Synthesis of Seco (+)- and ent-(-)-Oxaduocarmycin SA
J . Org. Chem., Vol. 62, No. 25, 1997 8873
16 (128 mg, 0.509 mmol) and finally 1-(3-(dimethylamino)pro-
pyl)-3-ethylcarbodiimide hydrochloride (EDCI) (244 mg, 1.272
mmol) and the mixture stirred at room temperature under
nitrogen for 18 h. The solvent was reduced to ∼1/2 the original
volume and ethyl acetate (20 mL) added. The organics were
washed with 0.1 N aqueous hydrochloric acid (2 × 10 mL),
water (10 mL), saturated sodium bicarbonate (10 mL), and
brine (10 mL) and then dried (MgSO4). Concentration of the
organics followed by purification of the resulting crude solid
by flash chromatography (gradient: 10-40% ethyl acetate/
hexanes) provided amide 17a (127 mg, 50%, HPLC (analytical
ChiraCel OD column; flow rate ) 1.0 mL/min; UV detection
at λ ) 254 nm; eluent, CH3CN:H2O 90:10): tR ) 11.08 min; 96
% ee) as a white powder: [R]23 +13.6° (c 0.5, CHCl3). mp
D
182-183.5 °C (EtOAc/hexanes, white needles); 1H NMR
(CDCl3, 300 MHz) δ 9.38 (brs, 1H), 8.31 (s, 1H), 7.56-7.52 (m,
3H), 7.43-7.28 (m, 3H), 6.96 (d, J ) 2.1 Hz, 1H), 6.87 (s, 1H),
5.35 (s, 2H), 4.71 (apparent t, J ) 10 Hz, 1H), 4.59 (dd, J )
10.9 and 4.0 Hz, 1H), 4.08 (s, 3H), 4.07-3.88 (m, 2H), 3.98 (s,
3H), 3.95 (s, 3H), 3.92 (s, 3H), 3.61 (dd, J ) 11 and 9.4 Hz,
1H); 13C NMR (CDCl3, 63 MHz) δ 159.9 (C), 159.3 (C), 150.1
(C), 146.7 (C), 144.7 (C), 143.1 (C), 141.0 (C), 140.5 (C), 138.8
(C), 136.0 (C), 129.6 (C), 128.5 (CH), 128.1 (CH), 127.7 (CH),
125.4 (C), 123.9 (C), 123.5 (C), 114.7 (C), 111.5 (CH), 106.4
(CH), 102.4 (CH), 97.6 (CH), 70.9 (CH2), 61.4 (CH3), 61.0 (CH3),
56.2 (CH3), 55.0 (CH2), 52.3 (CH3), 46.3 (CH2), 43.0 (CH); IR
(KBr) υmax 3459, 2936, 1732, 1622, 1494, 1308, 1203, 744, 697
cm-1; UV (EtOH) λmax 208.5 (ꢀ ) 35611), 297 (ꢀ ) 22216), 326
(ꢀ ) 24475) nm; FDMS m/z 604 (M+, 100). Anal. Calcd for
C32H29N2O8Cl: C, 63.52; H, 4.83; N, 4.63; Cl, 5.86. Found: C,
63.58; H, 4.87; N, 4.39; Cl, 6.02.
F igu r e 1. Typical chromatograms of the separation of race-
mate 14 on a Chiralpak AD (Amylose) column.
Cl: C, 63.63; H, 5.55; N, 2.97; Cl, 7.51; Found: C, 63.56; H,
5.53; N, 2.67; Cl, 7.72.
Meth yl (1R)-5-(Ben zyloxy)-3-(ter t-bu tyloxyca r bon yl)-
1-(ch lor om et h yl)-1,2-d ih yd r o-3H -fu r a n o[3,2-e]in d ole-7-
ca r boxyla te (14b). Second peak (tR ) 7.4 min, 95.5 % ee,
5.04 g, 48 % recovery) as a white solid: [R]23 +11.2° (c 0.5,
D
CHCl3). mp 131-133 °C dec; 1H NMR (CDCl3, 300 MHz) δ 7.90
(br s, 1H), 7.55-7.28 (m, 6H), 5.29 (s, 2H), 4.18 (dd, J ) 11.6
and 10 Hz,1H), 4.08-3.98 (m, 1H), 3.96 (s, 3H), 3.88-3.80 (m,
2Hl), 3.60 (apparent t, J ) 10.4 Hz, 1H), 1.57 (s, 9H); 13C NMR
(CDCl3, 63 MHz) δ 159.4 (C), 152.2 (C), 146.5 (C), 144.9 (C),
142.3 (C), 136 1 (C), 128.4 (CH), 128.0 (CH), 127.7 (CH), 111.6
(CH), 100.1 (C), 70.9 (CH2), 52.9 (CH2), 52.2 (CH3), 46.6 (CH3),
41.5 (C), 28.4 (3 × CH3); IR (KBr) υmax 2990, 1736, 1697, 1499,
1424, 1349, 1208, 1152, 1137, 762, 697 cm-1; UV (EtOH) λmax
219.5 (ꢀ ) 26377), 254.5 (ꢀ ) 37628), 284.5 (ꢀ ) 14440), 346.5
(ꢀ ) 2823) nm; FDMS m/z 470.9 (M+, 100). Anal. Calcd for
C25H26NO6Cl: C, 63.63; H, 5.55; N, 2.97; Cl, 7.51; Found: C,
63.91; H, 5.58; N, 3.13; Cl, 7.59.
(-)-(1R)-Meth yl 5-(Ben zyloxy)-1-(ch lor om eth yl)-1,2-d i-
h yd r o-3-[(5,6,7-t r im et h oxy-1H -in d ol-2-yl)ca r b on yl]-3H -
fu r a n o[3,2-e]in d ole-7-ca r boxyla te (17b). Amine 15b (216
mg, 0.530 mmol) was coupled to 5,6,7-trimethoxyindolecar-
boxylic acid 16, in the same manner described above, to furnish
amide 17b (161 mg, 50%, HPLC (analytical ChiraCel OD
column; flow rate ) 1.0 mL/min; UV detection at λ ) 254 nm;
eluent, CH3CN:H2O 90:10): 17b:: tR ) 8.42 min; 94 % ee) as
a white solid: [R]23 -13.2° (c 0.5, CHCl3); mp 138-140 °C;
Meth yl (1S)-5-(Ben zyloxy)-1-(ch lor om eth yl)-1,2-d ih y-
d r o-3H-fu r a n o[3,2-e]in d ole-7-ca r boxyla te (15a ). Boc in-
doline 14a (800 mg, 1.697 mmol) was added to a dry solution
of 4 N HCl in dioxane (25 mL) at 0 °C and under nitrogen.
The solution was stirred at 0 °C for 8 h and the solvent
removed at 0 °C under high vacuum to provide amine
hydrochloride salt 15a (690mg, 100%) as an unstable brown
solid: 1H NMR (DMSO-d6, 300 MHz) δ 8.07 (s, 1H), 7.55-
7.52 (m, 2H), 7.47-7.39 (m, 3H), 7.13 (s, 1H), 5.32 (s, 2H),
4.14-3.91 (m, 2H), 3.91 (s, 3H), 3.73-3.60 (m, 2H), 3.51-3.47
(m, 1H); IR (KBr) υmax 3400 (br), 1717, 1584, 1333, 1317, 1207,
1141, 1104, 915, 727 cm-1; UV (EtOH) λmax 243 (ꢀ ) 18536),
285 (ꢀ ) 12985), 359 (ꢀ ) 2272), 389 (ꢀ ) 1674) nm; FDMS
m/z 371 (Free amine, M+, 100). Anal. Calcd for C20H19NO4Cl2:
C, 58.84; H, 4.69; N, 3.43; Cl, 17.37. Found: C, 58.71; H, 4.85;
N, 3.13; Cl, 16.82.
D
1H NMR (CDCl3, 300 MHz) δ 9.41 (brs, 1H), 8.31 (s, 1H), 7.55-
7.51 (m, 3H), 7.43-7.33 (m, 3H), 6.95 (d, J ) 2.1 Hz, 1H), 6.86
(s, 1H), 5.35 (s, 2H), 4.70 (apparent t, J ) 9.9 Hz, 1H), 4.58
(dd, J ) 10.9 and 3.9 Hz, 1H), 4.08 (s, 3H), 4.04-3.88 (m, 2H),
3.98 (s, 3H), 3.94 (s, 3H), 3.91 (s, 3H), 3.60 (dd, J ) 10.8 and
9.6 Hz, 1H); 13C NMR (CDCl3, 63 MHz) δ 159.9 (C), 159.3 (C),
150.1 (C), 146.7 (C), 144.7 (C), 143.1 (C), 141.0 (C), 140.5 (C),
138.8 (C), 136.0 (C), 129.6 (C), 128.5 (CH), 128.1 (CH), 127.7
(CH), 125.4 (C), 123.9 (C), 123.5 (C), 114.7 (C), 111.5 (CH),
106.4 (CH), 102.4 (CH), 97.6 (CH), 70.9 (CH2), 61.4 (CH3), 61.0
(CH3), 56.2 (CH3), 55.0 (CH2), 52.3 (CH3), 46.3 (CH2), 43.0 (CH);
IR (KBr) υmax 2937, 1731, 1622, 1494, 1416, 1309, 1204, 1109,
744, 697 cm-1; UV (EtOH) λmax 209 (ꢀ ) 44076), 297.5 (ꢀ )
26058), 326 (ꢀ ) 30391) nm; FDMS m/z 603.7 (M+, 100). Anal.
Calcd for C32H29N2O8Cl: C, 63.53; H, 4.83; N, 4.63; Cl, 5.86.
Found: C, 63.74; H, 4.81; N, 4.40; Cl, 6.01.
Meth yl (1R)-5-(Ben zyloxy)-1-(ch lor om eth yl)-1,2-d ih y-
d r o-3H-fu r a n o[3,2-e]in d ole-7-ca r boxyla te (15b). Boc in-
doline 14b (1.00g, 2.12 mmol) was added to a dry solution of
4 N HCl in dioxane (28 mL) at 0 °C and under nitrogen. The
solution was stirred at 0 °C for 8 h and the solvent removed
at 0 °C under high vacuum to provide amine hydrochloride
salt 15a (865mg, 100%) as an unstable brown solid: 1H NMR
(DMSO-d6, 300 MHz) δ 8.08 (s, 1H), 7.55-7.52 (m, 2H), 7.47-
7.39 (m, 3H), 7.15 (s, 1H), 5.32 (s, 2H), 4.14-3.91 (m, 2H), 3.91
(s, 3H), 3.72-3.61 (m, 2H), 3.51-3.48 (m, 1H); IR (KBr) υmax
3400 (br), 1717, 1583, 1333, 1317, 1275, 1207, 1141, 1104, 728
cm-1; UV (EtOH) λmax 211 (ꢀ ) 26721), 243 (ꢀ ) 18796), 285 (ꢀ
) 13166), 359 (ꢀ ) 2189) nm; FDMS m/z 371 (Free amine, M+,
100). Anal. Calcd for C20H19NO4Cl2: C, 58.84; H, 4.69; N,
3.43; Cl, 17.37. Found: C, 58.78; H, 4.72; N, 3.18; (Cl, 16.82).
Meth yl (1R)-5-(Ben zyloxy)-1-(ch lor om eth yl)-1,2-d ih y-
dr o-3-[(5,6,7-tr im eth oxy-1H-in dol-2-yl)car bon yl]-3H-fu r a-
n o[3,2-e]in d ole-7-ca r boxyla te (17a ). To a dry solution of
amine hydrochloride salt 15a (173 mg, 0.424 mmol) in dimeth-
ylformamide (4.0 mL) was added sodium bicarbonate (178 mg,
2.12 mmol) followed by 5,6,7-trimethoxyindolecarboxylic acid
Meth yl (1S)-5-h yd r oxy-1-(ch lor om eth yl)-1,2-d ih yd r o-
3-[(5,6,7-tr im eth oxy-1H-in d ol-2-yl)ca r bon yl]-3H-fu r a n o-
[3,2-e]in d ole-7-ca r boxyla te (3a ). To a solution of benzyl
ether 17a (149 mg, 0.247 mmol) in tetrahydrofuran (5.80 mL)
was added 10% aqueous ammonium formate (560 µL). The
solution was cooled to 0 °C and 10% Pd-C (56 mg) added. The
reaction mixture was stirred for 5 h, filtered through a pad of
Celite, and concentrated to provide (+)-oxaduocarmycin SA
(3a ) (122 mg, 96%) as a yellow powder: [R]23 +1.73° (c 0.11,
D
1
DMF); mp 265-268 °C dec; H NMR (DMSO-d6, 300 MHz) δ
11.39 (d, J ) 1.14 Hz, 1H), 10.52 (s, 1H), 7.96 (s, 1H), 7.92 (s,
1H), 6.97 (d, J ) 1.7 Hz, 1H), 6.92 (s, 1H), 4.66 (apparent t, J
) 10 Hz, 1H), 4.34 (dd, J ) 10.6 and 3.54 Hz, 1H), 4.08-4.02
(m,1H), 3.98-3.94 (m, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.77 (s,
3H), 3.75 (s, 3H), 3.34-3.26 (buried m, 1H); 13C NMR (DMSO-
d6, 63 MHz) δ 160.0 (C), 159.1 (C), 149.2 (C), 145.6 (C), 142.6
(C), 141.9 (C), 140.9 (C), 139.9 (C), 139.1 (C), 131.0 (C), 125.3
(C), 124.2 (C), 123.2 (C), 114.3 (C), 113.0 (CH), 106.0 (CH),
104.0 (CH), 98.1 (CH), 61.1 (CH3), 61.0 (CH3), 56.0 (CH3), 54.8
(CH2) 52.3 (CH3), 47.4 (CH2), 41.4 (CH); IR (KBr) υmax 3449,