Total Synthesis of Mumbaistatin
m/z 311 (1, [M - tBu]+), 309 (7), 294 (3), 279 (13, [M - tBu -
2Me]+), 263 (96), 250 (33), 231 (40), 207 (65), 187 (95), 182
(31), 168 (29), 165 (15). HRMS (EI): m/z calcd for C16H27SiO4
(M - tBu+) 311.1678, found 311.168.
6-(ter t-Bu t yld im et h ylsila n oxy)-1-{2-[h yd r oxy-(8,9,10-
tr im eth oxy-3-m eth oxym eth oxya n th r a cen -1-yl)m eth yl]-
3-m eth oxym eth oxyp h en yl}h exa n -1-ol (11). In an argon-
flushed Schlenk tube 371 mg (0.83 mmol) of bromide 25 was
dissolved in 5 mL of dry THF. At -78 °C, 1.05 mL of nBuLi
(1.6 M in hexane, 1.65 mmol) was added and the resulting
yellow solution was stirred for 30 min. Then 267 mg (0.75
mmol) of aldehyde 13 in 5 mL of THF was added slowly, and
the mixture was stirred overnight while the temperature was
allowed to slowly rise to rt. After addition of 5 mL of saturated
NH4Cl solution the THF was distilled off the mixture. The
aqueous residue was extracted with dichloromethane (4 × 10
mL). The combined organic layers were washed with brine and
dried over MgSO4. After evaporation of the solvent the residue
was purified by flash chromatography (50 g of silica; cyclo-
hexane/ethyl acetate, 3:1) to give 284 mg (0.4 mmol, 52%) of
benzhydrol 11 as a brown oil. A 135 mg (0.367 mmol, 44%)
yield of debrominated starting material and 60 mg (0.17 mmol,
22%) of aldehyde 13 could also be collected. The product was
obtained as a 1.38:1 mixture of diastereomers (determined by
HPLC); the following presents the analytical data for the
mixture. TLC (cyclohexane/ethyl acetate, 2:1): Rf ) 0.2. IR
(ATR): ν˜ ) 3322, 2929, 2852, 1622, 1537, 1461, 1429, 1398,
1354, 1291, 1245, 1222, 1203, 1151, 1132, 1081, 1066, 1005,
833 cm-1. 1H NMR (300 MHz, CDCl3, 54 °C): δ ) 0.00/0.06 (s,
6 H), 0.81/0.86 (s, 9 H), 1.10-1.55 (m, 4 H), 1.25-1.61 (m, 2
H), 1.67-1.92 (m, 2 H), 3.28/3.30 (s, 3 H), 3.40/3.44 (s, 3 H),
3.46/3.52 (t, 2 H, J ) 6.5 Hz), 3.99/4.03 (s, 3 H), 4.03/4.04 (s,
3 H), 4.03/4.03 (s, 3 H), 4.91/5.10 (t, 1 H, J ) 7.5 Hz), 5.03/
5.10 (br d, 2 H), 5.09/5.22 (d, 2 H), 6.79/6.80 (d, 1 H, J ) 7
Hz), 6.84/6.84 (d, 1 H, J ) 2.5 Hz), 7.03/7.06 (m, 1 H), 7.33/
7.37 (m, 1 H), 7.32/7.39 (s, 1 H), 7.35/7.40 (m, 1 H), 7.32/7.41
(m, 1 H), 7.65/7.67 (d, 1 H, J ) 2.5 Hz), 7.84/7.85 (dd, 1 H, J
) 8.5 Hz, J ) 1 Hz). 13C NMR (75 MHz, CDCl3, 54 °C): δ )
-5.28/-5.35 (q, 2 C), 18.28/18.31 (s), 25.94/25.98 (s, 3 C), 25.98/
26.0 (t), 26.31/26.37 (t), 32.87/32.91 (t), 35.08 (br)/38.86 (t),
55.97/56.05 (q), 56.05/56.07 (q), 56.31/56.35 (q), 62.20/62.25 (q),
63.25/63.31 (t), 64.45/64.67 (q), 68.58/69.17 (d), 69.95/71.83 (d),
94.38/94.44 (t), 95.10/95.15 (t), 102.27/104.28 (d), 104.60/104.65
(d), 113.19/113.61 (d), 114.91/114.91 (d), 117.84/118.05 (s),
120.29/121.61 (d), 120.74/121.02 (s), 121.12/121.82 (d), 125.82/
125.82 (d), 127.81/128.08 (s), 128.18/128.26 (s), 128.18/129.85
(s), 128.76/129.00 (d), 141.62 (br)/142.17 (s), 145.97 (br)/148.54
(s), 147.89/147.92 (s), 149.29/149.74 (s), 153.67/153.92 (s),
154.42/154.85 (s), 156.59/156.71 (s). HPLC purity: 95%. MS
(EI, 70 eV): m/z 724 (3, [M]+), 705 (30), 682 (22), 661 (8), 615
1-(2′-Br om o-3′-m eth oxym eth oxyp h en yl)-6-(ter t-bu tyl-
d im eth ylsila n yloxy)h exa n -1-ol (25). In an argon-flushed
500 mL three-necked flask 7.320 g (19.9 mmol) of benzylic
alcohol 24 was dissolved in 200 mL of dry toluene. After the
solution was cooled to -43 °C, 43.5 mL of nBuLi (1.6 M in
hexane, 69.6 mmol) was added slowly via syringe. After 30
min the cooling bath was removed, and the reaction mixture
was stirred for 4 h at rt. The orange solution was cooled to
-43 °C, and 40 mL of dry THF was added. After 10 min 8.4
mL (69.6 mmol) of tetrafluordibromoethane was added drop-
wise. The reaction mixture was allowed to slowly warm to rt
while being stirred overnight. After the reaction was quenched
with 100 mL of saturated NH4Cl solution, the THF was
distilled off under reduced pressure. The reaction mixture was
extracted with dichloromethane (3 × 100 mL). The combined
organic layers were washed with brine and dried over MgSO4.
After evaporation of the solvent under reduced pressure, the
residue was purified through flash chromatography (300 g of
silica; cyclohexane/ethyl acetate, 7:1) to give 7.391 (16.5 mmol,
83%) of 25 as a pale yellow oil. TLC (cyclohexane/ethyl acetate,
7:1): Rf ) 0.2. IR (ATR): ν˜ ) 3419, 2927, 2854, 1462, 1437,
1255, 1203, 1153, 1086, 1019, 923, 833, 774 cm-1 1H NMR
.
(250 MHz, CDCl3): δ ) 0.01 (s, 6 H), 0.86 (s, 9 H), 1.34-1.70
3
(m, 8 H), 2.15 (d, 1 H, J ) 3.5 Hz), 3.49 (s, 3 H), 3.57 (t, 2 H,
3J ) 6.5 Hz), 5.09 (quin, 1 H, J ) 4 Hz), 5.22 (s, 2 H), 7.02 (dd,
4
3
1 H, J ) 2.5 Hz, J ) 7.5 Hz), 7.17-7.23 (m, 2 H). 13C NMR
(63 MHz, CDCl3): δ ) -5.3 (q, 2 C), 18.3 (s), 25.6 (t), 25.9 (q,
3 C), 26.9 (t), 32.7 (t), 37.5 (t), 56.4 (q), 63.2 (t), 72.9 (d), 95.1
(t), 112.7 (s), 114.6 (d), 120.3 (d), 128.1 (d), 145.8 (s), 153.4 (s).
GC purity: 97%. MS (EI): m/z 389 (>1, [M - tBu]+), 373 (1,
[M - tBu - O]+), 359 (7), 343/341 (6), 329/327 (5), 311/309
(19), 283/285 (7), 267 (19), 248 (13), 231/229 (19), 201 (8).
HRMS (EI): m/z calcd for C16H26BrSiO4 (M - tBu)+ 389.0783,
found 389.078.
2′-Br om o-1′-[6-(ter t-bu tyldim eth ylsilan yloxy)-1-tr ieth yl-
sila n yloxyh exyl]-3′- m eth oxym eth oxyben zen e (26). An
argon-flushed 100 mL Schlenk flask was charged with 895 mg
(2 mmol) of benzylic alcohol 25 in 15 mL of dry dichloro-
methane. After addition of 680 mg (10 mmol) of imidazole and
2 mg of DMAP the solution was cooled to 5 °C. Over 15 min a
solution of 0.5 mL (3 mmol) of (TES)Cl in 5 mL of anhydrous
dichloromethane was added drop by drop, and the resulting
solution was stirred for 8 h at rt. After the reaction was
quenched with 10 mL of saturated NH4Cl solution, the phases
were separated. The aqueous layer was extracted with di-
chloromethane (3 × 10 mL). The combined organic layers were
washed with brine and dried over MgSO4. After evaporation
of the solvent, the residue was purified by flash chromatog-
raphy (60 g of silica; cyclohexane/ethyl acetate, 30:1) to yield
1.045 g (1.86 mmol, 93%) of 26 as a pale yellow oil. TLC
(cyclohexane/ethyl acetate, 30:1): Rf ) 0.2. IR (ATR): ν˜ ) 2928,
2872, 2853, 1591, 1569, 1461, 1435, 1410, 1385, 1358, 1305,
1255, 1203, 1153, 1097, 999, 938, 923, 832 cm-1. 1H NMR (250
MHz, CDCl3): δ ) 0.02 (s, 6 H), 0.53 (t, 6 H, 3J ) 7.5 Hz),
0.87 (s, 9 H), 0.83-0.94 (m, 9 H), 1.30-1.62 (m, 8 H), 3.51 (s,
(5), 570 (2), 513 (5), 477 (5). HRMS (EI): m/z calcd for C40H56
-
SiO10 724.3643, found 724.364.
6-[3-Meth oxym eth oxy-2-(8-m eth oxy-3-m eth oxym eth oxy-
9,10-a n t h r a q u in on e-1-ca r b on yl)p h en yl]-6-oxoh exa n oic
Acid (27). A 200 mg (0.276 mmol) sample of diol 11 was
dissolved in 2 mL of acetone. At 0 °C 1.4 mL of J ones reagent
(5 mmol) was added dropwise. The brown mixture was stirred
for 3 h at rt. The mixture was diluted with 20 mL of ethyl
acetate, and 2-propanol was added dropwise. After filtration
through a pad of florisil and addition of 10 mL of water, the
phases were separated. The aqueous phase was extracted with
ethyl acetate (3 × 10 mL). The combined organic layers were
washed with brine and dried over MgSO4. After evaporation
of the solvent, the residue was purified by flash chromatog-
raphy (60 g of silica; cyclohexane/ethyl acetate, 1:2, + 1% acetic
acid) to give 89 mg (0.152 mmol, 55%) of acid 27 as a yellow
oil. TLC (cyclohexane/ethyl acetate/acetic acid, 33:66:1): Rf )
0.2. The NMR spectra showed that the product was a mixture
of the bis-MOM-protected diketoacid 27 and the corresponding
partially deprotected mono-MOM-protected diketoacid. HRMS
(ESI): m/z calcd for C32H30O11Na 613.1686, found 613.169.
3
4
3
3 H), 3.57 (t, 2 H, J ) 6.5 Hz), 5.07 (dd, 1 H, J ) 4 Hz, J )
7.5 Hz), 5.21, 5.23 (each d, AB system, 1 H, 2J ) 6.5 Hz), 6.99
(dd, 1 H, 3J ) 5.5 Hz, 4J ) 4 Hz), 7.16-7.23 (m, 2 H). 13C
NMR (63 MHz, CDCl3): δ ) -5.3 (q, 2 C), 4.7 (t, 2 C), 6.7 (q,
3 C), 18.4 (s), 25.5 (t), 25.7 (t), 26.0 (q, 3 C), 32.8 (t), 39.2 (t),
56.4 (q), 63.2 (t), 73.3 (d), 95.4 (t), 111.9 (s), 114.1 (d), 121.3
(d), 127.7 (d), 146.9 (s), 153.1 (s). GC purity: 98%. MS (EI):
m/z 503 (1, [M - tBu]+), 473 (5, [M - Et3]+), 451 (5), 429 (5),
379 (5), 361/359 (35), 341 (7), 329 (22), 327 (24), 311/309 (65),
287 (23), 285 (28), 267 (38), 265 (40), 248 (55). HRMS (EI):
m/z calcd for C22H40Si2O4Br (M - tBu)+ 503.1648, found
503.165.
6-[3-Hyd r oxy-2-(3-h yd r oxy-8-m eth oxy-9,10-a n th r a qu i-
n on e-1-ca r bon yl)p h en yl]-6-oxoh exa n oic Acid (10). In an
argon-flushed 10 mL Schlenk flask 65 mg of 27 was dissolved
in 2 mL of dichloromethane and 2 mL of acetonitrile. After
addition of 20 mg of powdered 4 Å molecular sieves, the
J . Org. Chem, Vol. 67, No. 26, 2002 9255