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1.1.9. 20-Isopropyl[2,40]bithiazolyl-4-carboxylic acid
ethyl ester (20). A solution of 19 (0.99 g, 5.3 mmol) and
ethyl bromopyruvate (1.14 g, 5.8 mmol) in absolute EtOH
(30 ml) was stirred for 1 h at reflux. The reaction mixture
was diluted with 7% aqueous NaHCO3 and extracted with
Et2O. The organic layer was washed with brine and dried
over MgSO4. The organic layer was evaporated to give a
crude residue, which was chromatographed on silica gel
(30 g, n-hexane/AcOEt¼30:1) to afford 20 (1.41 g, 94%).
Recrystallization of 20 from n-hexane provided colorless
(9H, m), 8.06 (1H, s). Anal. calcd for C28H26IN2PS2: C,
54.90; H, 4.28; N, 4.57. Found: C, 55.19; H, 4.28; N, 4.50.
MS (FAB) m/z: 485 (Mþþ1–I).
1.1.12. Wittig condensation of (1)-3 and 4. To a solution
of 4 (0.582 g, 0.95 mmol) in THF (5 ml) was added lithium
bis(trimethylisilyl)amide (1 M solution in THF, 0.95 ml,
0.95 mmol) at 08C under argon atmosphere and the whole
mixture was stirred for 20 min at the same temperature. A
solution of (þ)-3 (0.10 g, 0.46 mmol) in THF (2 ml) was
added to the above reaction mixture at 08C and the whole
mixture was stirred for 15 min at the same temperature. The
reaction mixture was diluted with H2O and extracted with
AcOEt. The organic layer was dried over MgSO4 and
evaporated to afford a crude product which was chromato-
graphed on silica gel (5 g, n-hexane/AcOEt¼20:1) to give
(þ)-2 (129 mg, 66%) and a colorless oil (þ)-23 (32 mg,
16%) in elution order. Recrystallization of (þ)-2 from
n-hexane/AcOEt (20/1) provided colorless needles 2. (þ)-2:
mp 111–1128C; [a]2D3þ109.3 (c¼0.53, CHCl3); IR (KBr):
2929, 1711, 1624, 1441, 1147 cm21; 1H NMR: d 1.22 (3H,
d, J¼6.8 Hz), 1.44 (6H, d, J¼6.8 Hz), 3.33 (3H, s), 3.38
(1H, sept, J¼6.8 Hz), 3.60 (3H, s), 3.67 (3H, s), 3.81 (1H, t,
J¼7.6 Hz), 4.18 (1H, dq, J¼6.8, 7.6 Hz), 4.97 (1H, s), 6.41
(1H, dd, J¼7.6, 16 Hz), 6.58 (1H, d, J¼16 Hz), 7.09 (1H, s),
7.85 (1H, s). 13C NMR: d 14.1, 23.2, 23.2, 33.3, 39.8, 50.8,
55.5, 57.0, 84.4, 91.1, 114.8, 115.0, 125.6, 131.6, 148.7,
154.4, 162.6, 167.7, 176.7, 178.6. HRMS (FAB) (m/z):
calcd for C20H27O4N2 S2 (Mþþ1): 423.1412. Found:
423.1440. (þ)-23: [a]2D3þ240.5 (c¼0.65, CHCl3); IR
1
needles 20. 20: mp 76–778C; IR (KBr): 1729 cm21; H
NMR: d 1.43 (3H, d, J¼7.1 Hz), 1.44 (6H, d, J¼6.9 Hz),
3.36 (1H, sept, J¼6.9 Hz), 4.44 (2H, q, J¼7.1 Hz), 8.02
(1H, s), 8.16 (1H, s). 13C NMR: d 14.4, 23.1, 33.4, 61.5,
116.1, 127.4, 147.5, 147.6, 161.3, 163.5, 178.4. Anal. calcd
for C12H14N2O2S2: C, 51.04; H, 5.00; N, 9.92. Found: C,
50.89; H, 5.02; N, 9.96. MS (FAB) m/z: 283 (Mþþ1).
1.1.10. 20-Isopropyl[2,40]bithiazolyl-4-methyleneiodide
(22). A mixture of 20 (1.787 g, 6.3 mmol) and LiBH4
(0.69 g, 31.6 mmol) in THF (20 ml) was stirred for 2 h at
room temperature. The reaction mixture was diluted with
H2O (10 ml) and the whole was stirred for 5 h at the same
temperature. The reaction mixture was extracted with
AcOEt and washed with brine, and dried over MgSO4.
The organic layer was evaporated to give a crude residue,
which was chromatographed on silica gel (10 g, n-hexane/
AcOEt¼5:1) to afford 21 (1.506 g, 99%). Recrystallization
of 21 from n-hexane provided colorless needles 21. 21: mp
1
56–588C; IR (KBr): 3247, 1536, 1447 cm21; H NMR: d
1
1.44 (6H, d, J¼7.2 Hz), 3.25–3.40 (1H, brs), 3.37 (1H, sept,
J¼7.2 Hz), 4.81 (2H, s), 7.19 (1H, t, J¼0.8 Hz), 7.84 (1H,
s). 13C NMR: d 23.1, 23.1, 33.4, 60.9, 115.0, 115.2, 148.4,
157.2, 163.7, 178.8. Anal. calcd for C10H12N2OS2: C, 49.97;
H, 5.03; N, 11.66%. Found: C, 50.27; H, 5.19; N, 11.43. MS
(FAB) m/z: 241 (Mþþ1).
(KBr): 2932, 1715, 1623, 1457, 1146 cm21; H NMR: d
1.25 (3H, d, J¼6.8 Hz), 1.45 (6H, d, J¼6.8 Hz), 3.33 (3H,
s), 3.34 (3H, s), 3.38 (1H, sept, J¼6.8 Hz), 3.67 (3H, s), 4.22
(1H, dq, J¼6.8, 9.2 Hz), 4.92 (1H, s), 5.10 (1H, t, J¼
9.2 Hz), 5.59 (1H, dd, J¼9.2, 12 Hz), 6.58 (1H, d, J¼
12 Hz), 7.21 (1H, s), 7.82 (1H, s). 13C NMR: d 14.8, 23.2,
23.2, 33.4, 39.3, 50.8, 55.1, 56.3, 78.6, 91.1, 114.6, 117.8,
125.4, 132.6, 148.9, 153.6, 161.6, 167.8, 176.6, 178.8.
HRMS (FAB) (m/z): calcd for C20H27O4N2 S2 (Mþþ1):
423.1412. Found: 423.1398.
To a mixture of 21 (1.0 g, 4.2 mmol), triphenylphosphine
(1.1 g, 4.2 mmol) and imidazole (0.375 g, 5.5 mmol) in
THF (25 ml) was added I2 (1.08 g, 4.3 mmol) under argon
atmosphere and the whole mixture was stirred for 30 min at
room temperature. The reaction mixture was diluted with
H2O and extracted with AcOEt. The organic layer was
washed with brine and dried over MgSO4. The organic layer
was evaporated to give a crude residue, which was
chromatographed on silica gel (10 g, n-hexane/AcOEt¼
40:1) to afford 22 (1.05 g, 72%). Recrystallization of 22
from n-hexane provided colorless needles 22. 22: mp 99–
1008C; IR (KBr): 1653, 1506 cm21; 1H NMR: d 1.44 (6H, d,
J¼6.8 Hz), 3.37 (1H, sept, J¼6.8 Hz), 4.56 (2H, s), 7.26
(1H, s), 7.86 (1H, s). 13C NMR: d 23.1, 23.1, 33.3, 85.1,
115.2, 116.7, 148.4, 154.0, 163.3, 178.7. Anal. calcd for
C10H11IN2S2: C, 34.29; H, 3.17; N, 8.00. Found: C, 34.34;
H, 3.19; N, 7.96. MS (FAB) m/z: 351 (Mþþ1).
References
1. This work was published as a preliminary communication:
Kato, K.; Nishimura, A.; Yamamoto, Y.; Akita, H.
Tetrahedron Lett. 2002, 43, 643–645, In this paper, the used
catalyst in the reaction of palladium-catalyzed cyclization–
methoxycarbonylation is mentioned to be Pd(OAc)2, but this
description was erroneous and should be revised as PdCl2.
2. (a) Gerth, K.; Irschik, H.; Reichenbach, H.; Trowitzsch, W.
J. Antibiot. 1980, 33, 1474–1479. (b) Trowiwitzsch, W.;
Reifenstahl, G.; Wray, V.; Gerth, K. J. Antibiot. 1980, 33,
¨
1480–1490. (c) Trowitzsch, W.; Hofle, G.; Sheldrick, W. S.
Tetrahedron Lett. 1981, 22, 3829–3832.
1.1.11. 20-Isopropyl[2,40]bithiazolyl-4-methylenetri-
phenylphosphonium Iodide (4). A mixture of 22 (0.80 g,
2.2 mmol) and triphenylphosphine (0.63 g, 2.4 mmol) in
benzene (7 ml) was stirred for 12 h at reflux. After cooling,
the resulting colorless needles 4 (1.12 g, 80%) were
3. Ojika, M.; Suzuki, Y.; Tsukamoto, A.; Sakagami, Y.; Fudou,
R.; Yoshimura, T.; Yamanaka, S. J. Antibiot. 1998, 51,
275–281.
4. (a) Isolation: Anke, T.; Hecht, H. J.; Schramm, G.; Steglich,
W. J. Antibiot. 1979, 32, 1112–1117. (b) Chiral synthesis:
Akita, H.; Koshiji, H.; Furuichi, A.; Horikoshi, K.; Oishi, T.
Tetrahedron Lett. 1983, 24, 2009–2010.
1
obtained by filtration. 4: mp 295–2978C; H NMR: d 1.40
(6H, d, J¼6.9 Hz), 3.32 (1H, sept, J¼6.9 Hz), 5.49 (2H, d,
J¼13.6 Hz), 7.27 (1H, s), 7.63–7.68 (6H, m), 7.77–7.84