K. Ohnishi et al.
Bioorganic&MedicinalChemistryxxx(xxxx)xxx–xxx
to give 24b (34.0 mg, 34%, 2 steps) as a yellow solid. [α]D −10 (c
23
J = 8.1 Hz, 1.1H), 7.14 (br d, J = 7.5 Hz, 1H), 5.84 (ddd, J = 17.3,
10.5, 3.9 Hz, 0.45H), 5.77 (ddd, J = 17.3, 10.7, 3.8 Hz, 0.55H), 5.36
(dd, J = 10.5, 2.1 Hz, 1.1H), 5.20 (d, J = 17.4 Hz, 0.9H), 4.64 (d,
J = 4.5 Hz, 0.45H), 4.52 (dd, J = 7.8, 2.7 Hz, 0.55H), 4.41–4.22 (m,
3H), 4.15 (dd, J = 15.3, 6.3 Hz, 0.45H), 4.04 (dd, J = 17.0, 5.9 Hz,
0.55H), 3.96 (br d, J = 8.4 Hz, 0.55H), 3.84 (dd, J = 17.0, 5.0 Hz,
0.55H), 3.57 (dd, J = 15.3, 5.7 Hz, 0.45H), 3.37 (br d, J = 12,6 Hz,
0.45H), 2.84 (br t, J = 11.7 Hz, 0.45H), 2.73 (br s, 1H), 2.59 (br t,
J = 12.0 Hz, 0.55H), 2.06 (s, 1.65H), 2.03 (s, 1.35H), 1.71–1.40 (m,
6H), 1.26–1.07 (m, 3H), 1.17 (d, J = 6.3 Hz, 1.65H), 1.07 (d,
J = 6.3 Hz, 1.35H), 0.99–0.82 (m, 1H); 13C NMR (75 MHz): δ = 172.6,
171.64, 171.58, 171.3, 169.5, 169.0, 134.6, 134.4, 133.5, 133.2, 131.8,
128.7, 127.9, 124.2, 124.0, 118.0, 117.9, 67.1, 66.2, 62.1, 58.5, 58.0,
56.4, 52.5, 51.3, 49.3, 44.4, 43.1, 42.8, 39.9, 39.1, 35.7, 34.3, 30.1,
29.7, 28.2, 25.8, 25.7, 25.1, 25.0, 23.0, 22.9, 19.4, 18.8; HRMS (ESI)
calcd for C26H35N4O5Na [M+Na]+:585.1683. Found: 585.1688.
0.17, CHCl3); Mp 133–135 °C; 1H NMR (300 MHz): δ = 7.84–7.81 (m,
0.36H), 7.61–7.49 (m, 3.64H), 7.45–7.37 (m, 5.78H), 7.34–7.32 (m,
6.42H), 7.14–7.09 (m, 6.44H), 6.96–6.93 (m, 0.36H), 6.77 (m, 0.36H),
6.66 (m, 0.42H), 6.65 (m, 0.22H), 5.36–5.33 (m, 0.22H), 4.97–4.94 (m,
0.42H), 4.88–4.83 (m, 0.36H), 4.64–4.60 (m, 0.22H), 4.45–4.42 (m,
0.36H), 4.38–4.17 (m, 2.78H), 4.08–3.97 (m, 0.42H), 3.92–3.85 (m,
0.42H), 3.80–3.70 (m, 0.44H), 3.68–3.64(m, 0.36H), 3.62–3.43 (m,
0.58H), 3.37–3.08 (m, 2.42H), 3.06–2.87 (m, 1.64H), 2.83–2.75 (m,
1.78H), 2.66–2.28 (m, 7.58H), 2.08 (s, 0.78H), 2.04 (s, 0.42H), 2.03 (s,
1.8H), 1.73–1.33 (m, 6H), 1.26–0.99 (m, 12H), 0.92–0.80 (m, 1H); 13C
NMR (75 MHz): δ = 172.5, 171.8, 171.6, 171.3, 169.4, 142.3, 140.3,
138.5, 137.8, 134.9, 131.5, 129.6, 129.5, 129.4, 128.9, 128.7, 128.6,
128.1, 123.9, 119.6, 119.5, 75.2, 66.0, 58.7, 58.6, 55.1, 49.3, 48.9,
45.2, 44.3, 40.4, 36.1, 30.0, 29.6, 28.2, 26.1, 26.0, 25.2, 23.0, 14.4,
14.2; HRMS (ESI) calcd for C54H67BrN7O5S2 [M+H]+: 1036.3823.
Found: 1036.3820.
4.20. Compound 24a
4.22. Compound 24c
A solution of 23 (56.2 mg, 0.1 mmol) in EtOAc (4 mL) at –78 °C was
treated with ozone gas until the solution changed from colorless to blue.
After that, Me2S (60 μL, 0.8 mmol) was added, and the mixture was
warmed to 25 °C and was stirred for 10 min. The mixture was extracted
with EtOAc. The organic layer was washed with H2O and brine, dried
over Na2SO4, filtered, and concentrated. The residue was roughly
purified by silica gel column chromatography (CHCl3/MeOH = 10:1).
The product was immediately used without further purification. Amine
21a (54.1 mg, 0.12 mmol) was added to a solution of above aldehyde in
CH2Cl2 (1 mL) at 0 °C. The mixture was stirred at 25 °C for 2 h and then
NaBH3CN (22 mg, 0.35 mmol) was added. The mixture was stirred for
30 min. The reaction was quenched with 1 M HCl and the whole was
extracted with EtOAc. The organic layer was washed with saturated
aqueous NH4Cl and brine, dried over Na2SO4, filtered, and con-
centrated. The residue was purified by flash column chromatography
(CHCl3/MeOH = 20:1) to give 24a (50 mg, 50%, 2 steps) as a colorless
A solution of 23 (56.2 mg, 0.1 mmol) in EtOAc (4 mL) at −78 °C was
treated with ozone gas as above and the product aldehyde was re-
ductively aminated by H-His(Trt)-N(OMe)Me (52.8 mg, 0.12 mmol)
using the same procedure described above. The product was purified by
flash column chromatography (CHCl3/MeOH = 20:1) to give 24c
25
(25.7 mg, 26%, 2 steps) as a white wax. [α]D −18.3 (c 0.43, CHCl3);
1H NMR (300 MHz): δ = 7.50 (d, J = 8.4 Hz, 1.8H), 7.43 (br d,
J = 8.4 Hz, 1.4H), 7.39 (d, J = 8.4 Hz, 1.8H), 7.32–7.30 (m, 10H),
7.12–7.09 (m, 6.1H), 6.93 (br d, J = 8.1 Hz, 0.65H), 6.78 (d,
J = 7.5 Hz, 0.25H), 6.61 (m, 0.1H), 6.65 (m, 0.65H), 6.51 (s, 0.25H),
5.36–5.34 (m, 0.25H), 5.12–5.07 (m, 0.1H), 4.82–4.80 (m, 0.1H), 4.72
(br t, J = 8.0 Hz, 0.65H), 4.44 (dd, J = 3.6, 2.4 Hz, 0.25H), 4.34–4.20
(m, 3.25H), 4.09–3.97 (m, 1.7H), 3.75–3.63 (m, 1H), 3.54 (s, 1.95H),
3.45–3.38 (m, 1.4H), 3.15 (s, 0.3H), 3.08 (s, 1.95H), 3.03 (s, 0.75H),
2.83–2.65 (m, 4H), 2.48–2.41 (m, 1H), 2.34–2.25 (m, 1H), 2.07 (s,
1.95H), 2.05 (s, 1.05H), 2.04–2.01 (m, 0.35H), 1.72–1.37 (m, 5H),
1.26–1.12 (m, 5H), 1.06 (d, J = 6.3 Hz, 3H), 0.99–0.83 (m, 2H); 13C
NMR (75 MHz): δ = 172.9, 171.8, 171.6, 169.1, 142.4, 138.2, 134.9,
131.7, 129.7, 128.6, 128.0, 123.9, 119.3, 75.1, 65.4, 58.4, 57.4, 54.5,
49.0, 48.6, 45.9, 45.0, 40.3, 36.0, 32.3, 29.9, 29.7, 28.3, 25.8, 25.2,
23.1, 19.7, 14.2, 14.1; HRMS (ESI) calcd for C52H61BrN8O7Na [M
+Na]+: 1011.3739. Found: 1011.3730.
25
oil. [α]D −18.8 (c 0.23, CHCl3); 1H NMR (300 MHz): δ = 7.61–7.52
(m, 1.2H), 7.48–7.37 (m, 4.8H), 7.33–7.31 (m, 10H), 7.14–7.03 (m,
6.67H), 6.98–6.93 (m, 0.33H), 6.87 (dd, J = 15.8, 7.7 Hz, 0.67H), 6.62
(dd, J = 15.8, 7.4 Hz, 0.33H), 6.62 (s, 0.33H), 6.53 (s, 0.67H), 5.84 (d,
J = 15.6 Hz, 0.67H), 5.73 (d, J = 15.6 Hz, 0.33H), 4.78 (br t,
J = 7.2 Hz, 1H), 4.44 (dd, J = 7.2, 2.1 Hz, 0.67H), 4.32–4.30 (m,
1.67H), 4.25–4.11 (m, 2.33H), 4.19 (qd, J = 7.2, 1.4 Hz, 2H),
3.94–3.93 (m, 1H), 3.84–3.79 (m, 0.33H), 3.58–3.51 (m, 0.66H),
3.47–3.40 (m, 0.67H), 3.34–3.28 (m, 0.67H), 2.86–2.57 (m, 4H),
2.43–2.34 (m, 1H), 2.04 (s, 1H), 2.02 (s, 2H), 1.71–1.40 (m, 5H),
1.31–1.19 (m, 3H), 1.28 (t, J = 7.1 Hz, 3H), 1.16 (d, J = 6.3 Hz, 1H),
1.07 (d, J = 6.3 Hz, 2H), 0.92–0.80 (m, 1H); 13C NMR (75 MHz):
δ = 172.8, 171.8, 171.6, 171.5, 171.2, 169.3, 168.7, 166.2, 166.1,
150.2, 150.0, 142.4, 142.3, 140.1, 136.6, 138.4, 137.4, 137.0, 134.8,
131.6, 129.7, 129.5, 129.1, 129.0, 128.7, 128.6, 128.0, 124.0, 122.1,
120.1, 119.5, 75.2, 66.7, 65.8, 60.3, 60.2, 59.9, 59.7, 58.6, 58.1, 54.9,
49.9, 49.1, 46.2, 45.7, 44.5, 42.9, 42.7, 40.2, 39.1, 35.9, 34.7, 33.5,
30.3, 29.9, 29.7, 28.2, 25.8, 25.1, 23.0, 19.6, 19.2, 14.2; HRMS (ESI)
calcd for C54H62BrN7O7Na [M+Na]+: 1022.3786. Found: 1022.3783.
4.23. Compound 25a
TFA (trifluoroacetic acid)/CH2Cl2/TIS (trisisopropylsilane)/H2O
(10:10:1.0:1.0, 2.2 mL) was added to 24a (50 mg, 0.05 mmol) and the
mixture was stirred at 25 °C for 30 min. The mixture was concentrated,
and the product was isolated by ether precipitation to afford detrity-
24
lated product 25a (37.8 mg, quant.) as a white amorphous. [α]D
−45.4 (c 1.19, MeOH); 1H NMR (300 MHz): δ = 8.87 (br s, 0.8H), 8.76
(br s, 0.2H), 8.45 (m, 0.4H), 7.93 (br d, J = 7.5 Hz, 1H), 7.66 (d,
J = 8.1 Hz, 1.6H), 7.59 (br d, J = 7.8 Hz, 1H), 7.52–7.43 (m, 1H),
7.37–7.28 (m, 0.8H), 7.25–7.17 (m, 0.2H), 6.92–6.81 (m, 0.8H), 6.70
(dd, J = 15.6, 8.6 Hz, 0.2H), 6.19 (d, J = 15.3 Hz, 0.8H), 5.78 (d,
J = 15.9 Hz, 0.2H), 5.04 (m, 1H), 4.39 (m, 1.2H), 4.28–4.15 (m, 4.8H),
4.11–3.78 (m, 3H), 3.69–3.39 (m, 3.2H), 3.32–2.77 (m, 2.8H),
2.12–2.03 (m, 0.2H), 2.08 (s, 2.4H), 2.03 (s, 0.6H), 1.81–1.66 (m, 4H),
1.55–1.52 (m, 1.8H), 1.42–1.20 (m, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.24
(d, J = 6.0 Hz, 3H), 1.00–0.97 (m, 1H); 13C NMR (75 MHz): δ = 174.7,
174.1, 174.0, 173.7, 172.5, 166.5, 163.1, 140.1, 136.4, 136.0, 135.8,
135.4, 133.4, 133.0, 131.1, 130.8, 130.1, 129.7, 128.2, 125.9, 125.1,
120.2, 119.7, 119.6, 118.7, 68.6, 68.3, 62.5, 62.3, 61.4, 61.0, 59.8,
54.0, 52.5, 51.8, 51.0, 50.6, 46.1, 44.7, 43.9, 43.6, 40.6, 39.6, 36.0,
35.6, 31.5, 31.0, 29.4, 28.6, 27.3, 26.7, 26.4, 22.9, 20.4, 14.7; HRMS
(ESI) calcd for C35H49BrN7O7 [M+H]+: 758.2871. Found: 758.2875.
4.21. Compound 24b
A solution of 23 (56.2 mg, 0.1 mmol) in EtOAc (4 mL) at −78 °C was
treated with ozone gas as above. To a solution of the resulting aldehyde
in CH2Cl2 (1 mL), amine 21b (58.4 mg, 0.12 mmol) was added at 0 °C.
The mixture was stirred at 25 °C for 2 h and then NaBH3CN (22 mg,
0.35 mmol) was added. The resultant mixture was stirred for 30 min.
The reaction was quenched with 1 M HCl and was extracted with
EtOAc. The organic layer was washed with saturated aqueous NH4Cl
and brine, dried over Na2SO4, filtered, and concentrated. The residue
was purified by flash column chromatography (CHCl3/MeOH = 20:1)
10