LETTER
Synthesis of a Mumbaistatin Analogue through Cross-Coupling
2573
residue, which was purified by column chromatography
(silica gel, cyclohexane–EtOAc, 7:3). After evaporation of
(250 MHz, CDCl3): d = 1.27–1.54 [m, 4 H, HO(CH2)2
(CH2)2], 1.40 (s, 9 H, COMe3), 1.55–1.90 (m, 4 H,
the solvent the desired product 14 (183 mg, 376 mmol, 39%;
still contaminated with impurities) was obtained as a yellow
solid in a total weight of 250 mg along with the
HOCH2CH2, HOCHCH2), 3.38 (s, 3 H, OMe), 3.56 (t, JH,H =
6.5 Hz, 2 H, HOCH2), 4.00 (s, 3 H, OMe), 4.43 (d, JH,H
16.0 Hz, 1 H, CH2Ar2), 4.83 (d, JH,H = 16.0 Hz, 1 H,
=
debrominated compound 11 (141 mg, 327 mmol, 34%).
Usually, the product 14 was used for the next step (Swern
oxidation) without further purification. For analytical
purposes a small sample of pure 14 was prepared by column
chromatography (silica gel, CH2Cl2–EtOAc, 30:1–10:1);
TLC: Rf 0.24 (cyclohexane–EtOAc, 2:1); mp 195 °C. 1H
NMR (250 MHz, CDCl3): d = 1.38 (s, 9 H, OCMe3), 2.99 (t,
3JH,H = 5.0 Hz, 1 H, CH2OH), 3.42 (s, 3 H, OMe at C-2¢),
4.01 (s, 3 H, OMe at C-3), 4.64 (d, 3JH,H = 4.5 Hz, 2 H,
CH2OH), 4.68 (s, 2 H, CH2-at C-1), 6.66 (dd, 4JH,H = 1.0 Hz,
CH2Ar2), 5.12–5.19 (m, 1 H, HCOH), 6.55–6.60 (m, 1 H, H-
5¢), 7.11–7.14 (m, 2 H, H-3¢, H-4¢), 7.63–7.68 (m, 2 H, H-6,
H-7), 7.74 (s, 1 H, H-4), 7.90–7.95, 8.13–8.17 (2 × m, 2 H,
H-5, H-8). 13C NMR (75 MHz, CDCl3): d = 25.60 (t, CH2),
25.90 (t, CH2), 28.01 (q, OCMe3), 29.80 (t, CH2Ar2), 32.67
(t, CH2), 37.48 (t, CH2), 55.23 (q, OMe at C-6¢), 56.29 (q,
OMe at C-3), 62.79 (t, HOCH2), 69.94 (d, CHOH), 82.98 (s,
OCMe3), 107.18 (d, C-4), 109.93 (d, C-5¢), 118.55 (d, C-3¢),
120.39 (s, C-2), 125.10, 125.66 (2 × s, C-4a, C-9a), 126.45,
127.02, 127.21 (3 × d, C-4¢, C-5, C-8), 132.19 (s, C-1¢),
133.11, 134.25 (2 × d, C-6, C-7), 135.11, 136.90 (2 × s, C-
8a, C-10a), 145.40, 145.51 (2 × s, C-2¢, C-1), 157.42 (s, C-
6¢), 159.59 (s, C-3), 166.47 (s, CO2t-Bu), 183.14, 183.59 (2
× s, C-9, C-10). IR: 3406 (m, br), 2936 (m), 1719 (s), 1668
(s), 1574 (vs), 1462 (s), 1330 (s), 1281 (vs), 1142 (vs), 1090
(s), 1088 (s), 714 (vs) cm–1. MS (EI-DIP; 70 eV): m/z (%) =
220, 205, 181, 177, 145, 91, 57. HRMS (ESI): m/z [M + Na]+
calcd for C34H38O8: 597.2465; found: 597.246 0.002.
6-{3-Methoxy-2-(4-methoxy-3,6,11-trioxo-1,3,6,11-
tetrahydroanthra[1,2-c]furan-1-yl)-phenyl}-6-
oxohexanoic Acid Methyl Ester (2): Compound 16 (165
mg, 0.28 mmol, 1.0 equiv), N-bromosuccinimide (98 mg,
0.55 mmol, 2.0 equiv) and benzoyl peroxide (3.3 mg, 0.01
mmol, 5 mol%) were dissolved in CCl4 (15 mL) and refluxed
under irradiation with a 150-W lamp for 3 h. After this time,
the reaction mixture was quenched with a sat. solution of
NaHCO3 and extracted with CH2Cl2. The organic layers
were dried over MgSO4, concentrated and purified by
column chromatography (silica gel, cyclohexane–EtOAc
3:7) to yield lactone 2 (124 mg, 0.23 mmol, 83%) as a yellow
solid; TLC: Rf 0.39 (cyclohexane–EtOAc, 3:7); mp 142.5°C.
1H NMR (250 MHz, CDCl3): d = 1.70–2.00 [m, 4 H,
MeO2CCH2 (CH2)2], 2.35–2.45 (m, 2 H, MeO2CCH2CH2),
3.25–3.45 (m, 2 H, ArCOCH2CH2), 3.35 (s, 3 H, OMe), 3.62
(s, 3 H, CO2Me), 4.19 (s, 3 H, OMe), 6.77–6.80 (m, 1 H, H-
5¢), 7.23–7.32 (m, 2 H, H-3¢, H-4¢), 7.49 (s, 1 H, CHOHAr2),
7.68–7.74 (m, 2 H, H-6, H-7), 7.83 (s, 1 H, H-4), 7.95–8.00,
8.18–8.23 (2 × m, 2 H, H-5, H-8). 13C NMR (75 MHz,
CDCl3): d = 23.53 (t, CH2), 24.61 (t, CH2), 33.99 (t, CH2),
41.71 (t, CH2), 51.45 (q, CO2Me), 55.68 (q, OMe at C-6¢),
56.88, 57.14 (d, q, CHOAr2, OMe at C-3), 109.30 (d, C-4),
114.19 (d, C-5¢), 119.61 (d, C-3¢), 120.56, 120.84 (2 × s, C-
2, C-1¢), 127.08, 127.40, 129.73 (3 × d, C-4¢, C-5, C-8),
132.75, 133.15 (2 × s, C-4a, C-9a), 133.91, 134.49 (2 ×d, C-
6, C-7), 139.43, 142.98 (2 × s, C-8a, C-10a), 155.98, 158.63
(2 × s, C-2¢, C-1), 161.36 (s, C-6¢), 167.25 (s, C-3), 173.95
(s, CO2Me), 180.43 (s, ArCO2), 182.35, 182.46 (2 × s, C-9,
C-10), 204.76 (s, COCH2). IR: 3093 (w), 2944 (m), 1763
(vs), 1733 (s), 1674 (vs), 1597 (vs), 1583 (vs), 1456 (s), 1333
(vs), 1292 (vs), 1275 (vs), 1060 (vs), 1009 (vs), 712 (s)
cm–1. HRMS (ESI): m/z [M + Na]+ calcd for C31H26O9:
565.1475; found: 565.147 0.002. The X-ray crystal
structure of compound 2 has been deposited at the
3JH,H = 8.0 Hz, 1 H, H-3¢), 7.01 (dd, 4JH,H = 1.0 Hz, 3JH,H
=
7.5 Hz, 1 H, H-5¢), 7.12 (app t, 3JH,H = 8.0 Hz, 1 H, H-4¢),
7.63–7.69 (m, 2 H, H-6, H-7), 7.73 (s, 1 H, H-4), 7.95–8.02,
8.13–8.20 (2 × m, 1 H, H-5, H-8), 13C NMR (75 MHz,
CDCl3): d = 27.88 (q, COMe3), 30.22 (t, CH2 at C-1), 55.53
(q, OMe at C-2¢), 56.27 (q, OMe at C-3), 63.30 (t, CH2OH),
83.01 (s, OCMe3), 107.20 (d, C-4), 110.98 (d, C-3¢), 121.91
(d, C-5¢), 125.70, 126.08 (2 × s, C-4a, C-9a), 126.08, 126.37,
126.98 (3 × d, C-4¢, C-5, C-8), 132.15 (s, C-2), 133.05,
134.17 (2 × d, C-6, C-7), 135.00 (s, C-8a, C-10a), 136.79 (s,
C-1), 140. 55 (s, C-6¢), 144.67 (s, C-1¢), 157.88 (s, C-2¢),
159.44 (s, C-3), 166.40 [s, C(O)Ot-Bu], 183.11, 183.41 (2 ×
s, C-9, C-10). IR: 3533 (br m), 3071 (w), 2976 (m), 1716 (s),
1667 (s), 1574 (vs), 1461 (s), 1280 (vs), 1141 (vs), 1097 (s),
1097 (s), 1020 (m), 713 (vs) cm–1. MS (EI–DIP; 70 eV):
m/z (%) = 488 ([M]+; 414, >1), 414 (35), 369 (100), 355 (11),
339 (9), 226 (8), 57 (33). HRMS (ESI): m/z [M + Na]+ calcd
for C29H28O7: 511.1733; found: 511.173 0.002.
1-[2-(1,6-Dihydroxyhexyl)-6-methoxybenzyl]-3-
methoxy-9,10-dioxo-9,10-dihydroanthracene-2-
carboxylic Acid tert-Butyl Ester (15): A solution of pent-
4-yn-1-ol (210 mg, 2.39 mmol, 4.0 equiv) in THF (4 mL)
was cooled to 0 °C. Then a 1.6 M solution of n-BuLi in
hexane (3.0 mL, 4.77 mmol, 8.0 equiv) was added slowly.
After 15 min, the stirred reaction mixture was cooled to
–60 °C, and TiCl(Oi-Pr)3 (1.32 g, 4.95 mmol, 8.3 equiv)
dissolved in THF (2 mL) was added. The solution was stirred
at –60 °C for further 1.5 h and aldehyde 3 (290 mg, 0.60
mmol, 1.0 equiv) in THF (6 mL) was added via cannula. The
reaction mixture was stirred at –60 °C for 30 min, warmed
from –60 °C to –20 °C, stirred for 15 h, quenched with sat.
NH4Cl, warmed to r.t., and diluted with CH2Cl2. The
aqueous phase was extracted with CH2Cl2 (2 ×), the
combined organic extracts were dried over MgSO4,
concentrated and purified by column chromatography (silica
gel, cyclohexane–EtOAc, 4:6) to give the corresponding
addition product(alkyne) as a yellow oil (305 mg, 0.54
mmol). To a solution of the alkyne (305 mg, 0.54 mmol, 1.0
equiv) in toluene (15 mL), Rh(PPh3)3Cl (52 mg, 0.06 mmol,
9 mol%) was added under argon. The resulting suspension
was then stirred under an atmosphere of hydrogen (3 atm) at
r.t. for 15 h. Then the solvent was evaporated and the residue
was purified by column chromatography (silica gel,
cyclohexane–ethyl acetate, 4:6) to give compound 15 (298
mg, 0.52 mmol, 87% overall yield) as a yellow solid; TLC:
Rf 0.31 (cyclohexane–EtOAc, 4:6); mp 66.0 °C. 1H NMR
Cambridge Crystallographic Data Centre and was allocated
the deposition number 632345.
Synlett 2007, No. 16, 2569–2573 © Thieme Stuttgart · New York