Asymmetric transfer hydrogenation of 2-tosyloxy-1-(4-hydroxyphenyl)ethanone derivatives: synthesis of (R)-tembamide, (R)-aegeline, (R)-octopamine, and (R)-denopamine

Article abstract of DOI:10.1016/j.tetasy.2007.10.046

Catalytic transfer hydrogenation of 2-tosyloxy-1-(4-hydroxyphenyl)ethanone derivatives leads to efficient synthesis of β-adrenergic agonists, (R)-tembamide, (R)-aegeline, (R)-octopamine, and (R)-denopamine.

Full text of DOI:10.1016/j.tetasy.2007.10.046

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2662–2667
Asymmetric transfer hydrogenation of 2-tosyloxy-1-
(4-hydroxyphenyl)ethanone derivatives: synthesis of (R)-tembamide,
(R)-aegeline, (R)-octopamine, and (R)-denopamine
Do-Min Lee,a,b Jong-Cheol Lee,a Nakcheol Jeongb and Kee-In Leea,*
aBio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yusong, Taejon 305-600, Republic of Korea
bDepartment of Chemistry and Division of Molecular Engineering and Chemistry, Korea University, Seoul 136-701, Republic of Korea
Received 13 September 2007; accepted 29 October 2007
Abstract—Catalytic transfer hydrogenation of 2-tosyloxy-1-(4-hydroxyphenyl)ethanone derivatives leads to efficient synthesis of
b-adrenergic agonists, (R)-tembamide, (R)-aegeline, (R)-octopamine, and (R)-denopamine.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
denopamine 4, as shown in Figure 1, are currently available
as racemates, recent studies have demonstrated that the
pharmacological efficacy and drug specificity resides
mainly in the (R)-enantiomers.
The 1,2-aminoalcohol functionality is a rich resource in
organic and medicinal chemistry.1 The functional group
is often found not only in the structural unit of many
building blocks, chiral auxiliaries, and ligands in organic
transformation, but also in the structural motif of many
biologically active compounds. In particular, optically
active 2-amino-1-arylethanols are of great importance as
b-adrenergic agonists in the therapy of asthma, bronchitis,
and congestive heart failure.2 Even though many b-ago-
nists, such as tembamide 1, aegeline 2, octopamine 3, and
Much attention has been paid to the enantioselective
synthesis of b-adrenergic agonists under catalytic enantio-
selective synthesis, classical/enzymatic resolution and
biotransformative pathway. The oxazaborolidine-catalyzed
reduction represents a reliable and industrially popular
choice for the enantioselective reduction of ketones with
its versatility and high enantioselectivity. Indeed, this
OH
H
OH
H
N
N
O
O
MeO
MeO
1
2
OH
OH
H
NH2
N
OMe
OMe
HO
HO
3
4
Figure 1. Single enantiomers of b-adrenergic agonists.
*
Corresponding author. Tel.: +82 42 860 7186; fax: +82 42 860 7160; e-mail: kilee@krict.re.kr
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.10.046

D.-M. Lee et al. / Tetrahedron: Asymmetry 18 (2007) 2662–2667
2663
approach have been intensively applied to the synthesis of
many aminoalcohols via the utilization of common precur-
sors, such as a-chloro, -bromo, and -tosyloxyacetophen-
ones.3 Recently, the b-agonists have been prepared through
microbial reduction of a-azido and -bromoketones4 or
lipase-mediated resolution of a-azidoalcohols.5 It has been
also noted that enantiomerically enriched cyanohydrin or
nitroaldol products lead to the synthesis of the b-agonists
from the corresponding benzaldehydes.6 Interestingly,
most of the reported methods involve a unique feature,
such as an easy access to versatile synthetic intermediates,
thus securing their wide application to the synthesis of
aminoalcohols.
oxy)iodo]benzene11 in refluxing acetonitrile. The well-de-
fined (S,S)-Rh catalyst
5
[(S,S)-TsDPEN–RhClCp*,
where Cp* = pentamethylcyclopentadienyl]12 also effec-
tively performed in asymmetric transfer hydrogenation of
tosyloxyketones 6a and 6b (substrate/catalyst ratio = 1000)
with azeotopic mixtures of formic acid/triethylamine
(molar ratio = 5:2)13 in ethyl acetate to produce (R)-
25
1-aryl-2-tosyloxyethanols 7a {½aꢀD ¼ ꢁ50:7 (c 0.79,
20
CHCl3); lit.10b ½aꢀD ¼ ꢁ18 (c 0.74, CHCl3), 15% ee}
25
20
and 7b {½aꢀD ¼ ꢁ42:5 (c 0.79, CHCl3); lit.9f ½aꢀD ¼ ꢁ41:9
(c 1.08, CHCl3)}, in 92% and 87% yield with 94% and
95% ee, respectively. The ee values were similar to those
reported for a-chloroketones,8b and thus the represented
a-tosyloxyketones are also good substrates for transfer
hydrogenation, as shown in Scheme 1. However, this
observation was in contrast to the previous report, presum-
ably, an in situ preparation of the catalyst in a neat formic
acid/triethylamine media and the simultaneous contact
with substrate may deteriorate the catalytic activity.10
Asymmetric transfer hydrogenation has broadened its
application to the enantioselective hydrogenation of unsatu-
rated carbonyl and imine groups.7 The asymmetric transfer
hydrogenation offers operational simplicity, since the
reaction does not involve molecular hydrogen and is insen-
sitive to air oxidation. Generally, catalysts consist of
bidentate ligands based on 1,2-aminoalcohols or monosulfon-
ylated diamines, bound to ruthenium, iridium or rhodium.
It has been proven that (1S,2S)- or (1R,2R)-N-(p-toluene-
sulfony)-1,2-diphenylethylenediamine (TsDPEN) is an
excellent ligand for the catalytic transfer hydrogenation of
aryl ketones, where the reaction can be routinely carried
out under azeotopic mixtures of formic acid/triethylamine
as hydrogen donors. A wide range of a-functionalized
aromatic ketones were subjected to transfer hydrogena-
tion producing enantiopure alcohols for establishing chira-
lity within target molecules.8 It shows that the Rh(III)
catalysts are preferable, notably in the reduction of a-
chloroketones. The a-sulfonyloxyketone is also particularly
interesting as a versatile intermediate for the preparation
of a large group of anti-depressants and a- and b-adre-
nergic drugs,9 however, to date, it has not found much
attention in asymmetric transfer hydrogenation.10 Herein,
we report a catalytic transfer hydrogenation of 2-tosyl-
oxy-1-(4-hydroxyphenyl)ethanone derivatives leading to
efficient and practical synthesis of b-adrenergic agonists,
(R)-tembamide, (R)-aegeline, (R)-octopamine, and (R)-
denopamine.
The absolute configuration was determined by comparing
the sign of the specific rotation with the literature data,
the ee values were measured by chiral HPLC analysis using
Daicel Chiralcel OD-H chiral column. Racemic alcohols
( )-7 were prepared by sodium borohydride reduction of
6 in THF, and used as standards for ee determination.
2.2. (R)-Tembamide and (R)-aegeline
With (R)-1-aryl-2-tosyloxyethanols 7a and 7b in hand, we
were able to access aminoethanols containing the 40-
hydroxylphenyl subunit, as shown in Figure 1. (R)-Temba-
mide and (R)-aegeline, which have been used in traditional
Indian medicines, are naturally occurring hydroxyamides
possessing hypoglycemic activity. As already established,
(R)-tembamide 1 and (R)-aegeline 2 were easily prepared
from methoxy-tosylate 7a according to the precedent, as
shown in Scheme 2.4b,5,9e Tosylate 7a was converted to
azide 8 by heating in DMSO with sodium azide, which
was then reduced under hydrogen over 5% Pd/C in MeOH
using Parr apparatus to give hydroxyamine 9. Selective
acylation on the amino group of 9 was conveniently
performed utilizing the Schotten–Baumann protocol.
Thus, the reaction of 9 with benzoyl chloride in aque-
2. Results and discussion
ous NaOH gave 92% yield of (R)-tembamide
1
25
20
2.1. Asymmetric transfer hydrogenation of 2-tosyloxy-1-(4-
hydroxyphenyl)ethanone derivatives
{½aꢀD ¼ ꢁ59:4 (c 0.57, CHCl3); lit.9e ½aꢀD ¼ ꢁ57:6 (c
0.3, CHCl3), 99% ee}, after recrystallization. Similarly,
25
(R)-aegeline 2 {½aꢀD ¼ ꢁ49:1 (c 0.27, MeOH); lit.9e
20
The 2-tosyloxyacetophenones 6a and 6b were prepared by
tosyloxylation of aryl methyl ketones with [hydroxy(tosyl-
½aꢀD ¼ ꢁ35:7 (c 0.5, CHCl3), >99% ee} was obtained in
84% yield, by treatment with (E)-cinnamoyl chloride. The
Ts
O
OH
Ph
N
(S,S)-Rh cat 5
OTs
OTs
Rh
HCO2H/Et3N
EtOAc, rt, 5-7h
Cl
N
Ph
H2
RO
RO
6a: R = OMe
6b: R = OBn
7a (94% ee)
7b (95% ee)
5
Scheme 1.

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D.-M. Lee et al. / Tetrahedron: Asymmetry 18 (2007) 2662–2667
OH
OH
OH
H
R1
NH2
N
R2
iii
ii
O
MeO
i
MeO
MeO
7a: R1 = OTs
8: R1 = N3
9
(R)-1: R2 = Ph
(R)-2: R2 = (E)-CH=CHPh
>
Scheme 2. Reagents and conditions: (i) NaN3, DMSO, 80 ꢁC, 2 h, 91%; (ii) 5% Pd/C, H2 (30 psi), MeOH, rt, 2 h, 95%; (iii) BzCl (for 1, 92%); (E)-
cinnamoyl chloride (for 2, 84%), aq NaOH, CH2Cl2–PhMe, 4–10 ꢁC, 1 h.
spectral and specific rotation data of 1 and 2 were in agree-
ment with those reported in the literature.
concise alternative. By treating tosylate 7b with 3,4-
dimethoxyphenethylamine, it was converted to hydroxyl-
amine 11 in 82% yield, without protection of the second-
ary alcohol.3b Final installation was accomplished with
2.3. (R)-Octopamine and (R)-denopamine
removal of the benzyl group in 11 to afford enantiomeri-
25
cally pure (R)-denopamine 4 {½aꢀD ¼ ꢁ27:7 (c 0.91,
25
(R)-Octopamine, a biogenic hydroxyamine with a similar
action to dopamine, has a b-adrenergic activity and is
currently used as a circulatory stimulant. As usual, access
to (R)-octopamine 3 was readily achieved from benzyl-
oxy-tosylate 7b, as shown in Scheme 3.9e,14 Tosylate 7b
converted to azide 10, followed by hydrogenation,
MeOH); lit.5 ½aꢀD ¼ ꢁ27:9 (c 1.0, MeOH)} in 86% yield,
after recrystallization.
3. Conclusion
along with sequential debenzylation, over 20% Pd(OH)2/C
25
to afford (R)-octopamine 3 {½aꢀD ¼ ꢁ37:3 (c 1.02, H2O);
The optically active 2-amino-1-arylethanols are of great
importance as b-adrenergic agonists in the therapy of
asthma, bronchitis, and congestive heart failure. To date,
many a-functionalized acetophenones have been success-
fully applied toward the synthesis of aminoalcohols. In this
study, we have represented a simple and highly efficient
procedure for the preparation of chiral alcohols from a-
tosyloxyketones under catalytic transfer hydrogenation,
as an alternative. Central to this approach is the demon-
stration of a-tosyloxy alcohols as versatile precursors for
the synthesis of b-adrenergic agonists, (R)-tembamide,
(R)-aegeline, (R)-octopamine, and (R)-denopamine. It is
noteworthy that a-tosyloxyalcohols are particularly inter-
esting since they have wide scope and would offer an alter-
native route to the synthesis of a number of chiral
aminoalcohols. Currently, their scope and applications
are under investigation.
25
lit.14 ½aꢀD ¼ ꢁ37:4 (c 1.0, H2O)} in 81% yield, after
recrystallization.
(R)-Denopamine, a selective b-adrenergic agonist that is
currently being used in the treatment of congestive heart
failure, is also available from 7b as shown in Scheme
4.3b,4a,b,5,6c,9f Previous approaches to the destination
depend highly on the precursor available. So far, a-azido
compounds, such as 10, have been transformed to an
amine. Subsequent acylation with an acyl halide and
reduction of the corresponding amide carbonyl,4b,5,6c or
a-halo precursor routinely gives the epoxide followed
by subsequent regioselective ring-opening with amine.4a
These approaches work very effectively for the synthesis
of 1,2-aminoalcohols, it has been secured that direct
displacement of 7b with an amine would offer a more
OH
OH
OH
OTs
i
N3
NH2
ii
BnO
BnO
HO
(R)-3
Scheme 3. Reagents and conditions: (i) NaN3, DMSO, 80 ꢁC, 2 h, 91%; (ii) 20% Pd(OH)2/C, H2 (60 psi), EtOH, rt, 9 h, 81%.
7b
10
OH
OH
H
H
N
OMe
OMe
N
OMe
OMe
ii
i
7b
BnO
HO
(R)-4
Scheme 4. Reagents and conditions: (i) 3,4-dimethoxyphenethylamine, Et3N, THF, 100 ꢁC, 5 h, 82%; (ii) 20% Pd(OH)2/C, H2 (60 psi), EtOH, rt, 2 h, 86%.
11

D.-M. Lee et al. / Tetrahedron: Asymmetry 18 (2007) 2662–2667
2665
4. Experimental
4.4. General procedure for asymmetric transfer hydrogena-
tion of 2-tosyloxy-1-(4-hydroxyphenyl)ethanones
4.1. General
4.4.1. (R)-1-(4-Methoxyphenyl)-2-(p-tolylsulfonyloxy)etha-
nol 7a. Onto a mixture of (S,S)-Rh catalyst 5 (3.98 mg,
0.005 mmol) and 6a (1.60 g, 5.0 mmol) was charged ethyl
acetate (35 mL), and then an azeotopic mixture of formic
acid/triethylamine (molar ratio = 5:2, 1.0 mL). The reac-
tion mixture was stirred at room temperature for 18 h.
After dilution with ethyl acetate (20 mL), the mixture was
washed with water. The organic layer was dried over anhy-
drous sodium sulfate, filtered, and concentrated to give a
residue. The residue was purified by column chromatogra-
phy on silica gel (EtOAc/CHCl3 = 1:20) to give 1.48 g (92%
The catalytic reactions were carried out under an argon
atmosphere with oven-dried glassware. The reactions were
monitored by TLC using silica gel plates and the products
were purified by flash column chromatography on silica gel
(230–400 mesh). Melting points were measured on an elec-
trothermal apparatus and are uncorrected. NMR spectra
were recorded at 300 MHz for 1H and 75 or 125 MHz
for 13C. Mass spectra were recorded on a GC/MS operat-
ing system at an ionization potential of 70 eV. Optical
rotations were measured on a high resolution digital polari-
meter. Enantiomeric excess (ee) values of the samples
were determined by HPLC analysis using Daicel Chiralcel
OD-H chiral column.
1
yield) of 7a. Mp 71–72 ꢁC; H NMR (300 MHz, CDCl3) d
7.77 (2H, d, J = 8.3 Hz), 7.33 (2H, d, J = 8.1 Hz), 7.23 (2H,
d, J = 6.9 Hz), 6.86 (2H, d, J = 6.8 Hz), 4.92 (1H, dd,
J = 8.4 and 3.5 Hz), 4.11 (1H, dd, J = 10.3 and 3.5 Hz),
4.03 (1H, dd, J = 10.4 and 8.5 Hz), 3.79 (3H, s), 2.45
(3H, s); 13C NMR (125 MHz, CDCl3) d 159.7, 145.0,
132.6, 130.3, 129.9, 127.9, 127.4, 114.0, 74.2, 71.4, 55.2,
21.6; EIMS (70 eV) m/z (rel intensity) 322 (M+, 44),
304 (69), 172 (89), 155 (83), 108 (100), 90 (99), 79 (88);
4.2. Materials
The starting a-tosyloxyketones were prepared by a-tosyl-
oxylation of the corresponding acetophenones with
[hydroxy(tosyloxy)iodo]benzene in refluxing acetonitrile,
according to the literature procedure.10b The (S,S)-Rh cata-
lyst was prepared from the reaction of dichloro(pentameth-
ylcyclopentadienyl)rhodium(III) dimer (99%) and (1S,2S)-
N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (98%)
in dichloromethane in the presence of triethylamine, accord-
ing to the literature procedure.12a The formic acid/tri-
ethylamine (molar ratio = 5:2) azeotrope was prepared
by the double distillation of the mixtures.13b All reagent-
grade chemicals and anhydrous solvents were purchased
from commercial suppliers and used without further
purification.
25
20
½aꢀD ¼ ꢁ50:7 (c 0.79, CHCl3) {lit.10b ½aꢀD ¼ ꢁ18 (c
0.74, CHCl3), 15% ee}; HPLC analysis (Chiralcel OD-
H, 250 · 4.6 mm, ethanol/hexane = 2:98, 1.2 mL/min),
94% ee.
4.4.2. (R)-1-(4-Benzyloxyphenyl)-2-(p-tolylsulfonyloxy)etha-
nol 7b. 85% yield; mp 91–92 ꢁC; 1H NMR (300 MHz,
CDCl3) d 7.77 (2H, d, J = 8.4 Hz), 7.43–7.32 (6H, m),
7.26–7.20 (3H, m), 6.93 (2H, d, J = 8.8 Hz), 5.05 (2H, s),
4.95 (1H, dt, J = 8.3 and 3.0 Hz), 4.13–3.99 (2H, m), 2.44
(3H, s); 13C NMR (75 MHz, DMSO-d6) d 158.9, 145.0,
136.7, 132.6, 130.5, 129.9, 128.5, 128.0, 127.9, 127.4,
127.4, 114.9, 74.2, 71.4, 69.9, 21.6; EIMS (70 eV) m/z (rel
4.3. General procedure for the preparation of 2-tosyloxy-1-
(4-hydroxyphenyl)ethanones
25
intensity) 398 (M+, 1), 213 (56), 91 (100); ½aꢀD ¼ ꢁ42:5 (c
20
0.79, CHCl3) {lit.9f ½aꢀD ¼ ꢁ41:9 (c 1.08, CHCl3)}; HPLC
analysis (Chiralcel OD-H, 250 · 4.6 mm, ethanol/hex-
According to the literature procedure, compounds 6a and
6b were conveniently prepared by a-tosyloxylation of the
corresponding acetophenones with [hydroxy(tosyloxy)-
iodo]benzene in refluxing acetonitrile.10b
ane = 2:98, 1.2 mL/min), 95% ee.
4.5. Preparation of (R)-tembamide, (R)-aegeline, (R)-octo-
pamine, and (R)-denopamine
4.3.1. 1-(4-Methoxyphenyl)-2-(p-tolylsulfonyloxy)ethanone
6a. 85% yield; mp 117–118 ꢁC; 1H NMR (300 MHz,
CDCl3) d 7.86–7.80 (4H, m), 7.34 (2H, d, J = 8.1 Hz),
6.93 (2H, d, J = 8.7 Hz), 5.20 (2H, s), 3.87 (3H, s), 2.44
(3H, s); 13C NMR (75 MHz, CDCl3) d 188.6, 164.2,
145.2, 132.6, 130.4, 129.8, 128.1, 126.7, 114.0, 69.7, 55.5,
21.6; EIMS (70 eV) m/z (rel intensity) 320 (M+, 6), 135
(100), 121 (3), 107 (5), 91 (9), 77 (10), 65 (4).
4.5.1. (R)-(ꢁ)-2-Azido-1-(p-methoxyphenyl)ethanol 8.
A
mixture of 7a (1.73 g, 5.38 mmol) and sodium azide
(0.7 g, 10.7 mmol) in DMSO (12 mL) was heated at 80 ꢁC
for 2 h and then cooled to room temperature. To this
was added water (15 mL) and the mixture was extracted
with ethyl acetate (3 · 10 mL). The combined extract was
dried over anhydrous Na2SO4, filtered, and concentrated
to give a residue. The residue was purified by column chro-
matography on silica gel (EtOAc/hexane = 1:7) to give
0.95 g (91%) of 8. Oil; 1H NMR (300 MHz, CDCl3) d
7.30 (2H, d, J = 8.5 Hz), 6.91 (2H, d, J = 8.8 Hz), 4.86–
4.81 (1H, m), 3.48 (1H, dd, J = 12.5 and 8.0 Hz), 3.81
(3H, s), 3.40 (1H, dd, J = 12.5 and 4.1 Hz), 2.29 (1H, d,
J = 3.1 Hz); 13C NMR (125 MHz, CDCl3) d 159.6, 132.6,
127.1, 114.0, 73.0, 58.0, 55.2; EIMS (70 eV) m/z (rel
intensity) 193 (M+, 5), 137 (39), 109 (70), 94 (97), 77
4.3.2. 1-(4-Benzyloxyphenyl)-2-(p-tolylsulfonyloxy)ethanone
6b. 86% yield; mp 131–132 ꢁC; 1H NMR (300 MHz,
CDCl3) d 7.78–7.80 (4H, m), 7.41–7.32 (7H, m), 7.00
(2H, d, J = 7.0 Hz), 5.19 (2H, s), 5.14 (2H, s), 2.44 (3H,
s); 13C NMR (75 MHz, CDCl3) d 188.9, 163.6, 145.4,
136.1, 132.9, 130.6, 130.1, 128.9, 128.5, 128.3, 127.7,
127.2, 115.2, 70.4, 70.0, 21.9; EIMS (70 eV) m/z (rel inten-
sity) 396 (M+, 12), 211 (100), 91 (65).
25
25
(100); ½aꢀD ¼ ꢁ86:1 (c 1.39, CHCl3) {lit.4b ½aꢀD ¼ ꢁ40:1

2666
D.-M. Lee et al. / Tetrahedron: Asymmetry 18 (2007) 2662–2667
25
(c 1.0, CHCl3), 99% ee; lit.5 ½aꢀD ¼ ꢁ116:9 (c 1.2, CHCl3),
4.5.5. (R)-(ꢁ)-2-Azido-1-(p-benzyloxyphenyl)ethanol 10.
A mixture of 7b (3.39 g, 8.51 mmol) and sodium azide
(1.11 g, 17.0 mmol) in DMSO (15 mL) was heated at
80 ꢁC for 2 h and then cooled to room temperature. To this
was added water (20 mL) and the mixture was extracted
with ethyl acetate (3 · 10 mL). The combined extract was
dried over anhydrous Na2SO4, filtered, and concentrated
to give a residue. The residue was purified by column chro-
matography on silica gel (EtOAc/hexane = 1:5) to give
20
98% ee; lit.9e ½aꢀD ¼ ꢁ117:4 (c 1.30, CHCl3), 99% ee}.
4.5.2. (R)-(ꢁ)-2-Amino-1-(p-methoxyphenyl)ethanol 9.
Azidoalcohol 8 (0.71 g, 3.68 mmol) was dissolved in
MeOH (6 mL) and the solution shaken using a Parr appa-
ratus under a hydrogen atmosphere (30 psi) in the presence
of 5% Pd/C (20 mg) for 2 h. The reaction mixture was fil-
tered on a pad of Celite and the filtrate was concentrated
to give 0.59 g (95%) of aminoalcohol 9. Mp 100–102 ꢁC;
1H NMR (300 MHz, CDCl3) d 7.27 (2H, d, J = 6.70 Hz),
6.89 (2H, d, J = 6.67 Hz), 4.57 (1H, dd, J = 7.8 and
4.0 Hz), 3.80 (3H, s), 2.96 (1H, dd, J = 12.7 and 4.1 Hz),
2.79 (1H, dd, J = 12.7 and 7.8 Hz); 13C NMR (75 MHz,
CDCl3) d 158.1, 134.6, 127.0, 113.3, 74.1, 55.0, 50.2; EIMS
(70 eV) m/z (rel intensity) 167 (M+, 8), 136 (91), 109
1
2.09 g (91%) of 10. Mp 69–70 ꢁC; H NMR (300 MHz,
CDCl3) d 7.45–7.27 (7H, m), 6.98 (2H, d, J = 8.8 Hz),
5.07 (2H, s), 4.86–4.81 (1H, m), 3.48 (1H, dd, J = 12.6
and 8.0 Hz) 3.40 (1H, dd, J = 12.6 and 4.1 Hz), 2.26 (1H,
d, J = 3.2 Hz); 13C NMR (75 MHz, DMSO-d6) d 158.7,
136.7, 132.9, 128.5, 128.0, 127.4, 127.2, 114.9, 72.9,
70.0, 57.9; EIMS (70 eV) m/z (rel intensity) 267 (M+,
25
25
20
3), 213 (37), 91 (100); ½aꢀD ¼ ꢁ70:3 (c 1.09, CHCl3)
(100), 94 (86); ½aꢀD ¼ ꢁ38:3 (c 0.49, EtOH) {lit.9e ½aꢀD
¼
25
20
{lit.5 ½aꢀD ¼ ꢁ72:5 (c 1.3, CHCl3), >99% ee; lit.9e ½aꢀD
¼
ꢁ39:9 (c 1.0, EtOH), 99% ee}.
ꢁ72:2 (c 1.1, CHCl3), 99% ee}.
4.5.3. (R)-(ꢁ)-Tembamide (R)-1. To a solution of 9
(0.16 g, 1.0 mmol) in dry CH2Cl2 (3 mL), a solution of
NaOH (0.24 g, 3.0 mmol) in water (3 mL) was added at
ice bath temperature and the mixture was stirred vigor-
ously for 10 min. A solution of benzoyl chloride (1.2 mmol)
in anhydrous toluene (1 mL) was added dropwise to the
reaction mixture, while vigorously stirring. After the addi-
tion was complete, the reaction mixture was stirred for a
further 1 h. The reaction mixture was diluted with water
and extracted with CH2Cl2. The organic layer was sepa-
rated and washed with brine. The solvent was evaporated
and then the resulting solid was recrystallized from etha-
nol/water (v/v = 80:20) to afford 0.27 g (92%) of (R)-(ꢁ)-
4.5.6. (R)-(ꢁ)-Octopamine (R)-3. Azidoalcohol 10 (0.54 g,
2 mmol) was dissolved in EtOH (10 mL) and the solution
shaken using a Parr apparatus under a hydrogen atmo-
sphere (60 psi) in the presence of 20% Pd(OH)2/C
(150 mg) for 9 h. The reaction mixture was filtered on a
pad of Celite and the filtrate was concentrated to give a
solid residue. The resulting solid was recrystallized from
water to afford 248 mg (81%) of (R)-3. Mp 245–246 ꢁC;
1H NMR (300 MHz, DMSO-d6) d 7.16 (2H, d, J =
8.5 Hz), 6.76 (2H, d, J = 8.5 Hz), 4.38 (1H, dd, J = 7.4
and 4.7 Hz), 2.69–2.56 (2H, m); 13C NMR (75 MHz,
DMSO-d6) d 146.5, 124.9, 117.3, 104.9, 64.5, 40.5;
EIMS (70 eV) m/z (rel intensity) 153 (M+, 4), 136 (11),
1
25
tembamide (R)-1. Mp 145–147 ꢁC; H NMR (300 MHz,
123 (100), 95 (30), 77 (23); ½aꢀD ¼ ꢁ37:3 (c 1.02,
20
CDCl3)
d 7.76 (2H, d, J = 6.9 Hz), 7.51 (1H, t,
H2O) {lit.9e ½aꢀD ¼ ꢁ37:6 (c 0.56, H2O), 100% ee; lit.14
25
J = 7.3 Hz), 7.43 (2H, t, J = 7.5 Hz), 7.33 (2H, d,
J = 8.7 Hz), 6.90 (2H, d, J = 8.7 Hz), 6.58 (1H, br s),
4.94–4.89 (1H, m), 3.93–3.85 (1H, m), 3.81 (3H, s), 3.56–
3.48 (1H, m), 3.09 (1H, d, J = 3.5 Hz); 13C NMR
(125 MHz, CDCl3) d 168.5, 159.3, 134.1, 133.8, 131.6,
128.6, 127.0, 126.9, 113.9, 73.3, 55.2, 47.7; EIMS (70 eV)
½aꢀD ¼ ꢁ37:4 (c 1.0, H2O)}.
4.5.7. (R)-1-(p-Benzyloxyphenyl)-2-[2-(3,4-dimethoxyphen-
yl)ethylamino]ethanol 11.
A
mixture of 10 (0.40 g,
(0.54 g,
1.0 mmol), 3,4-dimethoxyphenethylamine
3.0 mmol), triethylamine (0.20 g, 2.0 mmol) in THF
(20 mL) was stirred at 100 ꢁC for 5 h. After cooling to room
temperature, the reaction mixture was poured onto water
(3 mL), and then extracted with ethyl acetate (3 · 10 mL).
The combined organic layer was dried over anhydrous
MgSO4, filtered, and concentrated to give a residue. The
residue was purified by column chromatography on silica
gel (MeOH/EtOAc = 2:1) to give 0.33 g (82%) of 11. Mp
119–120 ꢁC; 1H NMR (300 MHz, CDCl3) d 7.43–7.28
(5H, m), 7.21 (2H, d, J = 8.7 Hz), 6.92 (2H, d,
J = 8.6 Hz), 6.84–6.69 (3H, m), 5.06 (2H, s), 4.67 (1H, dd,
J = 8.1 and 5.0 Hz), 3.79 (3H, s), 3.77 (3H, s), 2.86–2.68
(6H, m); 13C NMR (75 MHz, DMSO-d6) d 158.5, 149.3,
147.8, 137.5, 135.4, 132.4, 128.3, 127.6, 127.3, 127.0,
120.8, 114.6, 112.4, 112.0, 71.7, 69.7, 56.4, 55.3, 55.2, 50.4,
m/z (rel intensity) 254 (M+ꢁOH, 17), 150 (7), 134 (29),
25
105 (60), 77 (100); ½aꢀD ¼ ꢁ59:4 (c 0.57, CHCl3) {lit.4b
25
25
½aꢀD ¼ ꢁ59:6 (c 0.52, CHCl3); lit.5 ½aꢀD ¼ ꢁ58:7 (c 0.6,
20
CHCl3); lit.9e ½aꢀD ¼ ꢁ57:6 (c 0.3, CHCl3), 99% ee}.
4.5.4. (R)-(ꢁ)-Aegeline (R)-2. Acylation of aminoalcohol
9
(0.16 g, 1.0 mmol) with (E)-cinnamoyl chloride
(1.2 mmol) under the aforementioned conditions gave
0.25 g (84%) of (R)-(ꢁ)-aegeline (R)-2. Mp 194–195 ꢁC;
1H NMR (300 MHz, DMSO-d6)
d
8.14 (1H, t,
J = 5.6 Hz), 7.54 (2H, d, J = 6.4 Hz), 7.44–7.35 (3H, m),
7.27 (2H, d, J = 8.6 Hz), 6.89 (2H, d, J = 8.7 Hz), 6.72
(1H, d, J = 15.8 Hz), 5.44 (1H, d, J = 4.3 Hz), 4.63–4.58
(1H, m), 3.44–3.36 (1H, m), 3.26–3.17 (1H, m); 13C
NMR (125 MHz, DMSO-d6) d 165.0, 158.3, 138.4, 135.7,
134.9, 129.3, 128.9, 127.4, 127.1, 122.3, 113.4, 70.9,
34.9; EIMS (70 eV) m/z (rel intensity) 407 (M+, 2), 194
25
(35), 91 (100); ½aꢀD ¼ ꢁ19:2 (c 1.1, MeOH) {lit.5
25
20
55.0, 47.0; EIMS (70 eV) m/z (rel intensity) 297 (M+, 3),
½aꢀD ¼ ꢁ34:8 (c 1.2, CHCl3); lit.9f ½aꢀD ¼ ꢁ17:5 (c 1.09,
25
285 (21), 103 (15), 71 (56), 57 (100); ½aꢀD ¼ ꢁ49:1 (c 0.27,
24
MeOH)}.
MeOH) {lit.4b ½aꢀD ¼ ꢁ36:1 (c 0.45, CHCl3); lit.5
25
20
½aꢀD ¼ ꢁ35:9 (c 0.48, CHCl3); lit.9e ½aꢀD ¼ ꢁ35:7 (c 0.5,
4.5.8. (R)-(ꢁ)-Denopamine (R)-4. The benzylated denop-
amine 11 (0.20 g, 0.49 mmol) was dissolved in EtOH
CHCl3), >99% ee}.

D.-M. Lee et al. / Tetrahedron: Asymmetry 18 (2007) 2662–2667
2667
6. (a) Brown, R. F. C.; Jackson, W. R.; McCarthy, T. D.
(20 mL) and the solution was shaken using a Parr appara-
tus under a hydrogen atmosphere (60 psi) in the presence of
20% Pd(OH)2/C (50 mg) for 2 h. The reaction mixture was
filtered on a pad of Celite and the filtrate was concentrated
to give a solid residue. The resulting solid was recrystallized
from n-hexane/ethyl acetate (v/v = 7:3) to afford 134 mg
(86%) of (R)-4. Mp 162–164 ꢁC; 1H NMR (300 MHz,
CDCl3) d 7.12 (2H, d, J = 8.5 Hz), 6.83 (1H, d, J =
8.2 Hz), 6.79 (1H, d, J = 1.7 Hz), 6.73–6.69 (3H, m), 4.64
(1H, d, J = 8.2 and 4.9 Hz), 3.80 (3H, s), 3.79 (3H, s),
2.86–2.68 (6H, m); 13C NMR (75 MHz, DMSO-d6) d
156.9, 149.3, 147.8, 133.8, 132.4, 127.1, 120.8, 114.9,
112.4, 112.0, 71.8, 56.4, 55.3, 55.2, 50.5, 34.9; EIMS
´
Tetrahedron: Asymmetry 1993, 4, 2149; (b) Baeza, A.; Najera,
´
C.; Sansano, J. M.; Saa, J. M. Chem. Eur. J. 2005, 11, 3849;
(c) Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org.
Lett. 2002, 4, 2621; (d) Xiong, Y.; Wang, F.; Huang, X.; Wen,
Y.; Feng, X. Chem. Eur. J. 2007, 13, 829.
7. (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1995, 117, 7562; (b) Fujii, A.;
Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1996, 118, 2521; (c) Haack, K.-J.; Hashiguchi, S.;
Fujii, A.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997,
36, 285; (d) Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsum-
ura, K.; Ikariya, T.; Noyori, R. Angew. Chem., Int. Ed. 1997,
36, 288; (e) Matsumura, K.; Hashiguchi, S.; Ikariya, T.;
Noyori, R. J. Am. Chem. Soc. 1997, 119, 8738; (f) Noyori, R.;
Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97; (g) Murata, K.;
Ikariya, T.; Noyori, R. J. Org. Chem. 1999, 64, 2186; (h)
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Ikariya, T. Org. Lett. 1999, 1, 1119; (i) Okano, K.; Murata,
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(70 eV) m/z (rel intensity) 317 (M+, 1), 165 (37), 121
25
(34), 107 (63), 91 (86) 77 (100); ½aꢀD ¼ ꢁ27:7 (c
25
0.91, MeOH) {lit.4b ½aꢀD ¼ ꢁ27:8 (c 1.02, MeOH); lit.5
25
20
½aꢀD ¼ ꢁ27:9 (c 1.0, MeOH); lit.9f ½aꢀD ¼ ꢁ28:5 (c 0.98,
MeOH)}.
8. (a) Watanabe, M.; Murata, K.; Ikariya, T. J. Org. Chem.
2002, 67, 1721; (b) Hamada, T.; Torii, T.; Izawa, K.; Noyori,
R.; Ikariya, T. Org. Lett. 2002, 4, 4373; (c) Li, Y.; Li, Z.; Li,
F.; Wang, Q.; Tao, F. Org. Biomol. Chem. 2005, 3, 2513; (d)
Morris, D. J.; Hayes, A. M.; Wills, M. J. Org. Chem. 2006,
71, 7035; (e) Matharu, D. S.; Morris, D. J.; Clarkson, G. J.;
Wills, M. Chem. Commun. 2006, 3232; (f) Ros, A.; Magriz,
Acknowledgments
This work was supported by a grant for Industrial Tech-
nology Development Programs from the Ministry of Com-
merce, Industry and Energy of Korea (TS062-03).
´
A.; Dietrich, H.; Fernandez, R.; Alvarez, E.; Lassaletta, J. M.
Org. Lett. 2006, 8, 127; (g) Hamada, T.; Torii, T.; Onishi, T.;
Izawa, K.; Ikariya, T. J. Org. Chem. 2004, 69, 7391.
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