PAPER
Synthesis of Racemic Deoxypodophyllotoxin
1463
10:1; then hexane–EtOAc, 10:1) afforded 12 (4.46 g, 76%) and 10
(235 mg, 6%), and other tetracyclic isomers (200 mg, 5%).
CaromCHH), 2.80 (dd, J = 14.0, 6.1 Hz, 1 H, CHCHOt-Bu), 2.69
(ddd, J = 16.1, 12.0, 0.7 Hz, 1 H, CaromCHH), 2.56–2.47 (m, 1 H,
CH2CHCH2O), 1.34 (s, 9 H, t-C4H9).
13C NMR (125.8 MHz, CDCl3): d = 193.2 (s), 151.2 (s), 145.1 (s),
128.7 (s), 123.9 (s), 123.0 (d), 107.2 (d), 102.0 (t), 97.4 (d), 75.4 (s),
70.5 (t), 60.1 (d), 42.4 (d), 29.0 (q), 26.2 (t).
IR (CHCl3): 2978, 1673, 1604, 1504, 1489, 1448, 1360, 1254, 1040,
1004, 938 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.69 (dd, J = 8.2, 1.7 Hz, 1 Harom),
7.53 (d, J = 1.7 Hz, 1 Harom), 6.88 (d, J = 8.2 Hz, 1 Harom), 6.07 (d,
J = 1.4 Hz, 1 H, OCHHO), 6.06 (d, J = 1.4 Hz, 1 H, OCHHO), 5.38
(d, J = 3.2 Hz, 1 H, OCHOt-Bu), 4.15 (dd, J = 8.6, 7.2 Hz, 1 H,
CHHO), 3.82 (t, J = 8.3 Hz, 1 H, CHHO), 3.63 (dd, J = 6.8, 3.2 Hz,
1 H, CHCHOt-Bu), 3.31 (dd, J = 9.7, 6.4 Hz, 1 H, CHHI), 3.25 (dd,
J = 9.6, 7.9 Hz, 1 H, CHHI), 3.22–3.15 (m, 1 H, ICH2CHCH2O),
1.19 (s, 9 H, t-C4H9).
NOE Difference Spectra (500 MHz, d): 3.13 (CaromCHHO) → 2.56–
2.47 (6.6%); 2.68 (CaromCHHO) → 2.80 (6.3%), 2.56–2.47
(CH2CHCH2O) → 5.72 (2.7%).
FAB-MS: m/z (%) = 304 (M+, 30), 231 (100), 249 (58), 201 (12),
163 (21), 154 (96), 136 (66), 107 (22).
Anal. Calcd for C17H20O5 (304.34): C, 67.09; H, 6.62. Found: C,
67.00; H, 6.63.
13C NMR (125.8 MHz, CDCl3): d = 195.1 (s), 152.3 (s), 148.3 (s),
131.3 (s), 125.7(d), 108.6 (d), 107.9 (d), 102.1 (d), 101.98 (t), 75.3
(s), 72.5 (t), 61.5 (d), 43.3 (d), 28.8 (q), 6.5 (t).
6-tert-Butoxy-5-(3,4,5-trimethoxyphenyl)-5,5a,6,8,8a,9-hexahy-
drofuro[3¢,4¢:6,7]naphtho[2,3-d][1,3]dioxo-5-ol (13)
NOE Difference Spectra (500 MHz, d): 3.64–3.62 (CHCHOt-Bu)
→ 3.33–3.24 (4.2%); 3.27–3.15 (ICH2CHCH2O) → 5.38 (1.8%).
EI-MS: m/z (%) = 431 (M+ – 1, 5), 42 (100), 374 (99), 360 (65), 246
(42), 203 (70), 190 (42), 149 (75), 121 (55), 65 (82), 57 (95).
HRMS (ESI-MS in MeOH): m/z for C17H21IO5 + Na (M+ + Na):
To a solution of n-BuLi (2.2 mL, 5.34 mmol, 2.4 M in hexane) in
THF (15 mL) was slowly added 3,4,5-trimethoxyphenyl bromide
(1.32 g, 5.34 mmol) dissolved in THF (15 mL) at –78 °C. The mix-
ture was kept at this temperature for 30 min and LiCl (424 mg, 10
mmol) was added. A solution of 12 (813 mg, 2.67 mmol) in THF
(15 mL) was then slowly added and the mixture was kept at –78 °C
for 2 h. The mixture was allowed to warm up to r.t. overnight. H2O
was added and the mixture was extracted with Et2O. The organic
phase was washed with sat. NaHCO3 and brine, dried (MgSO4), and
concentrated in vacuo. FC (hexane–EtOAc, 7:3) afforded com-
pound 13 (664 mg) in 53% yield. When the reaction was run in the
absence of LiCl (same reaction conditions), the alcohol 13 was iso-
lated in 31% yield together with the isomerized ketone 14.
455.0331; found: 455.0349.
(r-6,t-5a,c-8a)-6-tert-Butoxy-5a,6,8a,9-tetrahydro-8H-fu-
ro[3¢,4¢:6,7]naphtho[2,3-d][1,3]dioxol-5-one (10) and (r-7,c-6a,t-
9a)-7-tert-Butoxy-6a,7,9a,10-tetrahydro-9H-fu-
ro[3¢,4¢:6,7]naphtho[1,2-d][1,3]dioxol-6-one (11) (Scheme 3)
To a solution of 12 (7.19 g, 16.6 mmol) and NaHCO3 (1.53 g, 18.3
mmol) in benzene (1.2 L) heated at reflux was added DLP (19.8 g,
49.8 mmol) by portions (3.3 g every 1 h) during 6 h. The reaction
mixture was cooled to r.t., filtered through a short pad of silica gel.
Evaporation of the solvent and purification by FC (hexane–EtOAc,
10:1) gave 10 (2.44 g, 48%) and 11 (1.22 g, 24%).
IR (CHCl3): 3009, 2977, 2939, 1589, 1504, 1482, 1412, 1367, 1321,
1234, 1130, 1041, 992, 940 cm–1.
1H NMR (500 MHz, CDCl3, 10% ethylbenzene): d = 6.75 (s, 1
Harom), 6.58 (s, 1 Harom), 6.48 (s, 2 H, 2 CHCOMe), 5.91(d, J = 1.3
10
Hz, 1 H, OCHHO), 5.90 (d, J = 1.3 Hz, 1 H, OCHHO), 5.01 (d,
J = 6.6 Hz, 1 H, OCHOt-Bu), 3.94 (dd, J = 7.7, 6.3 Hz, 1 H, CHCH-
HO), 3.83 (s, 3 H, OCH3), 3.76 (s, 6 H, 2 OCH3), 3.67 (dd, J = 9.9,
IR (CHCl3): 2980, 1690, 1618, 1504, 1479, 1436, 1403, 1368, 1328,
1286, 1242, 1024, 973, 940, 886 cm–1.
7.9 Hz, 1 H, CHCHHO), 2.96 (dd, J = 16.1, 5.4 Hz, 1 H, Carom
CHH), 2.91 (s, 1 H, OH), 2.73 (dd, J = 15.9, 11.4 Hz, 1 H, Carom
CHH), 2.49–2.39 (m, 1 H, CH2CHCH2O), 2.31 (dd, J = 13.2, 6.5
Hz, 1 H, CHCHOt-Bu), 1.29 (s, 9 H, t-C4H9).
13C NMR (125.8 MHz, CDCl3): d = 152.3 (s), 147.2 (s), 146.9 (s),
139.8 (s), 137.3 (s), 136.9 (s), 128.8 (s), 107.6 (d), 107.4 (d), 105.9
(d), 101.9 (t), 99.3 (d), 76.7 (s), 75.2 (s), 71.2 (t), 60.9 (q), 60.8 (q),
56.1 (d), 37.3 (d), 32.3 (t), 29.4 (q).
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1H NMR (500 MHz, CDCl3): d = 7.45 (s, 1 Harom), 6.68 (s, 1 Harom),
6.021 (d, J = 1.3 Hz, 1 H, OCHHO), 6.018 (d, J = 1.3 Hz, 1 H,
OCHHO), 5.69 (d, J = 6.1 Hz, 1 H, OCHOt-Bu), 4.03 (dd, J = 7.9,
6.2 Hz, 1 H, CHCHHO), 3.86 (dd, J = 10.7, 7.9 Hz, 1 H, CHCH-
HO), 3.01 (dd, J = 15.8, 4.2 Hz, 1 H, CaromCHH), 2.89 (ddd,
J = 15.7, 11.7, 1.0 Hz, 1 H, CaromCHH), 2.76 (dd, J = 14.1, 6.1 Hz,
1 H, CHCHOt-Bu), 2.56–2.46 (m, 1 H, CH2CHCH2O), 1.26 (s, 9 H,
t-C4H9).
13C NMR (125.8 MHz, CDCl3): d = 193.3 (s), 152.1 (s), 147.2 (s),
139.8 (s), 128.4 (s), 108.5 (d), 106.2 (d), 101.9 (t), 97.5 (d), 75.4 (s),
70.4 (t), 59.9 (d), 43.2 (d), 33.0 (t), 28.9 (q).
NOE difference spectra (500 MHz, d): 6.48 (2 CHCOMe) → 2.49–
2.39 (5.0%), 5.01 (3.0%); 5.01 (OCHOt-Bu) → 2.49–2.39 (2.8%);
3.94 (CHCHHO) → 2.49–2.39 (7.9%); 3.67 (CHCHHO) → 2.31
(5.1%).
EI-MS: m/z (%) = 472 (M+, 4), 59 (100), 397 (44), 364 (27), 352
(35), 334 (53), 319 (47), 43 (90).
NOE Difference Spectra (500 MHz, d): 3.01 (CaromCHHO) → 2.76
(5.8%); 2.89 (CaromCHHO) → 5.69 (1.2%), 2.56–2.46 (5.8%); 2.56–
2.46 (CH2CHCH2O) → 5.69 (2.5%).
FAB-MS: m/z (%) = 304 (M+, 24), 231 (100), 249 (44), 202 (16),
HRMS (EI-MS): m/z calcd for C22H32O8 (M+): 472.2097; found:
189 (36), 154 (29), 115 (11).
472.2114.
Anal. Calcd for C17H20O5 (304.34): C, 67.09; H, 6.62. Found: C,
67.00; H, 6.62.
14
IR (CHCl3): 2978, 1666, 1618, 1504, 1481, 1382, 1305, 1252, 1099,
1042, 1005 cm–1.
11
IR (CHCl3): 2979, 1694, 1631, 1592, 1467, 1358, 1260, 1107, 1010,
1H NMR (500 MHz, CDCl3): d = 7.41 (s, 1 Harom), 6.63 (s, 1 Harom),
6.10 (d, J = 1.3 Hz, 1 H, OCHHO), 5.99 (d, J = 1.3 Hz, 1 H,
OCHHO), 5.64 (d, J = 5.8 Hz, 1 H, CHOt-Bu), 4.10 (dd, J = 8.5,
6.3 Hz, 1 H, CHCHHO), 3.97 (dd, J = 8.5, 2.3 Hz, 1 H, CHCHHO),
3.31 (dd, J = 15.8, 12.05 Hz, 1 H, CaromCHHCH), 3.06 (dd,
J = 15.3, 12.1 Hz, 1 H, CHCHOt-Bu), 2.96–2.87 (m, 1 H,
977 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.67 (d, J = 8.2 Hz, 1 Harom), 6.80
(dd, J = 8.2, 0.4 Hz, 1 Harom), 6.064 (d, J = 9.9 Hz, 1 H, OCHHO),
6.061 (d, J = 9.9 Hz, 1 H, OCHHO), 5.72 (d, J = 6.1 Hz, 1 H,
OCHOt-Bu), 4.06 (dd, J = 7.9, 6.2 Hz, 1 H, CHCHHO), 3.89 (dd,
J = 10.6, 8.0 Hz, 1 H, CHCHHO), 3.13 (dd, J = 16.1, 4.2 Hz, 1 H,
Synthesis 2005, No. 9, 1459–1466 © Thieme Stuttgart · New York