F. Campos et al. / Tetrahedron: Asymmetry 11 (2000) 2705±2717
2715
45 min, after which time no starting material was detected by TLC. After cooling, the mixture
was diluted with 5 mL of MeOH and the precipitate ®ltered under vacuum. The ®ltrate was made
basic with 1 M NaOH and ®ltered again. The ®ltrate was concentrated, diluted with water and
extracted with CH2Cl2. The organic phase was washed with water and dried (MgSO4). After
®ltration and evaporation of the solvent, the residue was puri®ed by careful column chromatography
on neutral alumina (activity IV) eluting with hexane±ethyl acetate mixtures to provide amine
(R,R)-12 as a yellow gum (253 mg, 67%). Rf: 0.24 (SiO2, AcOEt:MeOH, 2:1). ꢁ2D0=^28.2
(CHCl3, c 1.01). IR, ꢂ: 3468, 3369, 3197, 3031, 2931, 1614, 1512, 1247, 1220, 1035, 808, 754 cm^1.
1H NMR (300 MHz, CDCl3), ꢀ: 7.46±7.29 (c, 5H), 7.07 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz,
2H), 6.80 (d, J=8.4 Hz, 1H), 6.74 (d, J=2.1 Hz, 1H), 6.64 (dd, J=8.3 Hz, J0=2.0 Hz, 1H), 5.06
(s, 2H), 4.47 (dd, J=8.7 Hz, J0=3.9 Hz, 1H), 3.83 (b, 2H), 3.78 (s, 3H), 2.88 (dd, J=6.5 Hz,
J0=6.5 Hz, 1H), 2.83 (dd, J=11.9 Hz, J0=4.1 Hz, 1H), 2.68 (dd, J=11.9 Hz, J0=8.9 Hz, 1H),
2.65 (dd, J=13.4 Hz, J0=6.9 Hz, 1H), 2.55 (dd, J=13.5 Hz, J0=6.6 Hz, 1H), 1.05 (d, J=6.3 Hz,
3H) ppm. 13C NMR (75 MHz, CDCl3), ꢀ: 158.0, 145.8, 137.1, 136.4, 135.7, 131.3, 130.2, 128.5,
128.0, 127.5, 115.7, 113.7, 112.6, 111.8, 71.7, 70.5, 55.2, 54.4, 54.3, 42.8, 20.3 ppm. HRMS: calcd
mass for C25H30N2O3: 406.225643; Found: 406.224823.
4.11. Formylation of amine (R,R)-12
To a solution of 243 mg (0.60 mmol) of amine (R,R)-12 in 15 mL of anh. pyridine were added
3.6 mL of anh. formic acid and the mixture heated at 60ꢀC for 6.5 h under an inert atmosphere.
Progress of the reaction was followed by HPLC on a Spherisorb ODS column 25 mm 12.5Â0.46
cm, isocratic CH3CN:buer soln. 65:35. The buer soln. contained Et3N±AcOH (40 mM) for
pH=6.8 (Rt of (R,R)-12: 4.9 min, (R,R)-13: 3.9 min). The solvent was evaporated o and the
residue diluted with 1 M Na2CO3 soln. and extracted with CH2Cl2. The organic phases were
washed with water, dried (MgSO4), ®ltered and the solvent removed. The residue was puri®ed by
column chromatography on neutral alumina (activity IV), eluting with hexane±ethyl acetate
mixtures, to aord 180 mg (69%) of formyl amine (R,R)-13 as a mixture of syn and anti (70:30)
conformers. Rf: 0.24 (SiO2, AcOEt:MeOH, 2:1). ꢁ2D0=^37.4 (CHCl3, c 1.68). IR, ꢂ: 3398, 3327,
1
3064, 3033, 2960, 2931, 1693, 1610, 1598, 1531, 1512, 1247, 1035, 788, 761 cm^1. H NMR (300
MHz, CDCl3), ꢀ: 8.75 (b, 1H anti conformer), 8.39 (d, J=1.8 Hz, 1H syn conformer), 8.33 (d,
J=2.1 Hz, 1H syn conformer), 7.82 (b, 1H syn conformer), 7.44±7.34 (c, 5H), 7.22 (d, J=1.8 Hz,
1H, anti conformer), 7.12 (d, J=2.1 Hz, 1H, anti conformer), 7.08 (dm, J=8.7 Hz, 3H), 6.93 (dd,
J=8,4 Hz, J0=1.5 Hz, 1H), 6.83 (dm, J=8.7 Hz, 2H), 5.08 (s, 2H), 4.53 (dd, J=9.0 Hz, J0=3.6
Hz, 1H syn), 4.50 (dd, J=9.0 Hz, J0=3.6 Hz, 1H anti), 3.78 (s, 3H), 2.91±2.80 (c, 2H), 2.72±2.52
(c, 3H), 1.08 (d, J=6.0 Hz, 1H anti), 1.05 (d, J=6.3 Hz, 1H syn). 13C NMR (75 MHz, CDCl3), ꢀ:
161.2, 158.7, 158.0, 146.9, 146.3, 136.1, 135.8, 135.7, 131.2, 131.0, 130.14, 130.10, 128.7, 128.5,
128.4, 127.9, 127.6, 126.7, 126.4, 122.3, 121.4, 118.2, 113.8, 112.4, 111.3, 71.4, 71.1, 70.94, 70.86,
55.2, 54.4, 54.3, 54.2, 42.8, 20.4, 20.3 ppm.
4.12. Formoterol (R,R)-1
A mixture of 89 mg (0.20 mmol) of (R,R)-13 dissolved in 3.4 mL of abs. ethanol and 76 mg
(0.072 mmol) of 10% Pd/C was hydrogenated at 3 kg/cm2 and room temperature overnight. The
mixture was ®ltered under vacuum and the catalyst thoroughly washed with ether, ethanol and
methylene chloride. Removal of the solvent left a residue which was chromatographed on a