Journal of Medicinal Chemistry
Article
J = 12.8, 7.2 Hz, 1H, H-5‴), 4.22−4.14 (m, 3H, H-5′, H-3″, H-5″),
4.14−4.11 (m, 2H, H-6″, H-6″), 4.01 (dd, J = 5.8, 4.7 Hz, 1H, H-5),
3.94 (dd, J = 7.1, 4.6 Hz, 1H, H-4), 3.77 (dd, J = 7.4 Hz, 1H, H-6),
3.68 (m, 1H, H-3), 3.59 (m, 1H, H-1), 3.45 (dd, J = 10.6, 3.8 Hz, 1H,
H-2′), 3.36 (dd, J = 13.4, 2.6 Hz, 1H, H-6′), 3.29 (dd, J = 13.4, 5.7 Hz,
1H, H-6′), 2.36 (ddd, J = 13.6, 5.7 Hz, 1H, H-2eq), 2.18 (s, 3H,
COCH3), 2.06 (s, 3H, COCH3), 2.04 (s, 3H, COCH3), 1.99 (s, 3H,
COCH3), 1.98 (s, 3H, COCH3), 1.63 (ddd, J = 13.8 Hz, 1H, H-2ax).
13C NMR (100 MHz, CDCl3) δ 170.7, 170.0, 169.8, 169.5, 166.2,
165.3, 133.9, 133.8, 133.5, 129.9, 129.8, 129.0, 128.7, 128.6, 107.0
(anomeric), 96.3 (anomeric), 95.6 (anomeric), 80.4, 79.9, 79.0, 78.6,
75.4, 72.0, 71.5, 70.7, 69.8, 69.5, 68.8, 68.4, 65.0, 62.1, 61.7, 60.5, 58.6,
58.2, 50.9, 30.2, 20.8, 20.7.
Compound 4c. Compound 4c was prepared as described for
compound 1a using acceptor 4b (310 mg, 0.41 mmol), donor (550
mg, 0.91 mmol), flame-dried 4-Å molecular sieves (900 mg),
anhydrous dichloromethane (6 mL), and BF3·OEt2 (30 μL).
Propagation of the reaction was monitored by TLC analysis (ethyl
acetate/petroleum ether, 3:7). The crude was purified by flash
chromatography (SiO2, ethyl acetate:dichloromethane) to yield 4c
(480 mg, 98%) as a white solid. LRMS (ESI): m/z calcd for
C52H55N15O20Na, 1232.36 [M + Na]+; found, 1231.99. 1H NMR (400
MHz, CDCl3) δ 8.07−8.03 (m, 2H, Bz), 8.00−7.95 (m, 2H, Bz),
7.89−7.85 (m, 2H, Bz), 7.59−7.47 (m, 3H, Bz), 7.40 (m, 4H, Bz),
7.31 (t, J = 7.8 Hz, 2H, Bz), 5.78 (m, 1H, H-2‴), 5.73 (m, 1H, H-3‴),
5.71 (bs, 1H, H-1‴), 5.48 (d, J = 3.7 Hz, 1H, H-1″), 5.38 (d, J = 3.4
Hz, 1H, H-1′), 4.86 (t, J = 9.9 Hz, 1H, H-4″), 4.79−4.73 (m, 2H, H-
2″, H-4‴), 4.70 (dd, J = 11.7, 4.0 Hz, 1H, H-5‴), 4.67−4.59 (m, 2H,
H-4′, H-5‴), 4.20−4.10 (m, 4H, H-3″, H-5″, H-6″, H-6″), 4.09−4.04
(m, 2H, H-4, H-5), 4.00 (ddd, J = 6.7, 6.2, 2.4 Hz, 1H, H-5′), 3.82 (dd,
J = 8.2, 6.1 Hz, 1H, H-6), 3.74 (m, 1H, H-3), 3.67 (ddd, J = 10.4, 8.3,
6.6 Hz, 1H, H-1), 3.35 (dd, J = 13.2, 2.3 Hz, 1H, H-6′), 3.31−3.23 (m,
2H, H-2′, H-6′), 2.38 (ddd, J = 13.8, 5.9 Hz, 1H, H-2eq), 2.32 (ddd, J
= 11.7, 4.3 Hz, 1H, H-3′eq), 2.15 (s, 3H, COCH3), 2.04 (s, 3H,
COCH3), 1.97 (s, 3H, COCH3), 1.96 (s, 3H, COCH3), 1.93 (ddd, J =
11.6 Hz, H-3′ax), 1.64 (ddd, J = 13.8, 10.3 Hz, 1H, H-2ax). 13C NMR
(100 MHz, CDCl3) δ 170.5, 169.8, 169.6, 169.3, 166.0, 165.1, 133.7,
133.6, 133.3, 129.7, 129.6, 128.9, 128.7, 128.6, 128.5, 128.4, 106.7
(anomeric), 95.8 (anomeric), 95.4 (anomeric), 80.5, 79.5, 79.0, 77.9,
75.3, 72.0, 71.4, 70.2, 68.8, 68.2, 66.9, 65.1, 62.0, 60.4, 58.6, 58.4, 56.3,
50.9, 30.4, 28.2, 20.9, 20.6, 20.52, 20.49.
Compound 5c. Compound 5c was prepared as described for
compound 1c using acceptor 5b (285 mg, 0.58 mmol), donor (520
mg, 0.86 mmol), flame-dried 4-Å molecular sieves (1.5 g), anhydrous
dichloromethane (10 mL), and BF3·OEt2 (40 μL). Propagation of the
reaction was monitored by TLC analysis (ethyl acetate/petroleum
ether, 3:7). The crude was purified by flash chromatography (SiO2,
ethyl acetate/dichloromethane) to yield 5c (465 mg, 86%) as a white
solid. LRMS (ESI): m/z calcd for C42H42N12O14Na, 961.28 [M +
Na]+; found, 961.48. 1H NMR (400 MHz, CDCl3) δ 8.11 (dd, J = 7.1,
1.4 Hz, 2H, Bz), 7.95 (dd, J = 7.2, 1.2 Hz, 2H, Bz), 7.89 (dd, J = 7.2,
1.2 Hz, 2H, Bz), 7.61−7.54 (m, 2H, Bz), 7.53−7.45 (m, 3H, Bz), 7.40
(t, J = 7.8 Hz, 2H, Bz), 7.34 (t, J = 7.8 Hz, 2H, Bz), 5.71 (dd, J = 6.7,
4.9 Hz, 1H, H-3″), 5.68 (d, J = 3.6 Hz, 1H, H-1′), 5.63 (dd, J = 4.8, 1.3
Hz, 1H, H-2″), 5.56 (d, J = 1.1 Hz, 1H, H-1″), 4.91 (dd, J = 12.2, 3.4
Hz, 1H, H-5″), 4.85 (t, J = 9.9 Hz, 1H, H-6), 4.69 (dt, J = 6.7, 3.8 Hz,
1H, H-4″), 4.63 (td, J = 10.6, 4.7 Hz, 1H, H-4′), 4.42 (dd, J = 12.1, 4.0
Hz, 1H, H-5″), 4.23 (ddd, J = 9.9, 5.8, 2.5 Hz, 1H, H-5′), 3.84 (dd, J =
9.1 Hz, 1H, H-5), 3.47 (dd, J = 9.9 Hz, 1H, H-4), 3.45−3.36 (m, 2H,
H-1, H-3), 3.32 (dd, J = 13.3, 2.4 Hz, 1H, H-6′), 3.27 (m, 1H, H-2′),
3.21 (dd, J = 13.2, 5.8 Hz, 1H, H-6′), 2.34−2.29 (m, 2H, H-2eq, H-
3′eq), 2.27 (s, 3H, COCH3), 2.05 (s, 3H, COCH3), 1.95 (ddd, J =
11.6 Hz, 1H, H-3′ax), 1.46 (ddd, J = 12.6 Hz, 1H, H-2ax). 13C NMR
(100 MHz, CDCl3) δ 170.0, 169.9, 166.3, 165.6, 165.3, 133.8, 133.6,
133.4, 130.2, 129.9, 129.8, 129.0, 128.9, 128.7, 128.6, 128.5, 107.4
(anomeric), 95.5 (anomeric), 80.7, 79.6, 77.1, 75.0, 74.3, 71.6, 69.6,
67.3, 63.5, 59.5, 58.5, 56.4, 51.4, 31.8, 28.5, 21.1, 21.0.
stirred overnight at ambient temperature. Upon completion (as shown
by TLC analysis, methanol/dichloromethane, 2:8), the solvent was
removed by evaporation and the crude product was purified by flash
column chromatography (SiO2, methanol/dichloromethane) to yield
1d (144 mg, 80%) as a white solid. LRMS (ESI): m/z calcd for
C23H35N12O15, 719.24 [M − H]−; found, 719.54. 1H NMR (500 MHz,
CD3OD) δ 5.52 (d, J = 3.7 Hz, 1H, H-1″), 5.41 (d, J = 3.9 Hz, 1H, H-
1′), 5.36 (d, J = 3.2 Hz, 1H, H-1‴), 4.03 (ddd, J = 9.9, 5.2, 2.3 Hz, 1H,
H-5′), 3.99 (dd, J = 5.9 Hz, 1H, H-3‴), 3.95 (dd, J = 7.7 Hz, 1H, H-5),
3.94−3.90 (m, 2H, H-5″, H-2‴), 3.87 (td, J = 5.9, 2.9 Hz, 1H, H-4‴),
3.83−3.63 (m, 10H, H-1, H-3, H-4, H-6, H-3′, H-3″, H-6″,H-6″, H-
5‴, H-5‴), 3.57 (dd, J = 13.2, 2.3 Hz, 1H, H-6′), 3.45−3.40 (m, 3H,
H-2′, H-6′,H-2″), 3.37−3.29 (m, 2H, H-4′, H-4″), 2.40 (ddd, J = 12.7,
4.7 Hz, 1H, H-2eq), 1.62 (ddd, J = 12.8 Hz, 1H, H-2ax). 13C NMR
(125 MHz, CD3OD) δ 109.4 (anomeric), 99.9 (anomeric), 98.5
(anomeric), 84.5, 81.4, 79.7, 78.3, 75.9, 74.5, 73.7, 73.6, 73.3, 72.3,
72.0, 70.9, 70.1, 67.9, 63.4, 62.1, 61.1, 60.9, 52.6, 32.5.
Compound 2d. Compound 2d was prepared as described for
compound 1d using 2c (200 mg, 0.14 mmol), methanol/dichloro-
methane (9:1, 10 mL), and K2CO3 (39 mg, 0.28 mmol). The reaction
mixture was stirred at ambient temperature overnight. Upon
completion (TLC analysis, methanol/dichloromethane, 2:8), solvent
was evaporated and the crude was purified by flash column
chromatography (SiO2, methanol/dichloromethane) to yield 2d (94
mg, 81%) as a white solid. LRMS (ESI): m/z calcd for C27H42N13O17,
1
820.28 [M − H]−; found, 820.59. H NMR (500 MHz, CD3OD) δ
5.39 (d, J = 3.8 Hz, 1H, H-1′), 5.35 (d, J = 2.4 Hz, 1H, H-1‴), 5.22 (d,
J = 3.4 Hz, 1H, H-1″), 4.14 (dd, J = 9.0, 3.5 Hz, 1H, (S)-(−)-4-amino-
2-hydroxybutyryl (Hα)), 4.06−4.00 (m, 3H, H-5′, H-2‴, H-3‴),
3.96−3.90 (m, 3H, H-1, H-5, H-4‴), 3.87−3.79 (m, 3H, H-5″, H-6″,
H-5‴), 3.75−3.57 (m, 8H, H-3, H-4, H-6, H-3′, H-6′, H-3″, H-6″, H-
5‴), 3.50−3.42 (m, 5H, H-2′, H-6′, H-2″, (S)-(−)-4-amino-2-
hydroxybutyryl (2Hγ)), 3.34−3.27 (m, 2H, H-4′, H-4″), 2.47 (ddd,
J = 12.9, 3.7 Hz, 1H, H-2eq), 2.09−2.02 (m, 1H, (S)-(−)-4-amino-2-
hydroxybutyryl (Hβ)), 1.84 (m, 1H, (S)-(−)-4-amino-2-hydroxybu-
tyryl (Hβ)), 1.45 (ddd, J = 12.0 Hz, 1H, H-2ax). 13C NMR (125 MHz,
CD3OD) δ 176.6, 109.0 (anomeric), 100.0 (anomeric), 99.4
(anomeric), 84.7, 82.4, 79.9, 78.6, 76.1, 74.9, 74.5, 73.7, 73.3, 72.7,
72.1, 71.4, 70.7, 69.9, 67.6, 63.8, 62.5, 60.8, 52.6, 34.6, 31.9.
Compound 3d. Compound 3d was prepared as described for
compound 1d using 3c (80.5 mg, 0.06 mmol), methanol/dichloro-
methane (9:1, 10 mL), and K2CO3 (14 mg, 0.10 mmol). The reaction
mixture was stirred at ambient temperature overnight. Upon
completion (TLC analysis, methanol/dichloromethane, 15:85),
solvent was evaporated, and the crude was purified by flash column
chromatography (SiO2, methanol/dichloromethane) to yield 3d (44.7
mg, 94%) as a white solid. LRMS (ESI): m/z calcd for
1
C23H35N15O14Na, 768.24 [M + Na]+; found, 768.10. H NMR (400
MHz, CD3OD) δ 5.67 (d, J = 3.8 Hz, 1H, H-1′), 5.39−5.38 (m, 2H,
H-1″, H-1‴), 4.08−3.69 (m, 16H, H-1, H-3, H-4, H-5, H-6, H-3′, H-
5′, H-2″, H-5″, H-6″, H-6″, H-2‴, H-3‴, H-4‴, H-5‴, H-5‴), 3.57
(dd, J = 13.2, 2.1 Hz, 1H, H-6′), 3.49−3.34 (m, 4H, H-4′, H-6′, H-3″,
H-4″), 3.24 (dd, J = 10.4, 3.8 Hz, 1H, H-2′), 2.40 (ddd, J = 13.0, 5.3
Hz, 1H, H-2eq), 1.59 (ddd, J = 12.8 Hz, 1H, H-2ax). 13C NMR (100
MHz, CD3OD) δ 108.9 (anomeric), 98.9 (anomeric), 97.5
(anomeric), 84.6, 80.3, 78.4, 77.9, 76.1, 73.8, 73.3, 72.5, 72.2, 71.6,
69.9, 67.8, 64.5, 64.0, 62.0, 60.4, 60.2, 52.6, 31.8.
Compound 4d. Compound 4d was prepared as described for
compound 1d using 4c (118 mg, 0.09 mmol), methanol/dichloro-
methane (4:1, 5 mL), and K2CO3 (24 mg, 0.17 mmol). The reaction
mixture was stirred at ambient temperature overnight. Upon
completion (TLC analysis, methanol/dichloromethane, 2:8), solvent
was evaporated and the crude was purified by flash column
chromatography (SiO2, methanol/dichloromethane) to yield 4d (55
mg, 77%) as a white solid. LRMS (ESI): m/z calcd for C23H34N15O13,
1
728.25 [M − H]−; found, 728.78. H NMR (500 MHz, CD3OD) δ
5.63 (d, J = 3.0 Hz, 1H, H-1′), 5.44 (d, J = 3.3 Hz, 1H, H-1″), 5.40 (s,
1H, H-1‴), 4.04−4.00 (m, 2H, H-5, H-3‴), 3.98−3.85 (m, 6H, H-5′,
H-5″, H-4, H-6, H-2‴, H-4‴), 3.84−3.69 (m, 7H, H-3″, H-6″, H-6″,
H-1, H-3, H-5‴, H-5‴), 3.61−3.53 (m, 2H, H-4′, H-6′), 3.46−3.34
Compound 1d. The fully protected ribosylated compound 1c (320
mg, 0.25 mmol) was dissolved in methanol/dichloromethane (9:1, 10
mL), and K2CO3 (62 mg, 0.45 mmol) was added. The mixture was
H
J. Med. Chem. XXXX, XXX, XXX−XXX