Configuration and Synthesis of (+)-Curacin A
J. Am. Chem. Soc., Vol. 119, No. 1, 1997 109
4-Pentynyl Acetate (20). To a solution of 13 (1.80 g, 21.4 mmol)
in dry pyridine (6 mL) was added acetic anhydride (2.4 mL, 25.4 mmol).
The solution was stirred for 20 h, diluted with water, and extracted
with pentane (40 mL). The pentane extract was washed with cold 5%
HCl solution (2 × 10 mL), water, and brine, dried over magnesium
sulfate, and concentrated. The residual oil was purified by fractional
distillation to give 20 (2.20 g, 82%) as a colorless oil: bp 50 °C (2
Torr); IR (neat) 3298, 2964, 2118, 1740, 1435, 1389, 1369, 1246, 1043,
stirred for 20 h under argon and poured into water. The mixture was
extracted with ether, and the extract was dried over magnesium sulfate
and concentrated. The residue was purified by chromatography on silica
(hexanes-ethyl acetate, 2:3) to give 28 (0.9 g, 57%) as a yellow oil:
[R]25 -31.3 (c 1.63, CHCl3); IR (neat) 2928, 1471, 1252, 1098, 837
D
1
cm-1; H NMR δ 0.04 (3H, s), 0.04 (3H, s), 0.88 (9H, s), 2.34 (1H,
dd, J ) 3, 4 Hz), 2.59 (1H, dd, J ) 1, 4 Hz), 2.94 (1H, m), 3.48 (1H,
dd, J ) 6, 10 Hz), 3.56 (1H, J ) 4, 10 Hz), 3.71 (3H, s); 13C NMR δ
-5.5, 18.2, 25.8, 36.0, 36.5, 51.8, 66.8, 126.9, 128.4, 128.8, 138.3;
MS m/z 311 (M+), 296, 254, 174, 137, 91; HRMS (CI) m/z 312.1816
(M+ + 1) (calcd for C16H30NOSSi 312.1817).
1
966, 877, 640, 608 cm-1; H NMR (CDCl3) δ 1.86 (2H, tt, J ) 7, 7
Hz), 1.97 (1H, dt, J ) 2, 1 Hz), 2.06 (3H, s), 2.30 (2H, dt, J ) 3, 7
Hz), 4.17 (2H, t, J ) 6 Hz); 13C NMR (CDCl3) δ 15.0, 20.6, 27.3,
62.7, 68.9, 82.8, 170.7;MS (CI) m/z 127 (M+ + 1), 111, 95, 85, 67,
61; HRMS (CI) m/z 127.0759 (M+ + 1) (calcd for C7H11O2 127.0759).
Amides 29 and 30. To a mixture of 28 (150 mg, 0.48 mmol), 1,3-
dicyclohexylcarbodiimide (108 mg, 0.52 mmol), sodium bicarbonate
(100 mg, 1.19 mmol), and 1-hydroxybenzotriazole (64 mg, 0.48 mmol)
was added (+)-8 (48 mg, 0.48 mmol) in DMF (6 mL) at room
temperature under argon. After 3 days, the mixture was diluted with
water, and extracted with ether. The ethereal extract was dried over
magnesium sulfate and concentrated under reduced pressure, and the
residue was chromatographed on silica (hexanes-ethyl acetate, 9:1)
to give a 1:1 mixture of 29 and 30 (174 mg, 92%) as a colorless oil:
IR (neat) 3735, 2929, 1652, 1646, 1111, 836 cm-1; 1H NMR (CDCl3)
δ 0.04 (3H, s), 0.05 (3H, s), 0.88 (9H, s), 1.09 (1H, m), 1.1-1.7 (6H,
m), 2.58 (2H, m), 3.61 (2H, m), 3.74 (2H, d, J ) 4 Hz), 3.85 (1H, m),
4.13 (1H, m), 5.91 (1H, m), 7.31 (5H, m); 13C NMR (CDCl3) δ -5.5,
12.0, 12.2, 14.6, 14.7, 18.2, 20.6, 24.6, 25.4, 25.7, 25.8, 32.1, 32.3,
34.8, 36.0, 36.3, 49.3, 49.4, 55.6, 62.7, 62.9, 126.8, 128.3, 128.4, 128.9,
128.9, 138.2, 170.7, 170.8; MS (CI) m/z 394 (M+ + 1), 336, 307, 272,
247, 225, 207, 153, 125; HRMS (CI) m/z 394.2238 (M+ + 1) (calcd
for C21H36NO2SiS 394.2236).
(4R,7E,9E)-(-)-4-Methoxy-7-methyltrideca-1,7,9-trienol (22). To
20 (60 mg, 476 µmol) was added catecholborane (70 µL, 657 µmol).
The mixture was heated at 70-80 °C for 2 h in a sealed tube under
Ar. The resulting catecholboronate was diluted with degassed THF
(3.3 mL) and added to a mixture of degassed 1 N NaOH (600 µL, 600
µmol), tetrakis(triphenylphosphine)palladium (3 mg, 2 µmol), and 18
(15 mg, 53 µmol). The mixture was stirred at 70 °C for 5 h, cooled to
room temperature, and diluted with ether (30 mL). The solution was
washed with water (3 × 20 mL) and brine (1 × 20 mL), dried over
magnesium sulfate, and concentrated. The residual oil was purified
by chromatography on silica (pentane-ether, 3:2) to give 22 (70 mg,
62%) as a pale yellow oil: [R]23D -1.4 (c 2.90, CDCl3); IR (neat) 3,360,
1
2934, 1643, 1443, 1095, 996, 964 cm-1; H NMR (CDCl3) δ 1.56-
1.72 (4H, m), 1.73 (3H, s), 2.09 (2H, m), 2.19 (2H, dt, J ) 7, 7 Hz),
2.27 (2H, m), 3.20 (1H, tt, J ) 6, 6 Hz), 3.34 (3H, s), 3.66 (2H, t, J )
6 Hz), 5.07 (2H, m), 5.58 (1H, m), 5.81 (2H, m), 6.27 (1H, m); 13C
NMR (CDCl3) δ 16.5, 29.2, 31.6, 32.4, 35.3, 37.6, 56.5, 62.4, 79.9,
116.9, 124.6, 127.2, 131.3, 134.7, 136.6; MS (CI) m/z 238 (M+), 206,
197, 179, 166, 147, 121, 105, 93; HRMS (CI) m/z 238.1934 (M+) (calcd
for C15H26O2 238.1933). Anal. Calcd for C15H26O2: C, 75.58; H,
10.99. Found: C, 75.21; H, 10.79.
Thiols 25 and 26. To a dark blue solution of sodium-ammonia
prepared from excess sodium and liquid ammonia (3 mL) was added
a solution of 29 and 30 (57 mg, 0.145 mmol) in THF (0.8 mL) at -60
°C. The cold bath was removed, and after all ammonia had evaporated,
the mixture was diluted with water and extracted with ether. The
ethereal extract was washed with brine, dried over magnesium sulfate,
and concentrated to leave a 1:1 mixture of 25 and 26 (42 mg, 96%) as
(4R,7E,9E)-(+)-4-Methoxy-7-methyl-13-iodotrideca-1,7,9-
triene (23). To a solution of 22 (17 mg, 71 µmol) in dry CH2Cl2 (3
mL) was added dry triethylamine (20 µL, 143 µmol) followed by
methanesulfonyl chloride (8 µL, 103 µmol) at -30 °C. After stirring
at -20 to -10 °C for 1 h, the solution was allowed to warm to room
temperature, concentrated under reduced pressure, and diluted with dry
acetone (3 mL). To the solution was added sodium iodide (50 mg,
333 µmol), and the mixture was stirred for 15 h at room temperature
and concentrated. The residue was taken up in hexane and concentrated
again under reduced pressure. The residual oil was purified by
chromatography on silica (hexanes-ethyl acetate, 4:1) to give 23 (24
mg, 100%) as a pale yellow oil: [R]23D -0.9 (c 4.35, CHCl3); IR (neat)
2928, 1639, 1442, 1357, 1217, 1097, 963, 914 cm-1; 1H NMR (CDCl3)
δ 1.59 (2H, dt, J ) 8, 6 Hz), 1.74 (3H, s), 1.91 (2H, tt, J ) 7 Hz), 2.09
(2H, m), 2.19 (2H, m), 2.27 (2H, m), 3.19 (3H, t, J ) 7 Hz), 3.34 (3H,
s), 5.07 (2H, m), 5.49 (1H, dt, J ) 16, 8 Hz), 5.81 (2H, m), 6.30 (1H,
dd, J ) 15, 11 Hz); 13C NMR (CDCl3) δ 6.5, 16.6, 31.5, 33.0, 33.4,
35.3, 37.6, 56.5, 79.8, 116.9, 124.4, 128.1, 129.4, 134.7, 137.0; MS
(CI) m/z 348 (M+), 317, 307, 275, 249, 147, 93, 85; HRMS m/z
348.0963 (M+) (calcd for C15H25OI 348.0950).
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a pale yellow oil: IR (neat) 3296, 2928, 1652, 1558, 837 cm-1; H
NMR (CDCl3) δ 4.94 (1H) and 6.02 (1H) (NHCO of each diastere-
omer); 13C NMR δ 12.3 and 12.4 (methyl of each diastereomer); MS
(CI) m/z 304 (M+ + 1), 246, 225, 172, 147; HRMS m/z 304.1764 (M+
+ 1) (calcd for C14H30NO2SSi 304.1766).
Methyl Esters 33 and 34. Into a stirred solution of a racemic cis-
trans mixture of 31 (156 mg, 1.92 mmol) in methanol (3 mL) was
introduced gaseous HCl for 3 h at 0 °C. The mixture was stirred for
1 h at 0 °C and then sealed and stored for 3 days at 0 °C. The resultant
precipitate was washed with petroleum ether to give the imidate 32 as
a white salt (226 mg, 79%): IR (neat) 3395, 2946, 1635, 1476, 1403,
1098, 872 cm-1; 1H NMR (CDCl3) δ 0.75 (1H, m, trans isomer (87%)),
0.95 (1H, m, cis isomer (13%)); 13C NMR (CDCl3) δ 60.1 (OMe, trans
isomer), 60.4 (OMe, cis isomer).
To 32 (47 mg, 0.314 mmol) and cysteine methyl ester hydrochloride
(54 mg, 0.314 mmol) in CH2Cl2 (1 mL) was slowly added triethylamine
(38 µL, 0.272 mmol). The resulting suspension was stirred for 24 h
and diluted with water, and the solution was extracted with CH2Cl2.
The CH2Cl2 extract was dried over magnesium sulfate and concentrated,
and the residue was chromatographed on silica (hexanes-ethyl acetate,
4:1) to give a 1:1 mixture of 33 and 34 (32 mg, 52%) as a colorless
[(4R,7E,9E)-(+)-4-Methoxy-7-methyltrideca-1,7,9-trien-13-yl]-
triphenylphosphonium Iodide (24). A solution of 23 (40 mg, 115
µmol) and triphenylphosphine (50 mg, 191 µmol) in dry acetonitrile
(2 mL) was refluxed under argon for 16 h. The solution was
concentrated, and the residue was purified by chromatography on silica
(CH2Cl2 to CH2Cl2-MeOH, 4:1) to give 24 (61 mg, 87%) as a white
1
oil: IR (neat) 2954, 1744, 1613, 1437, 1272, 1200, 1080 cm-1; H
NMR (CDCl3) δ 0.79 (1H, m), 1.13 (3H, d, J ) 6 Hz), 1.16 (1H, m),
1.39 (1H, m), 1.68 (1H, m), 3.51 (2H, m), 3.79 (3H, s), 5.01 (1H, m);
13C NMR (CDCl3) δ 17.7, 18.1, 18.2, 23.6, 35.1, 52.6, 77.7, 171.5,
176.6; MS (CI) m/z 200 (M+ + 1), 182, 169, 147, 140, 119; HRMS
(CI) m/z 200.0745 (calcd for C9H14NO2S (M+ + 1) 200.0745).
(2R,4R)-3-(tert-Butoxycarbonyl)-4-(hydroxymethyl)-2-phenyl-
thiazolidine (40). To a solution of (2R,4R)-4-carboxy-2-phenylthia-
zolidine (2.36 g, 11.48 mmol), prepared from cysteine following a
literature procedure,26 in triethylamine (6.6 mL) and MeOH (66 mL)
was added di-tert-butyl dicarbonate (5.0 g, 22.96 mmol) in one portion.
The mixture was stirred for 30 min at 50 °C and concentrated, and the
residue was taken up in 0.4 N hydrochloric acid (40 mL). The solution
was extracted with CH2Cl2, and the extract was dried over magnesium
sulfate and concentrated to leave a white solid (3.2 g, 90%). This was
used for the next step without purification.
foam: [R]23 0.0 (c 7.0, CHCl3); IR (neat) 2930, 2891, 1438, 1112,
D
1
996, 968, 916, 723, 691 cm-1; H NMR (CDCl3) δ 1.58 (2H, dt, J )
8, 7 Hz), 1.71 (3H, s), 1.72 (2H, m), 2.07 (2H, m), 2.26 (2H, m), 2.49
(2H, dt, J ) 7, 7 Hz), 3.18 (1H, tt, J ) 6, 6 Hz), 3.33 (3H, s), 3.75
(2H, m), 5.07 (2H, m), 5.41 (1H, dt, J ) 14, 7 Hz), 5.80 (2H, m), 6.31
(1H, dd, J ) 15, 11 Hz); 13C NMR (CDCl3) δ 16.5, 21.7, 22.4, 31.3,
32.9 (d, J ) 16 Hz), 35.0, 37.3, 56.2, 79.5, 116.7, 117.1, 118.2, 124.0,
128.8 (d, J ) 14 Hz), 130.3 (d, J ) 12 Hz), 133.4 (d, J ) 10 Hz),
134.4, 134.9, 137.6.
(R)-S-Benzylcysteinyl tert-Butyldimethylsilyl Ether (28). To a
stirred solution of (R)-S-benzylcysteinyl alcohol (27; 1.0 g, 5.07 mmol)
and imidazole (0.41 g, 6.08 mmol) in DMF (5 mL) was added tert-
butyldimethylsilyl chloride (0.916 g, 6.08 mmol). The solution was