Application of optically active 1,2-diol monotosylates for synthesis of β-azido and β-amino alcohols with very high enantiomeric purity. Synthesis of enantiopure (R)-octopamine, (R)-tembamide and (R)-aegeline

Article abstract of DOI:10.1016/S0957-4166(02)00322-1

A very convenient and highly efficient synthesis of near enantiopure β-azido and β-amino alcohols including biologically active substances such as (R)-octopamine, (R)-tembamide and (R)-aegeline from optically active 1,2-diol monotosylates is reported.

Full text of DOI:10.1016/S0957-4166(02)00322-1

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 1209–1217
Application of optically active 1,2-diol monotosylates for
synthesis of b-azido and b-amino alcohols with very high
enantiomeric purity. Synthesis of enantiopure (R)-octopamine,
(R)-tembamide and (R)-aegeline
Byung Tae Cho,* Sang Kyu Kang and Sung Hye Shin
Department of Chemistry, Hallym University, Chunchon, Kangwondo 200-702, South Korea
Received 16 May 2002; accepted 13 June 2002
Abstract—A very convenient and highly efficient synthesis of near enantiopure b-azido and b-amino alcohols including
biologically active substances such as (R)-octopamine, (R)-tembamide and (R)-aegeline from optically active 1,2-diol monotosyl-
ates is reported. © 2002 Elsevier Science Ltd. All rights reserved.
accompanied by the formation of undesired regioiso-
mers having the azido group at the benzylic posi-
tion.6b–f For other methods for synthesis of chiral 2-
amino-1-arylethanols, reduction of non-racemic aryl-
cyanohydrins,10 baker’s yeast-mediated reduction of
a-(acyl or alkoxycarbonylamino)-acetophenones and
lipase-catalyzed resolution of 2-(acyl or alkoxycarbonyl-
amino)-1-arylethanols have been published.11 On the
other hand, (R)-octopamine 1 is a potent chiral drug pos-
sessing b-adrenergic activity12 and (R)-tembamide 2
and (R)-aegeline 3 are naturally occurring biologically
active substances which are used in traditional Indian
medicine and have been shown to have hypoglycemic
activity.13 To date only a few methods for the prepara-
tion of these compounds have been presented, involving
the resolution of a racemic mixture12 and a multi-step
synthesis using optically active cyanohydrins as starting
materials.13 Very recently, the asymmetric synthesis of
(R)-2 and (R)-3 via enzymatic reduction of a-azido
arylketones has been reported.14 Recently, we reported
a convenient method for the preparation of 1,2-diol
monotosylates with high optical purity via CBS-oxaza-
borolidine-catalyzed borane reduction of 1-substituted-
2-(p-tosyloxy)ethanones.15 The results encouraged us to
develop a convenient route to the synthesis of optically
active b-azido alcohols that avoid the formation of
undesired regioisomers. We report herein a highly effec-
tive new method for synthesis of these compounds from
1,2-diol monotosylates and the corresponding b-amino
alcohols with very high enantiomeric purity including
(R)-1, (R)-2 and (R)-3 (Fig. 1).
1. Introduction
Optically active b-azido alcohols are of great signifi-
cance as potential precursors for non-racemic
aziridines1 and b-amino alcohols.2 The latter com-
pounds are not only a common structural component
in a vast group of naturally occurring and synthetic
molecules, but also can be widely used as versatile
chiral building blocks and chiral catalysts3 in organic
synthesis. In particular, chiral 2-amino-1-arylethanols
are important structural elements in pharmaceuticals
such as a- or b-adrenergic blockers and agonists in the
treatment of cardiovascular disease, cardiac failure,
asthma and glaucoma.4 Accordingly, the development
of practical methods for regio- and enantioselective
synthesis of enantiopure 2-azido-1-arylethanols is of
great interest. For the synthesis of these compounds,
many methods, including the enzymatic resolution of a
racemic mixture,5 enantio- or regioselective azidolysis
of aryloxiranes using biological6a and chemical meth-
ods,6b–f and reductions of 2-azido-1-arylethanones by
catalytic asymmetric hydrogenation,7a CBS-oxazaboro-
lidine-catalyzed borane,7b sodium borohydride in the
presence of b-cyclodextrin8 and baker’s yeast9 have
been reported. However, the resolution methods suffer
from the fact that the theoretical yields are limited to
50%.5b The azidolysis of aryloxiranes is commonly
* Corresponding author. Fax: +82-33-251-8491; e-mail: btcho@
hallym.ac.kr
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00322-1

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B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 1209–1217
OH
OH
NH2
NHCOR
2
HO
MeO
R = Ph: (R)-tembamide
R = (E)-PhCH=CH: (R)-aegeline
1
3
(R)-octopmine
Figure 1.
2. Results and discussion
1-(p-benzyloxyphenyl)-2-tosyloxyethanone 6d catalyzed
by (R)-CBS-oxazaborolidine afforded (R)-1-(p-benzyl-
oxyphenyl)-2-tosyloxyethanol (R)-7d in almost quanti-
tative yield. Azidation of (R)-7d with sodium azide in
DMSO provided (R)-8d with 99% e.e. in 96% yield
(entry 4 in Table 1). Subsequent reduction and deben-
zylation of (R)-8d by catalytic hydrogenation on 20%
Pd(OH)2/C at 55 psi for 15 h furnished enantiopure
(R)-1 in 94% yield. On the other hand, acylation of
b-amino alcohol (R)-9c (entry 3 in Table 2) with ben-
zoyl chloride in the presence of pyridine at 0°C gave
(R)-2 in 89% yield. Similarly (R)-9c was treated with
(E)-cinnamoyl chloride to afford (R)-3 in 88% yield
(Scheme 2).
According to our previous procedure,15 we carried out
(R)- or (S)-CBS-oxazaborolidine 4-catalyzed asymmet-
ric borane reduction of 1-substituted-2-(p-tosyl-
oxy)ethanones 6 using an environmentally benign
borane carrier, N-ethyl-N-isopropylaniline-borane
complex 5, as the hydride source. The reduction pro-
vided optically active 1,2-diol monotosylates 7 with
very high enantiomeric purity (approaching 100% e.e.)
by performing recrystallization when necessary. To pre-
pare non-racemic 2-azido alcohols 8, (R)- or (S)-7
obtained was treated with 2 equiv of sodium azide in
DMSO at 80°C for 2–3 h (Scheme 1). As shown in
Table 1, all the reaction proceeded smoothly to give the
desired products 8 in high yields. The enantiomeric
purities of 8, determined by HPLC analysis using
Whelk-O1, Chiralcel OD, Chiralcel OD-H chiral
columns or GC analysis using a- or b-Dex 120 chiral
columns, were very high, with near 100% e.e. for all the
products bearing aryl, alkyl and 2-thienyl groups. The
results indicate that no racemization occurred during
the azidation reaction. The b-azido alcohols 8 obtained
were hydrogenated under atmospheric pressure over
10% Pd/C to give the optically active 2-amino alcohols
9 in high yields. The results are summarized in Table 2.
3. Conclusion
We have developed a simple and highly efficient
method for obtaining optically active 2-azido and 2-
amino-1-substituted alcohols including biologically
active substances such as (R)-octopamine, (R)-tem-
bamide and (R)-aegeline with near 100% enantiomeric
purity from the corresponding chiral 1,2-diol monoto-
sylates. It is noteworthy that this method provides a
convenient route to optically active b-azido and b-
amino alcohols with near 100% e.e. that avoids the
formation of undesired regioisomers.
We applied this methodology to the synthesis of (R)-1,
(R)-2 and (R)-3. Thus asymmetric borane reduction of
i. 4 (0.1 eq)
ii. 5 (1.0 eq)
OH
OH
O
or
OTs-p
OTs-p
OTs-p
THF, 25o C
R
R
R
(S)-7
(R)-7
6
By (R)-4
By (S)-4
R = aryl, alkyl or 2-thienyl
Ph
Ph
O
Ph
Ph
Et
N
Ph
Pr-i
N
O
N
BH3
B
B
Me
(S)-4
Me
5
(R)-4
OH
OH
H2, 10% Pd/C
NaN3 (2eq)
(R)-7
(S)-7
N3
NH2
NH2
R
R
R
DMSO, 80o C
1 atm, MeOH, rt
(R)-9
(R)-8
OH
OH
H2, 10% Pd/C
NaN3 (2eq)
N3
R
DMSO, 80o C
1 atm, MeOH, rt
(S)-9
(S)-8
Scheme 1.

B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 1209–1217
Table 1. Preparation of optically active 2-azido-1-substituted ethanols 8a
1211

1212
B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 1209–1217
Table 2. Preparation of optically active 2-amino-1-substituted ethanols 9a
4. Experimental
ended needle. The reactions were monitored by TLC
using silica gel plates and the products were purified by
flash column chromatography on silica gel (Merck;
230–400 mesh). NMR spectra were recorded at 200 or
4.1. General
1
400 MHz for H and 50 or 100 MHz for 13C using
All operations with air-sensitive materials were carried
out under a nitrogen atmosphere with oven-dried glass-
ware. Liquid materials were transferred with a double-
Me4Si as the internal standard in CDCl3, DMSO-d6, or
DCl/D2O. Optical rotations were measured with a high

B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 1209–1217
OH
1213
[α]20D -37.6 (c 0.56, H2O)
H2, 20% Pd(OH)2/C
N3
(R)-1
55 psi, EtOH, rt
lit.12a [α]25D -37.4 (c 1.0, H2O)
BnO
MeO
(R)-8d
OH
[α]20D -56.4 (c 0.5, CHCl3)
lit.14 [α]25D -59.6 (c 0.5, CHCl3)
PhCOCl, Pyridine
CH2Cl2, 0o C
(R)-2
(R)-3
NH2
(E)-PhCH=CHCOCl
Pyridine
CH2Cl2, 0o C
[α]20D -35.7 (c 0.33, CHCl3)
(R)-9c
lit.13a [α]24D -35.6 (c 0.4, CHCl3)
Scheme 2.
resolution digital polarimeter. Melting points were
uncorrected. Enantiomeric excesses (e.e.s) of the
product 2-azido alcohols were determined with a HPLC
apparatus fitted with a 25 cm Whelk-O1 (Regis), Chi-
ralcel OD or Chiralcel OD-H (Daicel) chiral column
and/or a capillary GC using a 25 m a- or b-Dex 120
chiral column (Supelco).
141.2; Calcd. for C8H9N3O: C, 58.88; H, 5.56; N, 25.75.
Found: C, 58.92; H, 5.58; N, 25.80; [h]2D0 +104.5 (c 1.3,
CHCl3) {lit.9 [h]D25 −80.1 (c 0.78, CHCl3), R, 100% e.e.};
HPLC analysis showed it to be 99% e.e., S [iso-PrOH/
hexane: 1/99; tR(S) 13.58 min and tR(R) 16.07 min].
4.3.2. (S)-(+)-2-Azido-1-(p-tolyl)ethanol 8b. Rf 0.51;
96% yield; oil; IR (neat, cm−1) 3425, 2924, 2099, 1513,
1439; 1H NMR (200 MHz, CDCl3) l 2.30 (d, 1H,
J=2.44 Hz); 2.35 (s, 3H), 3.38–3.54 (m, 2H), 4.85 (m,
1H), 7.17–7.29 (m, 4H); 13C NMR (50 MHz, CDCl3) l
21.8, 58.7, 74.0, 126.5, 130.1, 138.3, 138.9; [h]2D0 +103.2
(c 1.46, CHCl3) {lit.9 [h]D25 −28.2 (c 1.2, CHCl3), R, 96%
e.e.}; HPLC analysis showed it to be 99% e.e., S [flow
rate=0.5 ml/min; tR(S) 9.36 min and tR(R) 10.27 min].
4.2. Materials
Most of the organic compounds utilized in this study
were commercial products of the highest purity. They
were further purified by distillation where necessary.
THF was distilled over sodium benzophenone ketyl and
stored in ampules under nitrogen atmosphere. (R)- and
(S)-CBS-oxazaborolidine reagent and N-ethyl-N-iso-
propylaniline-borane complex were purchased from the
Aldrich Chemical Company. Optically active 1.2-diol
monotosylates, (R)- or (S)-7 with 99% e.e., used as
starting materials were prepared from CBS-oxazaboro-
lidine-catalyzed borane reduction of 1-substituted-2-(p-
4.3.3. (R)-(−)-2-Azido-1-(p-methoxyphenyl)ethanol 8c.
Rf 0.48; 99% yield; oil; IR (neat, cm−1) 3451, 2930,
1
2100, 1611, 1512; H NMR (200 MHz, CDCl3) l 2.36
(br s, 1H); 3.34–3.53 (m, 2H), 3.81 (s, 3H), 4.82 (m,
1H), 6.90 (d, 2H, J=8.55 Hz), 7.29 (d, 2H, J=8.85
Hz); 13C NMR (50 MHz, CDCl3) l 55.9, 58.7, 73.7,
114.7, 127.9, 133.4, 160.3; [h]2D0 −117.2 (c 1.3, CHCl3)
{lit.9 [h]D25 −39.0 (c 1.0, CHCl3), R, 97% e.e.}; HPLC
analysis showed it to be 99% e.e., R [iso-PrOH/hex-
ane=1: 40; flow rate=0.8 ml/min; tR(S) 15.56 min and
tR(R) 20.07 min].
tosyloxy)ethanones
6
according to the reported
procedure.15
4.3. General procedure for preparation of optically active
b-azido alcohols 8 from 7
A mixture of (R)- or (S)-7 (2 mmol) and sodium azide
(4 mmol) in DMSO (5 mL) was heated at 80°C for 2–3
h and then cooled to room temperature. To this was
added water (5 mL) and the mixture was extracted with
CH2Cl2 (3×5 mL). The combined extract was dried over
anhydrous MgSO4, filtered and concentrated. The
crude 2-azido-1-arylethanols (R)- or (S)-8 obtained
were further purified by a flash column chromatogra-
phy on silica gel (230–400 mesh) using ethyl acetate/
hexane (1/2) unless otherwise indicated. The
enantiomeric excesses of 8 were determined by HPLC
analysis using a Whelk-O1 column [iso-PrOH/hexane:
1/9; flow rate: 1.0 mL/min; detector: 254 nm] unless
otherwise indicated. Absolute configurations were
assigned by comparison with those of 8 reported.9
4.3.4. (R)-(−)-2-Azido-1-(p-benzyloxyphenyl)ethanol 8d.
Rf 0.70 (EtOAc/hexane 1: 1); 96% yield; mp 69–70°C;
IR (KBr, cm−1) 3434, 3129, 3004, 2877, 2096, 1611,
1
1512, 1454; H NMR (200 MHz, CDCl3) l 2.33 (d, 1H,
J=3.05 Hz); 3.40–3.46 (m, 2H), 4.81 (m, 1H), 5.06 (s,
2H), 6.97 (d, 2H, J=8.85 Hz), 7.25–7.41 (m, 7H); 13C
NMR (50 MHz, CDCl3) l 58.7, 70.7, 73.7, 115.8, 118.7,
127.9, 128.1, 128.7, 129.3, 133.7, 137.5, 159.6; Calcd.
for C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C,
66.93; H, 5.29; N, 15.57; EIMS: m/z=267 (M+); [h]D20
−72.2 (c 1.1, CHCl3); HPLC analysis showed it to be
99% e.e., R [flow rate=0.5 ml/min; tR(S) 15.77 min and
tR(R) 18.69 min].
4.3.5. (S)-(+)-2-Azido-1-(p-fluorophenyl)ethanol 8e. Rf
0.45; 97% yield; mp 37–39oC; IR (KBr, cm−1) 3417,
2925, 2105, 1605, 1512, 1228; 1H NMR (200 MHz,
CDCl3) l 2.40 (d, 1H, J=3.36 Hz), 3.43–3.47 (m, 2H),
4.3.1. (S)-(+)-2-Azido-1-phenylethanol 8a. Rf 0.61; 99%
yield; oil; IR (neat, cm−1) 3414, 3065, 2922, 2093, 1493,
1
1452; H NMR (200 MHz, CDCl3) l 2.38 (br s, 1H),
3.40–3.55 (m, 2H), 4.89 (m, 1H), 7.26–7.39 (m, 5H); 13
C
4.87 (m, 1H), 7.02–7.11 (m, 2H), 7.32–7.39 (m, 2H); 13
C
NMR (50 MHz, CDCl3) l 58.7, 74.1, 126.6, 129.4,
NMR (50 MHz, CDCl3) l 58.7, 73.4, 116.1, 116.5,

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B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 1209–1217
128.3, 128.4, 136.9, 160.8; [h]2D0 +92.8 (c 2.07, CHCl3);
{lit.9 [h]D25 −14.7 (c 2.0, CHCl3), R, 98% e.e.}; HPLC
analysis showed it to be 99% e.e., S [iso-PrOH/hexane:
1/99; tR(S) 11.07 min and tR(R) 13.04 min].
HPLC analysis using Daicel OD chiral column showed it
to be 98% e.e., S [iso-PrOH/hexane=1: 40; flow rate=
0.8 ml/min; tR(S) 45.09 min and tR(R) 49.40 min].
4.3.11. (S)-(+)-1-Azido-3,3-dimethyl-2-butanol 8k. Rf
0.66; 85% yield; oil; IR (neat, cm−1) 3452, 2963, 2095,
1500, 1390; 1H NMR (200 MHz, CDCl3) l 0.94 (s, 9H),
2.05 (d, 1H, J=3.66 Hz), 3.28 (m, 1H), 3.40–3.46 (m,
2H); 13C NMR (50 MHz, CDCl3) l 26.4, 34.7, 54.4, 79.0;
EIMS: m/z=144 (M+H)+; [h]D20 +1.4 (c 1.05, CHCl3);
[h]2D0 −6.58 (c 1.05, CH2Cl2); {lit.5b [h]2D0 –6.8 (c 2,
CH2Cl2), R, >98% e.e.}; GC analysis using i-Dex 120
(Supelco) chiral capillary column showed it to be 98%
e.e., S [isothemal; 100oC; tR(S) 34.42 min and tR(R)
36.17 min].
4.3.6. (S)-(+)-2-Azido-1-(m-chlorophenyl)ethanol 8f. Rf
0.53; 96% yield; oil; IR (neat, cm−1) 3392, 2898, 2083,
1
1616, 1577; H NMR (200 MHz, CDCl3) l 2.48 (d, 1H,
J=3.36 Hz); 3.45 (d, 2H, J=5.80 Hz), 4.86 (m, 1H),
7.24–7.39 (m, 4H); 13C NMR (50 MHz, CDCl3) l 58.6,
73.4, 124.7, 126.8, 129.2, 130.7, 135.4, 143.2; Calcd. for
C8H8ClN3O: C, 48.62; H, 4.08; N, 21.26. Found: C,
48.73; H, 4.23; N, 21.25; EIMS: m/z=198 (M+H)+; [h]D20
+84.5 (c 1.42, CHCl3); HPLC analysis using Daicel
OD-H chiral column showed it to be 99% e.e., S [tR(R)
7.64 min and tR(R) 8.64 min].
4.3.12. (S)-(+)-2-Azido-1-(cyclohexyl)ethanol 8l. Rf 0.61;
94% yield; oil; IR (neat, cm−1) 3415, 2928, 2101, 1449; 1H
NMR (200 MHz, CDCl3) l 1.00–1.82 (m, 11H), 1.89 (d,
1H, J=4.58 Hz), 3.33–3.41 (m, 2H), 3.49 (m, 1H); 13C
NMR (50 MHz, CDCl3) l 26.5, 26.7, 26.9, 28.9, 29.6,
42.0, 55.8, 75.7; Calcd. for C8H15N3O: C, 56.78; H, 8.93;
N, 24.83. Found: C, 56.93; H, 8.74; N, 24.64; FAB MS:
m/z=169 (M+); [h]D20 +14.2 (c 1.04, CHCl3); GC analysis
using a-Dex 120 (Supelco) chiral capillary column
showed it to be 99% e.e., S [isothemal; 140oC; tR(S)
25.92 min and tR(R) 26.72 min].
4.3.7. (S)-(+)-2-Azido-1-(p-chlorophenyl)ethanol 8g. Rf
0.48; 98% yield; mp 47–49°C [lit.9 47–48.5°C]; IR (KBr,
cm−1) 3417, 2974, 2099, 1598, 1493; 1H NMR (200 MHz,
CDCl3) l 2.55 (br s, 1H); 3.43 (d, 2H, J=5.80 Hz), 4.86
(t, 1H, J=5.95 Hz), 7.26–7.38 (m, 4H); 13C NMR (50
MHz, CDCl3) l 58.6, 73.4, 128.0, 129.5, 134.8, 139.6;
Calcd. for C8H8ClN3O: C, 48.62; H, 4.08; N, 21.26.
Found: C, 48.78; H, 4.15; N, 21.29 [h]2D0 +96.4 (c 1.25,
CHCl3); {lit.9 [h]D25 −79.1 (c 1.25, CHCl3), R, 100% e.e.};
HPLC analysis showed it to be 99% e.e., S [iso-PrOH/
hexane=1: 99; tR(S) 11.72 min and tR(R) 13.42 min].
4.4. General procedure for preparation of optically
active 2-amino-1-substituted ethanols 9 from 8
4.3.8. (R)-(−)-2-Azido-1-(3’,4’-dichlorophenyl)ethanol 8h.
Rf 0.60 (EtOAc/hexane 1: 1); 98% yield; oil; IR (neat,
cm−1) 3421, 2924, 2092, 1390, 1469; 1H NMR (200 MHz,
CDCl3) l 2.49 (d, 1H, J=3.66 Hz); 3.45 (d, 2H, J=5.80
Hz), 4.85 (m, 1H), 7.22 (m, 1H), 7.43–7.50 (m, 2H); 13C
NMR (50 MHz, CDCl3) l 58.5, 72.8, 125.9, 128.7, 131.4,
133.0, 133.6, 141.4; Calcd. for C8H7Cl2N3O: C, 41.40; H,
3.04; N, 18.11. Found: C, 41.51; H, 3.24; N, 18.14;
EIMS: m/z=231 (M+); [h]D20 −103.9 (c 0.92, CHCl3);
HPLC analysis showed it to be >99% e.e., R [iso-PrOH/
hexane=1: 99; flow rate=0.8 ml/min; tR(S) 18.15 min
and tR(R) 19.07 min].
A mixture of 8 (2 mmol) and 10% Pd/C (140 mg) in MeOH
(1m mL) was hydrogenated using hydrogen balloon at
room temperature for 15 h, filtered on a celite pad and
the filtrate was concentrated. Solid products obtained
were washed with ether to give 9. If necessary, 9 was
further purified by a flash column chromatography on
silica gel (230–400 mesh) using n-BuOH/AcOH/H2O(3/1/
1). The enantiomeric excesses and absolute configurations
of 9 were determined by comparison of those reported
in literatures or on the base of the values for the
corresponding 2-azido alcohols 8 determined as above.
4.3.9. (S)-(+)-2-Azido-1-(2’-naphthyl)ethanol 8i. Rf 0.57;
99% yield; mp 81–82°C (lit.9 mp 80–81.5°C); IR (KBr,
cm−1) 3423, 2926, 2102, 1609, 1277; 1H NMR (200 MHz,
CDCl3) l 2.48 (d, 1H, J=3.05 Hz); 3.44—3.63 (m, 2H),
4.4.1. (S)-(+)-2-Amino-1-phenylethanol 9a. Rf 0.72; 99%
yield; mp 55–57oC (lit.16 55–57°C; IR (KBr, cm−1) 3357,
3248, 3123, 2922, 1640, 1611, 1492, 1466; 1H NMR (200
MHz, DMSO-d6) l 2.52–2.78 (m, 3H), 2.89–3.43 (m,
5.04 (m, 1H), 7.43–7.52 (m, 3H), 7.82–7.88 (m, 4H); 13
C
NMR (50 MHz, CDCl3) l 58.6, 74.2, 124.3, 125.7, 127.0,
127.1, 128.4, 128.7,129.2, 133.9, 138.6; Calcd. for
C12H11N3O: C, 67.59; H, 5.20; N, 19.71. Found: C,
67.59; H, 4.97; N, 19.67; [h]2D0 +125.2 (c 0.55, CHCl3);
{lit.9 [h]D25 −80.1 (c 0.55, CHCl3), R, 96% e.e.}; HPLC
analysis showed it to be 99% e.e., S [tR(S) 6.99 min and
tR(R) 8.30 min].
1
2H), 4.45 (t, 1H, J=5.80 Hz), 7.20–7.33 (m, 5H); H
NMR (200 MHz, 2.2 N DCl/D2O) l 2.43–2.61 (m, 2H),
4.29 (m, 1H), 6.70 (s, 5H); 13C NMR (50 MHz, DMSO-
d6) l 50.3, 74.4, 126.4, 127.2, 128.4, 144.8; Calcd. for
C8H11NO: C, 70.04; H, 8.08; N, 10.21. Found: C, 70.02;
H, 8.11; N, 10.32; [h]2D0 +48.6 (c 2.01, EtOH) from (S)-8a
with 99% e.e. {lit.16 [h]2D3 +47.9 (c 2.4, EtOH), S, 100%
e.e.}.
4.3.10. (R)-(+)-2-Azido-1-(2’-thienyl)ethanol 8j. Rf 0.58;
98% yield; oil; IR (neat, cm−1) 3418, 3100, 2924, 2104,
1438; 1H NMR (200 MHz, CDCl3) l 2.68 (d, 1H,
J=3.66 Hz); 3.42–3.64 (m, 2H), 5.12 (m, 1H), 6.98–7.04
(m, 2H), 7.29 (m, 1H); 13C NMR (50 MHz, CDCl3) l
58.4, 70.2, 125.3, 126.2, 127.6, 144.6; Calcd. for
C6H7N3OS: C, 42.59; H, 4.17; N, 24.83; S, 18.95. Found:
C, 42.71; H, 4.21; N, 24.91; S, 18.98; [h]2D0 +75.2 (c 1.0,
CHCl3); {lit.9 [h]D25 –34.2 (c 1.2, CHCl3), S, 92% e.e.};
4.4.2. (S)-(+)-2-Amino-1-(p-tolyl)ethanol 9b. Rf 0.71;
95% yield; mp 68–70°C [lit.10a 76–78°C]; IR (KBr, cm−1)
3433, 3216, 3101, 2973, 1513; 1H NMR (200 MHz,
DMSO-d6) l 2.35 (s, 3H), 2.49–2.84 (m, 2H), 3.52–4.04
1
(br s, 3H), 4.51(m, 1H), 7.18–7.30 (m, 4H); H NMR
(200 MHz, 2.2 N DCl/D2O) l 1.81 (s, 3H), 2.71–2.77 (m,
2H), 4.47 (m, 1H), 6.75–6.85 (m, 4H); 13C NMR (50

B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 1209–1217
1215
MHz, DMSO-d6) l 20.8, 50.0, 73.9, 125.9, 128.5, 135.7,
141.3; Calcd. for C9H13NO: C, 71.49; H, 8.67; N, 9.26.
Found: C, 71.52; H, 8.66; N, 9.28; [h]2D0 +42.3 (c 0.54,
EtOH); [h]2D0 +51.8 (c 0.24, Et2O) from (S)-8b with 99%
e.e. {lit.10a [h]D20 −49 (c 0.6, Et2O), >98% e.e., R}.
(m, 2H), 4.46 (m, 1H), 7.14–7.52 (m, 4H); 1H NMR (200
MHz, 2.2 N DCl/D2O) l 2.27–2.41 (m, 2H), 4.09 (m,
1H), 6.43–6.53 (s, 4H);13C NMR (50 MHz, DMSO-d6) l
50.0, 73.7, 127.8, 127.9, 131.2, 143.5; Calcd. for
C8H10ClNO: C, 55.99; H, 5.87; N, 8.16. Found: C, 56.12;
H, 5.91; N, 8.22; [h]D20 +40.5 (c 0.53, EtOH); [h]2D0 +67.4 (c
0.35, CHCl3) from (S)-8g with 99% e.e.; {lit.11a [h]D20
+65.1 (c 0.48, CHCl3), 99% e.e., S}.
4.4.3. (R)-(−)-2-Amino-1-(p-methoxyphenyl)ethanol 9c.
Rf 0.69; 98% yield; 100–102oC (lit.17 102–103°C); IR
(KBr, cm−1) 3350, 3199, 3083, 2977, 1627, 1513; 1H
NMR (200 MHz, CDCl3) l 1.68–2.12 (br s, 3H), 2.67–
3.02 (m, 2H), 3.80 (s, 3H), 4.58 (br s, 1H), 6.89 (d, 2H,
4.4.8.
(R)-(−)-2-Amino-1-(3%,4%-dichlorophenyl)ethanol
9h. Rf 0.74; 99% yield; oil; IR (neat, cm−1) 3362, 3179,
2922, 2740, 1589, 1566, 1467; 1H NMR (200 MHz,
DMSO-d6) l 2.67 (m, 1H), 2.97–3.92 (m, 4H), 4.50 (m,
1
J=8.24 Hz), 7.27 (d, 2H, J=8.24 Hz); H NMR (200
MHz, 2.2 N DCl/D2O) l 2.46–2.50 (m, 2H), 3.07 (s, 3H),
4.22 (m, 1H), 6.27 (d, 2H, J=8.85 Hz), 6.64 (d, 2H,
J=8.55 Hz); 13C NMR (50 MHz, CDCl3) l 51.3, 55.9,
74.8, 114.5, 127.8, 135.3, 159.8; Calcd. for C9H13NO2: C,
64.65; H, 7.84; N, 8.38. Found: C, 64.63; H, 7.59; N,
8.32; [h]2D0 –39.9 (c 1.03, abs. EtOH) from (R)-8c with
99% e.e. {lit.17 [h]D20 −38.6 (c 1.0, abs. EtOH), R, 96%
e.e.}.
1
1H), 7.31 (m, 1H), 7.55–7.96 (m, 2H); H NMR (200
MHz, 2.2 N DCl/D2O) l 2.12–2.24 (m, 2H), 3.96 (m,
1H), 6.25 (m, 1H), 6.46–6.52 (m, 2H); 13C NMR (50
MHz, DMSO-d6) l 49.4, 72.8, 126.4, 127.0, 129.1, 130.1,
130.6, 145.6; Calcd. for C8H9Cl2NO: C, 46.63; H, 4.40;
N, 6.80. Found: C, 46.66; H, 4.47; N, 6.76; EIMS:
m/z=206 (M+H)+; [h]D20 −34.7 (c 0.42, EtOH) from
(S)-8h with 100% e.e..
4.4.4. (R)-(−)-2-Amino-1-(p-benzyloxyphenyl)ethanol 9d.
Rf 0.81; 98% yield; mp 130–132 oC; IR (KBr, cm−1) 3345,
3063, 2908, 1611, 1586, 1502, 1468; 1H NMR (400 MHz,
DMSO-d6) l 2.50–2.71 (m, 3H), 2.94–3.15 (m, 2H), 4.46
(m, 1H), 5.08 (s, 2H), 6.95 (d, 2H, J=8.59 Hz), 7.23 (d,
2H, J=8.55 Hz), 7.30–7.45 (m, 5H); 1H NMR (200
MHz, 2.2 N DCl/D2O) l 2.70–3.09 (m, 2H), 4.72 (m,
1H), 6.82–7.07 (m, 2H), 7.13–7.50 (m, 7H); 13C NMR
(100 MHz, DMSO-d6) l 55.8, 70.0, 80.0, 115.1, 127.9,
128.0, 128.6, 129.3, 138.1, 158.1; Calcd. for C15H16NO2:
C, 74.05; H, 7.04; N, 5.76. Found: C, 74.11; H, 7.17; N,
5.78; EIMS: m/z=243 (M+); [h]2D0 –75.7 (c 0.53, EtOH)
from (R)-8d with 99% e.e..
4.4.9. (S)-(+)-2-Amino-1-(2’-naphthyl)ethanol 9i. Rf 0.81;
99% yield; mp 101–103°C [lit.10c 115–118°C]; IR (KBr,
cm−1) 3354, 3247, 3057, 2910, 1601; 1H NMR (200 MHz,
DMSO-d6) l 2.53–2.93 (m, 3H), 2.98–3.41 (m, 2H), 4.62
(m, 1H), 7.47–7.50 (m, 3H), 7.83–7.90 (m, 4H); 1H NMR
(200 MHz, DCl/D2O/DMSO–d6) l 2.24–2.48 (m, 2H),
4.54 (m, 1H), 6.73–6.76 (m, 3H), 7.11 (br s, 4H); 13C
NMR (50 MHz, DMSO-d6) l 49.9, 74.4, 124.2, 124.6,
125,4, 125.9, 127.3, 127.4, 127.6, 132.2, 132.8, 141.9;
Calcd. for C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found:
C, 76.97; H, 7.02; N, 7.50; [h]2D0 +40.0 (c 0.31, EtOH)
from (S)-8i with 99% e.e. {lit.10c [h]D20 −23.8 (c 0.322,
EtOH), 70% e.e., R}.
4.4.5. (S)-(+)-2-Amino-1-(p-fluorophenyl)ethanol 9e. Rf
o
0.65; 97% yield; mp 63–65 C; IR (KBr, cm−1) 3357,
4.4.10. (R)-(+)-2-Amino-1-(2’-thienyl)ethanol 9j. Rf 0.63;
98% yield; mp 59–61°C [lit.18 58–61°C]; IR (KBr, cm−1)
3418, 3282, 2955, 1591, 1491, 1438; 1H NMR (200 MHz,
CDCl3) l 1.93 –2.47 (br s, 3H), 2.77–3.19 (m, 2H), 4.88
(br s, 1H), 6.97–6.99 (m, 2H), 7.25 (m, 1H);
1H NMR (200 MHz, 2.2 N DCl/D2O) l 2.43–2.65 (m,
2H), 4.50 (m, 1H), 6.32 (m, 1H), 6.40 (m, 1H), 6.71
(m,1H); 13C NMR (50 MHz, DMSO-d6) l 49.8, 71.2,
124.3, 125.2, 127.5, 147.2; Calcd. for C6H9NOS: C,
50.32; H, 6.33; N, 9.78; S, 22.39. Found: C, 50.35; H,
6.20; N, 9.41; [h]D20 +18.1 (c 0.72, EtOH); [h]2D0 +31.0 (c
0.53, CH2Cl2) from (R)-8j with 98% e.e. {lit.18 [h]D20 +30.9
(c 1.03, CH2Cl2), R}.
2998, 2878, 1603, 1501; 1H NMR (200 MHz, DMSO-d6)
l 2.37–2.79 (m, 2H), 2.95–3.62 (m, 2H), 4.46 (m, 1H),
1
7.08–7.16 (m, 2H), 7.31–7.38 (m, 2H); H NMR (200
MHz, 2.2 N DCl/D2O) l 2.43–2.50 (m, 2H), 4.23 (m,
1H), 6.33–6.41 (m, 2H), 6.61–6.68 (m, 2H); 13C NMR
(50 MHz, DMSO-d6) l 50.0, 73.5, 114.4, 114.9, 127.7,
127.9, 140.6, 163.6; EIMS: m/z=155 (M+); [h]D20 +40.9 (c
0.48, EtOH) from (S)-8e with 99% e.e. {lit.7a [h]D20 −40.8
(c 1.68, EtOH), R, 96% e.e.}.
4.4.6. (S)-(+)-2-Amino-1-(m-chlorophenyl)ethanol 9f. Rf
0.69; 97% yield; mp 120–122°C; IR (KBr, cm−1) 3348,
2989, 2884, 1596, 1480, 1070; 1H NMR (200 MHz,
DMSO-d6) l 2.95–3.19 (m, 2H), 3.21–3.81 (m, 3H), 4.88
4.4.11. (S)-(+)-1-Amino-3,3-dimethyl-2-butanol 9k. Rf
0.63; 90% yield; mp 76–78°C; IR (KBr, cm−1) 3427, 3287,
2878, 1597, 1501; 1H NMR (200 MHz, CDCl3) l 0.91 (s,
9H), 2.17–2.64 (m, 3H), 2.90 (br s, 1H), 3.16 (br s, 1H),
1
(m, 1H), 7.23–7.65 (m, 4H); H NMR (200 MHz, 2.2 N
DCl/D2O) l 2.50–2.61 (m, 2H), 4.35 (m, 1H), 6.77 (s,
4H); 13C NMR (50 MHz, DMSO-d6) l 46.3, 69.6, 126.0,
127.6, 128.4, 142.3; Calcd. for C8H10ClNO: C, 55.99; H,
5.87; N, 8.16. Found: C, 56.01; H, 5.88; N, 8.19; EIMS:
m/z=171 (M+); [h]2D0 +78.9 (c 0.21, EtOH) from (S)-8f
with 99% e.e..
1
3.47 (s, 1H); H NMR (200 MHz, 2.2 N DCl/D2O) l
0.14 (d, 9H, J=2.14 Hz), 2.16 (m, 1H), 2.49 (m, 1H),
2.77 (m, 1H); 13C NMR (50 MHz, CDCl3) l 26.5, 34.5,
43.1, 80.0; EIMS: m/z=117 (M+); [h]D20 +25.9 (c 0.47,
EtOH) from (S)-8k with 98% e.e..
4.4.7. (S)-(+)-2-Amino-1-(p-chlorophenyl)ethanol 9g. Rf
0.70; 98% yield; mp 95–97°C [lit.11a 96–98°C]; IR (KBr,
cm−1) 3357, 3214, 3104, 2964, 2853, 1595, 1491; 1H NMR
(200 MHz, DMSO-d6) l 2.39–2.77 (m, 3H), 2.87–3.32
4.4.12. (S)-(+)-2-Amino-1-(cyclohexyl)ethanol 9l. Rf 0.78;
97% yield; mp 70–72°C (lit.10d 70–80°C); IR (KBr, cm−1)
3365, 2927, 2666, 1609, 1588; 1H NMR (200 MHz,

1216
B. T. Cho et al. / Tetrahedron: Asymmetry 13 (2002) 1209–1217
DMSO-d6) l 0.90–1.52 (m, 6H), 1.53–1.96 (m, 5H),
2.36–2.71 (m, 3H), 2.73–3.28 (m, 3H); H NMR (200
MHz, 2.2 N DCl/D2O) l 0.24–0.84 (m, 11H), 2.05 (m,
1H), 2.31 (m, 1H), 2.68 (m, 1H); 13C NMR (50 MHz,
DMSO–d6) l 25.5, 25.8, 26.0, 26.3, 27.9, 29.0, 45.0, 75.9;
EIMS: m/z=143 (M+); [h]2D0 +12.1 (c 0.37, EtOH) from
(S)-8l with 99% e.e..
7.39–7.45 (m, 3H), 7.53–7.57 (m, 2H), 8.16 (m, 1H); 13
C
1
NMR (50 MHz, DMSO-d6) l 47.1, 55.0, 71.0, 113.5,
122.4, 127.2, 127.5, 129.0, 129.4, 135.0, 135.8, 138.6,
158.4, 165.1; Calcd. for C18H19NO3: C, 72.71; H, 6.44; N,
4.71. Found: C, 72.72; H, 6.47; N, 4.75; [h]2D0 −35.7 (c 0.5,
CHCl3), >99% e.e., R {lit.14 [h]D25 −36.1 (c 0.45, CHCl3),
R; lit.13a [h]D24 −35.6 (c 0.4, CHCl3), R; lit.12b [h]2D5 −35.1
(c 0.4, CHCl3), R}.
4.5. Preparation of (R)-octopamine 1, (R)-tembamide 2
and (R)-aegeline 3
Acknowledgements
4.5.1. (R)-(−)-Octopamine 1. The azido alcohol (R)-8d
(539 mg, 2 mmol) was dissolved in EtOH (10 mL) and
stirred under a hydrogen atmosphere (55 psi) in the
presence of 20% Pd(OH)2 on charcoal (150 mg) at room
temperature for 12 h. The catalyst was filtered on a pad
of celite and the filtrate was concentrated and purified by
a flash column chromatography to give (R)-1; Rf 0.57
(n-BuOH/AcOH/H2O 3:1:1); 94% yield; mp 245–246°C
(lit.12a <254°C); IR (KBr, cm−1) 3344, 3152, 2925, 1605;
1H NMR (200 MHz, DMSO-d6) l 2.55 (br s, 3H),
2.93-3.38 (m, 3H), 4.29 (t, 1H, J=5.95 Hz), 6.83 (d, 2H,
This work was supported by the grant No. R05-2002-
000-00003-0 from the Basic Research Program of the
Korea Science and Engineering Foundation.
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J=8.55 Hz), 7.08 (d, 2H, J=8.24 Hz); H NMR (200
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alcohol (R)-9c (167 mg, 1 mmol) in CH2Cl2 (10 mL) in
the presence of pyridine (3 mL) was added benzoyl
chloride (1.1 mmol) dropwise through a syringe at 0°C
and the mixture was stirred at the same temperature for
2 h. The reaction mixture was added water (8 ml), stirred
and extracted with CH2Cl2 (3×5 mL). The organic layer
separated was washed with 10% HCl (5 mL) and brine (5
mL) and dried over anhydrous MgSO4. After MgSO4
was removed by filtration, the filtrate was concentrated
and purified by a flash column chromatography to give
(R)-5; Rf 0.54 (EtOAc/hexane 2:1); 89% yield; mp
145–146°C (lit.14 154–155°C); IR (KBr, cm−1) 3372,
1630, 1543, 1510, 1243; 1H NMR (200 MHz, DMSO-d6)
l 3.23–3.51 (m, 2H), 3.73 (s, 3H), 4.72 (m, 1H), 5.43 (d,
1H, J=4.27 Hz), 6.90 (d, 2H, J=8.55 Hz), 7.28 (d, 2H,
J=4.27 Hz), 7.42–7.52 (m, 3H), 7.81–7.85 (m, 2H), 8.49
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70.8, 113.5, 127.2, 128.2, 131.1, 134.6, 135.8, 158.4,
166.4; Calcd. for C16H17NO3: C, 70.83; H, 6.32; N, 5.16.
Found: C, 70.81; H, 6.47; N, 5.02; [h]2D0 −57.6 (c 0.3,
CHCl3), 99% e.e., R {lit.14 [h]D25 −59.6 (c 0.52, CHCl3), R;
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namoyl chloride under similar condition as described
above gave (R)-5; Rf 0.35 (EtOAc/hexane 2:1); 88%
yield; mp 194–196°C (lit.14 196–197°C); IR (KBr, cm−1)
3356, 2964, 1657, 1606, 1242; 1H NMR (200 MHz,
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1H), 5.45 (d, 1H, J=4.27 Hz), 6.72 (d, 1H, J=15.87 Hz),
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