Journal of Medicinal Chemistry
Article
(1H, d, J = 16.0 Hz, Hα-1), 2.30 (1H, dt, J = 14.5, 2.0 Hz, Hα-6), 2.21
(1H, s, H-9), 2.15 (3H, s, H-5′), 1.92 (3H, s, H-4′), 1.88 (1H, J = 14.5,
13.0, 2.0 Hz, Hβ-6), 1.84 (3H, d, J = 1.5 Hz, H-18), 1.37 (3H, s, H-19).
13C NMR (125 MHz, CD3OD) δ 194.4, 178.4, 169.7, 166.5, 159.6,
145.8, 130.4, 116.4, 84.8, 83.4, 78.6, 74.5, 70.9, 66.9, 51.4, 49.8, 46.2,
43.1, 42.7, 42.2, 30.1, 27.5, 20.5, 16.0, 13.4. HRESIMS m/z = 505.1706
[M − H]−(calcd for C25H29O11, 505.1715).
7.6 Hz, ArH), 6.28 (1H, br s, H-15), 6.08 (1H, s, OH-3), 5.62 (1H, s, H-
2′), 4.80 (1H, s, H-7), 4.69 (1H, d, J = 8.0 Hz, Ha-20), 4.49 (2H, t, J = 4.8
Hz, OCH2), 4.36, 4.24 (each 1H, m, OCH2), 4.24 (1H, br s, H-11), 4.22
(1H, s, H-12), 3.78 (1H, d, J = 8.0 Hz, Hb-20), 3.14 (1H, d, J = 11.6 Hz,
H-14), 2.98 (1H, d, J = 16.0 Hz, Hβ-1), 2.94 (1H, overlapped with Hβ-1,
H-5), 2.38 (1H, d, J = 16.0 Hz, Hα-1), 2.37 (1H, d, J = 14.4 Hz, Hα-6),
2.19 (3H, s, H-5′), 2.11 (1H, br s, H-9), 2.00 (2H, m, CH2), 1.93 (2H, m,
CH2), 1.92 (3H, s, H-4′), 1.84 (3H, s, H-18), 1.76 (1H, ddd, J = 14.4,
12.8, 2.0 Hz, Hβ-6), 1.39 (3H, s, H-19). 13C NMR (100 MHz, CDCl3) δ
192.0, 171.6, 167.0, 164.4, 161.1, 159.0, 144.0, 137.8, 135.7, 129.7, 128.6,
127.7, 114.0, 110.6, 82.3, 81.2, 75.8, 74.0, 71.0, 70.8, 65.8, 65.7, 51.6,
48.6, 45.5, 41.9, 41.8, 41.1, 29.1, 27.7, 25.4, 24.8, 20.7, 15.4, 13.3.
HRESIMS m/z = 803.2337 [M + H]+ (calcd for C37H43N2O16S,
803.2328).
General Procedures for the Preparation of 66, 68, and 70−73.
To a solution of 64 (20 mg, 0.032 mmol) in acetonitrile (1 mL) were
added potassium carbonate (22 mg, 0.16 mmol) and the corresponding
iodide or bromide (0.048 mmol). Then, the mixture was stirred at 50 °C
under an argon atmosphere for 5 h. The mixture was diluted with
CH2Cl2 (20 mL), and the insoluble matter was removed by filtration.
The filtrate was concentrated in vacuo, and the residue was purified by
column chromatography on silica gel (CH2Cl2/CH3OH = 50:1) to
remove the excess iodide or bromide. Then, the crude intermediate was
dissolved in THF and CH2Cl2, and 2−3 drops of acetic acid and excess
tetrabutylammonium fluoride solution (1.0 M solution in THF) were
added. The mixture was stirred at room temperature for 12 h. Water was
added to the mixture, and the entire mixture was extracted with CH2Cl2.
The organic layer was washed with brine, dried over Na2SO4, and
concentrated. The residue was purified by preparative HPLC (CH3CN/
H2O = 55:45, flow rate = 6 mL/min) to produce the compound.
Compound 66. The title compound was obtained starting from 64
and 18. White powder, 17.5% yield. 1H NMR (400 MHz, CDCl3) δ 8.05
(2H, br d, J = 7.6 Hz, ArH), 7.77 (1H, t, J = 7.6 Hz, ArH), 7.63 (2H, t, J =
7.6 Hz, ArH), 6.32 (1H, br s, H-15), 6.08 (1H, s, OH-3), 5.64 (1H, s, H-
2′), 4.80 (1H, s, H-7), 4.71 (1H, d, J = 7.6 Hz, Ha-20), 4.55 (2H, t, J = 6.0
Hz, OCH2), 4.49, 4.33 (each 1H, m, OCH2), 4.25 (1H, d, J = 2.8 Hz, H-
11), 4.22 (1H, s, H-12), 3.78 (1H, d, J = 7.6 Hz, Hb-20), 3.14 (1H, d, J =
11.6 Hz, H-14), 2.98 (1H, d, J = 16.0 Hz, Hβ-1), 2.95 (1H, overlapped
with Hβ-1, H-5), 2.39 (1H, d, J = 16.0 Hz, Hα-1), 2.39 (1H, overlapped
with Hα-1, Hα-6), 2.30 (2H, m, CH2), 2.19 (3H, s, H-5′), 2.12 (1H, br s,
H-9), 1.93 (3H, s, H-4′), 1.84 (3H, d, J = 1.2 Hz, H-18), 1.76 (1H, ddd, J
= 14.8, 12.8, 2.0 Hz, Hβ-6), 1.40 (3H, s, H-19). 13C NMR (100 MHz,
CDCl3) δ 191.9, 171.7, 167.0, 164.4, 161.4, 158.8, 144.0, 137.7, 135.8,
129.7, 128.6, 127.6, 113.9, 110.5, 82.3, 81.3, 75.8, 74.1, 71.0, 68.0, 65.7,
62.6, 51.7, 48.6, 45.5, 42.0, 41.8, 41.1, 29.1, 27.7, 27.7, 20.7, 15.4, 13.3.
HRESIMS m/z = 811.1979 [M + Na]+ (calcd for C36H40N2NaO16S,
811.1991).
Compound 70. The title compound was obtained starting from 64
and 29. White powder, 60.9% yield. 1H NMR (400 MHz, CDCl3) δ 7.86
(2H, dd, J = 8.0, 1.2 Hz, ArH), 7.56 (3H, m, ArH), 7.32 (2H, d, J = 8.4
Hz, ArH), 7.02 (2H, d, J = 8.4 Hz, ArH), 6.32 (1H, d, br s, H-15), 6.07
(1H, s, OH-3), 5.54 (1H, s, H-2′), 5.16, 5.11 (each 1H, d, J = 12.4 Hz,
OCH2), 5.13 (2H, s, OCH2), 4.78 (1H, s, H-7), 4.70 (1H, d, J = 8.0 Hz,
Ha-20), 4.25 (1H, d, J = 3.2 Hz, H-11), 4.20 (1H, s, H-12), 3.79 (1H, d, J
= 8.0 Hz, Hb-20), 3.10 (1H, d, J = 12.8 Hz, H-14), 2.98 (1H, d, J = 16.0
Hz, Hβ-1), 2.96 (1H, d, J = 12.8 Hz, H-5), 2.39 (1H, d, J = 16.0 Hz, Hα-
1), 2.39 (1H, overlapped with Hα-1, Hα-6), 2.17 (3H, s, H-5′), 2.13 (1H,
br s, H-9), 1.91 (3H, s, H-4′), 1.85 (3H, d, J = 1.2 Hz, H-18), 1.76 (1H,
ddd, J = 14.0, 12.8, 1.2 Hz, Hβ-6), 1.40 (3H, s, H-19). 13C NMR (100
MHz, CDCl3) δ 192.1, 171.4, 167.1, 164.4, 161.1, 157.2, 157.0, 144.0,
131.5, 130.2, 129.4, 128.5, 128.0, 127.6, 126.0, 115.1, 114.0, 112.0, 82.3,
81.3, 75.8, 73.9, 71.0, 67.4, 65.7, 58.4, 51.5, 48.5, 45.5, 41.8, 41.8, 41.1,
29.0, 27.7, 20.6, 15.4, 13.3. HRESIMS m/z = 787.2714 [M + H]+ (calcd
for C41H43N2O14, 787.2709).
The yield and spectroscopic data for compound 69 are included in the
Supporting Information.
General Procedures for the Preparation of 74 and 76. A
solution of 10 (315 mg, 0.76 mmol), EDCI (146 mg, 0.76 mmol), and
DMAP (185 mg, 1.52 mmol) in dry CH2Cl2 (20 mL) was stirred at 0 °C
for 3 h. Then 65 (385 mg, 0.76 mmol) was added to the solution and the
mixture was stirred at room temperature for 3 h. The solution was
washed with diluted HCl, dried over Na2SO4, and concentrated in
vacuo. The product was purified by preparative HPLC (CH3CN/H2O/
CF3COOH = 50:50:0.03, flow rate = 6 mL/min) to obtain the final
compound.
1
Compound 74. White powder, 32.3% yield. H NMR (500 MHz,
CDCl3) δ 8.05 (2H, br d, J = 8.0 Hz, ArH), 7.76 (1H, t, J = 7.5 Hz, ArH),
7.63 (2H, t, J = 8.0 Hz, ArH), 6.08 (1H, br s, H-15), 6.08 (1H,
overlapped with H-15, OH-3), 5.68 (1H, s, H-2′), 5.26 (1H, s, H-12),
4.82 (1H, s, H-7), 4.78 (1H, d, J = 6.5 Hz, Ha-20), 4.45 (2H, t, J = 6.0 Hz,
OCH2), 4.19 (1H, br s, H-11), 4.15 (2H, m, OCH2), 3.80 (1H, d, J = 6.0
Hz, Hb-20), 3.25 (1H, br s, H-14), 2.97 (1H, d, J = 13.0 Hz, H-5), 2.92
(1H, d, J = 17.0 Hz, Hβ-1), 2.67 (1H, d, J = 17.0 Hz, Hα-1), 2.62 (1H,
overlapped with Hα-1, Hα-6), 2.34−2.60 (4H, m, COCH2CH2CO),
2.16 (3H, s, H-5′), 2.16 (1H, overlapped with H-5′, H-9), 1.95 (2H, m,
CH2), 1.90 (3H, s, H-4′), 1.84 (3H, s, H-18), 1.81 (2H, m, CH2), 1.78
(1H, overlapped with CH2, Hβ-6), 1.37 (3H, s, H-19). 13C NMR (125
MHz, CDCl3) δ 192.3, 172.4, 171.5, 170.9, 167.1, 164.7, 160.8, 158.9,
144.0, 137.9, 135.7, 129.7, 128.6, 128.4, 114.2, 110.5, 82.6, 80.1, 74.7,
74.0, 71.0, 68.9, 65.5, 64.3, 51.3, 48.4, 45.2, 42.0, 41.8, 41.0, 29.3, 29.0,
28.8, 27.6, 25.2, 24.9, 20.5, 15.5, 13.4. HRESIMS m/z = 925.2316 [M +
Na]+ (calcd for C41H46N2NaO19S, 925.2308).
1
Compound 76. White powder, 23.1% yield. H NMR (500 MHz,
CDCl3) δ 8.04 (2H, br d, J = 7.5 Hz, ArH), 7.76 (1H, t, J = 7.5 Hz, ArH),
7.62 (2H, t, J = 7.5 Hz, ArH), 6.30 (1H, br s, H-15), 5.66 (1H, s, H-2′),
4.82 (1H, s, H-7), 4.69 (1H, br s, Ha-20), 4.44 (2H, t, J = 6.0 Hz, OCH2),
4.19 (2H, t, J = 6.0 Hz, OCH2), 4.19 (1H, overlapped with OCH2, H-
11), 4.11 (1H, s, H-12), 3.77 (1H, br s, Hb-20), 3.07 (1H, d, J = 10.5 Hz,
H-14), 3.07 (1H, overlapped with H-14, H-5), 2.91 (1H, overlapped
with COCH2, Hβ-1), 2.88 (2H, t, J = 6.0 Hz, COCH2), 2.71 (2H, t, J =
6.0 Hz, COCH2), 2.49 (1H, d, J = 14.0 Hz, Hα-1), 2.34 (1H, d, J = 12.0
Hz, Hα-6), 2.19 (1H, br s, H-9), 2.12 (3H, s, H-5′), 1.94 (2H, m, CH2),
1.88 (3H, s, H-4′), 1.82 (2H, m, CH2), 1.80 (1H, overlapped with CH2,
Hβ-6), 1.80 (3H, s, H-18), 1.41 (3H, s, H-19). 13C NMR (125 MHz,
CDCl3) δ 190.2, 172.7, 172.2, 170.6, 167.3, 165.0, 161.0, 158.9, 147.3,
141.9, 137.9, 135.7, 129.7, 128.5, 114.2, 110.5, 82.3, 80.9, 75.7, 73.7,
71.0, 70.7, 65.8, 64.2, 51.2, 49.7, 45.3, 42.8, 41.2, 40.7, 29.0, 28.7, 28.5,
27.6, 25.2, 24.9, 20.7, 15.5, 14.6. HRESIMS m/z = 925.2266 [M + Na]+
(calcd for C41H46N2NaO19S, 925.2308).
The yields and spectroscopic data for compounds 68 and 71−73 are
included in the Supporting Information.
General Procedures for the Preparation of 67 and 69. A
solution of 65 (24 mg, 0.047 mmol) and 2 or 8 (0.094 mmol) in dry
CH2Cl2 (20 mL) was treated with EDCI (18 mg, 0.094 mmol) and
DMAP (17 mg, 0.141 mmol). Then, the mixture was stirred at room
temperature. After 24 h, the solution was washed sequentially with water
and saturated NaCl solution, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by preparative
HPLC (CH3CN/H2O = 55:45, flow rate = 6 mL/min).
Compound 75. A solution of 10 (630 mg, 1.52 mmol), EDCI (292
mg, 1.52 mmol), and DMAP (556 mg, 4.56 mmol) in dry CH2Cl2 (20
mL) was stirred at 0 °C for 3 h. Then 65 (385 mg, 0.76 mmol) was added
to the solution and the mixture was stirred at room temperature for 24 h.
To improve the yield of 75, 10 (110 mg, 0.27 mmol), EDCI (52 mg, 0.27
mmol), and DMAP (50 mg, 0.41 mmol) were added to the reaction
mixture. The solution was stirred for a further 24 h and concentrated to
obtain the residue, which was chromatographed on Sephadex LH-20
(MeOH/H2O = 1:1) to obtain the product as a white powder (504 mg,
51.0% yield). 1H NMR (500 MHz, CDCl3) δ 8.04 (4H, br d, J = 7.5 Hz,
ArH), 7.75 (2H, t, J = 7.5 Hz, ArH), 7.62 (4H, t, J = 7.5 Hz, ArH), 6.08
Compound 67. The title compound was obtained starting from 65
and 2. White powder, 23.7% yield. 1H NMR (400 MHz, CDCl3) δ 8.05
(2H, br d, J = 7.6 Hz, ArH), 7.77 (1H, t, J = 7.6 Hz, ArH), 7.63 (2H, t, J =
J
dx.doi.org/10.1021/jm5007534 | J. Med. Chem. XXXX, XXX, XXX−XXX