Studies on the Total Synthesis of Lactonamycin
1
1713, 1672, 1596, 1467, 1431, 1336, 1271, 1219 cm-1; H NMR
(CDCl3, 300 MHz) δ 3.11 (s, 3H), 3.88 (s, 3H), 3.97 (s, 3H), 4.01
(s, 3H), 4.47 (s, 2H), 6.43 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
29.0, 51.7, 53.2, 56.1, 56.6, 95.0, 107.2, 113.8, 148.4, 160.9, 164.2,
165.3, 166.3; MS (CI, NH3) m/z 266 [M + H]+; HRMS (CI) m/z
calcd for C13H16NO5 [M + H]+ 266.1033, found [M + H]+
266.1028. Anal. Calcd for C13H15NO5: C, 58.86; H, 5.70; N, 5.28.
Found: C, 58.73; H, 5.80; N, 5.26.
4.42 (s, 2H), 4.49 (s, 2H), 4.52 (s, 2H), 6.33 (s, 1H), 6.70 (s, 1H),
6.79 (s, 1H); 13C NMR (CDCl3, 75.5 MHz) δ 29.0, 34.6, 51.6,
53.3, 55.3, 55.9, 58.3, 61.6, 69.6, 111.7, 113.8, 115.5, 117.3, 119.3,
132.0, 134.6, 146.9, 148.4, 149.9, 155.7, 159.0, 166.26, 166.33;
MS (CI, NH3) m/z 430 [M + H]+; HRMS (CI) m/z calcd for C23H27-
NO7H [M + H]+ 430.1866, found [M + H]+ 430.1866. Anal. Calcd
for C23H27NO7: C, 64.32; H, 6.34; N, 3.26. Found: C, 64.37; H,
6.42; N, 3.26.
5-(2,5-Dimethoxy-3-(methoxymethyl)benzyl)-7-methoxy-2-
methyl-1-oxo-2,3-dihydro-1H-isoindole-4-carboxylic Acid (6a).
LiOH‚H2O (662 mg, 27.6 mmol) was added at room temperature
to methyl ester 30a (663 mg, 1.54 mmol) in THF (14 mL), MeOH
(7 mL), and H2O (7 mL). After stirring for 24 h, saturated aqueous
NH4Cl (6 mL), 2 M HCl (2 mL), and H2O (5 mL) were added,
and the aqueous layer was extracted with CHCl3:iPrOH (4:1, 1 ×
50 mL, 5 × 30 mL). The combined organic layers were dried (Na2-
SO4) and rotary evaporated to give crude acid 6a (660 mg) as a
white solid: mp 153-155 °C (CHCl3:iPrOH 4:1); Rf 0.15 (CHCl3:
MeOH 10:1); IR (film) 1702, 1655, 1597, 1478, 1422, 1265, 1169,
1061, 895, 737 cm-1; 1H NMR (CDCl3, 300 MHz) δ 3.14 (s, 3H),
3.43 (s, 3H), 3.68 (2s, 6H), 3.82 (s, 3H), 4.49 (s, 2H), 4.51 (s, 2H),
4.61 (s, 2H), 6.40 (s, 1H), 6.68 (s, 1H), 6.81 (s, 1H), 6.53-6.99
(bs, 1H); 13C NMR (CDCl3, 75.5 MHz) δ 29.1, 34.6, 53.9, 55.4,
55.8, 58.4, 61.7, 69.6, 111.9, 113.7, 115.9, 116.7, 119.4, 132.0,
134.6, 147.9, 149.8, 150.1, 155.8, 159.5, 166.5, 169.9; MS (CI,
NH3) m/z 416 [M + H]+; HRMS (CI) m/z calcd for C22H26NO7
[M + H]+ 416.1709, found [M + H]+ 416.1706. Anal. Calcd for
C22H25NO7: C, 63.60; H, 6.07; N, 3.37. Found: C, 63.52; H, 6.14;
N, 3.27.
11-Acetoxy-8-methoxymethyl-2-methyl-4,7,10-trimethoxy-1,2-
dihydronaphtho[2,3-e]isoindol-3-one (5a). Me2CdC(Cl)NMe2 (32
µL, 0.24 mmol) was added with stirring to acid 6a (24 mg, 0.058
mmol) in CH2Cl2 (1.2 mL). After 3 h at room temperature, the
deep yellow mixture was cooled to 0 °C, ZnCl2 in Et2O (1.0 M;
100 µL) added, and the reaction mixture stirred for 30 min by which
time a color change to orange was observed. Pyridine (3 mL), Ac2O
(1 mL), and DMAP (cat.) were added, and after 15 h, the reaction
was quenched with H2O (2 mL) and 5 M HCl (6 mL). The aqueous
layer was extracted with EtOAc (3 × 15 mL), and the combined
organic layers were washed with saturated aqueous NaHCO3 (2 ×
5 mL) and brine (5 mL), dried (MgSO4), rotary evaporated, and
chromatographed (EtOAc to EtOAc:MeOH 15:1) to yield acetate
5a (21 mg, 82%) as a deep yellow to greenish oil: Rf 0.44 (EtOAc:
MeOH 10:1); 1H NMR (CDCl3, 300 MHz) δ 2.50 (s, 3H), 3.21 (s,
3H), 3.46 (s, 3H), 3.94 (s, 3H), 3.97 (s, 3H), 4.05 (s, 3H), 4.54 (bs,
1H), 4.68 (s, 2H), 4.82 (bs, 1H), 6.77 (s, 1H), 7.17 (s, 1H), 8.40 (s,
1H); 13C NMR (CDCl3, 75.5 MHz) δ 21.4, 29.2, 53.4, 55.8, 56.1,
58.4, 62.6, 68.8, 103.9, 105.0, 116.6, 116.9, 118.0, 123.9, 126.3,
129.7, 134.8, 141.5, 143.1, 146.7, 151.6, 154.4, 166.8, 169.5; MS
(CI, NH3) m/z 440 [M + H]+ 382, 288, 269, 162; HRMS (CI) m/z
calcd for C24H26NO7 [M + H]+ 440.1709, found [M + H]+
440.1705.
Methyl 7-Methoxy-2-methyl-1-oxo-5-trifluoromethanesulfo-
nyloxy-2,3-dihydro-1H-isoindole-4-carboxylate (8). BCl3 (95 mL,
95 mmol, 1.0 M in CH2Cl2) was added dropwise with stirring under
N2 to amide 15 (11.5 g, 43.3 mmol) so that the inside temperature
remained below -72 °C. After 3 h at -78 °C, 10% aqueous HCl
(150 mL) was added and the mixture allowed to warm to room
temperature and transferred to 10% aqueous HCl (1.3 L) and CH2-
Cl2 (500 mL). After stirring for 2 h, the aqueous layer was extracted
with CH2Cl2 and CHCl3 (3 × 250 mL) and CHCl3:iPrOH (5:1, 2
× 250 mL), and the combined organic layers were washed with
brine (300 mL), dried (MgSO4), rotary evaporated, and crystallized
to give the corresponding phenol (8.9 g, 82%) as a white solid:
mp 198-203 °C (pentane); Rf 0.44 (CH2Cl2:MeOH 15:1); IR (film)
1
1713, 1672, 1596, 1467, 1431, 1336, 1271, 1219 cm-1; H NMR
(CDCl3, 300 MHz) δ 3.14 (s, 3H), 3.97 (s, 3H), 4.00 (s, 3H), 4.47
(s, 2H), 6.47 (s, 1H), 11.42 (s, 1H); 13C NMR (CDCl3, 75 MHz) δ
29.0, 52.3, 53.4, 56.2, 99.3, 100.9, 114.0, 147.4, 162.4, 166.4, 167.2,
170.0; MS (CI, NH3) m/z 252 [M + H]+; HRMS (CI) m/z calcd
for C12H14NO5 [M + H]+ 252.0872, found [M + H]+ 252.0871.
The phenol (9.5 g, 38.0 mmol) was dissolved with heating in dry
CH2Cl2 (130 mL). After cooling to room temperature, Et3N (8.0
mL, 56.0 mmol) and PhNTf2 (16.3 g, 45.6 mmol) were added. The
mixture was heated at reflux for 72 h and cooled to room
temperature, when H2O (80 mL) was added. The aqueous layer
was extracted with CH2Cl2 (4 × 100 mL), and the combined organic
layers were washed with brine (80 mL), dried (MgSO4), and rotary
evaporated. The residue was crystallized from Et2O to give triflate
8 (11.5 g, 79%) as a white solid. The mother liquid was concentrated
and filtered through silica (100 g, EtOAc to EtOAc:MeOH 15:1)
to give, after recrystallization, triflate 8 (1.9 g, 13%): mp 152-
157 °C (Et2O); Rf 0.49 (CH2Cl2:MeOH 15:1); Rf 0.40 (EtOAc:
MeOH 20:1); IR (film) 3061, 2960, 1727, 1694, 1632, 1423, 1287,
1
1206, 1137 cm-1; H NMR (CDCl3, 300 MHz) δ 3.17 (s, 3H),
3.97 (s, 3H), 4.02 (s, 3H), 4.65 (s, 2H), 6.78 (s, 1H); 13C (CDCl3,
75 MHz) δ 29.2, 52.4, 53.2, 56.8, 105.9, 114.2 (q, J ) 362.9),
120.8, 121.1, 148.6, 151.6, 160.5, 163.1, 164.9; MS (CI, NH3) m/z
384 [M + H]+; HRMS (CI) m/z calcd for C13H13NSO7F3 [M +
H]+ 384.0365, found [M + H]+ 384.0367; Anal. Calcd for C13H12F3-
NO7S: C, 40.74; H, 3.16; N, 3.65. Found: C, 40.79; H, 3.14; N,
3.57.
Methyl 5-(2,5-Dimethoxy-3-methoxymethylbenzyl)-7-meth-
oxy-2-methyl-1-oxo-2,3-dihydro-1H-isoindole-4-carboxylate (30a).
Zn dust (3.8 g, 58.2 mmol) was placed in a Schlenk tube and heated
in a vacuum. After cooling, the tube was flushed with N2, THF (2
mL) and 1,2-dibromoethane (0.17 mL, 2.0 mmol) were added, and
the mixture was heated to reflux for 3 min and cooled to 0 °C.
Bromide 7a (1.6 g, 5.82 mmol) in THF (5 mL) was added within
90 min at 0 °C and the mixture stirred for 1 h at 0 °C. The resultant
organozinc compound was added via a filter cannula to the
previously freeze-thaw degassed triflate 8 (767 mg, 2.0 mmol) in
THF (20 mL) and Pd(PPh3)4 (116 mg, 0.1 mmol) at room
temperature. After 2.5 h at reflux, saturated aqueous NH4Cl (10
mL) and H2O (10 mL) were added, the aqueous layer was extracted
with EtOAc (4 × 25 mL), and the combined organic layers were
washed with brine (40 mL), dried (MgSO4), rotary evaporated, and
purified by chromatography (EtOAc to EtOAc:MeOH 15:1) to yield
30a (730 mg, 85%) as a white solid: mp 108-111 °C (EtOAc); Rf
0.14 (EtOAc); IR (film) 1689, 1596, 1478, 1432, 1277, 1160, 1058,
1009, 858, 734 cm-1; 1H NMR (CDCl3, 300 MHz) δ 3.31 (s, 3H),
3.42 (s, 3H), 3.67 (s, 3H), 3.69 (s, 3H), 3.80 (s, 3H), 3.86 (s, 3H),
11-Acetoxy-4-methoxy-8-methoxymethyl-2-methyl-3,7,10-tri-
oxo-2,3,7,10-tetrahydro-1H-naphtho[2,3-e]isoindole (33a). CAN
(94 mg, 0.17 mmol) in H2O (0.75 mL) was slowly added with
stirring to acetate 5a (25 mg, 0.057 mmol) in MeCN (4 mL) at 0
°C. After 10 min, stirring was continued for 20 h at room
temperature. H2O (5 mL) was added and the mixture extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed
with brine (10 mL), dried (MgSO4), rotary evaporated, and
chromatographed (EtOAc to EtOAc:MeOH 20:1) to yield quinone
33a (13 mg, 61%) as a yellow oil: Rf 0.51 (EtOAc:MeOH 10:1);
IR (film) 1771, 1706, 1659, 1604, 1586, 1456, 1427, 1246, 1181,
1111, 899, 842 cm-1; 1H NMR (CDCl3, 300 MHz) δ 2.63 (s, 3H),
3.25 (s, 3H), 3.51 (s, 3H), 4.09 (s, 3H), 4.46 (s, 2H), 4.59 (bs, 1H),
4.83 (bs, 1H), 6.97 (s, 1H), 7.29 (s, 1H), 8.39 (s, 1H); 13C NMR
(CDCl3; 75.5 MHz) δ 22.2, 29.8, 53.2, 56.7, 59.7, 68.3, 109.0,
117.4, 121.0, 126.0, 126.2, 130.8, 136.8, 139.9, 143.0, 147.8, 148.4,
158.1, 166.1, 169.1, 183.2, 183.9.
J. Org. Chem, Vol. 71, No. 21, 2006 8157