Synthesis of Caerulomycin B
J . Org. Chem., Vol. 67, No. 10, 2002 3275
Ta ble 2. Iod in e-Lith iu m Exch a n ge of 15a , 22, a n d 23
entry
starting material (R′, R)
electrophile
product
E
yield (%)
1
2
3
4
5
6
7
15a (H, CH2OMe)
15a (H, CH2OMe)
22 (OMe, CH2OMe)
23 (OMe, Me)
23 (OMe, Me)
23 (OMe, Me)
H2O
ClSnBu3
H2O
H2O
D2O
26a
26b
27
28a
28b
28c
28d
H
74
77
70
70
SnBu3
H
H
D
CH(OH)Ph
Cl
69 (95% d)
48
45
PhCHO
C2Cl6
23 (OMe, Me)
salt of 30 [made after treatment of 30 (2.0 mmol) with 55%
NaH (0.11 g, 2.4 mmol) in 3 mL of THF] and using DMF (0.16
mL, 2.0 mmol) at -75 °C with subsequent warming to room
temperature, gave 64% of 10 (eluent: CH2Cl2/Et2O 90:10): mp
159 °C; 1H NMR (CDCl3) δ 3.97 (s, 3H), 7.35 (ddd, 1H, J )
7.5, 5.2, 1.2 Hz), 7.47 (s, 1H), 7.92 (td, 1H, J ) 8.0, 1.6 Hz),
8.49 (dd, 1H, J ) 4.2, 1.5 Hz), 8.67 (dd, 1H, J ) 8.3, 1.2 Hz),
9.90 (s, 1H), 15.3 (s, 1H); 13C NMR (CDCl3) δ 55.2, 103.5, 120.1,
122.5, 134.5, 137.3, 143.8, 144.0, 150.2, 154.6, 156.4, 191.5;
IR (KBr) ν 2924, 2356, 1709, 1694, 1487, 1372, 1287, 1159,
1040, 802. Anal. Calcd for C12H10N2O3 (230.23): C, 62.61; H,
4.38; N, 12.17. Found: C, 62.53; H, 4.15; N, 12.02.
Sch em e 9
Ta ble 3. Cr oss-Cou p lin g Sta r tin g fr om 15a , 22, a n d 23
3,4-Dim eth oxy-2,2′-bip yr id in e-6-ca r boxa ld eh yd e (32).
The general procedure B, starting from 31 and using DMF
(0.16 mL, 2.0 mmol) at -75 °C with subsequent warming to
room temperature, gave 67% of 32 (eluent: AcOEt/NEt3 80:
20): mp 78-80 °C (lit.4 mp 80 °C).
starting
material
yield
(%)
entry
R
R′
R′′
product
1
2
3
15a
22
23
CH2OMe
CH2OMe
Me
H
OMe
OMe
H
H
Me
29
30
31
55
57
53
Gen er a l P r oced u r e C: Cr oss-Cou p lin g fr om 2-Lith io-
p yr id in es 22 a n d 23. After 15 min at -75 °C, an anhydrous
solution of ZnCl2 (0.82 g, 6.0 mmol) in THF (20 mL) was added
to the required lithiopyridine (2.0 mmol) at the same temper-
ature. The reaction mixture was then warmed to room tem-
perature. After the addition of 2-iodopyridine (0.82 g, 4.0 mmol)
and Pd(PPh3)4 (69 mg, 60 µmol), the mixture was heated at
reflux for 20 h, cooled, and evaporated to dryness. The residue
was dissolved in concentrated NH4OH (20 mL) and CH2Cl2
(50 mL) containing EDTA (3.7 g, 10 mmol). The mixture was
heated at reflux for 1 h.
Sch em e 10
3-Hyd r oxy-6-iod o-4-m eth oxy-2,2′-bip yr id in e (30). The
general procedure C, starting from 22, gave, after washing
with Et2O/petroleum ether 50:50, 57% of 30 (eluent: CH2Cl2/
1
petroleum ether 50:50): mp 164-166 °C; H NMR (CDCl3) δ
3.88 (s, 3H), 7.05 (s, 1H), 7.28 (ddd, 1H, J ) 7.5, 4.9, 1.2 Hz),
7.83 (td, 1H, J ) 7.6, 1.5 Hz), 8.44 (m, 2H), 14.6 (s, 1H); 13C
NMR (CDCl3) δ 56.7, 104.2, 118.0, 121.6, 123.7, 137.2, 138.5,
145.7, 148.1, 156.2, 157.5; IR (KBr) ν 3434, 2933, 1485, 1471,
1428, 1313, 1250, 1026, 836, 740. Anal. Calcd for C11H9IN2O2
(328.11): C, 40.27; H, 2.76; N, 8.54. Found: C, 40.14; H, 3.06;
N, 8.76.
6-Iod o-3,4-d im et h oxy-2,2′-b ip yr id in e (31). The gen-
eral procedure C, starting from 23, gave 53% of 31 (eluent:
CH2Cl2/Et2O 90:10): viscous oil; 1H NMR (CDCl3) δ 3.68 (s,
3H), 3.87 (s, 3H), 7.19 (s, 1H), 7.24 (ddd, 1H, J ) 7.9, 4.7, 1.5
Hz), 7.71 (m, 2H), 8.68 (dd, 1H, J ) 4.7, 1.5 Hz); 13C NMR
(CDCl3) δ 56.6, 61.9, 111.2, 118.8, 123.6, 124.9, 136.7, 145.2,
149.7, 152.5, 154.9, 160.3; IR (KBr) ν 3401, 2927, 2853, 1561,
1479, 1414, 1309, 1243, 1030. Anal. Calcd for C12H11IN2O2
(342.14): C, 42.13; H, 3.24; N, 8.19. Found: C, 42.34; H, 3.31;
N, 8.15.
(E)-3-H yd r oxy-4-m et h oxy-2,2′-b ip yr id in e-6-ca r b oxa l-
d eh yd e Oxim e (Ca er u lom ycin B) (1). A mixture of 10 (0.24
g, 1.0 mmol), hydroxylamine hydrochloride (0.36 g, 5.0 mmol),
pyridine (0.36 mL, 4.3 mmol), and EtOH (7 mL) was heated
at reflux for 1 h. The solvent was evaporated under vacuum,
and H2O (35 mL) was added. Filtration of the precipitate and
recrystallization from MeOH gave 50% of 1: mp 215 °C (lit.3
mp 215-217 °C); 1H NMR (DMSO-d6) δ 3.91 (s, 3H, OMe),
7.37 (s, 1H, H5), 7.54 (ddd, 1H, J ) 8.2, 4.8, 1.3 Hz, H5′), 8.04
(s, 1H, CH), 8.11 (td, 1H, J ) 8.2, 1.6 Hz, H4′), 8.51 (dd, 1H,
J ) 8.2, 1.3 Hz, H3′), 8.65 (dd, 1H, J ) 4.8, 1.6 Hz, H6′), 11.4
(s, 1H, NOH), 14.6 (s, 1H, OH); 13C NMR (DMSO-d6) δ 55.8
(OMe), 103.6 (C5), 120.6 (C5′), 123.8 (C3′), 134.2 (C3), 139.0
(C4′), 145.9 (C6), 148.9 (C6′), 155.2 (C2), 147.2 (CH), 155.3
(C2′), 156.8 (C4). Anal. Calcd for C12H11N3O3 (245.24): C,
added at room temperature Ag2CO3 (3.0 g, 11 mmol) and, 15
min later, MeI (3.1 mL, 50 mmol). The mixture was stirred in
the dark for 15 h. The silver salts were filtered on Celite and
washed with CH2Cl2. A 60% yield of 22 was obtained (eluent:
1
CH2Cl2): mp 80-82 °C; H NMR (CDCl3) δ 3.57 (s, 3H), 3.81
(s, 3H), 5.10 (s, 2H), 7.08 (s, 1H); 13C NMR (CDCl3) δ 56.6,
59.0, 99.0, 109.7, 115.2, 119.0, 144.2, 157.9; IR (KBr) ν 2937,
1549, 1530, 1427, 1326, 1026, 926, 866. Anal. Calcd for C8H9I2-
NO3 (420.97): C, 22.83; H, 2.15; N, 3.33. Found: C, 23.02; H,
2.10; N, 3.13.
2,6-Diiod o-3,4-d im eth oxyp yr id in e (23). From the pyri-
done 20, as previously described for the synthesis of compound
22: yield 65% (eluent: CH2Cl2/cyclohexane 60:40); mp 96-98
°C (lit.14 mp 97 °C); 13C NMR (CDCl3) δ 56.3, 60.6, 109.5, 114.4,
118.7, 146.7, 157.8.
Gen er a l P r oced u r e B: Iod in e-lith iu m Exch a n ge of
Iod op yr id in es 30 a n d 31. At -75 °C, the required 2-iodopy-
ridine (2.0 mmol) was added to a solution of BuLi (4.0 mmol)
in hexane (1.6 mL) and THF (10 mL). After 15 min at -75 °C,
the electrophile was added and allowed to react as mentioned
in the product description.
3-H yd r oxy-4-m et h oxy-2,2′-b ip yr id in e-6-ca r b oxa ld e-
h yd e (10). The general procedure B, starting from the sodium