Enantioselective synthesis of phenyl-ethanolamines through application of chiral sulfoxide

Article abstract of DOI:10.1080/00397910902765578

Efficient enantioselective synthesis of (R)- and (S)-enantiomers of 2-(tert-butylamino)-1-(p-methoxyphenyl)-ethanol has been achieved in high enantiomeric excess by using asymmetric sulfoxide as a chiral auxiliary. The present synthetic approach was further extended to the asymmetric synthesis of (R)-salbutamol. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910902765578

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Enantioselective Synthesis of
Phenyl-ethanolamines Through
Application of Chiral Sulfoxide
Aathimanivelu V. Sivakumar a , Anand M. Lahoti a &
Sujata V. Bhat a
a Department of Chemistry , Indian Institute of
Technology , Powai, Mumbai, India
Published online: 12 Aug 2009.
To cite this article: Aathimanivelu V. Sivakumar , Anand M. Lahoti & Sujata V. Bhat
(2009) Enantioselective Synthesis of Phenyl-ethanolamines Through Application
of Chiral Sulfoxide, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:18, 3338-3347, DOI:
10.1080/00397910902765578
To link to this article: http://dx.doi.org/10.1080/00397910902765578
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Synthetic Communications1, 39: 3338–3347, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902765578
Enantioselective Synthesis of
Phenyl-ethanolamines Through
Application of Chiral Sulfoxide
Aathimanivelu V. Sivakumar, Anand M. Lahoti, and Sujata V. Bhat
Department of Chemistry, Indian Institute of Technology,
Powai, Mumbai, India
Abstract: Efficient enantioselective synthesis of (R)- and (S)-enantiomers of 2-(tert-
butylamino)-1-(p-methoxyphenyl)-ethanol has been achieved in high enantiomeric
excess by using asymmetric sulfoxide as a chiral auxiliary. The present synthetic
approach was further extended to the asymmetric synthesis of (R)-salbutamol.
Keywords: b-Amino-arylethanols, asymmetric sulfoxide, bronchodilator, chiral
auxiliary, salbutamol
INTRODUCTION
The 2-amino-arylethanol derivatives form an important class of
compounds because of their presence in several natural products[1] and
their usefulness as pharmaceuticals, chiral auxiliaries, and chiral building
blocks.[2] The enantioselective synthesis of substituted (R)-phenylethano-
lamines such as isoproterenol (1), terbutaline (2a), salbutamol (2b)
(Figure 1), and a large number of related 2-amino-arylethanols has
received considerable interest as these compounds display b2-adrenergic
receptor agonist activity, resulting in antiasthmatic and bronchodilatory
properties. The prominent natural 2-amino-arylethanols include octopa-
mine (3a), tembemide (3b), and aegeline (3c), which display b-adrenergic
Received November 2, 2008.
Address correspondence to Sujata V. Bhat, Department of Chemistry, Indian
Institute of Technology, Powai, Mumbai 400 076, India. E-mail: Sujata8b@
gmail.com
3338

Phenyl-ethanolamine Synthesis
3339
Figure 1. Structural features of salbutamol, terbutaline, isoproterenol,
octopmine, tembemide, aegeline, and levamizole.
receptor agonist and hypoglycemic properties.[3] Moreover, (S)-2-amino-
phenylethanol derivatives find utility in the synthesis of (S)-levamisole (4)
analogues.[4]
In pharmaceuticals, selective interactions are profoundly important
because one of the enantiomers of a compound has beneficial effect,
whereas the second enantiomer may have disastrous results. (R)-Isopro-
terenol (1) possesses the desired bronchodilatory activity, whereas the
(S)-isomer is approximately 90 times less potent.[5] The stereo-controlled
induction of chirality into organic molecules remains an important
challenge to synthetic organic chemists. Some of the known methods
of obtaining optically active phenylethanolamines include resolution of
racemic mixture,[6] asymmetric reduction of a-halo-, a-azido-, or a-amino-
acetophenones,[7] and reduction of chiral cyanohydrins.[8] In addition,
the enzymatic conversions,[9] Sharpless dihydroxylation,[3] asymmetric
dihydroxylation,[4] and asymmetric Henry reaction[10] have also been
utilized for obtaining nonracemic b-amino-phenylethanol derivatives.
In recent years, the sulfoximines[11] and sulfoxides[12] have been used
as highly dependable chiral auxiliary in synthetic organic chemistry. We
report herein the use of asymmetric sulfoxide in the enantioselective
synthesis of 2-amino-1-arylethanols.
RESULTS AND DISCUSSION
The condensation of (þ)-(S)-n-butyl methyl sulfoxide (6) with p-anisalde-
hyde in the presence of n-BuLi at ꢀ78ꢁC yielded a diastereomeric mixture
of n-butyl (2-hydroxy-2-p-methoxyphenyl)-ethyl sulfoxides (2R-7a) and
(2S-8a) (Scheme 1). These diastereomers were separated in pure form

3340
A. V. Sivakumar, A. M. Lahoti, and S. V. Bhat
Scheme 1. Synthesis of (R)- and (S)-enantiomes of 1-p-methoxyphenyl-2-tert-
butylamino-ethanol and (R)-salbutamol using asymmetric sulfoxide as a chiral
auxiliary.
by fractional crystallization, and the diastereomeric excess (de) of sepa-
rated diastereomers was evaluated by chiral high-performance liquid
chromatography (HPLC; Chiracel OD analytical column) with hexane–
propan-2-ol (ratio 85:15) as the mobile phase. The isomers (2R)-7a and
(2S)-8a were obtained in a 1:4 ratio. Similarly, the condensation of
(þ)-(S)-n-butyl methyl sulfoxide (6) with 2,2-dimethyl-4H-benzo[3,4-
e]1,3-dioxin-6-carboxaldehyde in the presence of n-BuLi at ꢀ78ꢁC
yielded a diastereomeric mixture of (2R)-(7b) and (2S)-8b n-butyl
(2,2-dimethyl-4H-benzo[3,4-e]1,3-dioxin-6-yl)-ethyl sulfoxides. These
diastereomers were separated in pure form by fractional crystallization
and the diastereomeric excess (de) of separated diastereomers was evalu-
ated by chiral HPLC (Chiracel OD analytical column) with hexane–
propan-2-ol (ratio 85:15) as the mobile phase. The isomers (2R)-7b and
(2S)-8b were obtained in a 1:5 ratio.
The b-hydroxy sulfoxide (2S)-8a was further subjected to the
reduction with sodium hydrogen sulfite to obtain the b-hydroxy sulfide
9a. The sulfide 9a was converted into sulfonium iodide 10a by treatment
with methyl iodide.[13] The sulfonium iodide 10a was crystallized from the

Phenyl-ethanolamine Synthesis
3341
reaction mixture. The treatment of the sulfonium iodide 10a with dimsyl
sodium in dimethylsulfoxide (DMSO) yielded the (S)-p-methoxystyrene
oxide,[14] which on addition of t-butylamine in the presence of
[15]
LiClO4
gave (S)-1-p-methoxyphenyl-2-tert-butylamino-ethanol (11a,
ee 96%). The (R)-1-p-methoxyphenyl-2-tert-butylamino-ethanol (12a, ee
95%) and (R)-2-(N-tert-butylamino)-1-(2,2-dimethyl-4H-benzo[3,4-e]1,3-
dioxin-6-yl}-ethanol (12b, ee 96%) were similarly synthesized starting
from (2R)-b-hydroxy sulfoxides 7a and 7b respectively. The compound
12b has been converted to (R)-salbutamol acetate by the treatment with
aqueous acetic acid.[16]
EXPERIMENTAL
General Procedures
All solvents were purified by standard procedures. Infrared (IR) spectra
were recorded on a Perkin-Elmer model 681 spectrometer. 1H NMR spec-
tra were recorded on Varian (400 and 500 MHz) spectrometers in CDCl3
with tetramethylsilane (TMS) as internal standard. Chemical shifts (d) are
reported in parts per million (ppm) of the applied field, and coupling
constants are expressed in hertz (Hz). Optical rotations were measured
on a Jasco DIP-370 digital polarimeter. The enantiomeric excess (ee %)
of phenylethanol amine derivatives was determined by chiral HPLC
(Chiracel OD-H analytical column) with hexane–propan-2-ol (85:15) as
the mobile phase and ultraviolet (UV) detection at 230 nm. Microanalyses
were performed in a Carlo Erba Model 1106 elemental analyzer. Melting
points are uncorrected. The silica gel (100–200 mesh) for column chroma-
tography was activated by heating at 120ꢁC for 4 h.
Preparation of (þ)-(S)-N-Butyl Methyl Sulfoxide (6)
A solution of n-butyl lithium (8.2 g, 55 ml, 0.128 mol) in hexane was
added to a solution of (R)-methyl-p-tolyl sulfoxide 5 (5.0 g, 0.032 mol)
in ethyl ether (200 ml) at ꢀ78ꢁC under nitrogen to give a precipitate,
which rapidly dissolved to produce a clear tan-colored solution. The reac-
tion mixture was quenched after ½ h by addition of saturated ammonium
chloride solution and was extracted two times with chloroform. The
chloroform extract was washed with brine and dried over anhydrous
sodium sulfate, and the solvent was removed in vacuum. The chromato-
graphy of the residue on silica gel with ether=acetone as eluents gave
(S)-n-butyl methyl sulfoxide (6); yield 3.3 g (86%).

3342
A. V. Sivakumar, A. M. Lahoti, and S. V. Bhat
20
White solid; mp 53–54ꢁC; lit.[12b] mp 52–53ꢁC; ½aꢂD þ112ꢁ (c 1.00,
20
acetone); lit.[12b] ½aꢂD þ108ꢁ (c 1.00, acetone); 1H NMR (CDCl3,
500 MHz): d 0.98 (t, J ¼ 7 Hz, 3H), 1.44–1.56 (m, 2H), 1.69–1.80 (m,
2H), 2.57 (s, 3H), 2.61–2.80 (m, 2H). IR (KBr): 3230, 2934, 1341,
1163 cmꢀ1. Anal. calcd. for C5H12OS: C, 49.9; H, 10.1; S, 26.6. Found:
C, 49.6; H, 9.8; S, 26.4%.
Synthesis of N-Butyl (2-Hydroxy-2-p-methoxyphenyl)-ethyl
Sulfoxides (7a and 8a)
n-Butyl lithium (3.5 ml, 15% in hexane, 1.1 equiv.) was added to a cooled
(ꢀ78ꢁC) solution of (þ)-(S)-n-butyl methyl sulfoxide (6) (0.9 g, 7.5 mmol)
20
{½aꢂD þ112 (c 1.0, acetone)} in dry ether (distilled from sodium, 50 ml)
under nitrogen. The mixture was stirred for 10 min at ꢀ78ꢁC, and a
solution of p-anisaldehyde (0.83 mmol, 1.1 equiv.) in ether (10 ml) was
added all at once. The mixture was allowed to warm up to 0ꢁC for
5 min, and it was poured into an ammonium chloride solution. The ether
layer was separated, and the aqueous layer was extracted well with ether.
The organic extracts were combined, washed with brine, dried over
sodium sulfate, and evaporated to give a viscous residue, which was
crystallized from ether–hexane (ca. 50:50) at 25ꢁC to obtain a white crys-
talline solid, (2R)-7a (17%). The mother liquors were concentrated and
redissolved in hexane with the addition of only a small amount of ether.
Upon cooling to 0ꢁC, the diastereomer (2S)-8a (68%) was crystallized.
Compound (2R)-7a
20
White solid; mp 64–65ꢁC; ½aꢂD þ36.26ꢁ (c 1.00, acetone); 1H NMR
(500 MHz, CDCl3): d 0.97 (t, 3H), 1.74–1.43 (m, 4H), 3.07–2.71 (m,
4H), 3.81 (s, 3H), 4.22 (s, 1H), 5.34 (d, J ¼ 9 Hz, 1H), 6.90 (d, J ¼ 8.5 Hz,
2H), 7.34 (d, J ¼ 8.5 Hz, 2H). IR (KBr): 3243, 2953, 2927, 1518, 1466,
1077, 1038, 992, 827 cmꢀ1. Anal. calcd. for C13H20O3S: C, 60.9; H, 7.8;
S, 12.5. Found: C, 60.6; H, 7.4; S, 12.3%.
Compound (2S)-8a
20
1
White solid; mp 112–113ꢁC; ½aꢂD ꢀ38.99ꢁ (c 1.00, acetone); H NMR
(500 MHz, CDCl3): d 0.96 (t, 3H), 1.76–1.44 (m, 4H), 3.06–2.67 (m,
4H), 3.80 (s, 3H), 3.93 (d, J ¼ 4 Hz, 1H), 5.32 (d, J ¼ 10.5 Hz, 1H), 6.90
(d, J ¼ 8.5 Hz, 2H), 7.33 (d, J ¼ 8.5 Hz, 2H); IR (KBr): 3256, 2960,

Phenyl-ethanolamine Synthesis
3343
2927, 1518, 1466, 1255, 1018, 834, 683 cmꢀ1. Anal. calcd. for C13H20O3S:
C, 60.9; H, 7.8; S, 12.5. Found: C, 60.7; H, 7.7; S, 12.7%.
Synthesis of N-butyl {2-hydroxy-2-(2,2-dimethyl-4H-
benzo[3,4-e]1,3-dioxin-6-yl}-ethyl Sulfoxides (7b and 8b)
This procedure was repeated by substitution of p-anisaldehyde with
yield
2,2-dimethyl-4H-benzo[3,4-e]1,3-dioxin-6-carboxaldehyde
diastereomers of sulfoxides, (2R)-7b (18%) and (2S)-8b (70%).
to
Compound (2R)-7b
20
1
White solid; mp 57–58ꢁC; ½aꢂD þ13ꢁ (c 1.00, acetone); H NMR (CDCl3,
500 MHz): d 0.98–0.95 (t, 3H), 1.54 (s, 6H), 1.77–1.43 (m, 4H), 2.90–2.70
(m, 4H), 4.84 (s, 2H), 4.86 (s, 2H), 5.31 (d, J ¼ 10Hz, 1H), 6.81 (d,
J¼ 8.5 Hz, 1H), 7.06 (d, J ¼ 1.8 Hz, 1H), 7.16 (dd, J ¼ 8.5, 1.8 Hz, 1H); IR
(KBr): 3203, 2966, 2927, 1618, 1503, 1120, 1019, 906, 861 cmꢀ1. Anal. calcd.
for C16H24O4S: C, 61.5; H, 7.7; S, 10.2 Found: C, 61.3; H, 7.6; S, 10.4%.
Compound (2S)-8b
20
1
White solid; mp 104–106ꢁC; ½aꢂD ꢀ11.11ꢁ (c 1.00, acetone); H NMR
(CDCl3, 500 MHz): d 0.98–0.96 (t, 3H), 1.53 (s, 6H), 1.75–1.40 (m,
4H), 3.03–2.72 (m, 4H), 4.84 (s, 2H), 4.96–4.88 (bs, 1H), 5.31 (d,
J ¼ 10 Hz, 1H), 6.81 (d, J ¼ 8.5 Hz, 1H), 7.06 (d, J ¼ 1.8 Hz, 1H), 7.17
(d, J ¼ 8.5, 1.8 Hz, 1H); IR (KBr): 3203, 2927, 2874, 1637, 1499, 1268,
1150, 1123, 1012, 913, 867 cmꢀ1. Anal. calcd. for C16H24O4S: C, 61.5;
H, 7.7; S, 10.2. Found: C, 61.2; H, 7.8; S, 10.5%.
Synthesis of (ꢀ)-(S)-2-(n-Butylthio)-1-(p-methoxyphenyl)-ethanol (9a)
A mixture of sulfoxide (2S)-8a (0.5 g, 1.95 mmol), saturated aqueous
sodium bisulfite solution (50 ml), and methanol (5 ml) was refluxed for
4 h and then extracted with several portions of hexane. The organic
solution was dried over sodium sulfate and evaporated under reduced
pressure to yield sulfide 9a (0.44 g, 94%).
20
Colourless liquid; ½aꢂD ꢀ25.6ꢁ (c 1.00, acetone); 1H NMR (500 MHz,
CDCl3) d 0.93–0.90 (t, 3H), 1.61–1.40 (m, 4H), 2.91–2.52 (m, 4H), 2.97
(bs, 1H), 3.80 (s, 3H), 4.69 (d, J ¼ 9 Hz, 1H), 7.11 (d, J ¼ 8.5 Hz, 2H),

3344
A. V. Sivakumar, A. M. Lahoti, and S. V. Bhat
7.30 (d, J ¼ 8.5 Hz, 2H). IR (KBr): 3461, 2929, 2864, 1611, 1507, 1462,
1254, 1047, 839, 605 cmꢀ1. Anal. calcd. for C13H20O2S: C, 64.9; H, 8.3;
S, 13.3. Found: C, 64.6; H, 8.0; S, 13.5%.
Synthesis of (2S)-n-Butyl [2-Hydroxy-2-(p-methoxyphenyl)-
ethyl)-sulfonium Iodide (10a)
The sulfide 9a (0.4 g, 1.66 mmol) was dissolved in methyl iodide (4 ml),
and the mixture was allowed to stand at 25ꢁC for 24 h. The reaction
mixture was diluted with diethyl ether (75 ml) and cooled to 0ꢁC over-
night. A white solid was crystallized out, which was filtered, washed with
cold ether, and dried to obtain compound 10a (0.585 g, 91%).
1
White solid; mp 91–92ꢁC; H NMR (CDCl3, 500 MHz): d 0.98–0.91
(t, 3H), 1.61–1.40 (m, 4H), 2.91–2.53 (m, 4H), 2.05 (s, 1H), 3.80 (s, 3H),
3.82 & 3.77 (2s, 3H), 4.70 (d, J ¼ 9 Hz, 1H), 6.89 (d, J ¼ 9 Hz, 2H), 7.03
(d, J ¼ 8.5 Hz, 2H); IR (KBr): 3441, 2929, 2844, 1611, 1527, 1254, 1469,
1183, 1047, 845, 768 cmꢀ1. Anal. calcd. for C14H23IO2S: C, 43.9; H, 6.0;
S, 8.3. Found: C, 44.2; H, 6.2; S, 8.5%.
Synthesis of (þ)-(S)-2-(tert-butylamino)-1-(4-methoxyphenyl)-ethanol (11a)
A solution of the sulfonium iodide 10a (0.55 g, 1.516 mmol) in
dry dimethyl sulfoxide (2 ml) (distilled from CaH) and dry THF (4 ml)
(distilled from sodium) was cooled to ꢀ10ꢁC under nitrogen. Then,
freshly prepared 1 M sodium methylsulfinylmethide (dimsyl sodium)
solution (2 ml) was added over 1 min. The mixture was allowed to
warm up to 20ꢁC over 1 h after an additional 20 min at 20–25ꢁC, the
mixture was poured into water, and the solution was extracted well with
ether. The ether solution was washed twice with water and dried over
sodium carbonate. The solvent was removed, and the residue was dried
in vacuo.
The crude mixture of (S)-p-methoxy-styrene oxide and n-butylmethyl
sulfide (0.3 g) was dissolved in acetonitrile (10 ml), and anhydrous lithium
perchlorate (1.5 equiv.) was added with stirring. The resulting solution
was treated under stirring at room temperature with tert-butyl amine
(2 equiv.), and the reaction mixture was stirred for 8 h at room tempera-
ture. The solvent was removed in vacuo, and the residue was diluted with
water and extracted with ether. The crude mixture was chromatographed
over alumina. Elution with 50:50 of methanol–ethyl acetate gave (þ)-(S)-
1-(p-methoxyphenyl)-2-(tert-butylamino)-ethanol (11a), 176 mg [58%; ee
96%; HPLC tR (R)-12a 11.05 min; tR (S)-11a 13.25 min].

Phenyl-ethanolamine Synthesis
3345
Compound 11a
20
White solid; mp 110–112ꢁC, ½aꢂD þ57ꢁ (c 1.00, CHCl3); 1H NMR
(400 MHz, CDCl3 & one drop of D2O): d 1.24 (s, 9H), 2.96 (dd,
J ¼ 12 Hz, 9.2 Hz, 1H), 3.13 (d, J ¼ 12 Hz, 1H), 3.77 (s, 3H), 5.28 (d,
J ¼ .9.2 Hz, 1H), 6.82 (d, J ¼ 8.8 Hz, 2H), 7.33 (d, J ¼ 8.8 Hz, 2H); IR
(KBr): 3423, 2999, 2890, 1963, 1614, 1494, 1250, 1036 cmꢀ1. Anal. calcd.
for C13H21NO2: C, 69.9; H, 9.5; N, 6.2. Found: C, 69.7; H, 9.2; N, 6.1%.
Syntheses of (ꢀ)-(R)-2-(tert-butylamino)-1-(p-methoxyphenyl)-ethanol
(12a) and (ꢀ)-(R)-2-(tert-Butylamino)-1-(2,2-dimethyl-4H-
benzo[3,4-e]1,3-dioxin-6-yl)-ethanol (12b)
The compounds (ꢀ)-(R)-12a (ee 95%) and (ꢀ)-(R)-12b (ee 96%) were
prepared similarly from sulfoxide 7a and 7b respectively.
Compound 12a
20
Mp 112–113ꢁC, ½aꢂD ꢀ55ꢁ (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3):
d 1.14 (s, 9H), 2.56 (dd, J ¼ 11.5 Hz, 8.2 Hz, 1H), 2.87 (dd, J ¼ 11.5,
4.1 Hz, 1H), 3.77 (s, 3H), 4.48 (dd, J ¼ .4.1, 8.2 Hz, 1H), 6.83 (d,
J ¼ 8.8 Hz, 2H), 7.34 (d, J ¼ 8.8 Hz, 2H); IR (KBr): 3423, 2999, 2890,
1963, 1614, 1494, 1250, 1036 cmꢀ1. Anal. calcd. for C13H21NO2: C,
69.9; H, 9.5; N, 6.2. Found: C, 69.8; H, 9.5; N, 6.0%.
Compound 12b
20
Mp 103–104ꢁC; lit.[16] mp 102–103ꢁC; ½aꢂD ꢀ18.7ꢁ (c 1.0, MeOH); lit.[16]
20
1
½aꢂD ꢀ18.9ꢁ (c 1.5, MeOH); H NMR (500 MHz, CDCl3) d 1.10 (s, 9H),
1.53 (s, 3H), 1.54 (s, 3H), 2.55 (dd, J ¼ 11.7, 9.2 1H), 2.86 (dd,
J ¼ 11.7,3.5 Hz), 4.50 (dd, J ¼ 9.2, 3.5 Hz, 1H), 4.85 (s, 2H), 6.79 (d,
J ¼ 8.5 Hz, 1H), 7.06 (d, J ¼ 1.6 Hz, 1H), 7.14 (d, J ¼ 8.5, 1.6 Hz, 1H); IR
(KBr): 3203, 2966, 2927, 1618, 1503, 1120, 1019, 906, 861 cmꢀ1. Anal. calcd.
for C16H25NO3: C, 68.8; H, 9.0; N, 5.0. Found: C, 68.6; H, 9.2; N, 5.2%.
CONCLUSIONS
Efficient enantioselective syntheses of (S)- and (R)-1-p-methoxyphenyl-2-
tert-butylamino-ethanols and (R)-salbutamol were achieved through the
application of chiral sulfoxide.

3346
A. V. Sivakumar, A. M. Lahoti, and S. V. Bhat
ACKNOWLEDGMENT
We thank the Department of Science and Technology, New Delhi, for
financial support.
REFERENCES
1. (a) Ibrahim, K. E.; Couch, M. W.; Williams, C. H.; Fregly, M. J.; Midgley, J. M.
Octopamine in mammalian sympathetic nerves. J. Neurochem. 1985, 94, 1862–
1867; (b) Albonico, S. M.; Kuck, A. M.; Deulofeu, V. Tembamide from Fagara
hyemalis (St. Hill) Engler. J. Chem. Soc. C 1967, 327–1328.
2. Garry, S. W.; Neilson, D. G. The preparation and absolute configuration
of the optically active forms of the diastereomeres of 2-(1-phenylethyl)-
amino-1-phenylethanol and their use as chiral auxiliaries to the asymmetric
reduction of acetophenone with modified lithium aluminium hydride.
J. Chem. Soc. Perkin Trans. 1 1987, 601–605.
3. Sadyandy, R.; Fernandes, R. A.; Kumar, P. An asymmetric dihydroxylation
route to (R)-(ꢀ)-octopamine, (R)-(ꢀ)-tembamide and (R)-(ꢀ)-aegeline.
Arkivoc 2005, 3, 36–43.
4. Takeda, H.; Tachinami, T.; Aburatani, M.; Takahashi, H.; Morimoto, T.;
Achiwa, K. Efficient asymmetric hydrogenation of a-aminoacetophenone
derivatives leading to practical asymmetric synthesis of (S)-(ꢀ)-levamisole.
Tetrahedron Lett. 1989, 30, 363–366.
5. Corey, E. J.; Link, J. B. The first enantioselective synthesis of R and S
isoproterenol. Tetrahedron Lett. 1990, 31, 601–604.
6. Hawkins, J.; Klease, G. T. Resolution of (ꢃ)-adrenaline b-sympathomimetic
amines. Aust. J. Chem. 1973, 26, 2553–2554.
7. (a) Hayashi, T.; Katsumura, A.; Konishs, M.; Kumada, M. Asymmetric
synthesis of 2-amino-1-arylethanols by catalytic hydrogenation. Tetrahedron
Lett. 1979, 20, 425–428; (b) Tramontini, M. Stereospecific synthesis of
diastereomeric amino alcohols from aminocarbonyl compounds by reduction
or by addition of organometallic reagents. Synthesis 1982, 8, 605–644; (c)
Samaddar, A. K.; Konar, S. K.; Nasipuri, D. Asymmetric synthesis, Part 6:
Asymmetric reduction of aminoketones with (ꢀ)-bornan-2-exoaryloxyalumi-
nium dichloride. J. Chem. Soc., Perkin Trans. 1 1983, 1449–1451; (d) Brown,
H. C.; Pai, G. G. Asymmetric reduction of prochiral a-haloketones with
b-3-pinonyl-9-borabicyclo[3.3.1]nonane. J. Org. Chem. 1983, 48, 1784–1786;
(e) Cho, B. T.; Shin, S. H. Efficient synthesis of optically active 2-N-Boc (or
Cbz)-amino-1-arylethanols as key intermediates for synthesis of chiral drugs
via asymmetric reduction. Bull. Korean Chem. Soc. 2004, 25, 747–750; (f)
Cordes, D. B.; Kwong, T. J.; Morgan, K. A.; Singaram, B. Chiral styrene oxi-
des from a-haloacetophenones using NaBH4 and TarB-NO2 a chiral Lewis
acid. Tetrahedron Lett. 2006, 47, 349–351; (g) Ramachandran, P. V.; Gong,
B.; Brown, H. C. Chiral synthesis via organoboranes, the utility of b-
chlorodiisopinocamphenylborane for a general synthesis of enantiomerically

Phenyl-ethanolamine Synthesis
3347
pure drugs. Chirality 2004, 7, 103–110; (h) Li, L.; Wu, J.; Wang, F.; Uao, J.;
Zhang, H.; Lian, C.; Zhu, J.; Deng, J. Asymmetric transfer hydrogenation of
ketones and imines with novel water-soluble chiral diamines as ligand in neat
water. Green Chem. 2007, 9, 23–25.
8. (a) Becker, W.; Freund, H.; Pfeil, E. Stereospecific synthesis of D-hydroxy-
nitriles and optically active ethanol amines. Angew. Chem., Int. Ed. Engl.
1965, 4, 1079–1081; (b) Elliol, J. D.; Choi, V. M. F.; Johnson, W. S. Asym-
metric synthesis via acetal template: Five reactions with cyanomethylsilane
enantioselective preparation of cyanohydrins and derivatives. J. Org. Chem.
1983, 48, 2294–2295; (c) Jackson, W. R.; Jacobs, H. A.; Matthews, B. R.;
Jayatelake, G. S. Stereoselective synthesis of ephedrine and related
2-aminoalcohols of high optical purity from protected cyanohydrins. Tetra-
hedron Lett. 1990, 31, 1447–1450.
9. (a) Yamada, H.; Shimizu, S. Microbial and enzymatic processes for the
production of biologically and chemically useful compounds. Angew. Chem.,
Int. Ed. Engl. 1988, 27, 622–642; (b) Steinreiber, J.; Schumann, M.; Asemma,
F.; Wolberg, M.; Fesko, K.; Reisinger, C.; Mink, D.; Griengl, H. Synthesis of
aromatic 1,2-amino alcohols using a bienzymatic dynamic asymmetric trans-
formation. Adv. Synth. Catal. 2007, 349, 1379–1386; (c) Izumi, T.; Fukaya, K.
Baker’s yeast reduction of a-(acylamino)-acetophenones and lipase-catalyzed
resolution of 2-acylamino-1-arylethanols. Bull. Chem. Soc. Jpn. 1993, 66,
1216–1221.
10. (a) Xiaong, Y.; Wang, F.; Huang, X.; Wen, Y.; Feng, X. A new copper (I)–
tetrahydrosalen–catalyzed asymmetric Henry reaction and its extension to the
synthesis of (S)-norphenylephrine. Chemistry 2007, 13, 829–831; (b) Fujita,
M.; Urata, Y.; Sasai, H.; Shibasaki, M. Optically active nitroalcohols and
optically active amino alcohols. US Patent 7205425, April 2007.
11. Davis, F. A.; Zhou, P.; Chen, B. C. Asymmetric synthesis of amino acids
using sulfinimines. Chem. Soc. Rev. 1998, 27, 13–18.
12. (a) Sivakumar, A. V.; Babu, G. S.; Bhat, S. V. Asymmetric synthesis of
b-amino acids using chiral sulfoxide. Tetrahedron: Asymmetry 2001, 12,
1095–6389; (b) Lockard, J. P.; Schroeck, C. W.; Johnson, C. R. Optically
active dialkylsulfoxide from arylalkylsulfoxide. Synthesis 1973, 485–488.
13. Johnson, C. R.; Bacon, C. C.; Rigau, J. J. Reductions of sulfoxides with
sodium hydrogen sulfite. J. Org. Chem. 1972, 37, 919–920.
14. Corey, E. J.; Chaykovsky, M. Dimethyl sulfinyl carbanion formation and
applications. J. Am. Chem. Soc. 1965, 87, 1341–1353.
15. Chini, M.; Crotti, P.; Macchia, F. Metal salts as new catalysts for mild and
efficient aminolysis of oxiranes. Tetrahedron Lett. 1990, 31, 466–468.
16. Caira, M. R.; Hanter, R.; Nassimbeni, L. R.; Stevens, A. T. Resolution of
albuterol acetonide. Tetrahedron: Asymmetry 1999, 10, 2175–2189.