18 (24.4 g, 28%) as a white crystalline solid: LCMS tR 3.72 min,
100%; ESϩve m/z 366 (MH Ϫ C4H9)ϩ; δH (CDCl3) 7.78 (1H, dd,
J 8, 2 Hz), 7.65 (1H, br s), 6.87(1H, d, J 8 Hz), 4.97 (2H, s), 4.88
(2H, s), 1.56 (6H, s) and 1.48 (18 H, s); δC (CDCl3) 192.0, 155.9,
152.3, 128.4, 127.7, 125.3, 119.4, 117.3, 100.6, 82.8, 60.7,
51.7, 28.0 and 24.8 (Found: C, 62.3, H, 7.6, N, 3.4. C22H21NO7
requires C, 62.7, H, 7.4, N, 3.3%). Further concentration of the
mother liquors gave additional product (17.32 g, 20%). A third
crop (4.34 g, 5%) was obtained after purifying the mother
liquors by chromatography on silica gel eluting with heptane–
ethyl acetate (5 : 1), evaporating the appropriate fractions and
re-crystallising from diethyl ether.
water (1000 ml). The organic phase was washed with brine (250
ml), dried and evaporated. The solid was triturated with diethyl
ether to give 14 (8.84 g, 70%) as a white crystalline solid: [α]2D0
Ϫ20 (c 1.379 in CHCl3); LCMS tR 2.49 min, 100%; ESϩve m/z
250 (M ϩ H)ϩ, 267 (M ϩ NH4)ϩ, 516 (2M ϩ NH4)ϩ; ESϪve
m/z 294 (M ϩ HCO2)Ϫ; δH (CDCl3) 7.16 (1H, dd, J 9 and 2 Hz),
7.03 (1H, d, J 2 Hz), 6.84 (1H, d, J 9 Hz), 6.28 (1H, br s), 5.53
(1H, t, J 8 Hz), 4.85 (2H, s), 3.93 (1H, t, J 8 Hz), 3.53 (1H, t,
J 8 Hz) and 1.54 (6H, s); δC (CDCl3) 160.0, 151.8, 130.1, 126.0,
122.6, 119.8, 117.6, 99.9, 77.9, 60.8, 48.3, 24.8, and 24.7
(Found: C, 62.7; H, 6.1; N, 5.75. C13H15NO4 requires C, 62.6; H,
6.1; N, 5.6%). Chiral HPLC on a Whelk-O 1 column (25 cm ×
0.46 cm) eluting with ethanol–heptane (35 : 65) at a flow rate of
1 ml minϪ1 and detecting at 215 nm: tR 8.11 min, 0.9%; tR 10.38
min, 99.1% (racemate: tR 7.99 min and 10.50 min).
tert-Butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl-
carbamate (19)
Trifluoroacetic acid (10.2 ml, 132 mmol) was added to a stirred
solution of 18 (46.37 g, 110 mmol) in dichloromethane (500 ml)
at 20 ЊC and the reaction was stirred for 4 h. Aqueous sodium
hydroxide solution (0.5 M; 400 ml) was added and the phases
were separated. The organic layer was washed with water
(500 ml), dried, evaporated and the residue crystallised from
diethyl ether to give 19 (15.15 g, 43%): LCMS tR 3.24 min,
100%; ESϩve m/z 322 (M ϩ H)ϩ; δH (CDCl3) 7.78 (1H, d, J 8
Hz), 7.65 (1H, s), 6.87(1H, d, J 8Hz), 5.56 (1H, br s), 4.87
(2H, s), 4.58 (2H, d, J 4 Hz), 1.56 (6H, s) and 1.47 (9H, s);
δC (CDCl3) 192.9, 155.6, 155.8, 128.4, 127.2, 125.4, 119.5, 117.5,
100.8, 79.8, 60.6, 47.1, 28.4 and 24.8. (Found: C, 63.85, H, 7.0;
N, 4.15. C17H23NO5 requires C, 63.5, H, 7.2, N, 4.4%). Further
product (14.60 g, 41%) was obtained from the mother liquors
after evaporation and chromatography on silica gel eluting with
cyclohexane–ethyl acetate (5 : 1).
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-3-[6-(4-phenyl-
butoxy)hexyl]-1,3-oxazolidin-2-one (22)
A solution of 14 (504 mg, 2.02 mmol) in dimethylformamide
(10 ml) was added dropwise to a stirred suspension of sodium
hydride (60% dispersion in oil, 90 mg, 2.25 mmol) in di-
methylformamide (5 ml) at 5 ЊC under an atmosphere of nitro-
gen. After 5 min a solution of 6-bromohexyl 4-phenylbutyl
ether30 (21) (0.97 g, 3.10 mmol) in dimethylformamide (5 ml)
was added dropwise. The reaction mixture was stirred at 5 ЊC
for 1 h then at 20 ЊC for 3 h. After re-cooling to 5 ЊC the reaction
was quenched with 2 M hydrochloric acid, the mixture was
partitioned between ethyl acetate (100 ml) and water (100 ml).
The organic phase was separated, washed with brine (50 ml),
dried and concentrated. The residue was purified by chromato-
graphy on a silica Bond Elut cartridge (10 g) eluting with cyclo-
hexane, dichloromethane and diethyl ether to give 22 (745 mg,
77%) as a colourless gum: LCMS tR 3.91 min, 100%; ES ϩve
m/z 499 (M ϩ NH4)ϩ, 980 (2M ϩ NH4)ϩ; ESϪve m/z 526
(M ϩ HCO2)Ϫ; δH (CDCl3) 7.31–7.24 (3H, m), 7.19–7.14 (2H,
m), 7.12 (1H, dd, J 8 and 2 Hz), 7.00 (1H, d, J 2 Hz), 6.84 (1H,
d, J 8Hz), 5.39 (1H, t, J 8 Hz), 4.84 (2H, s), 3.84, (1H, t, J 8 Hz),
3.42 (2H, t, J 7Hz), 3.38 (2H, t, J 7 Hz), 3.37–3.20 (2H, m), 2.63
(2H, t, J 7 Hz), 1.72–1.52 (14H, m) and 1.42–1.30 (4H, m); δC
(CDCl3) 157.9, 151.7, 142.5, 130.5, 128.4, 128.3, 125.7, 122.3,
119.8, 117.5, 99.8, 74.2, 70.7, 60.8, 52.1, 44.1, 35.7, 29.6, 29.4,
28.1, 27.3, 26.5, 25.9, 24.8 and 24.7; HRMS (ES ϩve) m/z
482.2897 [(M ϩ H)ϩ calcd. for C29H40NO5 482.2906].
tert-Butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-
hydroxyethylcarbamate (20)
A solution of borane–tetrahydrofuran complex in tetra-
hydrofuran (1 M; 47 ml) was added slowly to a solution of
(R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c]-
[1,3,2]oxazaborole in toluene (1 M; 4.7 ml) at 5 ЊC under nitro-
gen. After 0.25 h a solution of 19 (15.08 g, 46.92 mmol) in
tetrahydrofuran (500 ml) was added slowly. The reaction was
allowed to warm to room temperature and stirred for 2 h. After
cooling to 5 ЊC the reaction mixture was quenched by the drop-
wise addition of 2 M hydrochloric acid. The mixture was par-
titioned between ethyl acetate (1 L) and water (1 L) and the
organic layer was washed with brine and dried. The solvent was
removed by evaporation to give 20 (15.1 g, 99%) as a white
solid: [α]2D0 Ϫ36 (c 1.315 in CHCl3); LCMS tR 2.96 min, 100%;
ESϩve m/z 647 (2M ϩ H)ϩ, 306 (MH Ϫ H2O)ϩ; δH (CDCl3)
7.13 (1H, br d, J 8 Hz), 6.98 (1H, br s), 6.89 (1H, d, J 8Hz), 4.99
(1H, br s), 4.82 (2H, s), 4.72 (1H, br s), 3.40 (1H, m), 3.32 (2H,
m), 1.53 (6H, s) and 1.44 (9H, s); δC (CDCl3) 156.9, 150.8,
133.8, 125.7, 122.2, 119.4, 117.1, 99.6, 79.8, 73.6, 60.9, 48.4,
28.4, 24.8 and 24.6 (Found: C, 63.2, H, 7.75, N, 4.2. C17H25NO5
requires C, 63.1, H, 7.8, N, 4.3%). Chiral HPLC on a chiralpak
AD column (25 cm × 0.46 cm) eluting with ethanol–heptane
(1 : 9) at a flow rate of 1 ml minϪ1 and detecting at 215 nm: tR
13.13 min, 98%; tR 15.16 min, 2% (racemate: tR 13.20 min and
15.18 min).
(1R)-1-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-{[6-(4-phe-
nylbutoxy)hexyl]amino}ethanol (23)
Potassium trimethylsilanolate (90% pure; 285 mg, 2.00 mmol)
was added to a stirred solution of 22 (519 mg, 1.08 mmol) in
tetrahydrofuran (10ml). The resultant mixture was heated at
reflux for 1 h then cooled to room temperature. The mixture
was partitioned between ethyl acetate (100 ml) and water
(75 ml). The organic phase was washed with brine (50 ml),
dried and concentrated to give 2325 (472 mg, 96%). LCMS tR
3.20 min, 100%; ESϩve m/z 456 (M ϩ H)ϩ; ESϪve m/z 500
(M ϩ HCO2)Ϫ; δH (CDCl3) 7.30–7.24 (3H, m), 7.19–7.15 (2H,
m), 7.12 (1H, dd, J 8 and 2 Hz), 7.00 (1H, d, J 2 Hz), 6.79 (1H,
d, J 8Hz), 4.84 (2H, s), 4.60 (1H, dd, J 3 and 9 Hz), 3.41 (2H, t,
J 7Hz), 3.38 (2H, t, J 7 Hz), 2.86 (1H, dd, J 4 and 12 Hz), 2.71–
2.58 (5H, m), 1.71–1.45 (14H, m) and 1.40–1.30 (4H, m).
(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-
2-one (14)
2-(Hydroxymethyl)-4-((1R)-1-hydroxy-2-{[6-(4-phenylbutoxy)-
hexyl]amino}ethyl)phenol (24)
A solution of 20 (16.40 g, 50.71 mmol) in dimethylformamide
(150 ml) was added dropwise to a stirred suspension of sodium
hydride (60% oil dispersion; 2.65 g, 66.2 mmol) in di-
methylformamide (50 ml) at 5 ЊC under nitrogen. The mixture
was stirred at 20 ЊC for 3 h. The mixture was re-cooled to 0 ЊC
and quenched by the addition of 2 M hydrochloric acid. The
mixture was partitioned between ethyl acetate (1000 ml) and
A solution of 23 (20 mg, 0.04 mmol) in methanol (0.25 ml) and
acetic acid (0.25 ml) was stirred at 20 ЊC for 3 days. The reaction
mixture was partitioned between ethyl acetate and aqueous
sodium bicarbonate solution. The organic phase was separated
and washed with brine, dried, filtered and evaporated under
reduced pressure to give 24 (13 mg, 80%) as a colourless gum.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 1 0 6 – 1 1 1 1
1110