1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-[(1S )-2-methoxy-
1-phenylethylamino]ethanol (11)
δH (CD3OD, 600 MHz) 1.53 (3H, s), 1.54 (3H, s), 2.82 (1H,
dd, J 14.1, 5.8 Hz), 3.74 (1H, dd, J 14.1, 7.4 Hz), 4.12 (1H, dd,
J 5.8, 3.6 Hz), 4.63 (2H, m), 4.75 (1H, dd, J 7.4, 5.8 Hz), 4.84
(2H, s), 6.79 (1H, d, J 8.4 Hz), 6.98 (1H, s), 7.09 (1H, d,
J 8.4 Hz), 7.25 (2H, d, J 7.2 Hz), 7.42 (1H, t, J 7.2 Hz) and
7.46 (2H, t, J 7.2 Hz); δC (CD3OD, 150 MHz) 24.9, 25.0,
49.9, 61.1, 61.8, 71.1, 71.5, 100.8, 118.0, 121.0, 123.8, 127.2,
128.3, 130.1, 130.3, 135.5, 139.2, 152.4 and 160.9; HRMS
(ESI ϩ ve) m/z 392.1475 [(M ϩ Na)ϩ calcd. for C21H23NNaO5
392.1474].
Calcium chloride (67 mg, 0.60 mmol) was added in one portion
to a solution of 10 (107 mg, 0.30 mmol) in methanol (2 ml) at
0 ЊC and stirred for 10 min. Polystyryl(trimethyl)ammonium
borohydride (241 mg, 0.6 mmol) was added in one portion and
the reaction mixture was allowed to warm to room temper-
ature over 2 h. The reaction mixture was filtered and the
solvent removed under reduced pressure. The residue was dis-
solved in ethyl acetate and the solution was washed with water
and brine, and dried (Na2SO4) to give an inseparable mixture of
isomers of 11 in a 9:2 ratio (98 mg, 91%) as a colourless oil:
νmax/cmϪ1 3405, 1619, 1594, 1498, 1453, 1384, 1373, 1261,
1199, 1142 and 1116; δH (CDCl3, 400 MHz) 1.51 (6H, s), 2.50
(0.18H, dd, J 12.0, 9.9 Hz), 2.69–2.71 (1.64H, m), 2.78 (0.18H,
dd, J 12.0, 3.2 Hz), 2.91 (2H, br s), 3.36 (2.46H, s), 3.38 (0.54H,
s), 3.45–3.47 (2H, m), 3.88 (0.82H, dd, J 7.4, 5.3 Hz), 3.96
(0.18H, dd, J 8.7, 4.0 Hz), 4.47 (0.82H, dd, J 7.6, 4.5 Hz), 4.64
(0.18H, dd, J 9.9, 3.2 Hz), 4.78 (0.36H, s), 4.80 (1.64H, s), 6.73
(0.18H, d, J 8.3 Hz), 6.74 (0.82H, d, J 8.4 Hz), 6.92 (1H, s), 7.04
(1H, d, J 8.4 Hz) and 7.26–7.34 (5H, m); δC (100 MHz, CDCl3)
24.6, 55.3, 58.9, 60.9, 63.2, 72.2, 77.4, 99.4, 116.9, 119.2, 122.1,
125.7, 127.5, 127.7, 128.5, 134.5, 140.6 and 150.6; HRMS
(ESI ϩ ve) m/z 380.1823 [(M ϩ Na)ϩ calcd. for C21H27NNaO4
380.1838].
6-(4-Phenylbutoxy)hexanal (17)
A mixture of dimethyl sulfoxide (100 ml) and NaHCO3
(14.1 g, 167 mmol) was thoroughly de-gassed and then heated
to 150 ЊC under nitrogen. 6-(4-Phenylbutoxy)hexyl bromide12
(16) (10.0 g, 32 mmol) was then added in one portion and the
mixture was stirred at 150 ЊC for 5–6 min before it was cooled to
20 ЊC over a 10 min period. Diethyl ether (100 ml) was added,
followed by water (100 ml). The layers were separated and
the aqueous layer extracted with diethyl ether. The combined
organic layers were washed with water, dried (MgSO4) and
evaporated under reduced pressure to give 17 (7.93 g, 100%)
as a colourless oil: LCMS tR 12.03 min, 99%; ES ϩ ve m/z 249
(M ϩ H)ϩ; δH (CDCl3, 400 Mz): 1.35–1.43 (2H, m), 1.54–1.72
(8H, m), 2.43 (2H, dt, J 2, 7 Hz), 2.63 (2H, t, J 7 Hz), 3.39 (2H,
t, J 7 Hz), 3.41 (2H, t, J 7 Hz), 7.15–7.2 (3H, m), 7.24–7.3 (2H,
m) and 9.76 (1H, t, J 2 Hz); δC (CDCl3, 100 Mz): 21.9, 25.9,
28.1, 29.4, 29.5, 35.7, 43.9, 70.6, 70.8, 125.7, 128.3, 128.4, 142.3
and 202.8.
(4S )-3-[2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl]-
4-phenyl-1,3-oxazolidin-2-one (12)
Carbonyldiimidazole (146 mg, 0.90 mmol) was added to a
stirred solution of 4 (154 mg, 0.45 mmol) in dichloromethane
(5 ml). After 15 min, the solution was filtered through a pad
of silica and evaporated to give 12 (151 mg, 91%) as a white
foam: [α]2D5 ϩ135 (c 1.43 in MeOH); νmax/cmϪ1 1755, 1686, 1582,
1499, 1420, 1265, 1221 and 1111; δH (CDCl3, 400 MHz) 1.53
(6H, s), 3.92 (1H, d, J 18 Hz), 4.18 (1H, t, J 8.5 Hz), 4.76 (1H, t,
J 8.5 Hz), 4.83 (2H, s), 4.94 (1H, d, J 18 Hz), 5.14 (1H, t, J 8.5
Hz), 6.81 (1H, d, J 8.6 Hz), 7.28 (2H, dd, J 7.8, 2.0 Hz), 7.35–
7.40 (3H, m), 7.55 (1H, d, J 2 Hz) and 7.67 (1H, dd, J 8.6, 2 Hz);
δC (CDCl3, 100 MHz) 24.7, 24.8, 47.4, 60.2, 60.2, 60.6, 70.3,
100.7, 117.4, 119.5, 125.5, 127.2, 128.5, 129.2, 129.4, 137.3,
156.3, 158.8 and 191.8; HRMS (EI ϩ ve) m/z 367.1417 (Mϩ
calcd. for C21H21NO5 367.1420).
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[(1S )-2-
hydroxy-1-phenylethyl][6-(4-phenylbutoxy)hexyl]amino}ethanol
(18)
Sodium triacetoxyborohydride (433 mg, 2 mmol) was added in
one portion under nitrogen to a cloudy mixture of 7 (500 mg,
1.45 mmol) and crude 17 (400 mg, 1.6 mmol) in CH2Cl2 (3 ml).
A gelatinous mixture formed initially which thinned over a
15 min period. The resulting light yellow solution was stirred
for 18 h before it was partitioned between ethyl acetate and
saturated aqueous NaHCO3. The aqueous layer was extracted
with ethyl acetate and the combined organic layers were dried
(MgSO4), concentrated and purified by column chromato-
graphy eluting with ethyl acetate–light petroleum (1:8) to give
18 (725 mg, 87%) as a colourless gum: LCMS tR 7.92 min,
100%; ES ϩ ve m/z 576 (M ϩ H)ϩ; [α]2D0 Ϫ9.0 (c 1.6 in CHCl3);
δH (CDCl3, 400 Mz): 1.18–1.38 (5H, m), 1.53 (6H, s), 1.40–1.71
(9H, m), 2.33–2.42 (1H, m), 2.59–2.70 (4H, m), 2.82 (1H, dd,
J 13, 5 Hz), 3.37 (2H, t, J 7 Hz), 3.41 (2H, t, J 7 Hz), 3.80 (1H,
dd, J 9, 4 Hz), 3.90–4.00 (2H, m), 4.60 (1H, dd, J 9, 5 Hz), 4.83
(2H, s), 6.79 (1H, d, J 8 Hz), 6.96 (1H, d, J 2 Hz), 7.09 (1H, dd,
J 8, 2 Hz), 7.15–7.2 (3H, m) and 7.21–7.37 (7H, m); δC (CDCl3,
100 Mz): 24.6, 24.8, 26.1, 27.1, 28.1, 28.4, 29.4, 29.7, 35.7, 51.3,
60.1, 61.0, 61.8, 67.0, 70.7, 70.8, 72.0, 99.5, 117.0, 119.4, 122.2,
125.7, 125.8, 127.8, 128.3, 128.4, 128.5, 134.5, 137.7, 142.5 and
150.8.
(4S )-3-[(2R)-2-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-
hydroxyethyl]-4-phenyl-1,3-oxazolidin-2-one (13) and (4S )-3-
[(2S )-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxy-
ethyl]-4-phenyl-1,3-oxazolidin-2-one (14)
Calcium chloride (54 mg, 0.48 mmol) was added to a stirred
solution of 12 (89 mg, 0.24 mmol) in methanol (2 ml) at 0 ЊC.
After 10 min, polystyryl(trimethyl)ammonium borohydride
(194 mg, 0.48 mmol) was added and the mixture stirred for 2 h,
warming slowly to room temperature. The reaction mixture was
filtered through a pad of silica to give a 1:1 mixture of diastereo-
isomers 13 and 14 (49 mg, 87%). Purification by flash column
chromatography, eluting with ethyl acetate–petroleum ether
(3:7) yielded isomer A (18 mg, 32%) as a white crystalline solid:
[α]2D5 ϩ29.8 (c 1.21 in CD3OD); νmax/cmϪ1 3427, 1732, 1620 and
1594; δH (CD3OD, 600 MHz) 1.52 (6H, s), 2.92 (1H, dd, J 14.3,
8.4 Hz), 3.51 (1H, dd, J 14.3, 4.3 Hz), 4.18 (1H, dd, J 8.8, 6.3
Hz), 4.71 (1H, t, J 8.8 Hz), 4.84 (1H, m), 4.84 (2H, s), 5.15 (1H,
dd, J 8.8, 6.3 Hz), 6.75 (1H, d, J 8.4 Hz), 7.00 (1H, s), 7.12 (1H,
d, J 8.4 Hz), 7.33 (2H, d, J 7.3 Hz), 7.41 (1H, t, J 7.3 Hz) and
7.46 (2H, t, J 7.3 Hz); δC (CD3OD, 150 MHz) 24.9, 25.0, 50.5,
61.8, 62.7, 71.6, 73.0, 100.7, 117.8, 120.9, 123.4, 126.9, 128.4,
130.0, 130.3, 135.5, 139.7, 152.2 and 160.9; HRMS (ESI ϩ ve)
m/z 392.1465 [(M ϩ Na)ϩ calcd. for C21H23NNaO5 392.1474]
and isomer B (9 mg, 16%) as an amorphous white solid: [α]2D5
ϩ60.4 (c 0.57 in CD3OD); νmax/cmϪ1 3430, 1731, 1619 and 1593;
(R)-(–)-2-Hydroxymethyl-4-{1-hydroxy-2-[6-(4-phenylbutoxy)-
hexylamino]ethyl}phenol (19)
A solution of 18 (110 mg, 0.19 mmol) in ethanol (75 ml), was
hydrogenated over Pearlman’s catalyst [Pd(OH)2–C, 60% H2O,
55 mg) for 18 h. The catalyst was removed by filtration through
a short plug of Celite and the residue was washed with ethanol.
The combined filtrate and washings were concentrated and then
applied to a 10 g SCX-2 ion exchange cartridge. The cartridge
was eluted with ethanol and then with 10% aqueous 880 NH3
in ethanol. The ammoniacal eluent was concentrated under
reduced pressure to give 19 (69 mg, 87%) as a colourless gum:
LCMS tR 6.27 min, 100%; ES ϩ ve m/z 416 (M ϩ H)ϩ; [α]2D0
J. Chem. Soc., Perkin Trans. 1, 2002, 2237–2242
2241