Journal of Medicinal Chemistry
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solvent was removed under reduced pressure. Purification by flash
2″, H-5′, H-5, H-10, H-6, H-4′, H-4″, H-2′, SCH2CH2OCH2CH2S
(8H)), 3.55−2.98 (m, 4H, H-1, H-3, H-9, H-13), 3.40−3.32 (m, 3H,
H-3″, H-6′, H-21), 3.18 (m, 1H, H-6′), 3.02 (m, 1H, H-6″), 2.96 (m,
1H, H-15), 2.87 (s, 3H, NCH3), 2.86−2.65 (m, 9H, SCH2CH2-
OCH2CH2S (8H), H-6″), 2.48 (dt, J1 = 12.6 Hz, J2 = 4.2 Hz, 1H, H-
2eq), 2.34 (m, 2H, H-21, H-16), 2.22 (m, 2H, H-16, H-3eq), 2.00 (s,
3H, SCH3), 1.98−1.82 (m, 3H, H-2ax, H-3ax, H-17), 1.38−1.19 (m,
4H, H-18 (2H) H-19 (2H)), 1.14 (d, J = 6.9 Hz, 3H, H-14), 0.81 (m,
3H, H-20) (Figure S17). 13C NMR (125 MHz, D2O) δ 169.3, 162.8
(q, J = 35.6 Hz, CF3CO2H), 116.3 (q, J = 291.7 Hz, CF3CO2H),
100.7, 94.5, 88.4, 83.8, 77.6, 74.2, 72.6, 72.3, 70.5, 70.3 (2C), 69.7,
69.2, 68.6, 68.4, 68.0 (2C), 67.7, 64.4, 62.9 (2C), 54.6, 50.4, 49.5, 48.3,
47.8, 41.0, 40.4, 39.8, 37.5, 37.2, 35.8, 33.4, 32.7, 31.8, 30.0, 29.3, 27.8,
20.5, 14.5, 13.5, 13.3, 13.2 (Figure S18). HRMS (ESI) m/z calcd for
C44H85N7O15S5 [M + H]+ 1112.4786, found 1112.4791.
Compound 19. Cs2CO3 (79 mg, 0.24 mmol), compound 12 (70
mg, 0.24 mmol), and a catalytic amount of TBAI were added to
compound 5 (265 mg, 0.24 mmol) dissolved in anhydrous THF (1
mL). The reaction mixture was stirred at 40 °C. The reaction progress
was monitored by TLC (25:5:75 EtOAc/MeOH/CH2Cl2). After 16 h,
the reaction mixture was partitioned between H2O and EtOAc. The
organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. Purification by flash chromatog-
raphy (SiO2, 90:5:5 to 70:25:5 CH2Cl2/EtOAc/MeOH) afforded 19
(235 mg, 73%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.20
(d, J = 8.6 Hz, 1H, H-7), 7.67 (d, J = 8.8 Hz, 1H, H-8), 5.17 (d, J = 2.6
Hz, 1H, H-9), 5.11 (br s, 1H, H-1′), 5.05 (d, J = 3.7 Hz, 1H, H-1″),
4.19 (ddd, J1 = 7.8 Hz, J2 = 6.1 Hz, J3 = 2.6 Hz, 1H, H-10), 4.11 (m,
1H, H-5″), 3.79 (dd, J1 = 10.8 Hz, J2 = 7.3 Hz, 1H, H-11), 3.78−3.33
(m, 17H, H-11, H-2′, H-4′, H-5′, H-6′, H-1, H-3, H-4, H-5, H-6, H-3″,
H-2″, H-4″, SCH2CH2OCH2CH2S (4H)), 3.26−3.13 (m, 3H, H-12,
H-6′), 3.04 (m, 1H, H-6″), 2.83−2.66 (m, 2H, SCH2CH2-
OCH2CH2S), 2.74−2.66 (m, 1H, H-6″), 2.51 (t, J = 6.3 Hz, 2H,
SCH2CH2OCH2CH2S), 2.14 (d, J = 12.9 Hz, 1H, H-2eq), 2.04 (m,
1H, H-3eq), 1.70−1.59 (m, 2H, H-3ax, H-2ax), 1.45 (m, 45H, 5 ×
CO2C(CH3)3). 13C NMR (100 MHz, CD3OD) δ 170.8 (2C), 158.0,
157.8, 156.5, 156.3, 150.6, 147.1, 126.9 (2C), 122.8 (2C), 98.3, 98.0,
82.6, 80.9, 79.0 (4C), 75.6, 72.5, 72.1, 70.7, 70.5, 70.2, 69.9, 65.1, 61.1,
58.1, 56.6, 55.6, 50.1, 49.7, 49.5, 40.6, 35.0, 34.4, 33.6, 32.9, 32.0, 31.2,
27.4 (15C). LRMS (ESI) m/z calcd for C58H98N7O24S2 [M + H]+
1340.60, found 1340.67.
chromatography (SiO2, 6:4 petroleum ether/EtOAc to 96:4 EtOAc/
1
MeOH) afforded 14 (125 mg, 78%) as a white solid. H NMR (400
MHz, CD3OD) δ 8.40 (ddd, J1 = 4.9 Hz, J2 = 1.7 Hz, J3 = 0.9 Hz, 1H,
H-1′), 8.19 (d, J = 8.8 Hz, 2H, H-1), 7.93 (dd, J1 = 8.1 Hz, J2 = 1.2 Hz,
1H, H-3′), 7.83 (ddd, J1 = 8.04 Hz, J2 = 4.9 Hz, J3 = 1.7, Hz, 1H, H-
2′), 7.68 (d, J = 8.8 Hz, 2H, H-2), 7.23 (ddd, J1 = 7.4 Hz, J2 = 4.9 Hz,
J3 = 1.1 Hz, 1H, H-4′), 5.18 (d, J = 2.6 Hz, 1H, H-3), 4.21 (ddd, J1 =
7.4 Hz, J2 = 5.8 Hz, J3 = 2.7 Hz, 1H, H-4), 3.80 (dd, J1 = 10.8 Hz, J2 =
7.3 Hz, 1H, H-5), 3.65 (m, 3H, H-5, SCH2CH2OCH2CH2S (2H)),
3.51 (t, J = 6.3 Hz, 2H, SCH2CH2OCH2CH2S), 3.23 (d, J = 14.9 Hz,
1H, H-6), 3.18 (d, J = 14.9, 1H, H-6), 3.03 (t, J = 6.0 Hz, 2H,
SCH2CH2OCH2CH2S), 2.52 (t, J = 6.4 Hz, 2H, SCH2CH2-
OCH2CH2S) (Figure S13). 13C NMR (100 MHz, CD3OD) δ 172.2,
161.7, 152.0, 150.2, 148.5, 139.2, 128.3 (2C), 124.2 (2C), 122.3, 121.2,
71.6, 71.3, 69.5, 62.5, 58.0, 39.9, 36.5, 32.7 (Figure S14). LRMS (ESI)
m/z calcd for C20H25N3O6S3Cl [M + Cl]− 534.06, found 534.17.
Compound 16. Compound 16 was synthesized as previously
reported.27 Purity = 97% (Table S2 and Figure S32). H NMR (400
1
MHz, CD3OD) δ 5.79 (d, J = 3.7 Hz, 2H, H-1′), 5.08 (d, J = 3.7 Hz,
4H, H-1″), 4.13 (t, J = 9.6 Hz, 2H, H-4), 3.99 (m, 4H, H-5′, H-5″),
3.94−3.89 (m, 4H, H-2″, H-5), 3.82−3.73 (m, 6H, H-5, SCH2CH2-
OCH2CH2S (4H)), 3.69 (t, J = 6.4 Hz, 4H, SCH2CH2OCH2CH2S),
3.58 (m, 10H, H-1, H-3, H-2′, H-4′, H-4″), 3.46−3.37 (m, 4H, H-6′,
H-3″), 3.21−3.07 (m, 4H, H-6′, H-6″), 2.91 (t, J = 6.3 Hz, 4H,
SCH2CH2OCH2CH2S), 2.87−2.79 (m, 6H, SCH2CH2OCH2CH2S
(4H), H-6″), 2.57 (dt, J1 = 12.5 Hz, J2 = 4.3 Hz, 2H, H-2eq), 2.23 (dt,
J1 = 12.0 Hz, J2 = 4.5 Hz, 2H, H-3eq), 2.19−2.04 (m, 4H, H-3ax, H-
3eq) (Figure S15). 13C NMR (125 MHz, D2O) δ 162.5 (q, J = 36.2
Hz, CF3CO2H), 116.0 (q, J = 290.9 Hz, CF3CO2H), 100.6 (2C), 94.3
(2C), 83.8 (2C), 77.4 (2C), 74.2 (2C), 72.5 (2C), 70.3 (2C), 69.1
(2C), 67.9 (4C), 64.4 (2C), 54.6 (2C), 49.5 (2C), 48.2 (2C), 47.8
(2C), 39.8 (2C), 37.0 (2C), 32.6 (2C), 31.8 (2C), 29.5 (2C), 29.2
(2C), 27.7 (2C) (Figure S16). HRMS (ESI) m/z calcd for
C44H88N10O18S4 [M + H]+ 1173.5239, found 1173.5245.
Compound 17. A solution of 7 (127 mg, 0.106 mmol) in MeOH
(1 mL) was added to a solution of 9 (50 mg, 0.095 mmol) in MeOH
(1 mL), and the mixture was stirred at 23 °C. The reaction progress
was monitored by TLC (9:1 CH2Cl2/MeOH). Upon completion, the
solvent was removed under reduced pressure. Purification by flash
chromatography (SiO2, 99:1 to 91:9 CH2Cl2/MeOH) afforded 17
(135 mg, 88%) as a white solid. 1H NMR (400 MHz, CD3OD) δ 5.27
(d, J = 5.6 Hz, 1H, H-7), 5.13 (bs, 1H, H-1′), 5.06 (d, J = 3.7 Hz, 1H,
H-1″), 4.42 (ddd, J1 = 9.7 Hz, J2 = 4.0 Hz, J3 = 1.5 Hz, 1H, H-12),
4.16−4.08 (m, 2H, H-8, H-11), 3.78−3.71 (m, 8H, H-4, H-5′, H-2″,
H-5″, SCH2CH2OCH2CH2S (4H)), 3.68−3.61 (m, 7H, H-5, H-6, H-
10, SCH2CH2OCH2CH2S (4H)), 3.58−3.33 (m, 10H, H-1, H-3, H-2′,
H-4′, H-6′, H-3″, H-4″, H-9, H-13, H-21), 3.23 (dd, J1 = 8.6 Hz, J2 =
5.8 Hz, 1H, H-6′), 3.06−3.02 (m, 1H, H-6″), 2.99 (dd, J1 = 10.5 Hz, J2
= 4.9 Hz, 1H, H-15), 2.93−2.89 (m, 4H, SCH2CH2OCH2CH2S),
2.85−2.87 (m, 4H, SCH2CH2OCH2CH2S), 2.75−2.65 (m, 1H, H-6″),
2.43 (s, 3H, NCH3), 2.25−1.94 (m, 7H, H-16 (2H), H-21, H-2eq,
SCH3), 1.90−1.80 (m, 1H, H-3eq), 1.68−1.55 (m, 2H, H-2ax, H-3ax),
1.54−1.27 (m, 50H, H-17, 5 × CO2C(CH3)3, H-18 (2H), H-19
(2H)), 1.35 (d, J = 7.0 Hz, 3H, H-14), 1.34 (q, J = 2.4 Hz, 3H), 0.92
(m, 3H, H-20). 13C NMR (100 MHz, CD3OD) δ 176.9, 158.0, 157.8,
156.5, 156.3, 148.7, 98.47, 97.99, 88.9, 82.5, 80.9, 79.3, 79.1, 79.0, 78.8,
72.6, 72.1, 70.6, 70.3, 69.4, 69.0, 68.7, 68.5, 68.1, 55.6, 50.5, 50.1, 49.6,
49.6, 40.7, 39.8, 39.8, 38.2, 38.2, 37.5, 37.3, 35.6, 34.4, 33.7, 32.9, 32.1,
29.8 (15C), 21.2, 14.1, 13.2, 12.7. LRMS (ESI) m/z calcd for
C69H126N7O25S5 [M + H]+ 1612.73, found 1613.10.
Compound 20. Neat TFA (0.7 mL) was added to compound 19
(30 mg, 0.022 mmol) at room temperature. After 3 min, the TFA was
removed under reduced pressure, and the product was redissolved in a
minimal volume of H2O and freeze-dried to afford 20 (32 mg, quant)
1
as a white foam. Purity = 99% (Table S2 and Figure S34). H NMR
(400 MHz, D2O) δ 8.12 (d, J = 8.7 Hz, 1H, H-7), 7.52 (d, J = 8.5 Hz,
1H, H-8), 5.63 (d, J = 3.6 Hz, 1H, H-1′), 5.07 (d, J = 2.9 Hz, 1H, H-
9), 4.97 (d, J = 3.7 Hz, 1H, H-1″), 4.14 (td, J1 = 6.5 Hz, J2 = 2.9 Hz,
1H, H-10), 3.92−3.59 (m, 10H, H-2″, H-4″, H-5″, H-11, H-4′, H-5′,
H-4, H-5, H-6), 3.59−3.24 (m, 9H, H-2′, H-3″, H-6′, H-1, H-3,
SCH2CH2OCH2CH2S (4H)), 3.16−3.02 (m, 3H, H-12a, H-12b, H-
6′), 2.96 (dd, J1 = 14.2 Hz, J2 = 2.5 Hz, 1H, H-6″), 2.66 (m, 3H,
SCH2CH2OCH2CH2S (2H), H-6″), 2.44 (dt, J1 = 12.6 Hz, J2 = 4.3
Hz, 1H, H-2eq), 2.34 (dt, J1 = 13.6 Hz, J2 = 6.4 Hz, 1H,
SCH2CH2OCH2CH2S), 2.25 (dt, J1 = 13.6 Hz, J2 = 6.3 Hz, 1H,
SCH2CH2OCH2CH2S), 2.18 (dt, J1 = 12.0 Hz, J2 = 4.3 Hz, 1H, H-
3eq), 1.87 (q, J = 12.0 Hz, 1H, H-3ax), 1.82 (q, J = 12.6 Hz, 1H, H-
2ax) (Figure S19). 13C NMR (100 MHz, D2O) δ 172.4, 162.7 (q, J =
35.9 Hz, CF3CO2H), 149.4, 147.0, 127.0 (2C), 123.6 (2C), 116.2 (q, J
= 291.4 Hz, CF3CO2H), 100.6, 94.5, 83.9, 77.6, 74.3, 72.6, 70.8, 69.1,
68.8, 68.0, 64.4, 61.3, 58.1 (2C), 56.5, 54.7, 49.5, 48.3, 47.9, 39.8, 34.9,
32.7, 31.8, 31.0, 29.3, 27.8 (Figure S20). HRMS (ESI) m/z calcd for
C33H57N7O14S2 [M + H]+ 840.3483, found 840.3841.
Compound 18. Neat TFA (0.7 mL) was added to compound 17
(30 mg, 0.018 mmol) at room temperature. After 3 min, the TFA was
removed under reduced pressure, and the product was redissolved in a
minimal volume of H2O and freeze-dried to afford 18 (32 mg, quant)
Compound 21. A solution of 13 (40 mg, 0.10 mmol) in MeOH
(1.5 mL) was added to a solution of 7 (135 mg, 0.11 mmol) in MeOH
(1.5 mL), and the mixture was stirred at 23 °C. The reaction progress
was monitored by TLC (95:5 CH2Cl2/MeOH). Upon completion, the
solvent was removed under reduced pressure. Purification by flash
chromatography (SiO2, 99:1 to 94:6 CH2Cl2/MeOH) afforded 21
1
as a white foam. Purity = 96% (Table S2 and Figure S33). H NMR
(500 MHz, D2O) δ 5.67 (d, J = 3.6 Hz, 1H, H-1′), 5.28 (d, J = 5.9 Hz,
1H, H-7), 5.01 (d, J = 3.5 Hz, 1H, H-1″), 4.51 (dd, J1 = 8.2 Hz, J2 =
1.9 Hz, 1H, H-12), 4.22 (dt, J1 = 8.0 Hz, J2 = 3.6 Hz, 1H, H-11), 4.13
(m, 1H, H-8), 4.08−3.99 (m, 2H, H-4, H-5″), 3.95−3.70 (m, 16H, H-
5621
dx.doi.org/10.1021/jm400707f | J. Med. Chem. 2013, 56, 5613−5625