References and Notes
<A NAME="RD13007ST-1">1</A>
Rickards RW.
Rothschild JM.
Willis AC.
de Chazal NM.
Kirk J.
Kirk K.
Saliba KJ.
Smith GD.
Tetrahedron
1999,
55:
13513
<A NAME="RD13007ST-2A">2a</A>
Kelly TR.
Zhao Y.
Cavero M.
Torneiro M.
Org. Lett.
2000,
2:
3735
<A NAME="RD13007ST-2B">2b</A>
Bernardo PH.
Chai CLL.
J. Org. Chem.
2003,
68:
8906
<A NAME="RD13007ST-2C">2c</A>
Bernardo PH.
Chai CLL.
Elix JA.
Tetrahedron Lett.
2002,
43:
2939
<A NAME="RD13007ST-2D">2d</A>
Sissouma D.
Collet SC.
Guingant AY.
Synlett
2004,
2612
<A NAME="RD13007ST-2E">2e</A>
Sissouma D.
Maingot L.
Collet S.
Guingant A.
J. Org. Chem.
2006,
71:
8384
<A NAME="RD13007ST-2F">2f</A>
Tohyama S.
Choshi T.
Matsumoto K.
Yamabuki A.
Ikegata K.
Nobuhiro J.
Hibino S.
Tetrahedron Lett.
2005,
46:
5263
<A NAME="RD13007ST-2G">2g</A>
Yamabuki A.
Fujinawa H.
Choshi T.
Tohyama S.
Matsumoto K.
Ohmura K.
Nobuhiro J.
Hibino S.
Tetrahedron Lett.
2006,
47:
5859
<A NAME="RD13007ST-2H">2h</A>
Bennasar ML.
Roca T.
Ferrando F.
Org. Lett.
2006,
8:
561
<A NAME="RD13007ST-2I">2i</A>
Sperry J.
McErlean CSP.
Slawin AMZ.
Moody CJ.
Tetrahedron Lett.
2006,
48:
231
<A NAME="RD13007ST-3">3</A>
Rubenstein L.
J. Chem. Soc.
1925,
1998
<A NAME="RD13007ST-4">4</A>
Harayama T.
Akamatsu H.
Okamura K.
Miyagoe T.
Akiyama T.
Abe H.
Takeuchi Y.
J. Chem. Soc., Perkin Trans. 1
2001,
523
<A NAME="RD13007ST-5">5</A>
Wolfe JP.
Buchwald SL.
J. Org. Chem.
2000,
65:
1144
<A NAME="RD13007ST-6">6</A>
Furukawa H.
Ito C.
Yogo M.
Wu T.-S.
Chem. Pharm. Bull.
1986,
34:
2672
<A NAME="RD13007ST-7">7</A>
Knölker H.-J.
Reddy KR.
Chem. Rev.
2002,
102:
4303
<A NAME="RD13007ST-8A">8a</A>
Cadogan JIG.
Cameron-Wood M.
Mackie RK.
Searle RJG.
J. Chem. Soc.
1965,
4831
<A NAME="RD13007ST-8B">8b</A>
Cadogan JIG.
Mackie RK.
Todd M.
J. Chem. Soc, Chem. Commun.
1966,
491
<A NAME="RD13007ST-9">9</A>
Appukkuttan P.
Van der Eycken E.
Dehaen W.
Synlett
2005,
127
<A NAME="RD13007ST-10">10</A>
3-Bromo-
N
-(2-iodophenyl)-2,5-dimethoxybenzamide (
14): 3-Bromo-2,5-dimethoxybenzoic acid (12, 1 g, 3.8 mmol) was dissolved in SOCl2 (25 mL) and refluxed for 30 min under argon. The reaction mixture was cooled to r.t.,
and the solvent was quickly removed in vacuo. The residue was dissolved in anhyd THF
(20 mL) and kept under argon. To this solution were added 2-iodoaniline (0.84 g, 3.8
mmol) and anhyd K2CO3 (1.05 g, 7.6 mmol). The reaction mixture was stirred for a further 16 h. The reaction
was quenched with sat. NaHCO3 solution (10 mL) and the organic layer was separated. The aqueous layer was further
extracted with EtOAc (2 × 20 mL). The combined organic layer was dried with MgSO4, filtered, and the solvent was removed in vacuo to obtain the crude product. Flash
chromatography on silica gel (EtOAc-hexanes, 2:3) gave the title compound as a cream-colored
solid (1.61 g, 3.5 mmol, 91% yield); R
f
0.83 (EtOAc-hexanes, 2:3); mp 99-101 °C. 1H NMR (300 MHz, CDCl3): δ = 3.82 (s, 3 H, OMe), 3.96 (s, 3 H, OMe), 6.91 (m, 1 H, ArH), 7.30-7.43 (m, 2
H, ArH), 7.66 (s, 1 H, ArH), 7.86 (m, 1 H, ArH), 8.49 (d, J = 8 Hz, 1 H, ArH), 10.11 (s, 1 H, NH). 13C NMR (75 MHz, CDCl3; rotamer 1): δ = 55.8 (OMe), 62.8 (OMe), 99.6, 111.9, 117.8, 121.0, 126.0, 129.5,
130.4, 132.1, 139.9, 140.4, 147.3, 155.3, 168.0 (CO). 13C NMR (75 MHz, CDCl3; rotamer 2): δ = 55.9, 62.7, 89.4, 115.0, 118.2, 122.4, 123.6, 128.0, 129.0, 130.0,
139.2, 139.3, 148.6, 156.3, 162.4. MS (EI): m/z (%) = 463 (100) [M+], 461 (100) [M+], 459 (95) [M - H]+, 458 (90) [M - H]+, 446 (68), 444 (68). Two molecular ion peaks [M+] and two [M - OMe]+ peaks were observed due to 81Br and 79Br isotopes. HRMS (EI): m/z calcd for C15H13
79BrINO3: 460.9124; found: 460.9127. FTIR (KBr): 724 (w), 755 (w), 784 (w), 863 (w), 992 (m),
1042 (m), 1239 (m), 1295 (m), 1420 (m), 1471 (s), 1525 (m), 1599 (m), 1678 (m), 1713
(m), 2853 (m), 2925 (m), 3436 (br) cm-1.
3-Bromo-
N
-(2-iodophenyl)-2,5-dimethoxy-
N
-methoxy-methylbenzamide (
16): To a solution of 3-bromo-N-(2-iodophenyl)-2,5-dimethoxybenzamide (14, 0.88 g, 1.9 mmol) in anhyd THF (10 mL) under nitrogen were added MOMCl (0.30 mL,
3.9 mmol) and NaH (0.10 g, 4.1 mmol). The reaction mixture was stirred for 16 h at
30 °C following which the reaction mixture was poured into a sat. NaHCO3 solution (20 mL) to quench the reaction. The organic layer was separated and the
aqueous layer was further re-extracted with CH2Cl2 (3 × 15 mL). The combined organic layers were dried with MgSO4, filtered and the solvent was removed in vacuo to yield the crude product. Column
chromatography on silica gel (EtOAc-hexanes, 2:3) gave the desired compound as a viscous
yellow oil which solidified upon standing (0.93 g, 1.8 mmol, 98% yield). Two distinct
sets of methoxy signals (three methoxy signals per set) in a ratio of 4:1 were observed
in the 1H NMR spectrum which suggested the presence of rotamers, but the aromatic hydrogen
signals overlapped. The 13C NMR spectrum showed distinct sets of signals for each rotamer; the carbon resonances
of each rotamer are reported below.
R
f
0.72 (EtOAc-hexanes, 2:3); mp 40-42 °C. 1H NMR (300 MHz, CDCl3): δ = 3.62 (s, 3 H, OMe), 3.66, 3.78 (s, 3 H, OMe), 3.80, 3.93 (s, 3 H, OMe), 4.60
(d, J = 10 Hz, 1 H, CH
aHb), 5.87 (d, J = 10 Hz, 1 H, CHa
H
b), 6.88-6.91 (m, 2 H, ArH), 7.00-7.08 (m, 1 H, ArH), 7.20 (m, 1 H, ArH), 7.36-7.39
(m, 1 H, ArH), 7.74 (d, J = 8 Hz, 1 H, ArH). 13C NMR (75 MHz, CDCl3; rotamer 1): δ = 55.6 (OMe), 56.7 (OMe), 62.3 (OMe), 76.6 (CH2), 99.5, 109.5, 117.1, 119.9, 128.8, 129.9, 131.3, 132.7, 139.2, 141.8, 146.1, 155.3,
168.2 (CO). 13C NMR (75 MHz, CDCl3; rotamer 2): δ = 55.6 (OMe), 56.7 (OMe), 62.8 (OMe), 76.6 (CH2), 99.5, 111.7, 112.5, 117.6, 120.8, 129.3, 129.9, 131.6, 132.0, 139.7, 147.1, 155.2,
167.8 (CO). MS (EI): m/z (%) = 507 (15) [M+], 505 (15) [M+], 380 (42) [M - I]+, 378 (42) [M - I]+, 245 (97), 243 (100), 45 (92). Two molecular ion peaks [M+] and two [M - I]+ peaks were observed due to 81Br and 79Br isotopes. HRMS (EI): m/z calcd for C17H17
79BrINO4: 504.9380; found: 504.9380. FTIR (KBr): 648 (w), 681 (w), 725 (w), 747 (w), 856 (w),
911 (w), 994 (m), 1018 (m), 1044 (s), 1082 (s), 1225 (s), 1278 (m), 1306 (m), 1374
(m), 1420 (s), 1473 (s), 1562 (w), 1598 (m), 1669 (s), 2831 (w), 2937 (m), 3436 (br)
cm-1. Anal. Calcd for C17H17BrINO4: C, 40.34; H, 3.39; N, 2.77. Found: C, 40.66; H, 3.48; N, 2.48.
8-Bromo-7,10-dimethoxy-5-methoxymethyl-phenanthridin-6-one (
18): To a solution of the tertiary benzamide 16 (0.18 g, 0.35 mmol) in degassed anhyd DMF (15 mL) were added PPh3 (28 mg, 0.11 mmol), anhyd K2CO3 (97 mg, 0.70 mmol) and Pd(OAc)2 (8 mg, 0.035 mmol). The reaction mixture was stirred at 100 °C under an argon atmosphere
for 16 h following which the reaction mixture was cooled to r.t. and filtered through
Celite. An aliquot of acetone (10 mL) was filtered through the Celite, and the combined
filtrates were removed under reduced pressure to yield the crude product. Purification
via column chromatography on silica gel (EtOAc-hexanes, 1:1) gave the desired compound
as a brown solid (0.12 g, 0.32 mmol, 92% yield); R
f
0.74 (EtOAc-hexanes, 1:1); mp 102-104 °C. 1H NMR (400 MHz, CDCl3): δ = 3.51 (s, 3 H, OMe), 3.95 (s, 3 H, OMe), 4.03 (s, 3 H, OMe), 5.77 (s, 2 H, CH2), 7.25-7.29 (m, 2 H, ArH), 7.49 (s, 1 H, ArH), 7.52-7.58 (m, 1 H, ArH), 9.13 (d,
J = 8 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 56.4 (OMe), 56.7 (OMe), 61.7 (OMe), 74.2 (CH2), 115.1, 118.1, 118.4, 119.9, 121.3, 122.5, 125.4, 128.7, 129.3, 136.7, 152.0, 153.4,
159.5 (CO). MS (EI): m/z (%) = 379 (90) [M+], 377 (86) [M+], 347 (50), 345 (48), 336 (52), 334 (68), 319 (100), 317 (88), 304 (73). HRMS (EI):
m/z calcd for C17H16
79BrNO4: 377.0263; found: 377.0265. HRMS (EI): m/z calcd for C17H16
81BrNO4: 379.0242; found: 379.0252. FTIR (KBr): 758 (w), 1052 (s), 1076 (s), 1224 (m), 1276
(w), 1297 (w), 1363 (w), 1458 (s), 1655 (s), 2824 (w), 2932 (w), 2962 (w), 3435 (br)
cm-1. Anal. Calcd for C17H16BrNO4: C, 53.99; H, 4.26; N, 3.70. Found: C, 53.84; H, 4.56; N, 3.68.
8-(Nitrophenyl-2-yl)-7,10-dimethoxy-5-methoxymethyl-phenanthridin-6-one (
27): To a rigorously degassed solution of the 8-bromophenanthridinone 18 (0.1 g, 0.26 mmol) in DMF (10 mL) were added K2CO3 (73 mg, 0.53 mmol), PPh3 (21 mg, 0.082 mmol, 30 mol%), and Pd(OAc)2 (6 mg, 0.026 mmol, 10 mol%). To the reaction mixture was added nitrophenyl-2-boronic
acid (26, 2 equiv). The reaction mixture was stirred at 150 °C for 16 h under argon. The reaction
mixture was cooled to r.t. and sat. NaHCO3 (10 mL) was added. The solvent was then removed under reduced pressure, and the residue
was partitioned between CHCl3 (20 mL) and sat. NaHCO3 (20 mL). The aqueous layer was further extracted with CHCl3 (2 × 20 mL) and the combined organic layer was dried with MgSO4, filtered, and the solvent was removed in vacuo to obtain the crude product. Purification
by column chromatography on silica gel gave the desired product as a yellow solid
(0.106 g, 0.25 mmol, 96% yield); R
f
0.34 (EtOAc-hexanes, 1:2); mp 146-148 °C. 1H NMR (400 MHz, CDCl3): δ = 3.51 (s, 3 H, OMe), 3.56 (s, 3 H, OMe), 4.02 (s, 3 H, OMe), 5.78 (br s, 2 H,
NCH2), 7.18 (s, 1 H, ArH), 7.26 (app. t, J = 7 Hz, 1 H, ArH), 7.50 (app. t, J = 7 Hz, 1 H, ArH), 7.52 (m, 3 H, ArH), 7.69 (app. t, J = 7 Hz, 1 H, ArH), 8.05 (d, J = 7 Hz, 1 H, ArH), 9.20 (d, J = 8 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 56.4 (OMe), 56.7 (OCMe), 61.6 (OMe), 74.1 (CH2), 115.1, 116.5, 118.5, 120.3, 122.5, 124.3, 126.1, 128.7, 128.8, 129.3, 132.3, 132.4,
132.5, 132.7, 136.9, 149.2, 151.9, 153.2, 160.2 (CO). MS (EI): m/z (%) = 420 (40) [M+], 405 (25) [M - OMe]+, 393 (30), 381 (45), 343 (56), 331 (52), 293 (100), 281 (77), 269 (43), 243 (85),
231 (97), 219 (80). HRMS (EI): m/z calcd for C23H20N2O6: 420.1321; found: 420.1363. Anal. Calcd for C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found: C, 65.30; H, 4.97; N, 6.25.
Intramolecular Cyclization of the Nitrophenylphen-anthridinone 27 via Microwave-Assisted
Cadogan Reaction: A solution of 8-(nitrophenyl-2-yl)-7,10-dimeth-oxy-5-methoxymethylphenanthridin-6-one
(27, 0.10 g, 0.24 mmol) in triethylphosphite (1 mL) was heated at 174 °C for 1 h in a
sealed vessel using the Biotage InitiatorTM EXP microwave reactor. The reaction mixture was cooled to r.t. and the solvent was
removed in vacuo. The residue was partitioned between CHCl3 (10 mL) and sat. NaHCO3 (10 mL). The organic layer was dried with MgSO4, filtered, and the solvent was removed. Purification via column chromatography on
silica gel (EtOAc-hexanes, 1:1) gave the desired product 25 as a yellow solid (82 mg, 0.21 mmol, 89% yield); R
f
0.21 (EtOAc-hexanes, 1:3). 1H NMR (400 MHz, CDCl3): δ = 3.55 (s, 3 H, OMe), 3.90 (s, 3 H, OMe), 4.20 (s, 3 H, OMe), 5.82 (br s, 2 H,
NCH2), 7.28-7.36 (m, 2 H, ArH), 7.48 (m, 3 H, ArH), 7.59 (d, J = 8 Hz, 1 H, ArH), 8.42 (d, J = 8 Hz, 1 H, ArH), 8.67 (br s, 1 H, NH), 9.17 (d, J = 8 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 56.6 (OMe), 60.2 (OMe), 61.6 (OMe), 73.8 (CH2), 110.7, 111.3, 115.3, 118.8, 118.9, 121.0, 122.8, 122.8, 123.7, 125.0, 126.9, 127.4,
129.0, 136.6, 137.8, 138.3, 139.9, 155.7, 161.1 (CO). MS (ESI): m/z (%) = 412 (38) [M + Na]+, 390 (100) [M + H]+. HRMS (ESI): m/z [M+ H]+ calcd for C23H20N2O4: 389.1496; found: 389.1499.
LiAlH
4
-Mediated Reduction of the Pentacyclic Lactam 25 to 7,10-dimethoxyindolo[3,2-
j
]phenanthridine (
8): To a solution of the lactam 25 (10 mg, 0.026 mmol) in anhyd Et2O (1 mL) at 0 °C were added freshly crushed pellets of LiAlH4 (3 mg, 0.08 mmol). The reaction mixture was warmed to r.t. and stirred for a further
1 h. The reaction was stopped by the careful addition of distilled H2O (1 mL). The reaction was then acidified to pH 1 using 6 N HCl. The mixture was stirred
for a further 1 h. The reaction mixture was then made basic by the slow addition of
1 M NaOH until a clear biphasic solution was obtained. The organic layer was separated,
and the aqueous layer was further extracted with EtOAc (10 mL). The combined organic
layer was dried with MgSO4 and filtered. The solvent was removed in vacuo to obtain the crude product; R
f
0.86 (EtOAc-hexanes, 1:1). 1H NMR (400 MHz, CDCl3): δ = 4.07 (s, 3 H, OMe), 4.16 (s, 3 H, OMe), 7.01 (app. t, J = 7 Hz, 1 H, ArH), 7.48 (m, 2 H, ArH), 7.70 (app. t, J = 7 Hz, 1 H, ArH), 7.92 (d, J = 8 Hz, 1 H, ArH), 8.02 (d, J = 8 Hz, 1 H, ArH), 8.09 (d, J = 8 Hz, 1 H, ArH), 8.95 (d, J = 8 Hz, 1 H, ArH), 9.57 (br s, 1 H, ArH), 11.07 (br s, 1 H, NH).
Conversion of 8 into Calothrixin B (
2): To a solution of the crude dimethyl ether 8 in anhyd CH2Cl2 (1 mL) at 0 °C was added 1 M BBr3 (0.1 mL). The reaction mixture was warmed to r.t. and stirred for 1 h. The reaction
was stopped by the addition of anhyd MeOH (1 mL) and stirred in the presence of air
for 1 h. The solvent was carefully removed in vacuo, and the residue was partitioned
between sat. NaHCO3 (10 mL) and EtOAc (10 mL). The organic layer was dried with MgSO4 and filtered, and the solvent was removed under reduced pressure. Purification by
column chromatography on silica gel yielded calothrixin B as a red solid (7.5 mg,
0.025 mmol, 97% yield over 2 steps from 25); R
f
0.47 (EtOAc-hexanes, 1:2); mp >>300 °C (Lit.
[1]
>>300 °C). 1H NMR (400 MHz, DMSO-d): δ = 7.40 (app. t, J = 7 Hz, 1 H, ArH), 7.47 (app. t, J = 7 Hz, 1 H, ArH), 7.62 (d, J = 8 Hz, 1 H, ArH), 7.89 (app. t, J = 8 Hz, 1 H, ArH), 7.96 (app. t, J = 8 Hz, 1 H, ArH), 8.17 (d, J = 8 Hz, 1 H, ArH), 8.18 (d, J = 8 Hz, 1 H, ArH), 9.58 (d, J = 9 Hz, 1 H, ArH), 9.62 (s, 1 H, ArH).
