9356
I. S. Kim et al. / Tetrahedron 62 (2006) 9349–9358
ꢀ66.0 (c 0.1, CDCl3); IR (CH2Cl2) 3330, 2938, 2836, 1710,
1612, 1514, 1464, 1296, 1246, 1181, 1101, 1034 cmꢀ1; 1H
NMR (500 MHz, CDCl3) d 3.32 (s, 3H), 3.66 (s, 3H), 3.81
(s, 3H), 3.86–3.93 (br, 1H), 4.72–4.80 (br, 1H), 5.26 (dd,
1H, J¼11.0, 2.0 Hz), 5.29 (dd, 1H, J¼17.5, 2.0 Hz), 5.35–
5.42 (m, 1H), 5.50–5.60 (br, 1H), 6.86 (dd, 2H, J¼8.0,
2.0 Hz), 7.23 (dd, 2H, J¼8.0, 2.0 Hz); 13C NMR
(125 MHz, CDCl3) d 52.37, 55.45, 57.08, 57.72, 85.08,
113.77, 119.71, 129.30, 131.17, 135.06, 156.52, 159.10;
Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28.
Found: C, 63.50; H, 7.25; N, 5.33.
4.2.4. (2R,3R)-2-Methoxy-3-methoxycarbonylamino-3-p-
methoxyphenylpropan-1-ol (11). Ozone was bubbled
through a solution of anti-1,2-amino alcohol 3a (0.70 g,
2.64 mmol) in anhydrous CH2Cl2 (10 mL) and MeOH
(20 mL) at ꢀ78 ꢁC until blue color persisted, the excess
was then purged out with N2 until decolorization, and
NaBH4 (1.00 g, 26.38 mmol) was added at ꢀ78 ꢁC. The re-
action mixture was slowly warmed to 0 ꢁC, stirred at 0 ꢁC for
1 h and concentrated in vacuo. The residue was dissolved in
H2O (30 mL) and EtOAc (50 mL), the organic layer was
separated and washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (hexane/EtOAc 1:2) to give
0.67 g (94%) of alcohol 11 as a colorless syrup; Rf 0.21
(hexane/EtOAc 1:2); [a]2D9 ꢀ48.6 (c 0.1, CDCl3); IR
(CH2Cl2) 3390, 2951, 2836, 1704, 1612, 1514, 1463, 1295,
4.2.2. (1R,2R)-Methyl N-(2-methoxy-1-p-methoxy-
phenylbut-3-enyl)carbamate (3b). The above general pro-
cedure was followed using syn-1,2-dimethyl ether 5 (2.96 g,
13.32 mmol), Na2CO3 (6.35 g, 59.93 mmol), and CSI
(3.48 mL, 39.95 mmol) in anhydrous hexane (67 mL) at
ꢀ78 ꢁC. The reaction mixture was purified by column chro-
matography (hexane/EtOAc 3:1) to afford 3.21 g (91%,
syn:anti¼9.3:1) of syn-1,2-amino alcohol 3b as a white
solid; Rf 0.28 (hexane/EtOAc 3:1); [a]2D9 +55.4 (c 0.1,
CDCl3); IR (neat) 3340, 2938, 2852, 1725, 1612, 1514,
1247, 1180, 1115, 1063 cmꢀ1
;
1H NMR (500 MHz,
CDCl3) d 2.20–2.28 (br, 1H), 3.43 (ddd, 1H, J¼7.5, 5.5,
3.5 Hz), 3.46 (s, 3H), 3.50–3.56 (br d, 1H, J¼2.0 Hz), 3.68
(s, 3H), 3.64–3.75 (br, 1H), 3.82 (s, 3H), 4.97–5.03 (br,
1H), 5.82 (br d, 1H, J¼8.5 Hz), 6.89 (dd, 2H, J¼7.0,
2.0 Hz), 7.25 (dd, 2H, J¼7.0, 2.0 Hz); 13C NMR
(125 MHz, CDCl3) d 52.59, 55.24, 55.55, 58.21, 61.19,
82.84, 114.28, 128.42, 131.52, 157.15, 159.24; HRMS (CI)
calcd for C13H19NO5 [M+H+] 270.1341, found 270.1341.
1
1463, 1295, 1246, 1179, 1098 cmꢀ1; H NMR (500 MHz,
CDCl3) d 3.24 (s, 3H), 3.65 (s, 3H), 3.75–3.82 (br, 1H),
3.81 (s, 3H), 4.65–4.72 (br, 1H), 5.28 (dd, 1H, J¼17.0,
1.0 Hz), 5.30 (dd, 1H, J¼10.5, 1.0 Hz), 5.50–5.58 (br, 1H),
5.78 (ddd, 1H, J¼17.0, 10.5, 7.5 Hz), 6.87 (dd, 2H, J¼7.5,
2.0 Hz), 7.26 (dd, 2H, J¼7.5, 2.0 Hz); 13C NMR
(125 MHz, CDCl3) d 52.46, 55.50, 57.11, 58.07, 85.24,
113.93, 119.36, 128.39, 133.05, 135.53, 156.96, 159.08;
Anal. Calcd for C14H19NO4: C, 63.38; H, 7.22; N, 5.28.
Found: C, 63.51; H, 7.25; N, 5.23.
4.2.5. (2R,3R)-3-Methoxycarbonylamino-3-p-methoxy-
phenylpropane-1,2-diol (12). To a stirred solution of alco-
hol 11 (0.50 g, 1.86 mmol) in anhydrous CH2Cl2 (20 mL)
was added BBr3 (2.04 mL, 2.04 mmol, 1.0 M in CH2Cl2)
at 0 ꢁC under N2. The reaction mixture was stirred at 0 ꢁC
for 30 min, quenched with saturated NaHCO3 aqueous solu-
tion. The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (10 mLꢂ3). The combined
organic layer was washed with H2O and brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography (hexane/EtOAc 1:4) to give
0.38 g (80%) of diol 12 as a white solid; Rf 0.31 (CHCl3/
MeOH 6:1); mp 81–84 ꢁC; [a]D29 ꢀ60.0 (c 0.1, CDCl3); IR
(CH2Cl2) 3347, 2953, 2836, 1699, 1612, 1514, 1462,
4.2.3. (1R,2R)-Methyl N-(1-p-methoxyphenyl-2-methyl-
but-3-enyl)carbamate (8a) and (1S,2R)-methyl N-(1-p-
methoxyphenyl-2-methylbut-3-enyl)carbamate (8b).
The above general procedure was followed using 6
(50 mg, 0.24 mmol), Na2CO3 (58 mg, 0.55 mmol), and
CSI (32 mL, 0.36 mmol) in CH2Cl2 (2 mL) at ꢀ78 ꢁC. The
reaction mixture was purified by column chromatography
(hexane/EtOAc 3:1) to give inseparable mixture (55 mg,
91%) of anti-homoallyl ether 8a and syn-homoallyl ether
8b (ratio¼1:1.8) as a white solid; 8a: Rf 0.31 (hexane/EtOAc
3:1); 1H NMR (500 MHz, CDCl3) d 0.98 (d, 3H, J¼7.0 Hz),
6.86 (dd, 2H, J¼8.5, 2.5 Hz), 2.60 (ddq, 1H, J¼8.0, 7.0,
7.0 Hz), 3.66 (s, 3H), 3.82 (s, 3H), 4.58–4.65 (br, 1H),
4.95–5.05 (br, 1H), 5.06 (dd, 1H, J¼10.5, 1.5 Hz), 5.09
(dd, 1H, J¼16.0, 1.5 Hz), 5.60 (ddd, 1H, J¼16.0, 10.5,
8.0 Hz), 6.86 (dd, 2H, J¼8.5, 2.5 Hz), 7.12 (dd, 2H, J¼8.5,
2.5 Hz); 13C NMR (125 MHz, CDCl3) d 17.41, 43.42,
52.38, 55.50, 58.72, 113.85, 116.35, 128.53, 132.68,
139.96, 156.54, 159.01. Compound 8b: IR (CH2Cl2) 3329,
2958, 2857, 1699, 1612, 1514, 1459, 1247, 1179,
1
1296, 1248, 1179, 1101, 1031 cmꢀ1; H NMR (500 MHz,
CDCl3) d 2.42–2.48 (br, 1H), 2.62–2.72 (br, 1H), 3.67 (s,
3H), 3.60–3.75 (br, 2H), 3.80 (s, 3H), 3.84–3.93 (br d, 1H,
J¼13.5 Hz), 4.72 (dd, 1H, J¼8.0, 7.0 Hz), 5.40–5.46 (br,
1H), 6.90 (dd, 2H, J¼9.5, 2.0 Hz), 7.25 (dd, 2H, J¼9.5,
2.0 Hz); 13C NMR (125 MHz, CDCl3) d 52.73, 55.54,
57.04, 63.53, 74.04, 114.48, 128.75, 130.94, 157.48,
159.53; Anal. Calcd for C12H17NO4: C, 56.46; H, 6.71; N,
5.49. Found: C, 56.34; H, 6.73; N, 5.39.
4.2.6. (4R,5R)-5-Hydroxymethyl-4-p-methoxyphenyl-
1,3-oxazolidin-2-one [(L)-cytoxazone] (1). To a stirred
solution of diol 12 (0.30 g, 1.18 mmol) in anhydrous THF
(12 mL) was added NaH (52 mg, 1.29 mmol, 60% in min-
eral oil) at 0 ꢁC under N2. The reaction mixture was stirred
at 0 ꢁC for 2 h and quenched with H2O (10 mL), then
extracted with EtOAc (10 mLꢂ2). The organic layer was
washed with H2O and brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by column chroma-
tography (hexane/EtOAc 1:4) to give 0.25 g (95%) of
(ꢀ)-cytoxazone (1) as a white solid; Rf 0.37 (CHCl3/
MeOH 6:1); mp 118–120 ꢁC; [a]2D4 ꢀ70.9 (c 0.1, MeOH);
1H NMR (500 MHz, DMSO-d6) d 2.94–2.99 (m, 2H), 3.75
1
1034 cmꢀ1; H NMR (500 MHz, CDCl3) d 0.99 (d, 3H,
J¼6.5 Hz), 2.53 (ddq, 1H, J¼8.0, 7.0, 6.5 Hz), 3.64 (s,
3H), 3.81 (s, 3H), 4.42–4.53 (br, 1H), 4.95–5.05 (br, 1H),
5.08 (dd, 1H, J¼10.5, 1.5 Hz), 5.11 (dd, 1H, J¼16.5,
1.5 Hz), 5.74 (ddd, 1H, J¼16.5, 10.5, 8.0 Hz), 6.87 (dd,
2H, J¼8.5, 2.5 Hz), 7.17 (dd, 2H, J¼8.5, 2.5 Hz); 13C
NMR (125 MHz, CDCl3) d 16.79, 43.97, 52.36, 55.51,
59.01, 114.24, 116.47, 128.02, 133.76, 139.98, 156.64,
158.98; HRMS (CI) calcd for C14H19NO3 [M+H+]
250.1443, found 250.1451.