Delgado et al.
3
mL). The organic layer was dried (Na2SO4) and concentrated in
vacuo and the crude product was purified by flash chromatography
(P/Et2O ) 60:40) to yield rac-8 (181 mg, 453 µmol, 91%) as a
1.21 (s, 9 H), 1.28 (t, J ) 7.0 Hz, 3 H), 1.71 (s, 3 H), 1.74 (s, 3
H), 4.28 (t, 3J ) 7.0 Hz, 2 H), 4.99 (d, 3J ) 7.7 Hz, 1 H), 5.16 (d,
3J ) 7.7 Hz, 1 H), 7.36 (br s, 5 H), 8.48 (s, 1 H); 13C NMR (DMSO-
d6, T ) 60 °C, 90 MHz) δ 14.0, 25.7, 27.6, 60.6, 65.4, 94.9, 126.8,
128.4, 128.6, 128.9, 136.6, 145.7, 160.4, 170.7.
1
pale yellow oil. Rf 0.46 (P/Et2O ) 50:50); H NMR (CDCl3, 360
3
3
MHz) δ 1.25 (s, 9 H), 3.32 (d, J ) 3.0 Hz, 1 H), 5.17 (dd, J )
3
3
2.5 Hz, J ) 9.2 Hz, 1 H), 5.49 (br s, 1 H), 5.59 (d, J ) 9.2 Hz,
1 H), 7.17 (s, 1 H), 7.26-7.38 (m, 6 H); 13C NMR (CDCl3, 90
MHz) δ 28.1, 57.9, 74.2, 80.4, 117.5, 124.5, 126.0, 127.9, 128.4,
139.4, 155.4, 172.5. Anal. Calcd for C16H19BrN2O3S (399.30): C,
48.13; H, 4.80; N, 7.02. Found: C, 48.02; H, 4.99; N, 6.68.
(()-(4S*,5R*)-4-(4-Bromothiazol-2-yl)-2,2-dimethyl-5-phenyl-
oxazolidine-3-carboxylic Acid tert-Butyl Ester (rac-9). A solution
of rac-8 (149 mg, 373 µmol), p-TSA (7.6 mg, 10 mol %), and
2,2-dimethoxypropane (1.11 mL) in 2.5 mL of CH2Cl2 was stirred
at room temperature for 24 h. After that the reaction mixture was
diluted with CH2Cl2 (10 mL), washed with saturated aq NaHCO3
solution (5 mL), and dried (Na2SO4). The solvent was removed in
vacuo and the crude product purified by flash chromatography (P/
Et2O ) 75:25) to give rac-9 (134 mg, 305 µmol, 82%) as colorless
(()-(1S*,2R*)-2-(tert-Butyldimethylsilyloxy)-1,2-diphenyleth-
ylamine (rac-17).37b A solution of hexamethyldisilazane (91.0 µL,
70.9 mg, 440 µmol) in THF (3 mL) was cooled to -78 °C, and
n-BuLi (160 µL, 400 µmol, 2.5 M in pentane) was added dropwise.
The mixture was warmed to room temperature, stirred for 10 min,
and again cooled to -78 °C. A solution of aldehyde rac-16 (100
mg, 400 µmol) in THF (2 mL) was added, followed after 15 min
by PhLi (278 µL, 500 µmol, 1.8 M in hexanes). After an additional
15 min of stirring at -78 °C the reaction mixture was slowly
warmed to room tempearture, quenched with saturated aq NH4Cl
solution (20 mL), and extracted with ether (30 mL). The organic
layer was washed with H2O (20 mL) and brine (20 mL), dried (Na2-
SO4), and concentrated in vacuo. The crude product was purified
by column chromatography (P/EtOAc ) 75:25) to yield 60.0 mg
(183 µmol, 46%) of rac-17 as a yellow oil in diastereomerically
pure form. The analytical data were in accordance with the
1
crystals. Mp 129-130 °C; Rf 0.49 (P/Et2O ) 75:25); H NMR
(DMSO-d6, T ) 60 °C, 360 MHz) δ 1.24 (s, 9 H), 1.70 (s, 3 H),
3
3
1
1.72 (s, 3 H), 4.95 (d, J ) 7.8 Hz, 1 H), 5.11 (d, J ) 7.8 Hz, 1
H), 7.32-7.38 (m, 5 H), 7.77 (s, 1 H); 13C NMR (DMSO-d6, 90
MHz) δ 25.6, 26.2, 27.8, 65.6, 80.1, 82.8, 95.0, 118.6, 123.2, 127.2,
128.6, 129.0, 136.5, 150.7, 171.3. Anal. Calcd for C19H23BrN2O3S
(439.37): C, 51.94; H, 5.28; N, 6.38. Found: C, 51.67; H, 5.25;
N, 6.31.
literature.37b Rf 0.25 (P/ EtOAc ) 75:25); H NMR (CDCl3, 360
MHz) δ -0.23 (s, 3 H), -0.13 (s, 3 H), 0.85 (s, 9 H), 1.74 (br s,
1 H), 3.98 (d, 3J ) 5.5 Hz, 1 H), 4.65 (d, 3J ) 5.5 Hz, 1 H), 7.11-
7.22 (m, 10 H); 13C NMR (CDCl3, 90 MHz) δ -5.5, -4.8, 18.2,
25.9, 63.2, 80.5, 126.7, 126.9, 127.1, 127.5, 127.7, 127.8, 142.5,
142.6.
(()-2-[(1S*,2R*)-tert-Butoxycarbonylamino-(tert-butyldimeth-
ylsilyloxy)-2-phenylethyl]thiazole-4-carboxylic Acid Ethyl Ester
(rac-13). A solution of t-BuLi (1.15 mL, 1.95 mmol, 1.5 M in
pentane) in ether (1 mL) was cooled to -78 °C and the solution of
rac-7 (250 mg, 489 µmol) in ether (2 mL) was added dropwise.
After 10 min of stirring at -78 °C powdered CO2 (3 g) was added
and the reaction mixture was allowed to warm to room temperature.
The solvent was removed in vacuo and the residue dissolved in
DMF (6 mL). After the addition of K2CO3 (668 mg, 4.89 mmol)
and EtI (0.41 mL, 766 mg, 4.89 mmol) the solution was stirred at
room temperature for 72 h. The reaction mixture was diluted with
EtOAc (50 mL), washed with H2O (3 × 50 mL) and brine (50
mL), and dried (Na2SO4). The solvent was removed in vacuo and
the residue purified by flash chromatography (P/Et2O ) 75:25) to
yield the 4-ethoxycarbonylthiazole rac-13 (116 mg, 229 µmol, 47%)
as a colorless oil. Rf 0.45 (P/Et2O ) 50:50); 1H NMR (DMSO-d6,
360 MHz) δ -0.31 (s, 3 H), -0.29 (s, 3 H), 0.71 (s, 9 H), 1.27-
1.31 (m, 12 H), 4.26-4.33 (m, 2 H), 5.00 (dd, J ) 3.2 Hz, J )
9.1 Hz, 1 H), 5.36 (d, 1 H, 3J ) 3.2 Hz), 7.23-7.43 (m, 6 H), 8.41
(s, 1 H); 13C NMR (DMSO-d6, 90 MHz) δ -5.5, -4.9, 14.4, 17.9,
25.7, 28.2, 59.9, 60.8, 76.0, 79.0, 126.7, 127.6, 128.0, 129.2, 141.1,
146.2, 155.4, 160.9, 173.2. Anal. Calcd for C25H38N2O5SSi
(506.73): C, 59.26; H, 7.56; N, 5.53. Found: C, 59.59; H, 7.34;
N, 5.46.
(()-(4R*,5R*)-Diphenyloxazolidin-2-one (rac-18).45 A solution
of rac-17 (48.6 mg, 148 µmol) in acetonitrile (1 mL) and HF (1
mL, 50% in H2O) was stirred for 16 h at 50 °C. After the solution
was cooled to room temperature the pH value was adjusted to 12
with NaOH solution (5% in H2O). H2O (50 mL) was added, and
the aqueous layer was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried (Na2SO4) and concentrated in
vacuo. The residue was treated with methanol (3 mL) and HCl
(0.5 mL, 36% in H2O) and again concentrated in vacuo. The
remaining solid and triethylamine (63.0 µL, 46.0 mg, 450 µmol)
were dissolved in CH2Cl2 (2.0 mL) and cooled to 0 °C. Diphosgene
(11.0 µL, 17.8 mg, 90.0 µmol) was added and the mixture was
stirred for 1 h at 0 °C. The solvents were removed in vacuo, and
the residue was suspended in H2O (5 mL) and stirred at room
temperature overnight. The solid was filtered, washed with HCl
solution (10% in H2O) and H2O, and dried in vacuo to yield rac-
18 (18.2 mg, 76.1 µmol, 51%) as pale yellow crystals. The analytical
data were in accordance with the literature.45 1H NMR (CDCl3, 360
MHz) δ 4.74 (d, 3J ) 7.3 Hz, 1H), 5.28 (d, 3J ) 7.3 Hz, 1 H), 5.75
(s, 1 H), 7.21-7.39 (m, 10 H); 13C NMR (CDCl3, 90 MHz) δ 64.9,
86.1, 125.0, 125.6, 128.0, 128.2, 128.2, 128.4, 137.3, 138.4, 158.6.
(+)-(1R,2S)-[1-(4-Bromothiazol-2-yl)-2-(tert-butyldimethylsi-
lyloxy)-2-phenylethyl]-(4-methoxybenzyl)amine (20). Method A:
To a stirred solution of aldehyde (S)-16 (200 mg, 0.798 mmol) in
CH2Cl2 (2 mL) were added p-methoxybenzylamine (125 µL, 0.958
mmol) and MgSO4 (483 mg, 4.00 mmol) at room temperature and
the stirring was continued for 2 h. Filtration of the magnesium salts
and removal of the solvent in vacuo gave the corresponding imine,
which was subsequently used without further purification. To a
stirred solution of n-BuLi (319 µL, 0.798 mmol, 2.5 M in hexane)
in Et2O (2 mL) at -78 °C was added a solution of 2,4-
dibromothiazole (5) (193 mg, 0.798 mL) in Et2O (3 mL) and the
mixture was stirred for 1 h. A solution of freshly prepared imine,
prepared as described above, in Et2O (2 mL) was added to the
reaction mixture via cannula. After 2 h at -78 °C, the reaction
mixture was allowed to warm to 0 °C and saturated aq NH4Cl
solution (10 mL) was carefully added. The mixture was extracted
with Et2O (3 × 10 mL). The combined organic extracts were dried
(MgSO4) and concentrated in vacuo. Purification by flash chro-
matography (P/Et2O ) 95:5) yielded amine 20 (285 mg, 0.534
mmol, 67%) as a pale yellow oil. Method B: To a stirred solution
of amine ent-6 (220 mg, 0.53 mmol), p-anisaldehyde (71 µL, 79
3
3
(()-(4R*,5S*)-4-(4-Ethoxycarbonylthiazol-2-yl)-2,2-dimethyl-
5-phenyloxazolidine-3-carboxylic Acid tert-Butyl Ester (rac-
14).13a A solution of rac-13 (87.0 mg, 172 µmol) in THF (5 mL)
was cooled to 0 °C and TBAF (0.34 mL, 340 µmol, 1 M in THF)
was added dropwise. The cooling bath was removed and the reaction
mixture was stirred for 2 h at room temperature. After dilution with
EtOAc (20 mL) it was washed with H2O (2 × 20 mL) and brine
(10 mL). The organic layer was dried (Na2SO4) and concentrated
in vacuo. The residue was dissolved in CH2Cl2 (2 mL) and p-TSA
(6.5 mg, 10 mol %) and 2,2-dimethoxypropane (0.5 mL) were
added, and the solution was stirred at room temperature for 24 h.
The reaction mixture was diluted with CH2Cl2 (20 mL), washed
with NaHCO3 solution (20 mL, 5% in H2O), and dried (Na2SO4).
After the solvent was removed the crude product was purified by
flash chromatography (P/Et2O ) 80:20 f 70:30) to yield rac-14
(53.7 mg, 124 µmol, 72%) as colorless crystals. The analytical data
are in accordance with the literature.13a Mp 129-130 °C; Rf 0.48
1
(P/Et2O ) 50:50); H NMR (DMSO-d6, T ) 60 °C, 360 MHz) δ
4606 J. Org. Chem., Vol. 71, No. 12, 2006