMR (200 MHz,
1
CDCl3): dZ4.68 (2H, d, JZ4.0 Hz), 5.29–5.54 (2H, m),
6.08–6.24 (1H, m), 6.78 (1H, d, JZ8.1 Hz), 7.34–7.49 (4H,
m), 7.76–7.81 (1H, m), 8.29–8.34 (1H, m); 13C NMR
(50 MHz, CDCl3): dZ68.6, 104.9, 117.0, 120.2, 122.0,
125.0, 125.7, 126.2, 127.3, 133.2, 134.4, 154.2; Analysis:
C13H12O requires C, 84.75; H, 6.57; found C, 84.69; H,
6.51%.
4.2.2. Allyl 2-methoxyphenyl ether (3b). Yield: 1.62 g,
99%; gum; IR (neat, cmK1): 742, 927, 997, 1026, 1124,
1224, 1251, 1454, 1504, 1593, 2835, 2935; 1H NMR
(200 MHz, CDCl3): dZ3.85 (3H, s), 4.57–4.67 (2H, m),
5.24–5.45 (2H, m), 6.00–6.24 (1H, m), 6.87–6.90 (4H, m);
13C NMR (50 MHz, CDCl3): dZ55.5, 69.5, 111.5, 113.4,
117.5, 120.4, 121.0, 133.2, 147.8, 149.2; MS m/z (% rel
intensity): 164 (MC, 80), 149 (10), 123 (94), 109 (25), 95
4.2.7. Allyl-2-acetyl-4-nitrophenyl ether (3g). Yield: 2 g,
95%; white solid; mp: 78–80 8C; IR (CHCl3, cmK1): 3020,
2405, 1690, 1523, 1345, 1275, 1215, 1117, 756, 667; H
NMR (200 MHz, CDCl3): dZ2.66 (3H, s), 4.78 (2H, d, JZ
4.0 Hz), 5.38–5.52 (2H, m), 6.00–6.19 (1H, m), 8.31–8.42
(2H, m), 8.61 (1H, d, JZ2.0 Hz); 13C NMR (50 MHz,
CDCl3): dZ31.4, 70.1, 112.9, 119.2, 126.0, 128.3, 131.0,
141.0, 159.5, 161.9, 196.9; Analysis: C11H11NO4 requires
1

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I. A. Sayyed et al. / Tetrahedron 61 (2005) 2831–2838
C, 59.72; H, 5.011, N, 6.33; found: C, 59.79; H, 5.43; N,
6.48%.
13C NMR (50 MHz, CDCl3): dZ21.2, 63.4, 68.8, 70.4,
111.2, 115.1, 121.7, 129.0, 139.2, 158.2; MS m/z (% rel
intensity): 182 (MC, 30), 133 (12), 121 (18), 109 (100), 92
(23), 77 (20); Analysis: C10H14O3 requires C, 65.92; H,
7.74; found C, 65.86; H, 7.79%.
4.3. Preparation of 1-(aryloxy)-2,3-dihydroxypropane
4a–g
A 100 mL RB flask was charged with K3Fe(CN)6
(18.0 mmol), K2CO3 (18.0 mmol), (DHQD)2-PHAL
(0.24 mmol) and t-BuOH/H2O (1:1, 60 mL) and the
resulting mixture was stirred for 10 min at 25 8C. It was
then cooled to 0 8C and a solution of OsO4 (256 mL,
0.124 mmol, 0.5 M solution in toluene) was added. The
resulting reaction mixture was stirred at 0 8C for 5 min and
then one of the olefins 3a–g (6 mmol) was added. The
reaction mixture was stirred at 0 8C for 20–22 h (monitored
by TLC). It was quenched with sodium sulfite (4.0 g) and
extracted with ethyl acetate (4!25 mL). Combined organic
extracts were washed with brine (20 mL), dried over
anhydrous Na2SO4 and evaporated under reduced pressure.
The crude product was purified by column chromatography
using 50% EtOAc in pet. ether as eluent to yield pure diols
4a–g as white solids in 84–98% yield.
4.3.4. (2S)-1-(2-Cyanophenoxy)-2,3-propanediol (4d).
Yield: 960 mg, 84%; white solid; mp: 140–142 8C (hexane
and EtOAc); [a]25D: C21.8 (c 0.5, EtOH); 65% ee, (lit.11
[a]25 C9.4 (c 0.49, EtOH) for 28% ee); IR (CHCl3,
cmK1D): 3421, 3018, 2229, 1598, 1492, 1450, 1290, 1215; 1H
NMR (200 MHz, CDCl3)): dZ3.50–3.90 (4H, m), 4.10–
4.25 (3H, m), 7.90–7.05 (2H, m), 7.45 (1H, d, JZ8.0 Hz);
13C NMR (50 MHz, CDCl3): dZ63.2, 69.8, 70.0, 101.4,
112.4, 116.5, 120.9, 133.3, 134.5, 160.2; MS (m/z, RI): 193
(MC, 10), 162 (12), 149 (4), 133 (38), 119 (100), 104 (42),
91 (80), 85 (4), 75 (16), 64 (22), 57 (12); Analysis:
C10H11NO3 requires C, 62.17; H, 5.73; N, 7.25; found C,
62.10; H, 5.75; N, 7.25%.
4.3.5. (2S)-1-(4-Acetamidophenoxy)-2,3-propanediol
(4e). Yield: 1.14 g, 85%; white solid; mp: 142–144 8C
(EtOAc); [a]25 C7.0 (c 1.0, EtOH); HPLC; 80% ee,
D
4.3.1. (2S)-1-(1-Naphthoxy)-2,3-propanediol (4a). Yield:
1.25 g, 96%; white solid; mp: 113–114 8C; [a]25D: C6.10 (c
1.1, MeOH), (lit.8 C4.01 (c 1.1, MeOH), 60% ee); HPLC:
91% ee, Chiralcel OD-H, 5% EtOH/hexane, 1 mL/min.
Retention time: (R): 13.23 min, (S): 16.55 min; IR (CHCl3,
cmK1): 740, 780, 845, 993, 1020, 1130, 1257, 1379, 1390,
Chiralcel OD-H, lZ254 nm, 10% 2-propanol/hexane,
1 mL/min. Retention time: (S) 11.464. (R) 17.358 min; IR
(CHCl3, cmK1): 3321, 3240, 3138, 3077, 2941, 2882, 1663,
1604, 1554, 1514, 1414, 1284, 1254, 1113, 1050; 1H NMR
(200 MHz, DMSO-d6): dZ2.10 (3H, s), 3.60–3.75 (2H, m),
3.90–4.05 (3H, m), 4.24 (1H, br s), 4.45 (1H, br s), 6.84 (2H,
d, JZ8.0 Hz), 7.46 (2H, d, JZ8.0 Hz), 9.35 (1H, br s); 13C
NMR (50 MHz): dZ23.4, 62.7, 69.8, 69.8, 114.1, 120.6,
132.1, 154.5; Mass (m/z, RI): 225 (MC, 10), 183 (4), 151
(16), 135 (4), 117 (5), 110 (8), 109 (100), 108 (15), 93 (7),
74 (4), 65 (8), 60 (6), 57 (15); Analysis: C11H15NO4 requires
C, 58.63; H, 6.71; N, 6.22; found C, 58.63; H, 6.79; N,
6.26%.
1
1458, 1515, 1598, 2845, 2910, 3280; H NMR (200 MHz,
CDCl3): dZ3.55 (1H, br s), 3.80–3.95 (3H, m), 4.10–4.25
(3H, m), 6.83 (1H, d, JZ6.1 Hz), 7.32–7.49 (4H, m), 7.77–
7.81 (1H, m), 8.24–8.29 (1H, m); 13C NMR (50 MHz,
CDCl3): dZ63.7, 69.1, 70.4, 104.8, 120.3, 121.7, 124.9,
125.4, 125.6, 126.2, 127.2, 134.3, 154.2; MS m/z (% rel
intensity): 218 (MC, 70), 144 (100), 127 (10), 115 (43), 89
(7), 77 (5); Analysis: C13H14O3 requires C, 71.54; H, 6.47;
found C, 71.52; H, 6.49%.
4.3.6. (2S)-1-(2,3-Dimethylphenoxy)-2,3-dihydroxy-
propane (4f). Yield: 1.1 g, 94%; colourless solid; mp:
4.3.2. (2S)-1-(2-Methoxyphenyl)-2,3-propanediol (4b).
104–105 8C (EtOH); [a]25 C4.25 (c 1.0, CHCl3); IR
Yield: 1.1 g, 94%; white solid; mp: 101–102 8C; [a]25
:
D
D
(CHCl3, cmK1): 3431–3414, 3019, 2400, 1639, 1215, 751;
1H NMR (200 MHz, CDCl3): dZ2.14 (3H, s), 2.27 (3H, s),
2.55 (OH, br s), 3.0 (OH, br s), 3.77–3.90 (2H, m), 3.99 (2H,
d, JZ6.0 Hz), 4.05–4.2 (1H, m), 6.68 (1H, d, JZ8.0 Hz),
6.78 (1H, d, JZ8.0 Hz), 7.00 (1H, t, JZ8.0 Hz); 13C NMR
(50 MHz, CDCl3): dZ11.5, 19.9, 63.8, 69.2, 70.6, 109.1,
122.7, 125.0, 125.8, 137.9, 156.2; Mass (m/z, RI):196 (MC,
18), 165 (0.2), 147 (8), 123 (100), 107 (40), 91 (12), 77 (8),
65 (0.2); Analysis: C11H16O3 requires C, 67.32; H, 8.22%;
found: C, 67.21; H, 8.16%.
C6.70 (c 1.1, MeOH), 73% ee (lit.9 C5.8 (c 1.1, MeOH),
63% ee); HPLC: 73% ee, Chiralcel OD-H, 5% EtOH/
hexane, 1 mL/min. Retention time: (R): 11.18 min, (S):
15.21 min; IR (CHCl3, cmK1): 744, 837, 993, 1022, 1128,
1257, 1377, 1456, 1510, 1593, 2854, 2953, 3234; 1H NMR
(200 MHz, CDCl3): dZ3.75–3.84 (2H, m), 3.86 (3H, s),
4.04–4.17 (3H, m), 6.90–6.97 (4H, m); 13C NMR (50 MHz,
CDCl3): dZ55.9, 63.2, 69.8, 70.6, 111.5, 113.6, 120.6,
121.1, 147.7, 148.9, 159.4; MS m/z (% rel intensity): 198
(MC, 28), 149 (10), 124 (100), 109 (80), 77 (13); Analysis:
C10H14O4 requires C, 60.60; H, 7.12; found C, 60.56; H,
7.14%.
4.3.7. (2S)-1-(2-Acetyl-4-nitrophenyl)-2,3-propanediol
(4g). Yield: 1.46 g, 96%; yellow gum; [a]25D: K5.31 (c
1.1, EtOH); HPLC: 97% ee, Chiracel-OD (25 cm) lmax:
4.3.3. (2S)-1-(3-Methylphenyl)-2,3-propanediol (4c).
Yield: 1.06 g, 98%; white solid; mp: 61–62 8C; [a]25
:
254 nm, 70:30 pet. ether/isopropanol, 1 mL/min. Retention
time: (S): 7.08 min, (R): 8.26 min; IR: (CHCl3, cmK1): 740,
780, 845, 993, 1020, 1130, 1257, 1379, 1390, 1458, 1515,
D
C7.86 (c 1, EtOH) 80% ee (lit.10 C9.5 (c 1, EtOH) 97%
ee); HPLC: 80% ee, Chiralcel OD-H, 5% EtOH/hexane,
1 mL/min. Retention time: (R): 19.18 min, (S): 24.15 min;
IR (CHCl3, cmK1): 690, 775, 933, 1055, 1159, 1259, 1290,
1453, 1490, 1585, 1602, 2877, 2927, 3390; 1H NMR
(200 MHz, CDCl3): dZ2.30 (3H, s), 3.65–3.80 (2H, m),
4.00–4.25 (3H, m), 6.66–6.85 (3H, m), 7.20–7.30 (1H, m);
1
1598, 2845, 2910, 3280; H NMR (200 MHz, acetone-d6):
dZ2.66 (3H, s), 3.83–3.87 (2H, m), 4.16–4.34 (3H, m), 7.10
(1H, d, JZ9.3 Hz), 8.33 (1H, dd, JZ2.9, 9.0 Hz), 8.58 (1H,
d, JZ4.0 Hz); 13C NMR (50 MHz, acetone-d6): dZ31.0,
62.8, 69.8, 70.4, 112.7, 125.6, 127.6, 128.2, 140.5, 162.1,

I. A. Sayyed et al. / Tetrahedron 61 (2005) 2831–2838
2835
196.9; Analysis: C11H13NO6 requires C, 51.76; H, 5.13; N,
5.48; found C, 51.52; H, 5.08; N, 5.45%
944, 1097, 1208, 1291, 1347, 1444, 1584, 2431, 2926, 3020;
1H NMR (200 MHz, CDCl3): dZ2.33 (3H, s), 4.01–4.14
(2H, m), 4.45–4.51 (1H, m), 4.78–4.86 (1H, m), 5.23–5.28
(1H, m), 6.68–6.84 (3H, m), 7.14–7.26 (1H, m); 13C NMR
(50 MHz, CDCl3): dZ21.2, 65.5, 69.5, 79.1, 111.3, 115.4,
122.8, 129.3, 139.8, 157.4; MS m/z (% rel intensity): 244
(MC, 23), 228 (16), 147 (10), 121 (96), 108 (92), 91 (100),
77 (15); Analysis: C10H12SO5 requires C, 49.17; H, 4.95; S,
13.13; found C, 49.21; H, 4.86; S, 13.06%.
4.4. Preparation of cyclic sulfates 5a–g
A. To a solution of one of the diols 4a–g (4 mmol) and
triethylamine (2.21 mL, 16 mmol) in CH2Cl2 (10 mL) at
0 8C was added freshly distilled thionyl chloride (0.44 mL,
6 mmol) drop-wise under nitrogen atmosphere. The reaction
mixture was stirred at 0 8C for 30–45 min (monitored by
TLC). The reaction mixture was quenched by the addition of
cold water (10 mL). The organic layer was separated and the
aqueous layer extracted with EtOAc (3!15 mL). The
combined organic extracts were washed with water, brine
and dried over anhydrous Na2SO4. Evaporation of solvent
under reduced pressure yielded pale yellow colored liquid,
which was purified by the column chromatography using
10% EtOAc in pet. ether as a eluent to afford the
corresponding cyclic sulfite as viscous yellow liquid in
96–99% yield.
4.4.4. (2R)-1-(2-Cyanophenoxy)-1,3,2-dioxathiolane-2,2-
dioxide (5d). Yield: 657 mg, 86%; gum; [a]25D C8.6 (c 2.0,
EtOH); IR (CHCl3, cmK1): 3082, 2873, 2227, 1649, 1598,
1579, 1492, 1450, 1425, 1411, 1365, 1290, 1259, 1234,
1
1166, 1110, 1043, 995, 933, 839, 756, 590, 497; H NMR
(200 MHz, CDCl3): dZ4.35–4.55 (1H, m), 4.90 (1H, d, JZ
2.0 Hz) 5.05 (1H, d, JZ6.0 Hz), 5.25–5.45 (1H, m), 6.95–
7.20 (2H, m), 7.50–7.70 (2H, m); 13C NMR (50 MHz,
CDCl3): dZ96.9, 70.0, 78.8, 102.0, 112.6, 115.6, 122.1,
133.6, 134.5, 158.7; MS (m/z, RI): 255 (MC, 6), 232 (3),
218 (4), 204 (4), 193 (11), 176 (4), 162 (15), 146 (6), 134
(15), 133 (56), 119 (100), 104 (45), 102 (15), 91 (72), 80
(27), 75 (24), 64 (45), 57 (26); Analysis: C10H9NSO5
requires C, 47.05; H, 3.55; N, 5.48; found C, 47.01; H, 3.66;
N, 5.49%.
B. To a solution of one of the cyclic sulfites (3 mmol) in
CH3CN: H2O mixture (9:1, 8 mL) at 0 8C was added solid
NaIO4 (0.963 g, 4.5 mmol) and RuCl3$3H2O (0.012 g,
0.06 mmol). The reaction mixture was stirred for 30–
40 min at 0 8C (monitored by TLC). After the reaction was
completed, it was filtered through a pad of celite. Solvent
evaporated under reduced pressure to give the crude
product, which was purified by column chromatography
using pet. ether/EtOAc (8:2) as eluent to afford cyclic
sulfates 5a–g in 86–98% yield.
4.4.5. (4R)-4-(4-Acetamidophenoxy)-1,3,2-dioxathiolane-
2,2-dioxide (5e). Yield: 740 mg, 86%; gum; IR (CHCl3,
cmK1): 3409, 3018, 1652, 1627, 1419, 1215, 1053, 1029,
757; 1H NMR (200 MHz, DMSO-d6): dZ2.13 (3H, s), 4.28
(2H, d, JZ4.0 Hz), 4.70 (1H, dd, JZ2.0, 6.0 Hz), 4.86 (1H,
dd, JZ2.0, 6.0 Hz), 5.20–5.40 (1H, m), 6.84 (1H, d, JZ
8.0 Hz), 7.50 (2H, d, JZ8.0 Hz), 9.10 (1H, s); 13C NMR
(50 MHz): dZ23.6, 67.8, 70.9, 81.9, 116.1, 123.0, 156.1,
158.7, 171.5; Analysis: C11H13NSO6 requires C, 45.79; H,
4.57; N, 4.89; S, 11.16; found C, 51.93; H, 4.47; N, 4.82; S,
11.13%.
4.4.1. (4S)-4-(1-Naphthoxymethyl)-1,3,2-dioxathiolane-
:
2,2-dioxide (5a). Yield: 789 mg, 94%; gum; [a]25
D
C17.4 (c 0.5, EtOH); IR (CHCl3, cmK1): 651, 753, 984,
1024, 1130, 1190, 2113, 1255, 1398, 1460, 1510, 1600,
1
2854, 2940; H NMR (200 MHz, CDCl3): dZ4.25–4.29
(2H, m), 4.60–4.67 (1H, m), 4.88–4.96 (1H, m), 5.36–5.41
(1H, m), 6.79 (1H, d, JZ8.1 Hz), 7.26–7.53 (4H, m), 7.70–
7.84 (1H, m), 8.16–8.21 (1H, m); 13C NMR (50 MHz,
CDCl3): dZ66.5, 68.3, 77.9, 104.7, 121.1, 121.4, 125.0,
125.4, 126.5, 127.3, 134.3, 153.3; MS m/z (% rel intensity):
280 (MC, 100), 157 (55), 144 (56), 137 (25), 123 (28), 118
(10), 91 (8); Analysis: C13H12SO5 requires C, 55.71; H,
4.32; S, 11.44; found C, 55.56; H, 4.29; S, 11.42%.
4.4.6. (4S)-4-[(2,3-Dimethyl) methyl]-1,2,3-dioxathio-
lane-2,2-dioxide (5f). Yield: 665 mg, 86%; colourless
solid; mp: 230–231 8C; [a]25 K8.8 (c 1.0, CHCl3); IR
D
(CHCl3, cmK1) 3020, 2926, 2431, 1584, 1444, 1347, 1291,
1208, 1097, 944, 819, 750, 652; 1H NMR (200 MHz,
CDCl3): dZ2.15 (3H, s), 2.28 (3H, s), 4.26 (2H, d, JZ
4.0 Hz), 4.78–4.88 (2H, m), 5.2–5.35 (1H, m), 6.65 (1H, d,
JZ6.0 Hz), 6.84 (1H, d, JZ6.0 Hz), 7.0 (1H, t, JZ8.0 Hz);
13C NMR (50 MHz, CDCl3): d 11.5, 19.9, 63.8, 68.6, 78.1,
108.9, 123.3, 125.3, 125.8, 138.3, 155.7; Mass (m/z, RI):
258 (MC, 32), 162 (12), 159 (20), 145 (30), 135 (78), 122
(72), 105 (65), 91 (60), 77 (100), 65 (0.5); Analysis:
C11H14O5S requires: C, 51.15; H, 5.46, S, 12.41%; found: C,
51.19; H, 5.39, S, 12.61%.
4.4.2. (4S)-4-[(2-Methoxyphenyl)methyl]-1,3,2-dioxa-
thiolane-2,2-dioxide (5b). Yield: 756 mg, 97%; gum;
[a]25D: C20.12 (c 1, EtOH); IR (CHCl3, cmK1): 651,
754, 819, 981, 1026, 1126, 1178, 1213, 1255, 1392, 1456,
1506, 1595, 2839, 2935, 3018; 1H NMR (200 MHz, CDCl3):
dZ3.85 (3H, m), 4.31 (2H, t, JZ6.2 Hz), 4.81 (1H, d, JZ
6.2 Hz), 4.85 (1H, d, JZ2.1 Hz), 5.22–5.28 (1H, m), 6.94–
7.10 (4H, m); 13C NMR (50 MHz, CDCl3): dZ55.6, 68.0,
69.7, 79.2, 112.4, 116.9, 120.9, 123.6, 146.9, 150.2; MS m/z
(% rel intensity): 260 (MC, 100), 216 (5), 137 (45), 123
(65), 109 (58), 95 (46), 77 (50); Analysis: C10H12SO6
requires C, 46.15; H, 4.65; S, 12.32; found C, 46.21; H,
4.63; S, 12.26%.
4.4.7. (4S)-4-[(2-Acetyl-4-nitrophenyl) methyl]-1,3,2-
dioxathiolane-2,2-dioxide (5g). Yield: 932 mg, 98%;
solid; mp: 138–140 8C; [a]25D: K2.97 (c 0.4, EtOH); IR:
(CHCl3, cmK1): 651, 753, 984, 1024, 1130, 1213, 1255,
1
1460, 1510, 1600, 1688, 2854, 2940; H NMR (200 MHz,
acetonitrile-d3): dZ2.36 (3H, s), 4.39–4.54 (2H, m), 4.59
(1H, dd, JZ4.1, 9.0 Hz), 4.74 (1H, dd, JZ4.2, 9.0 Hz),
5.29–5.35 (1H, m), 7.00 (1H, d, JZ9.3 Hz), 8.05 (1H, dd,
JZ2.9, 9.0 Hz), 8.26 (1H, d, JZ4.1 Hz); 13C NMR
(50 MHz, acetonitrile-d3): d 32.5, 69.0, 71.5, 81.7, 115.4,
4.4.3. (4S)-4-[(3-Methylphenyl)methyl]-1,3,2-dioxathio-
:
lane-2,2-dioxide (5c). Yield: 717 mg, 98%; gum; [a]25
D
C21.39 (c 1, EtOH); IR (CHCl3, cmK1): 652, 750, 819,

2836
I. A. Sayyed et al. / Tetrahedron 61 (2005) 2831–2838
127.3, 130.2, 143.66, 162.7, 199.0; Analysis: C11H11NSO8
requires C, 41.64; H, 3.49; N, 4.41; S, 10.10; found C,
41.62; H, 3.45; N, 4.46; S, 9.78%.
C13.43 (c 2.2, EtOH); IR (neat, cmK1): 690, 775, 860, 900,
1041, 1053, 1161, 1261, 1290, 1454, 1488, 1585, 1602,
2871, 2923, 2999; H NMR (200 MHz, CDCl3): dZ2.33
1
(3H, s), 2.73–2.76 (1H, m), 2.87–2.92 (1H, m), 3.32–3.36
(1H, m), 3.91 (1H, dd, JZ12.1, 3.1 Hz), 4.15 (1H, dd, JZ
12.1, 4.1 Hz), 6.71–6.80 (3H, m), 7.13–7.25 (1H, m); 13C
NMR (50 MHz, CDCl3): dZ21.4, 44.6, 50.1, 68.6, 111.5,
115.5, 112.0, 129.2, 139.5, 158.5; MS m/z (% rel intensity):
164 (MC, 100), 134 (13), 119 (30), 108 (98), 91 (93), 77
(91), 65 (31), 57 (30); Analysis: C10H12O2 requires C,
73.15; H, 7.37; found C, 73.21; H, 7.42%.
4.5. Preparation of epoxides 6a–g
A. To a solution of one of the cyclic sulfates 5a–g
(2.5 mmol) in dry THF (15 mL) was added anhydrous
LiBr (1.04 g, 12 mmol) and the resulting reaction mixture
was stirred for 40–50 min (monitored by TLC for the
disappearance of cyclic sulfate) at 25 8C. After completion
of the reaction the solvent was removed under reduced
pressure. In the resulting residue diethyl ether (25 mL)
and 20% H2SO4 (25 mL) were added and stirred at 25 8C for
4–5 h (monitored by TLC). After completion of the reaction
the two layers were separated, the aqueous layer extracted
with diethyl ether (3!15 mL), combined organic extracts
were washed with saturated NaHCO3, water and brine, dried
over anhydrous sodium sulfate and evaporated under
reduced pressure to give the corresponding bromoalcohols.
4.5.4. (2S)-1-(2-Cyanophenoxy)-1,2-epoxypropane (6d).
Yield: 393 mg, 90%; gum; [a]25D C2.3 (c 2.3, CHCl3); IR
(CHCl3, cmK1): 4217, 3614, 3020, 2399, 2231, 1600, 1514,
1505, 1450, 1290, 1261, 1210, 1045, 1026, 908, 760, 669;
1H NMR (200 MHz, CDCl3)): dZ2.80–2.95 (2H, m), 3.35–
3.45 (1H, m), 4.05 (1H, dd, JZ6.0 Hz each), 4.30 (1H, dd,
JZ4.0, 8.0 Hz), 6.95 (2H, dd, JZ8.0 Hz), 7.45–7. 65 (2H,
m); 13C NMR (50 MHz, CDCl3): dZ44.2, 49.6, 69.2, 102.0,
112.5, 116.1, 121.2, 133.6, 134.3, 159.9; MS (m/z, RI): 175
(MC, 8), 162 (10), 149 (10), 133 (28), 119 (45), 104 (36),
102 (32), 91 (80), 90 (32), 77 (20), 76 (18), 75 (28), 64 (52),
63 (45), 57 (100), 77 (72); Analysis: C10H9NO2 requires C,
68.56; H, 5.17; N, 7.99; found C, 68.59; H, 5.17; N, 7.98%.
B. The above crude bromoalcohol (2 mmol) was dissolved
in MeOH (20 mL) and treated with anhydrous K2CO3
(1.10 g, 8 mmol) at 0 8C. The resulting reaction mixture was
stirred at 0 8C for 2 h (monitored by TLC). After completion
the reaction was quenched by the addition of saturated
NH4Cl solution (10 mL) and extracted with CH2Cl2 (4!
15 mL), washed with water and brine, dried over anhydrous
Na2SO4, evaporated under reduced pressure to give crude
product. It was then purified by column chromatography
using pet. ether/EtOAc (8:2) as eluents to give pure
epoxides 6(a–g) as oil in 80–85% yield.
4.5.5. (2S)-3-(4-Acetamidophenoxy)-1,2-epoxypropane
(6e). Yield: 414 mg, 80%; crystalline solid; mp: 104 8C
(EtOAc and hexane); [a]25 C14.0 (c 2.0, EtOH); IR
D
(CHCl3, cmK1): 3299, 2931, 1664, 1604, 1540, 1510, 1411,
1
1240, 1038, 828; H NMR (200 MHz, CDCl3)): dZ2.15
(3H, s), 2.76 (1H, dd, JZ5.0, 3.0 Hz), 2.89 (1H, dd, JZ5.0,
3.0 Hz), 3.25–3.45 (1H, m), 3.85 (1H, dd, JZ8.0, 5.0 Hz),
4.15 (1H, dd, JZ8.0, 5.0 Hz), 6.85 (2H, d, JZ8.0 Hz), 7.40
(2H, d, JZ8.0 Hz); 13C NMR (50 MHz, CDCl3): dZ24.0,
44.5, 50.1, 68.9, 114.8, 121.9, 131.5, 154.7, 168.7; Analysis:
C11H13NO3 requires C, 63.75; H, 6.32; N, 6.75; found C,
63.77; H, 6.35; N, 6.66%.
4.5.1. (2S)-3-(1-Naphthyloxy)-1,2-epoxypropane (6a).
Yield: 400 mg, 80% overall in two steps; gum; [a]25
:
D
C10.91 (c 1.3, EtOH); IR (neat, cmK1): 748, 790, 916,
1021, 1123, 1190, 1240, 1260, 1454, 1510, 1590, 2890,
2990; 1H NMR (200 MHz, CDCl3): dZ2.75–2.79 (1H, m),
2.86–2.95 (1H, m), 3.39–3.44 (1H, m), 3.89 (1H, dd, JZ
12.1, 6.2 Hz), 4.28 (1H, dd, JZ12.1, 2.1 Hz), 6.73 (1H, d,
JZ8.14 Hz), 7.28–7.48 (4H, m), 7.74–7.79 (1H, m), 8.26–
8.31 (1H, m); 13C NMR (50 MHz, CDCl3): dZ44.5, 50.0,
68.8, 104.9, 120.7, 121.9, 125.2, 125.6, 126.4, 127.3, 134.4,
154.1; MS m/z (% rel intensity): 200 (MC, 100), 157 (28),
144 (65), 127 (18), 115 (53), 89 (10); Analysis: C13H12O2
requires C, 77.98; H, 6.04; found C, 77.96; H, 6.04%.
4.5.6. (2S)-3-(2,3-Dimethylphenyl)-1,2-epoxypropane
(6f). Yield: 240 mg, 53.3%; gum; [a]25 K6.52 (c 2.3,
D
CHCl3); IR (CHCl3, cmK1) 3020, 2926, 2431, 1584, 1444,
1347, 1291, 1208, 1097, 944, 819, 750, 652; 1H NMR
(200 MHz, CDCl3): dZ2.17 (3H, s), 2.27 (3H, s), 2.75 (1H,
dd, JZ2.0 Hz each), 2.87 (1H, t, JZ6.0 Hz), 3.34–3.39
(1H, m), 3.91 (1H, dd, JZ4.0, 6.0 Hz), 4.16 (1H, dd, JZ
4.0 Hz each), 6.66 (1H, d, JZ10.0 Hz), 6.78 (1H, d, JZ
8.0 Hz), 7.0 (1H, t, JZ8.0 Hz);13C NMR (50 MHz, CDCl3):
dZ11.5, 19.9, 44.6, 50.3, 69.2, 109.6, 122.9, 125.8, 138.0,
156.5, 159.7; Analysis: C11H14O2 requires: C, 74.13; H,
7.92%; found C, 74.41; H, 7.69%.
4.5.2. (2S)-3-(2-Methoxyphenyl)-1,2-epoxypropane (6b).
:
Yield: 382 mg, 85% overall in two steps; gum; [a]25
D
C9.83 (c 1.2, EtOH); IR (neat, cmK1): 746, 779, 916, 1027,
1124, 1180, 1224, 1255, 1454, 1504, 1593, 2837, 2929,
1
3001; H NMR (200 MHz, CDCl3): dZ2.72 (1H, dd, JZ
6.1, 4.0 Hz), 2.89 (1H, t, JZ4.0 Hz), 3.35–3.44 (1H, m),
3.87 (3H, s), 3.99 (1H, dd, JZ12.1, 6.1 Hz), 4.20 (1H, dd,
JZ12.1, 4.0 Hz), 6.90–6.93 (4H, m); 13C NMR (50 MHz,
CDCl3): dZ44.7, 50.1, 55.9, 70.3, 112.5, 115.5, 120.9,
122.1, 148.3, 150.0; MS m/z (% rel intensity): 180 (MC,
98), 150 (13), 137 (20), 124 (100), 109 (80), 95 (37), 81
(30), 77 (43), 65 (21); Analysis: C10H12O3 requires C,
66.65; H, 6.71; found C, 66.67; H, 6.81%.
4.5.7. (2S)-3-(2-Acetyl-4-nitrophenyl)-1,2-epoxypropane
:
(6g). Yield: 503 mg, 85%; solid; mp: 80–83 8C; [a]25
D
K10.7 (c 0.9, EtOH); IR: (CHCl3, cmK1): 413, 430, 440,
459, 471, 487, 756, 1017, 1116, 1216, 1277, 1345, 1485,
1
1523, 1586, 1610, 1685, 2930, 3020; H NMR (200 MHz,
CDCl3): dZ2.70 (3H, s), 2.28 (1H, dd, JZ2.1, 9.0 Hz), 3.00
(1H, dd, JZ2.0, 9.0 Hz), 3.43–3.49 (1H, m), 4.57 (1H, dd,
JZ2.0, 10.0 Hz), 7.09 (1H, d, JZ9.3 Hz), 8.34 (1H, dd, JZ
2.9, 9.0 Hz), 8.63 (1H, d, JZ4.0 Hz); 13C NMR (50 MHz,
CDCl3): dZ31.5, 44.3, 49.3, 70.3, 112.9, 126.4, 128.5,
141.6, 159.6, 161.7, 196.9; MS m/z (% rel intensity): 237
4.5.3. (2S)-3-(3-Methylphenyl)-1,2-epoxypropane (6c).
:
Yield: 344 mg, 84% overall in two steps; gum; [a]25
D

I. A. Sayyed et al. / Tetrahedron 61 (2005) 2831–2838
2837
(MC, 20), 192 (8), 178 (40), 164 (18), 148 (10), 132 (60),
118 (30), 99 (35), 89 (10), 77 (20), 63 (35), 43 (100);
Analysis: C11H11NO5 requires C, 55.69; H, 4.67; N, 5.90;
found C, 55.52; H, 4.61; N, 5.82%.
(2H, m), 4.55–4.63 (1H, m), 6.71–6.79 (3H, m), 7.10–7.18
(1H, m), 8.50 (1H, br s), 8.57 (1H, br s); 13C NMR (50 MHz,
CDCl3): dZ18.6, 18.8, 21.2, 47.8, 51.2, 65.5, 69.3, 111.2,
115.1, 121.8, 129.0, 139.3, 158.0; MS m/z (% rel intensity):
259 (MC, 2), 236 (30), 223 (9), 208 (13), 179 (19), 108 (7),
91 (10), 72 (100); Analysis: C13H22ClNO2 requires C,
60.11; H, 8.54; Cl, 13.65; N, 5.39; found C, 60.20; H, 8.55;
Cl, 13.75; N, 5.41%.
4.6. Preparation of (S)-propranolol (1a), (S)-moprolol
(1b), (S)-toliprolol (1c), (S)-bunitrolol (1d), (S)-practolol
(1e), (S)-xibenolol (1f) and (S)-celiprolol (1g) via opening
of epoxides 6a–g
4.6.4. (S)-Bunitrolol (1d). Yield: 279 mg, 75%; white solid;
One of the epoxides 6a–g (1.5 mmol) was dissolved in
appropriate amines (10 mL) and refluxed in presence of
water (0.5 mL) for 1 h. Excess of amine was removed under
reduced pressure to afford 1(a–g).
mp: 162 8C (EtOH) (lit.11 163–165 8C); [a]25 K10.0 (c
D
1.4, H2O); HPLC: 60% ee, ChiraSpher NT, lZ254 nm,
(n-hexane/EtOH/MeOH (60:20:20)/0.05% NH3 (25%)),
0.5 mL/min. Retention time: (S) 9.359 min, (R)
12.354 min; IR (CHCl3, cmK1): 3400, 3019, 2995, 1485,
1
In case of toliprolol, the resulting gum after evaporation of
isopropylamine was dissolved in ether and dry HCl gas was
passed through it for 15 min, the solvent was removed under
reduced pressure and resulting solid recrystallized from
MeOHCEtOAc afford (S)-toliprolol (1c) as its
hydrochloride salt.
1410, 2227, 1554, 1490, 1215, 756; H NMR (200 MHz,
CDCl3): dZ1.14 (9H, s), 2.37 (1H, br s), 2.70 (1H, dd, JZ
4.0, 6.0 Hz), 2.86 (1H, dd, JZ4.0, 6.0 Hz), 3.80–4.15 (3H,
m), 6.90 (2H, d, JZ8.0 Hz), 7.45 (2H, d, JZ8.0 Hz); 13C
NMR (50 MHz, CDCl3): dZ28.6, 44.4, 50.6, 67.7, 71.6,
101.8, 112.4, 116.2, 120.8, 133.4, 134.2, 160.3; Analysis:
C14H20N2O2 requires C, 67.71; H, 8.11; N, 11.28; found C,
67.75; H, 8.16; N, 11.25%.
In case of celiprolol, the nitro group was hydrogenated at
20 psi H2 pressure with 10% Pd/C as catalyst at room
temperature to get the amine which was condensed with
diethyl carbomyl chloride (DECC) to afford the corrospond-
ing (S)-celiprolol.
4.6.5. (S)-Practolol (1e). Yield: 280 mg, 70%; white solid;
mp: 125 8C (dioxane); lit.5n 128–129 8C; [a]25 K2.6 (c
D
1.0, EtOH); 82%ee (lit.5n [a]25D C3.5 (c 1.0, EtOH) for (R)-
Practolol]; IR (CHCl3, cmK1): 3314, 3284, 2975, 2359,
1715, 1665, 1511, 1398, 1220, 1040, 769; 1H NMR
(200 MHz, CDCl3): dZ0.95 (6H, d, JZ6.0 Hz), 1.93 (3H,
s), 3.30–3.50 (2H, m), 3.55–3.70 (1H, m), 3.80–4.10 (4H,
m), 6.75 (2H, d, JZ8.0 Hz), 7.44 (2H, d, JZ8.0 Hz); 13C
NMR (50 MHz, CDCl3): dZ23.7, 45.0, 49.9, 52.1, 69.0,
73.5, 115.9, 123.0, 133.7, 156.3, 171.4; Mass (m/z, RI): 248
(4), 222)3), 178 (5), 151 (40), 136 (20), 109 (100), 98 (15),
91 (10), 80 (32), 64 (60); Analysis: C14H22N2O3 requires C,
63.14; H, 8.31; N, 10.51; found C, 63.10; H, 8.25; N,
11.02%.
4.6.1. (S)-(K)-Propranolol (1a). Yield: 384 mg, 99%;
colourless solid; mp: 73–74 8C, (lit.12 72–73 8C); [a]25
:
D
K9.00 (c 0.5, EtOH), 90% ee (lit.12 K9.9 (c 0.5, EtOH)); IR
(CHCl3, cmK1): 570, 667, 750, 1029, 1120, 1175, 1210,
1240, 1450, 1500, 1594, 2930, 2960, 3300, 3432; 1H NMR
(200 MHz, CDCl3): dZ1.09 (6H, d, JZ6.1 Hz), 2.76–3.01
(5H, m), 4.08–4.19 (3H, m), 6.79 (1H, d, JZ8.1 Hz), 7.34–
7.51 (4H, m), 7.76–7.81 (1H, m), 8.22–8.27 (1H, m); 13C
NMR (50 MHz, CDCl3): dZ22.8, 48.7, 49.6, 68.4, 70.7,
104.8, 120.4, 121.7, 125.0, 125.4, 125.7, 126.2, 127.3,
134.4, 154.3; MS m/z (% rel intensity): 259 (MC, 3), 144
(13), 115 (20), 84 (100), 72 (50), 69 (23), 56 (33); Analysis:
C16H21NO2 requires C, 74.10; H, 8.16; N, 5.40; found C,
74.25; H, 8.16; N, 5.30%.
4.6.6. (S)-Xibenolol (1f). Yield: 214 mg, 57%; gum; [a]25
D
K17.58 (c 1.0, CHCl3); 67% ee (lit.5o K25.4 (c 1.0,
CHCl3)]; IR (CHCl3, cmK1): 3421–3501, 2926, 2928, 2856,
1649, 1580, 1458, 1375, 1263, 1194 H NMR (200 MHz,
1
4.6.2. (S)-(K)-Moprolol (1b). Yield: 351 mg, 98%; solid;
mp: 84–85 8C, (lit.12 82–83 8C); [a]25D: K3.90 (c 4.5,
EtOH), 68%ee(lit.11 K5.6(c4.5,EtOH)];IR(CHCl3, cmK1):
667, 757, 1029, 1124, 1178, 1217, 1253, 1454, 1506, 1593,
CDCl3): dZ1.49 (9H, s), 2.12 (3H, s), 2.23 (3H, s), 3.07–
3.36 (3H, m), 3.90–4.11 (2H, m), 4.66 (1H, br s), 6.62 (1H,
d, JZ8.0 Hz), 6.75–6.78 (1H, d, JZ6.0 Hz), 6.96–7.03 (1H,
t, JZ8.0 Hz); 13C NMR (50 MHz, CDCl3): dZ11.4, 19.6,
25.6, 45.5, 57.4, 65.7, 69.9, 109.1, 122.6, 124.9, 125.7,
137.6, 156.0; Mass (m/z, RI): 233 (MC–H2O, 40), 218 (65),
161 (100), 147 (20), 122 (55), 112 (70), 91 (10), 77 (5);
Analysis: C15H25NO2 requires: C, 71.67; H, 10.02; N,
5.57%; found: C, 71.51; H, 9.89%; N, 5.51%.
1
2933, 2966, 3313, 3400; H NMR (200 MHz, CDCl3): dZ
1.07 (6H, d, JZ6.0 Hz), 2.69–2.90 (5H, m), 3.85 (3H, s),
3.97–4.07 (3H, m), 6.86–6.97 (4H, m); 13C NMR (50 MHz,
CDCl3): dZ23.0, 48.8, 49.3, 55.9, 68.6, 73.1, 112.4, 115.3,
121.1, 121.9, 148.6, 150.1; MS m/z (% rel intensity): 239
(MC, 5), 224 (10), 195 (52), 124 (7), 109 (6), 77 (12), 72
(100), 56 (12); Analysis: C13H21NO3 requires C, 65.25; H,
8.84; N, 5.85; found C, 65.11; H, 8.64; N, 5.75%.
4.6.7. (S)-(K) Celiprolol (1g). Yield: 511 mg, 90%; solid;
mp 116–118 8C; lit.5p mp 117–118 8C; [a]25D: K12.5 (c
1.76, EtOH), HPLC: 97% ee, Chiracel-OD 10% diethyl-
amine/2-propanol, 1 mL/min. Retention time: (S):
10.35 min, (R): 12.67 min; IR: (CHCl3, cmK1): 673, 759,
824, 1044, 1076, 1162, 1221, 1307, 1382, 1430, 1500, 1651,
4.6.3. (S)-(K)-Toliprolol (1c) hydrochloride. Yield:
383 mg, 99%; gum; mp: 117–118 8C, (lit.5k 119 8C);
[a]25D: K21.54 (c 1.01, EtOH) 78% ee; (lit.5k K27.4 (c
1.01, EtOH)); IR (CHCl3, cmK1): 694, 775, 968, 1062,
1110, 1257, 1294, 1379, 1461, 1488, 1585, 1612, 2711,
1
1677, 2794, 2966, 3320; H NMR (200 MHz, CDCl3): dZ
1.39 (6H, t, JZ10.0 Hz), 1.48 (9H, s), 2.57 (3H, s), 2.99
(1H, br s) 3.11–3.13 (3H, m), 3.38 (8H, m), 4.01–4.05 (2H,
m), 6.84 (1H, d, JZ10.0 Hz), 7.53 (1H, d, JZ10.0 Hz), 7.70
1
2852, 2933, 3257, 3303; H NMR (200 MHz, CDCl3): dZ
1.48 (6H, s), 2.30 (3H, s), 3.19–3.48 (3H, m), 3.94–4.15

2838
I. A. Sayyed et al. / Tetrahedron 61 (2005) 2831–2838
(1H, s); 13C NMR (50 MHz, CDCl3): dZ8.5, 13.8, 25.6,
31.0, 41.4, 46.0, 57.6, 65.2, 71.0, 113.5, 123.4, 126.9, 127.4,
133.1, 153.2, 155.4, 159.6, 199.8; Analysis: C20H33N3O4
requires C, 63.30; H, 8.76; N, 11.07; found C, 63.29; H,
8.81; N, 11.10.
Takahashi, H.; Takeda, H.; Achiwa, K. Chem. Pharm. Bull.
1995, 43, 738. (h) Sessai, H.; Suzuki, T.; Itoh, N.; Shibasaki,
M. Appl. Organomet. Chem. 1995, 9, 421. Moprolol: (i)
Kazunori, K.; Akimasa, M.; Shigeki, H.; Takehisa, O.;
Kiyoshi, W. Agri. Biol. Chem. 1985, 49, 207. (j) Ferrari, G.,
Vecchietti, V. US. 4683245 1980. Toliprolol: (k) Howe, R.;
Rao, B. S. J. Med. Chem. 1968, 11, 1118. Bunitrolol: (l)
Zhenya, H. Gongye, Y. 1987 18, 339 (Chinese). Practolol: (m)
Thakkar, N. V.; Banerji, A. A.; Berinakatti; Hanumanthsa, S.
Biotechnology Lett. 1995, 17, 217 (n) Danilewicz, J. C.; Kemp,
J. E. G. J. Med. Chem. 1973, 16, 168. Xibenolol: (o) Hunma,
S.; Ito, T.; Kambekawa, A. Chem. Pharm. Bull. 1985, 33, 760.
Celiprolol: (p) Zoelss, G. Arzneim-forsch. 1983, 33(1A),
2(German). (q) Joshi, R. A.; Gurjar, M. K.; Tripathy, N. K.
Org. Proc. Res. Dev. 2001, 5, 176.
Acknowledgements
IAS, VVT, MDN, GKD and SPK thank CSIR, New Delhi
for the award of research fellowship. We also thank Dr. B.
D. Kulkarni, Head, CEPD, for his constant encouragement.
Financial support from DST, New Delhi is gratefully
acknowledged.
6. (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483. (b) Johnson, R. A.; Sharpless,
K. B. In Catalytic Asymmetric Synthesis Ojima I; Ojima, I.,
Ed.; VCH Publishers: New York, 1993; Chapter 4,
pp 227–270.
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