X. Just-Baringo, F. Albericio, M. Álvarez
FULL PAPER
[
α]
D
= –38.3 (c = 1.00, CH
2
Cl
385, 1162 cm . H NMR (400 MHz, CDCl
H), 1.65 (s, 9 H), 1.92–2.11 (m, 2 H), 2.24–2.49 (m, 2 H), 3.41–
.71 (m, 2 H), 3.89 (br. s, 3 H), 5.13–5.33 (m, 1 H), 7.86 (s, 1 H), (100 MHz, CDCl
.02 (d, J = 8.0 Hz, 1 H), 8.18–8.21 (m, 2 H), 8.32 (d, J = 8.0 Hz, and 28.8 (q), 33.1 and 34.4 (t), 46.9 and 47.3 (t), 52.4 (q), 59.3 and
2
). IR (KBr): ν˜ = 2975, 1732, 1699,
3.36–3.70 (m, 2 H), 3.96 (s, 3 H), 4.46 (q, J = 7.2 Hz, 2 H), 5.09–
–1 1
1
9
3
8
1
2
3
): δ = 1.30–1.56 (m,
5.29 (m, 1 H), 7.39 (br. s, 1 H), 8.20 (s, 1 H), 8.24 (d, J = 8.0 Hz,
1
3
1 H), 8.32 (s, 1 H), 8.37 (d, J = 8.0 Hz, 1 H) ppm. C NMR
): δ = 12.2 (q), 14.7 (q), 23.6 and 24.3 (t), 28.6
3
H) ppm. 13C NMR (100 MHz, CDCl
8.4 (q), 28.5 (q), 33.0 and 34.3 (t), 46.8 (t), 53.0 (q), 59.2 and 59.6
d), 80.6 (s), 82.5 (s), 115.7 and 116.0 (d), 118.7 (d), 120.5 (d), 128.9
s), 129.5 (d), 138.1 (d), 149.8 (s), 150.1 (s), 151.1 (s), 154.1 (s),
): δ = 23.5 and 24.2 (t),
59.6 (d), 62.0 (t), 80.7 (s), 115.1 and 115.5 (d), 118.9 (d), 121.6 (d),
122.8 (s), 128.7 (s), 130.5 (d), 141.0 (d), 149.0 (s), 149.1 (s) 151.4
and 151.5 (s), 154.2 (s) and 154.4 (s), 157.1 (s), 159.0 (s), 161.6
(s); 162.1 (s), 163.2 (s), 169.1 (s), 176.7 (s) ppm. HRMS: calcd. for
3
(
(
1
54.1 (s), 160.6 (s), 162.3 (s), 168.7 (s), 169.2 (s) ppm. HRMS:
C
32
H
33
N
6
O
7
S
3
[M + H] 709.1590; found 709.1567.
calcd. for C30 [M + H] 656.1666; found 656.1666.
34 6 5 3
H O N S
(
S)-2-{2Ј-[N-(tert-Butoxycarbonyl)pyrrolidin-2-yl]-2,4Ј-bithiazol-4-
Methyl 2-(2-Acetylthiazol-4-yl)-6-[4-(tert-butoxycarbonyl)thiazol-2-
yl]nicotinate (18cb): The reaction was performed according to the
general procedure for Negishi cross-coupling by using 9 (1.4 mL,
yl}-3-[5-methyl-4-(methoxycarbonyl)oxazol-2-yl]-6-[4-(iso-
propoxycarbonyl)thiazol-2-yl]pyridine (24): A solution of 22 in
DMA (0.21 m, 9.2 mL, 1.94 mmol) was added to a Schlenk tube
0
.30 mmol), Pd(PPh
3
)
4
(34 mg, 0.03 mmol) and 17cb (61 mg,
charged with 17aa (170 mg, 0.24 mmol) and Pd(PPh
0.05 mmol). The mixture was stirred at 45 °C. After 16 h EtOAc
(50 mL) the mixture was added and washed with H O (4ϫ50 mL),
dried (Na SO ) and concentrated in vacuo. The crude product was
3 4
) (55 mg,
0.15 mmol) in DMA (1.9 mL). The crude product was purified by
silica flash column chromatography (hexanes/EtOAc, 8:2). The title
product was obtained as a yellowish solid (26 mg, 39 %), m.p.
2
2
4
–
1 1
(Et
2
O) 129–133 °C. IR (KBr): ν˜ = 2977, 2929, 1730, 1690 cm . H
purified by silica flash column chromatography (hexanes/EtOAc,
NMR (400 MHz, CDCl
3
): δ = 1.65 (s, 9 H), 2.72 (s, 3 H), 3.92 (s, 7:3 to 6:4). The desired product was obtained as a pale solid
3
1
H), 8.05 (d, J = 8.2 Hz, 1 H), 8.20 (s, 1 H), 8.37 (d, J = 8.2 Hz,
H), 8.50 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl
): δ = 26.1 (c = 1.00, CH
(148 mg, 85%), m.p. (CH
2 2 D
Cl ) decomp. above 130 °C. [α] = –37.2
Cl ). IR (KBr): ν˜ = 3122, 2975, 1700, 1386, 1239,
1214, 1105 cm . H NMR (400 MHz, CDCl ): δ = 1.27–1.53 (m,
3
2
3
2
–
1 1
(
(
q), 28.4 (q), 52.8 (q), 82.6 (s), 119.2 (d), 127.2 (d), 128.7 (s), 129.6
d), 138.5 (d), 149.1 (s), 150.2 (s), 151.4 (s), 155.2 (s), 160.5 (s),
15 H), 1.89–2.03 (m, 2 H), 2.18–2.45 (m, 2 H), 2.53 (s, 3 H), 3.36–
3.68 (m, 2 H), 3.96 (s, 3 H), 5.10–5.36 (m, 2 H), 7.39 (br. s, 1 H),
8.20 (s, 1 H), 8.24 (d, J = 8.0 Hz, 1 H), 8.28 (s, 1 H), 8.38 (d, J =
1
66.5 (s), 168.3 (s), 168.6 (s), 191.5 (s) ppm. HRMS: calcd. for
[M + H] 446.0839; found 446.0843.
20 20 5 3 2
C H O N S
1
3
8
.0 Hz, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 12.2 (q), 22.3
Isopropyl 2-Bromothiazole-4-carboxylate (20): A solution of lithium
hydroxide (1.16 g, 27.62 mmol) in H O (13 mL) was added to a
stirring solution of ethyl 2-bromothiazole-4-carboxylate[ (3.26 g,
3.81 mmol) in THF (130 mL). The mixture was stirred at room
(
q), 23.6 and 24.3 (t), 28.6 and 28.8 (q), 33.1 and 34.4 (t), 46.9 and
2
4
1
7.3 (t), 52.4 (q), 59.3 and 59.7 (d), 69.6 (d), 80.7 (s), 115.1 and
15.5 (d), 118.9 (d), 121.6 (d), 122.8 (s), 128.7 and 128.9 (s), 130.2
10]
1
(
d), 141.0 (d), 149.1 (s), 149.4 (s), 151.4 and 151.6 (s), 154.2 and
temp. for 18 h and then concentrated under vacuum before aqueous
HCl (2 m, 150 mL) was then added. The resulting mixture was ex-
1
1
54.5 (s), 157.2 (s), 159.0 (s), 161.2 (s), 162.1 (s), 163.2 (s), 169.0 (s),
76.7 (s) ppm. HRMS: calcd. for C33 [M + H] 723.1735;
35 7 6 3
H O N S
tracted with EtOAc (3ϫ 200 mL), dried (Na
trated in vacuo. The resulting white solid was dissolved in dry
CH Cl (28 mL) and cooled in an ice/water bath. Oxalyl chloride
2.3 mL, 27.68 mmol) and dimethylformamide (DMF; 3 drops)
2 4
SO ) and concen-
found 723.1724.
Supporting Information (see footnote on the first page of this arti-
cle): General procedures and NMR spectra of compounds 2, 4, 5,
2
2
(
7
2
, 8, 10, 14, 15a–15c, 16aa–16cb, 17aa–17cb, 18aa–18cb, 20, 23 and
4 as well as those of non-numbered intermediates.
were added dropwise and the resulting mixture was stirred allowing
it to reach room temp. After 1 h all volatiles were evaporated under
reduced pressure. The residue was dissolved in iPrOH (100 mL)
and stirred for 2 h. Volatiles were evaporated and the crude product
purified by silica flash column chromatography (hexanes/EtOAc,
Acknowledgments
9
5:5). The title product was obtained as a white solid (2.80 g, 81%),
m.p. (CH Cl ) 58–59 °C. IR (KBr): ν˜ = 3084, 2975, 1713, 1431,
226, 1111, 1015 cm . H NMR (400 MHz, CDCl
J = 6.2 Hz, 6 H), 5.27 (h, J = 6.2 Hz, 1 H), 8.08 (s, 1 H) ppm.
NMR (100 MHz, CDCl ): δ = 21.8 (q), 69.6 (d), 130.5 (d), 136.6
s), 147.7 (s), 159.7 (s) ppm. HRMS: calcd. for C BrNO S [M +
H] 249.9531; found 249.9532.
The authors gratefully acknowledge financial support from the
Spanish Science and Innovation Ministry (CICYT) (CTQ2009-
07758 and CTQ2012-30930) and the Generalitat de Catalunya
2
2
–
1 1
1
3
): δ = 1.38 (d,
1
3
C
(
(
2009SGR 1024). X. J. thanks the Instituto de Salud Carlos III
ISCIII) for a PFIS grant.
3
(
7
H
8
2
[
[
1] a) E. Riego, D. Hernández, F. Albericio, M. Álvarez, Synthesis
(
S)-2-{2Ј-[N-(tert-Butoxycarbonyl)pyrrolidin-2-yl]-2,4Ј-bithiazol-4-
2
005, 12, 1907; b) F. Gianfranco, Curr. Bioactive Compd. 2010,
yl}-6-[4-(ethoxycarbonyl)thiazol-2-yl]-3-[5-methyl-4-(methoxy-
carbonyl)oxazol-2-yl]pyridine (23): A solution of 21 in DMA
6
, 284; c) Z. Jin, Nat. Prod. Rep. 2013, 30, 869.
2] For reviews on thiopeptide syntheses, see: a) R. S. Roy, A. M.
Gehring, J. C. Milne, P. J. Belshaw, C. T. Walsh, Nat. Prod. Rep.
1999, 16, 249; b) M. C. Bagley, J. W. Dale, E. A. Merritt, X.
Xiong, Chem. Rev. 2005, 105, 685; c) R. A. Hughes, C. J.
Moody, Angew. Chem. 2007, 119, 8076; Angew. Chem. Int. Ed.
(
0.21 m, 2.2 mL, 0.456 mmol) was added to a Schlenk tube charged
with 17aa (40 mg, 0.057 mmol) and Pd(PPh (13 mg,
.011 mmol). The mixture was stirred at 45 °C. After 2 h EtOAc
20 mL) the mixture was added and washed with H O (2ϫ5 mL),
) and concentrated in vacuo. The crude product was
3 4
)
0
(
2
2
007, 46, 7930; d) C. Li, W. L. Kelly, Nat. Prod. Rep. 2010, 27,
2 4
dried (Na SO
1
53.
purified by silica flash column chromatography (hexanes/EtOAc,
:1 to 1:1). The desired product was obtained as a yellowish solid
32 mg, 79%), m.p. (CH Cl ) decomp. above 106 °C. [α] = –34.7
c = 1.00, CH Cl ). IR (KBr): ν˜ = 3122, 2975, 2924, 1694, 1386,
239, 1201, 1105 cm . H NMR (400 MHz, CDCl
m, 12 H), 1.91–2.07 (m, 2 H), 2.17–2.46 (m, 2 H), 2.53 (s, 3 H);
[
3] As a selection of landmark total syntheses of thiopeptides, see:
a) M. C. Bagley, K. E. Bashford, C. L. Hesketh, C. J. Moody,
J. Am. Chem. Soc. 2000, 122, 3301; b) K. C. Nicolaou, B. S.
Safina, M. Zak, A. A. Estrada, S. H. Lee, Angew. Chem. 2004,
116, 5197; Angew. Chem. Int. Ed. 2004, 43, 5087; c) R. A.
Hughes, S. P. Thompson, L. Alcaraz, C. J. Moody, J. Am.
9
(
(
1
(
2
2
D
2
2
–1 1
3
): δ = 1.27–1.59
6418
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Eur. J. Org. Chem. 2013, 6404–6419