Modified Geldanamycin Analogues
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 10 3271
79.4, 81.7, 83.3, 111.0, 125.7, 128.1, 130.5, 131.9, 134.5, 136.6,
137.8, 155.9, 156.9, 168.6, 183.9, 184.1. HRMS calculated for
C30H42N2O9Na (M+ + Na): 597.2783. Found 597.2770.
and evaporated to dryness. The crude product was purified by flash
chromatography on silica gel, giving 13 as a purple solid (∼7 mg).
This solid was dissolved in dichloromethane (1 mL) and stirred
with trichloroacetyl isocyanate (20 µL) for 1 h at room temperature.
The mixture was concentrated in vacuo and redissolved in methanol
(1 mL). The solution was cooled to 0 °C, and potassium carbonate
(20 mg) was added. After the mixture was stirred from 0 °C to
room temperature over 2 h, dichloromethane (5 mL) was added.
The mixture was washed with saturated NaHCO3 (5 mL), and brine
(5 mL) and dried over MgSO4. The crude product was purified by
flash chromatography on silica gel to give 14 as a purple solid (6.5
mg). HPLC purity 98%. 1H NMR (CDCl3) δ: 0.00 (s, 9H), 0.7-0.9
(m, 2H), 0.94 (d, J ) 6.4 Hz, 3H), 1.02 (d, J ) 6.4 Hz, 3H), 1.35
(s, 3H), 1.52-1.60 (m, 2H), 1.67 (s, 3H), 2.03 (s, 3H), 2.10 (m,
1H), 2.38 (m, 2H), 2.70 (AB, 1H), 3.07 (br s, 1H), 3.14 (m, 1H),
3.29 (s, 3H), 3.55-3.70 (m, 2H), 4.00 (m, 2H), 4.35-4.55 (m,
3H), 4.64 (m, 5H), 4.98 (d, J ) 9.2 Hz, 1H), 5.09 (d, J ) 10.4 Hz,
1H), 5.15-5.30 (m, 3H), 5.60 (d, J ) 8.8 Hz, 1H), 5.90 (m, 1H),
6.32 (m, 2H), 6.45 (s, 1H). 13C NMR (CDCl3): δ 0.5 (3C), 12.3,
14.1, 16.4, 17.9, 18.5, 21.5, 30.0, 33.6, 33.9, 36.3, 56.1, 57.6, 58.4
(2C), 68.2, 74.8, 75.2, 78.7, 79.6, 82.0, 83.5, 108.7, 109.4, 115.3,
126.1, 127.8, 129.9, 131.4, 132.1, 134.9, 136.3, 140.0, 145.7, 155.8,
General Procedure for the Synthesis of 11-O-Methyl-17-alkyl-
amino-17-demethoxygeldanamycin (3a-h) As Exemplified by
11-O-Methyl-17-[2-(dimethylamino)ethyl]amino-17-demethoxy-
geldanamycin (3e). To a solution of 2 (1.28 g, 2.23 mmol) in 1,2-
dichloroethane (20 mL) (DMSO was used when the amine is a
salt, and triethylamine was used to release the amine) was added
N,N-dimethylethylenediamine (0.5 mL, 4.6 mmol). After being
stirred at 20 °C for 16 h, the mixture was diluted in ethyl acetate
(50 mL), washed with saturated NaHCO3 (50 mL) and brine (50
mL). The organic layer was dried over MgSO4, filtered, and
evaporated to dryness. The crude product was purified by flash
chromatography on silica gel, eluted using methanol/dichlo-
romethane. The product was obtained as a purple solid (1.32 g,
1
94%). HPLC purity 99%. H NMR (CDCl3): δ 0.93 (d, J ) 6.4
Hz, 3H), 1.07 (d, J ) 6.8 Hz, 3H), 1.43 (m, 1H), 1.55-1.65 (m,
2H), 1.70 (s, 3H), 2.00 (s, 3H), 2.15 (dd, J ) 9.2, 13.6 Hz, 1H),
2.26 (s, 6H), 2.55 (t, J ) 6.0 Hz, 2H), 2.65 (m, 1H), 2.94 (d, J )
14.0 Hz, 1H), 3.32 (s, 3H), 3.35 (s, 3H), 3.36 (m, 1H), 3.45 (m,
1H), 3.52 (s, 3H), 3.55-3.65 (m, 2H), 4.48 (d, J ) 7.6 Hz, 1H),
4.79 (br s, 2H), 5.49 (d, J ) 9.2 Hz, 1H), 5.54 (s, 1H), 5.85 (dd,
J ) 7.6, 11.2 Hz, 1H), 6.51 (t, J ) 10.6 Hz, 1H), 6.81 (br s, 1H),
7.01 (d, J ) 10.8 Hz, 1H), 7.09 (s, 1H), 9.47 (s, 1H). 13C NMR
(CDCl3): δ 12.3, 14.1, 16.4, 21.6, 30.4, 33.6, 33.9, 36.4, 42.5, 44.8,
56.1, 57.4, 57.5, 59.8, 78.7, 79.5, 82.1, 83.5, 108.0, 108.7, 125.9,
127.8, 130.0, 132.1, 134.8, 136.4, 140.7, 145.1, 155.9, 168.7, 179.3,
184.4. HRMS calculated for C33H51N4O8 (M+ + H): 631.3701.
Found 631.3692.
169.0, 177.7, 186.3. HRMS calculated for C40H62N3O9Si (M+
H): 756.4250. Found 756.4294.
+
To a solution of 14 (5 mg, 6.6 µmol) in dichloromethane (0.1
mL) cooled at 0 °C was added 5% (v/v) trifluoroacetic acid in
dichloromethane (0.5 mL). After the mixture was stirred from 0
°C to room temperature over 30 min, it was diluted with ethyl
acetate (2 mL) and quenched with NaHCO3. The organic layer was
washed with brine (2 mL) and dried over MgSO4. The crude product
was purified by HPLC in a C-18 column eluted with a gradient of
acetonitrile in water, giving 15 as a purple solid (0.8 mg), 99%
purity. HRMS calculated for C34H47N3O8Na (M+ + H): 648.3255.
Found 648.3266.
11-O-Allyl-17-(1-azetidinyl)-17-demethoxygeldanamycin (15). To
a solution of 9 (90 mg, 0.16 mmol) in dichloromethane (10 mL) at
-60 °C under nitrogen atmosphere was added 2,6-lutidine (85 µL,
0.73 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate
(83 µL, 0.36 mmol). The mixture was stirred at -60 °C for 30
min and then allowed to warm to room temperature over 1 h. The
reaction mixture was diluted with ethyl acetate (20 mL) and washed
with saturated NaHCO3 (20 mL) and saturated brine (20 mL). After
the mixture was dried over MgSO4, the crude product was purified
by flash chromatography on silica gel, eluted using 1-10%
methanol in dichloromethane to give 10 as a purple solid (95 mg).
To a solution of 10 (600 mg, 0.9 mmol) in dry tetrahydrofuran
(100 mL) was added sodium hydride in oil dispersion (400 mg).
The mixture was stirred at room temperature until the color of the
solution turned dark-blue (∼2 h). Chloromethyl 2-trimethylsilylethyl
ether (0.75 mL, 4.2 mmol) was added. After being stirred at room
temperature for another hour, the mixture was diluted with ethyl
acetate (150 mL) and carefully quenched with water (5 mL). The
organic layer was washed sequentially with water (100 mL),
saturated NaHCO3 (100 mL), and brine (100 mL), dried over
MgSO4, filtered, and evaporated to dryness. The crude product was
purified by flash chromatography on silica gel, eluted using 15%
ethyl acetate in dichloromethane. Compound 11 was obtained as a
purple solid (510 mg).
To a solution of 11 (10 mg, 12 µmol) in 1:1:1 (v/v/v) DMSO/
Et2O/THF (0.9 mL) cooled at -10 °C was added allyl bromide
(10 µL, 120 µmol). A 0.5 M solution of potassium tert-butoxide in
1:1 (v/v) DMSO/THF was added in 50 µL portions until the color
of the solution started to turn brown from purple (∼10 min). The
reaction was quenched immediately by addition of ethyl acetate
(10 mL) and 0.1 M HCl (1 mL). The organic layer was washed
with saturated NaHCO3 (10 mL) and brine (10 mL), dried over
MgSO4. The crude product was purified by flash chromatography
on silica gel, eluted with 20% ethyl acetate in hexane to give 12 as
a purple solid (5 mg).
Compounds 4a-g. Compounds 4c-f were obtained from the
National Cancer Institute. Compounds 4a, 4b, and 4g were
synthesized according to reported methods.37
11-O-(Hydrzinocarbonyl)-17-[2-(dimethylamino)ethylamino]-17-
demethyoxygeldanamycin (5). To a solution of 17-DMAG (62 mg,
0.1 mmol) in 1,2-dichloroethane (5 mL) was added 1,1′-carbonyl-
diimidazole (81 mg, 0.5 mmol) and 4-dimethylaminopyridine (12
mg, 0.1 mmol). After the mixture was stirred at room temperature
for 2 days, it was diluted in dichloromethane and washed with
NaHCO3 and brine. The organic layer was dried over Na2SO4,
filtered, and evaporated to dryness. The crude product was purified
by flash chromatography, giving the CDI-adduct as a purple solid
(70 mg, 98%). To a solution of the CDI-adduct (15 mg, 0.02 mmol)
in a mixture of 1,2-dichloroethane (0.5 mL) and ethanol (0.1 mL)
was added hydrazine (3 µL, 0.1 mmol). After the mixture was
stirred at room temperature overnight, it was evaporated to dryness.
The crude solid was redissolved in water-acetonitrile and purified
by HPLC on a C-18 column, eluted using a gradient of acetonitrile
in water. The product was obtained of as a purple solid, 7 mg.
HPLC purity 99%. 1H NMR (CDCl3) δ: 0.97 (d, J ) 6.4 Hz, 3H),
0.99 (d, J ) 6.4 Hz, 3H), 1.25 (m, 1H), 1.57 (m, 2H), 1.71 (s, 3H),
2.00 (s, 3H), 2.00 (m, 1H), 2.26 (s, 6H), 2.54 (t, J ) 5.8 Hz, 2H),
2.81 (m, 2H), 3.32 (s, 6H), 3.40-3.80 (m, 5H), 4.50 (d, J ) 6.8
Hz, 1H), 4.91 (br s, 2H), 5.34 (d, J ) 10 Hz, 1H), 5.42 (s, 1H),
5.84 (dd, J ) 7.6, 10.8 Hz, 1H), 5.91 (br s, 1H), 6.52 (t, 1H, J )
11.4 Hz), 6.80 (br s, 1H), 7.09 (s, 1H), 7.21 (br s, 1H), 9.41 (s,
1H). 13C NMR (CDCl3) δ: 12.3, 14.2, 15.9, 21.7, 30.4, 33.6, 33.9,
36.0, 42.5, 44.8, 56.1, 57.4, 57.5, 78.2, 79.0, 79.8, 80.2, 107.7,
108.4, 126.1, 128.1, 128.5, 133.1, 134.6, 135.8, 141.2, 145.2, 152.2,
155.6, 155.9, 169.1, 179.4, 184.3. HRMS calculated for C33H51N6O9
(M+ + H): 675.7911. Found 675.7929.
To a solution of 12 (30 mg, 36 µmol) in acetonitrile (2 mL)
cooled at 0 °C was added 5% HF in acetonitrile (0.5 mL). The
mixture was stirred at 0 °C for 1 h and then allowed to warm to
room temperature over 2 h. The reaction mixture was diluted with
ethyl acetate (5 mL) and washed with saturated NaHCO3 (5 mL)
and brine (5 mL). The organic layer was dried over MgSO4, filtered,
General Procedure for the Synthesis of 11-Keto Compounds
(6a-d) As Exemplified by 17-[2-(dimethylamino)ethylamino]-11-
oxo-17-demethyoxygeldanamycin (6d). To a solution of 17-DMAG
(250 mg, 0.4 mmol) in dichloromethane (15 mL) was added
Dess-Martin periodinane (340 mg, 0.8 mmol). After the mixture
was stirred at room temperature overnight, it was diluted in ethyl