J. Goswami et al. / Tetrahedron: Asymmetry 12 (2001) 3343–3348
3347
7.58 (9H, m, aromat H
6
); IR (neat, cm−1) 2950, 1600,
CH
6
OH, dd, J=3.8 and 2.6 Hz), 4.22 (2H, ArCH2
6
OH,
1520, 1295, 755; EIMS m/z: 226 (M+). Anal. calcd for
s), 5.24 (2H, ArCH
6
2OC, s), 7.10–7.79 (8H, aromat-H6 ,
m); IR (thin film/cm−1) 3050, 2950, 1600, 1525, 1355,
755; EIMS m/z 256 (M+). Anal. calcd for C16H16O3: C,
75.00; H, 6.25; found: C, 74.87; H, 6.05%.
C15H14O2: C, 79.64, H, 6.19; found: C, 79.62; H, 6.14%.
4.4.5. Benzylated denopamine 7. A mixture of phenethyl-
amine 6 (0.094 mL, 0.48 mmol), anhydrous DMSO (10
mL) and N,O-bis(trimethylsilyl)acetamide (320 mL) was
stirred under nitrogen for 30 min at room temperature.
A solution of the (R)-epoxide 5 (0.113 g, 0.48 mmol)
and anhydrous DMSO (10 mL) was added and the
resulting mixture heated at 85°C for 35 h. The mixture
was cooled, the solvent distilled off (0.1 mm) and the
resulting crude purified by column chromatography
over neutral alumina, eluting with hexane–ethyl acetate
mixtures. A gummy material was obtained (0.142 g,
4.4.8. Preparation of benzylated (R)-(−)-salmeterol, (R)-
2. A mixture of amine 11 (0.1 g, 0.4 mmol), anhydrous
DMSO (10 mL) and N,O-bis(trimethylsilyl) acetamide
(220 mL) was stirred under nitrogen for 30 min at room
temperature. A solution of the epoxide 10 (0.10 g, 0.4
mmol) in anhydrous DMSO (10 mL) was added and
the resulting mixture was heated at 85°C for 50 h. The
mixture was cooled, the solvent distilled off (0.1 mm)
and the resulting crude purified by column chromatog-
raphy in neutral alumina eluting with hexane–ethyl
acetate mixtures. A gummy material was obtained (0.13
1
70%); [h]2D5=−34.3 (c 1.00, CHCl3); H NMR l 1.14
(1H, OH, bs) 2.63–2.88 (6H, CH
6
2NHCH2
6
CH2
6
, m), 3.84
OH,
1
g, 66%); [h]2D5=−25 (c 1.00, CHCl3); H NMR l: 1.18–
(3H, OCH3, s), 3.90 (3H, OCH3, s), 4.69 (1H, CH
6
6
6
1.5 (12H, m), 2.54–2.96 (4H, m), 3.19–3.30 (4H, m),
4.17–5.11 (5H, m), 5.30 (2H, b, exchangable), 6.61–7.20
(13H, m); IR (thin film/cm−1) 3280, 2933, 1610, 1454,
1035, 750; m/z 505 (M+). Anal. calcd for C32H43NO4:
C, 76.03; H, 8.51; N, 2.72; found: C, 75.88; H, 8.39; N,
2.61%.
dd, J=8.23 and 3.77 Hz), 6.61–7.20 (12H, m, aromat.
H); IR (thin film/cm−1) 3280, 2933, 1610, 1454, 1035,
750; EIMS m/z: 407 (M+). Anal. calcd for C25H29NO4:
C, 73.71; H, 7.12; N, 3.44; found: C, 73.68; H, 7.05; N,
3.41%.
4.4.6. (R)-(−)-Denopamine (R)-1. A mixture of the
gummy material obtained above (0.1 g, 0.24 mmol) and
10% Pd–C (0.015 g) was suspended in absolute alcohol
and hydrogenated at 50 psi at room temperature for 12
h. The mixture was filtered under vacuum and the
catalyst thoroughly washed with ether, ethanol and
dichloromethane. Removal of the solvent left a residue
which on purification through column chromatography
over neutral alumina (E. Merck) yielded (R)-(−)-
denopamine, (R)-1 (0.051 g, 65%); mp 161°C (lit.23
4.4.9. Preparation of (R)-(−)-salmeterol, (R)-2. A mix-
ture of the gummy material obtained above (0.12 g,
0.23 mmol) and Pd–C (0.015 g, 15 mol% of 12) was
taken in absolute alcohol and hydrogenated at 50 psi at
room temperature for 12 h. The mixture was filtered
under vacuum and the catalyst thoroughly washed with
ether, ethanol and dichloromethane. Removal of the
solvent left a residue, which on purification through
column chromatography using neutral alumina (E.
Merck) yielded 0.064 g (61%) (R)-(−)-salmeterol as an
oil; [h]2D5=−21.5 (c 1.00, MeOH) (lit.18=−22.8). The
enantiomeric excess obtained was 94% based on HPLC
data.15 1H NMR l: 1.18–1.5 (12H, m), 2.54–2.96 (4H,
m), 3.19–3.30 (4H, m), 4.17–5.03 (3H, m), 5.30 (2H, b,
exchangable), 6.61–7.18 (8H, m); IR (thin film/cm−1)
3300, 2967, 1670, 1610, 1440, 1030, 800; EIMS m/z 415
(M+). Anal. calcd for C25H37NO4: C, 72.28; H, 8.91; N,
3.37; found: C, 72.12; H, 8.78; N, 3.29%.
1
163°C) [h]2D5=−26.8 (c 1.00, MeOH) [lit.10 −27.7]; H
NMR (CDCl3) 2.52 (1H, OH
(4H, 2×CH2, m), 2.85 (2H, 1×CH2
exchangeable, bs), 3.74 (3H, OCH
OCH3, s), 4.55 (1H, CHOH, m), 5.24 (1H, OH
6
exchangeable, bs), 2.69
, m), 3.53 (1H, NH
3, s) and 3.76 (3H,
6
6
6
6
6
6
6
exchangeable, bs), 6.67 (3H, aromat H, m); 6.82 (1H,
aromat. H, d, J=1.68 Hz); 6.85 (1H, aromat. H, d
J=8.21); 7.08 (2H, 2×aromat. H, d J=8.3 Hz); IR
(KBr, cm−1) 3225, 2980, 1625, 1575, 1515; EIMS m/z
317 (M+). Anal. calcd for C18H23NO4; C, 68.13; H,
7.25; N, 4.41 found: C, 68.09; H, 7.21; N, 4.40%.
Acknowledgements
4.4.7. Preparation of epoxide 10. (R)-(−)-2-Bromo-1-(4-
benzyloxy-3-hydroxymethylphenyl)ethanol 9 (0.22 g,
0.6 mmol) was dissolved in dry THF (15 mL) and the
solution was treated with anhydrous potassium carbon-
ate (0.14 g, 0.9 mmol). The mixture was stirred under
reflux for 2 h, cooled and filtered. The filtrate was
concentrated under reduced pressure, water was added
to the residue and the solution was extracted with ethyl
acetate (3×20 mL). The solution was dried over anhy-
drous sodium sulfate, filtered and concentrated under
reduced pressure to afford the crude epoxide 10. The
product was purified by passing through a silica gel
column using 50% dichloromethane in petroleum ether
as eluent to afford epoxide 10 as an oil. Yield of
(R)-(−)-10 0.11 g, (67%); [h]2D5=−19.0 (c 1.00, CHCl3);
We thank the Department of Biotechnology, New
Delhi, for the financial support and the Director Dr. J.
S. Sandhu FNA of the Regional Research Laboratory,
Jorhat for providing the facilities to carry out this
work. We also thank one of the referees for suggesting
some more references to improve the manuscript.
References
1. (a) Deutsch, D. H. Chemtech 1991, 157–159; (b) Rao, A.
V. R. Chem. Wkly. 1992, 117–133; (c) Sheldon, R. A. J.
Chem. Tech. Biotechnol. 1996, 67, 1–14.
2. (a) Faber, K. Biotransformation in Organic Chemistry;
Springer Verlag, 1992; pp. 147–148; (b) Turner, N. Chem.
Ind. 1994, 592–595.
1H NMR l: 2.76 (1H, CH2
3.15 (1H, CH2OH, dd, J=5.1 and 4.2 Hz), 3.85 (1H,
6 OH, dd, J=5.3 and 2.4 Hz),
6