Total Synthesis of Cystothiazoles A and C
J . Org. Chem., Vol. 66, No. 25, 2001 8467
(R)-4-Ben zyl-3-[(2R,3S)-(E)-3-h yd r oxy-5-(2′-isop r op yl-
[2,4′]bith ia zolyl-4-yl)-2-m eth ylp en t-4-en oyl]oxa zolid in -2-
on e (16). To a solution of (R)-4-phenyl-2-oxazolidinone 15 (343
mg, 1.47 mmol) in CH2Cl2 (5 mL) at 0 °C was added freshly
distilled dibutylboron triflate (513 µL, 1.71 mmol). After the
solution was stirred for 5 min at 0 °C, triethylamine (307 µL,
2.20 mmol) was added carefully to the mixture, maintaining
the internal temperature below 3 °C. After being stirred for 5
min at 0 °C, the solution was cooled to -78 °C, and aldehyde
12 (323 mg, 1.22 mmol) in CH2Cl2 (1.2 mL) was added via
cannula. The mixture was stirred at -78 °C for 30 min, slowly
warmed to 0 °C, and stirred for an additional 2 h. The reaction
was then quenched by addition of 2:1 MeOH/aqueous pH 7
phosphate buffer (6 mL), followed by careful addition of 2:1
MeOH/30% aqueous H2O2 (6 mL). The mixture was stirred at
0 °C for 1 h, and the volatiles were removed in vacuo. The
resultant slurry was diluted with EtOAc (10 mL) and washed
with aqueous saturated NaHCO3 (15 mL) solution. The aque-
ous layer was re-extracted with EtOAc (2 × 15 mL), and the
combined organic phases were dried (MgSO4), filtered, and
concentrated in vacuo. The crude residue was purified by flash
silica gel chromatography (15% EtOAc/CH2Cl2) to afford 526
mg (72%) of aldol product 16 as a light yellow foam: Rf ) 0.42
in 50% EtOAc/hexanes; [R]28D -33.3 (c 0.35, CHCl3); IR (neat)
3450, 3105, 2967, 2925, 1778, 1697, 1209 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.92 (s, 1H), 7.35-7.20 (m, 5H), 7.10 (s, 1H),
6.73 (dd, J ) 1.2, 15.6 Hz, 1H), 6.64 (dd, J ) 5.2, 15.6 Hz,
1H), 4.72 (m, 2H), 4.25-4.17 (m, 2H), 4.02 (dq, J ) 4.0, 7.2
Hz), 3.34 (sept, J ) 6.8 Hz, 1H), 3.26 (dd, J ) 3.0, 13.6 Hz),
3.11 (br s, 1H), 2.81 (dd, J ) 9.6, 13.6 Hz), 1.44 (d, J ) 6.8 Hz,
6H), 1.33 (d, J ) 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
178.6, 176.6, 162.8, 154.2, 153.1, 148.7, 135.1, 131.8, 129.4,
129.0, 127.2, 115.8, 115.0, 72.1, 66.2, 55.2, 42.9, 37.8, 33.3, 23.1,
11.3; HRMS m/e calcd for C25H27N3O4S2 (M+) 497.1443, found
497.1419.
4.03 (dd, J ) 6.4, 7.4 Hz, 1H), 3.67 (s, 3H), 3.36 (sept, J ) 6.8
Hz, 1H), 3.33 (s, 3H), 2.71 (dq, J ) 6.8, 6.8 Hz, 1H), 1.42 (d, J
) 6.8 Hz, 6H), 1.24 (d, J ) 6.8 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 178.6, 174.5, 162.8, 153.8, 148.5, 130.1, 126.2, 115.9,
115.0, 82.8, 57.1, 51.7, 45.0, 33.3, 23.1, 12.1; HRMS m/e calcd
for C17H22N2O3S2 (M+) 366.1072, found 366.1074.
(E)-(2R,3S)-5-(2′-Isopr opyl[2,4′]bith iazolyl-4-yl)-2-m eth yl-
3-tr iisop r op ylsila n yloxy-4-p en ten oic Acid Meth yl Ester
(18a ). To a solution of alcohol 17 (275 mg, 0.780 mmol) in CH2-
Cl2 (4 mL) was added 2,4,6-collidine (476 µL, 3.59 mmol). The
mixture was cooled to 0 °C, and triisopropylsilyl trifluo-
romethanesulfonate (344 µL, 1.28 mmol) was added dropwise.
After the mixture was stirred for 45 min, it was diluted with
CH2Cl2 (5 mL) and quenched with aqueous saturated NH4Cl
(10 mL). The layers were separated, and the aqueous phase
was extracted with CH2Cl2 (2 × 10 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified by flash silica gel chromatog-
raphy (2.5% EtOAc/hexanes) to afford 357 mg (90%) of 18a as
a colorless oil: Rf ) 0.67 in 25% EtOAc/hexanes; [R]28 +40.7
D
(c 1.46, CHCl3); IR (neat) 2944, 2866, 1738 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.85 (s, 1H), 7.09 (s, 1H), 6.63 (dd, J ) 6.8,
15.6 Hz, 1H), 6.56 (d, J ) 15.6 Hz, 1H), 4.76 (dd, J ) 4.8, 6.8
Hz, 1H), 3.66 (s, 3H), 3.38 (sept, J ) 7.2 Hz, 1H), 2.70 (dq, J
) 4.8, 6.8 Hz, 1H), 1.44 (d, J ) 7.2 Hz, 6H), 1.24 (d, J ) 6.8
Hz, 3H), 1.06-1.05 (m, 21H); 13C NMR (101 MHz, CDCl3) δ
178.7, 174.7, 162.7, 154.3, 148.8, 133.8, 124.0, 115.9, 115.4,
75.2, 51.5, 47.2, 33.4, 23.2, 18.1, 13.0, 12.6, 11.6; HRMS m/e
calcd for C25H40N2O3S2Si (M+) 508.2250, found 508.2225. Anal.
Calcd for C25H40N2O3S2Si: C, 59.01; H, 7.92; N, 5.51; S, 12.60.
Found: C, 59.19; H, 8.01; N, 5.30; S, 12.23.
(E)-(2S,3S)-5-(2′-Isop r op yl[2,4′]bith ia zolyl-4-yl)-3-m eth -
oxy-2-m eth yl-4-p en ten -1-ol (19b). To a solution of ester 18b
(0.11 g, 0.30 mmol) in THF (3.0 mL) at -78 °C was added
diisobutylaluminum hydride (1.0 mL of a 1.0 M in hexanes,
1.0 mmol) dropwise. The mixture was stirred at -78 °C for 1
h. The reaction was quenched with careful addition of acetone
(2 mL) and warmed to room temperature. After dilution with
CH2Cl2 (50 mL) and aqueous 20% sodium potassium tartrate
(50 mL), the biphasic solution was stirred vigorously for 16 h.
The phases were separated, and the aqueous phase was re-
extracted with EtOAc (2 × 20 mL). The combined organic
phases were dried (MgSO4), filtered, and concentrated in
vacuo. The residue was purified by flash silica gel chromatog-
raphy (25% EtOAc/CH2Cl2) to afford 100 mg (98%) of alcohol
(E)-(2R,3S)-3-Hyd r oxy-5-(2′-isop r op yl[2,4′]bith ia zolyl-
4-yl)-2-m eth yl-4-p en ten oic Acid Meth yl Ester (17). Me-
thylmagnesium bromide (1.38 mL of a 3.0 M solution in Et2O,
4.14 mmol) was added to methanol (7 mL) at 0 °C. After the
suspension was stirred for 5 min at 0 °C, oxazolidinone 16 (515
mg, 1.04 mmol) in methanol (2.2 mL) was added. The reaction
was stirred at 0 °C for 3 h before quenching with aqueous
saturated NH4Cl (10 mL). The aqueous phase was extracted
with CH2Cl2 (2 × 15 mL). The combined organic phases were
dried (MgSO4), filtered, and concentrated in vacuo. The residue
was purified by flash silica gel chromatography (25% EtOAc/
hexanes) to afford 292 mg (80%) of methyl ester 17 as a light
19b: Rf ) 0.10 in 25% EtOAc/hexanes; [R]25 +42.4 (c 1.25,
D
CHCl3); IR (neat) 3414, 3101, 2966, 2929, 1182, 1081, 1034
yellow viscous oil: Rf ) 0.50 in 50% EtOAc/hexanes; [R]28
cm-1; H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.11 (s, 1H),
1
D
+13.2 (c 0.5, CHCl3); IR (neat) 3445, 3113, 2969, 1732, 1151
6.71 (d, J ) 15.6 Hz, 1H), 6.54 (dd, J ) 6.8, 15.6 Hz, 1H), 3.91
(dd, J ) 4.0, 6.8 Hz, 1H), 3.73 (dd, J ) 7.6, 10.6 Hz, 1H), 3.59
(dd, J ) 4.4, 10.6 Hz, 1H), 3.36 (sept, J ) 6.8 Hz, 1H), 3.34 (s,
3H), 2.77 (br s, 1H), 2.09 (m, 1H), 1.43 (d, J ) 6.8 Hz, 6H),
0.94 (d, J ) 6.8 Hz, 3H): 13C NMR (101 MHz, CDCl3) δ 178.7,
162.9, 153.9, 148.5, 129.8, 126.2, 115.7, 115.1, 85.5, 65.9, 57.0,
39.8, 33.3, 23.1, 12.2; HRMS m/e calcd for C16H22N2O2S2 (M+)
338.1123, found 338.1123.
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.09 (s, 1H),
6.72 (dd, J ) 1.2, 15.6 Hz, 1H), 6.61 (dd, J ) 5.0, 15.6 Hz,
1H), 4.69 (m, 1H), 3.74 (s, 3H), 3.38 (sept, J ) 6.8 Hz, 1H),
2.81 (br s, 1H), 2.77 (dq, J ) 4.0, 7.2 Hz), 1.44 (d, J ) 6.8 Hz,
6H), 1.25 (d, J ) 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
178.6, 175.8, 162.8, 154.1, 148.6, 131.7, 124.2, 115.8, 115.0,
72.3, 51.9, 44.6, 33.3, 23.1, 11.1; HRMS m/e calcd for
C
16H20N2O3S2 (M+) 352.0915, found 352.0911.
(E)-(2S,3S)-5-(2′-Isop r op yl[2,4′]bith ia zolyl-4-yl)-2-m eth -
yl-3 tr iisop r op ylsila n yloxy-4-p en ten -1-ol (19a ). To a solu-
tion of ester 18a (333 mg, 0.654 mmol) in THF (3.5 mL) at
-78 °C was added diisobutylaluminum hydride (1.96 mL of a
1.0 M in hexanes, 1.96 mmol) dropwise. The mixture was
stirred at -78 °C for 1.5 h. The reaction was quenched with
acetone (2 mL) and warmed to room temperature. After
dilution with CH2Cl2 (100 mL) and aqueous 20% sodium
potassium tartrate (100 mL), the biphasic solution was stirred
vigorously for 16 h. The phases were separated, and the
aqueous phase was re-extracted with CH2Cl2 (2 × 75 mL). The
combined organic phases were dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by flash silica
gel chromatography (10% EtOAc/CH2Cl2) to afford 294 mg
(94%) of alcohol 19a as a viscous light yellow oil: Rf ) 0.46 in
25% EtOAc/hexanes; IR (neat) 3414, 2961, 2942, 2864, 1086,
1044 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.09 (s,
1H), 6.71 (dd, J ) 6.4, 15.6 Hz, 1H), 6.61 (d, J ) 15.6 Hz, 1H),
4.57 (dd, J ) 4.0, 6.4 Hz, 1H), 3.80 (m 1H), 3.54 (m, 1H), 3.38
(E)-(2R,3S)-5-(2′-Isopr opyl[2,4′]bith iazolyl-4-yl)-3-m eth -
oxy-2-m eth yl-4-p en ten oic Acid Meth yl Ester (18b). To a
solution of alcohol 17 (120 mg, 0.34 mmol) in DMSO/THF (2:
1) (3.5 mL) with a trace amount of water (2 µL) was added
methyl iodide (7 mL). The mixture was cooled to 0 °C, and
sodium hydroxide (450 mg, powdered by mortar and pestle)
was added in small portions. After being stirred at 0 °C for 30
min, the reaction mixture was diluted with CH2Cl2 (10 mL)
and pH 3 phosphate buffer (15 mL) was added. The layers were
separated, and the aqueous phase was extracted with CH2Cl2
(2 × 7 mL). The combined organic phases were washed with
aqueous saturated NaCl (15 mL), dried (MgSO4), filtered, and
concentrated in vacuo. The residue was purified by flash silica
gel chromatography (15% EtOAc/hexanes) to afford 116 mg
(93%) of 18b: Rf ) 0.42 in 25% EtOAc/hexanes; [R]25 +9.7 (c
D
2.25, CHCl3); IR (neat) 3101, 2967, 2931, 2823, 1738, 1181,
1089 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.11 (s,
1H), 6.62 (d, J ) 15.6 Hz, 1H), 6.49 (dd, J ) 7.4, 15.6 Hz, 1H),