Journal of Medicinal Chemistry
Article
33.1, 31.5, 17.6, 17.5, 17.4, 17.3, 17.3, 17.2, 17.2, 17.2, 17.1, 17.1, 14.1,
13.9, 13.0, 12.4. HRMS: [M + Na]+ calcd for C35H59NO10Si2Na
732.35752; found 732.3587.
7-[2-Deoxy-α-L-fucopyranosyl-(1 → 4)-3-amino-2,3-dideoxy-α-L-
fucopyranoside]-doxorubicinone (5). To a solution of 23 (30.5 mg,
29.6 μmol) in pyridine (3.0 mL) in a PTFE tube was added HF·pyr
complex (70 wt % HF, 232 μL) at 0 °C. Over the course of 4 h, two
additional such portions of HF·pyr complex were added. Then, solid
NaHCO3 was added to quench, and the mixture was stirred until
cessation of effervescence. It was then filtered off and concentrated in
vacuo. Column chromatography on neutral silica (0:100−20:80
MeOH/DCM) gave the title compound as a red solid (15.1 mg, 22.4
μmol, 76%). 1H NMR (500 MHz, pyridine-d5) δ 7.78 (d, J = 7.7 Hz,
1H), 7.46 (t, J = 8.1 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 5.52 (d, J = 3.0
Hz, 1H), 5.17 (d, J = 3.9 Hz, 1H), 5.12 (d, J = 2.3 Hz, 2H), 5.06 (d, J =
3.8 Hz, 1H), 4.36 (dt, J = 12.1, 3.9 Hz, 1H), 4.33−4.19 (m, 2H), 3.80
(d, J = 2.9 Hz, 1H), 3.68 (s, 3H), 3.54 (s, 1H), 3.41 (t, J = 8.7 Hz, 1H),
3.34−3.12 (m, 2H), 2.51 (d, J = 14.4 Hz, 1H), 2.30 (td, J = 12.2, 3.9 Hz,
1H), 2.22 (dd, J = 14.3, 5.1 Hz, 1H), 2.08 (dd, J = 12.3, 4.9 Hz, 1H),
1.97 (dd, J = 9.2, 2.8 Hz, 2H), 1.27 (d, J = 6.4 Hz, 3H), 1.06 (d, J = 6.4
Hz, 3H). 13C NMR (126 MHz, Pyr) δ 215.4, 187.5, 161.9, 157.5, 156.2,
135.2, 121.6, 120.1, 119.9, 112.3, 112.0, 101.9, 101.9, 81.6, 77.1, 72.4,
70.9, 69.0, 68.8, 66.7, 66.2, 57.1, 48.0, 37.9, 34.6, 34.4, 34.2, 18.1.
HRMS: [M + H]+ calcd for C33H40NO14 674.24488; found 674.2456.
7-[2-Deoxy-α-L-fucopyranosyl-(1 → 4)-3-dimethylamino-2,3-di-
deoxy-α-L-fucopyranoside]-doxorubicinone (7). To a solution of 23
(102 mg, 99 μmol) in EtOH (20 mL) and 37% aq CH2O (245 μL, 30
equiv) was added NaBH(OAc)3 (40 mg, 0.193 mmol, 1.95 equiv). The
mixture was stirred for 1.5 h before being poured into sat. aq NaHCO3.
This was extracted with DCM, dried over Na2SO4, and concentrated in
vacuo. Column chromatography chromatography (3:97 acetone/
toluene) gave the dimethylated amine as a red solid (75 mg, 70.9
μmol, 71%). 1H NMR (500 MHz, chloroform-d) δ 13.92 (s, 1H), 13.24
(s, 1H), 8.01 (dd, J = 7.7, 1.0 Hz, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.43−
7.37 (m, 1H), 5.54 (d, J = 3.8 Hz, 1H), 5.25 (dd, J = 4.1, 2.1 Hz, 1H),
5.01 (d, J = 3.4 Hz, 1H), 4.98−4.84 (m, 2H), 4.79 (s, 1H), 4.49−4.34
(m, 2H), 4.09 (s, 3H), 3.95 (t, J = 1.8 Hz, 1H), 3.91 (q, J = 6.5 Hz, 1H),
3.75 (s, 1H), 3.38−3.35 (m, 1H), 3.18 (dd, J = 18.9, 1.9 Hz, 1H), 2.98
(d, J = 18.8 Hz, 1H), 2.32 (dt, J = 14.7, 2.3 Hz, 1H), 2.19 (s, 6H), 2.17−
2.06 (m, 3H), 2.06−1.96 (m, 2H), 1.89 (td, J = 12.8, 4.0 Hz, 1H), 1.80
(dd, J = 13.0, 4.1 Hz, 1H), 1.26 (d, J = 6.6 Hz, 3H), 1.19 (d, J = 6.4 Hz,
3H), 1.07 (ddt, J = 9.4, 7.4, 4.6 Hz, 24H), 0.96 (s, 9H), 0.14 (d, J = 2.9
Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 211.4, 187.2, 186.8, 161.1,
156.6, 156.0, 135.8, 135.6, 134.3, 134.2, 121.0, 119.9, 118.5, 111.5,
111.4, 101.5, 99.9, 74.1, 73.8, 70.6, 69.6, 68.8, 67.3, 66.7, 61.8, 56.8,
43.5, 35.7, 34.1, 33.4, 26.0, 18.1, 17.8, 17.8, 17.7, 17.6, 17.6, 17.5, 17.5,
17.4, 17.4, 14.4, 14.3, 13.2, 12.7. HRMS: [M + H]+ calcd for
C53H84NO15Si3 1058.51488; found 1058.51488. To a solution of the
above compound (38 mg, 35.9 μmol) in pyridine (3.6 mL) in a PTFE
tube was added HF·pyr complex (70 wt % HF, 282 μL) at 0 °C. Over
the course of 4.5 h, three additional such portions of HF·pyr complex
were added. Then, solid NaHCO3 was added to quench, and the
mixture was stirred until cessation of effervescence. It was then filtered
off and concentrated in vacuo. Column chromatography on neutral
silica (DCM; 10:90 MeOH/DCM) gave the title compound as a red
solid (20.3 mg, 28.9 μmol, 81%). 1H NMR (500 MHz, chloroform-d +
MeOD) δ 8.02 (d, J = 7.6 Hz, 1H), 7.81 (t, J = 8.0 Hz, 1H), 7.42 (t, J =
7.3 Hz, 1H), 5.55 (d, J = 4.0 Hz, 1H), 5.28 (s, 1H), 5.05 (d, J = 3.9 Hz,
1H), 4.76 (d, J = 5.6 Hz, 2H), 4.41 (q, J = 6.6 Hz, 1H), 4.14−4.03 (m,
4H), 3.97 (q, J = 6.6 Hz, 1H), 3.83 (d, J = 6.5 Hz, 1H), 3.24 (dd, J =
18.9, 5.9 Hz, 1H), 3.02 (dd, J = 19.2, 6.3 Hz, 1H), 2.39−2.08 (m, 8H),
2.07−1.80 (m, 4H), 1.29 (d, J = 6.7 Hz, 3H), 1.21 (d, J = 6.6 Hz, 3H).
13C NMR (126 MHz, CDCl3 + MeOD) δ 213.6, 187.2, 186.8, 161.1,
o-Cyclopropylethynylbenzoyl-2-deoxy-3,4-tetraisopropyldisilox-
ane-α-L-fucopyranosyl-(1 → 4)-3-N-allyloxycarbonyl-2,3-dideoxy-L-
fucopyranoside (21). Prepared according to General Procedure A and
B from 19 (1.69 g, 2.38 mmol) to give after column chromatography
(10:90−20:80 EtOAc/pentane) the title compound as a white foam
(1.54 g, 1.99 mmol, 84% over two steps, α/β 1:8). 1H NMR (500 MHz,
chloroform-d) δ 8.00−7.85 (m, 1H), 7.47 (dd, J = 7.8, 1.4 Hz, 1H), 7.41
(ddd, J = 9.1, 6.0, 1.4 Hz, 1H), 7.35−7.24 (m, 1H), 6.35 (d, J = 7.6 Hz,
1H), 5.99 (dd, J = 10.0, 2.3 Hz, 1H), 5.96−5.84 (m, 1H), 5.36−5.15
(m, 2H), 4.93 (d, J = 3.9 Hz, 1H), 4.56 (qdt, J = 13.3, 5.6, 1.5 Hz, 2H),
4.45 (ddd, J = 12.1, 4.5, 2.5 Hz, 1H), 4.11−4.06 (m, 1H), 4.01 (d, J =
2.5 Hz, 1H), 3.87 (dddd, J = 12.1, 7.1, 4.1, 2.6 Hz, 1H), 3.85−3.79 (m,
1H), 3.48−3.44 (m, 1H), 2.22 (ddd, J = 11.9, 4.1, 2.2 Hz, 1H), 2.14 (td,
J = 12.4, 4.0 Hz, 1H), 1.99 (dd, J = 12.4, 4.6 Hz, 1H), 1.85 (td, J = 12.3,
10.0 Hz, 1H), 1.51 (tt, J = 7.2, 5.7 Hz, 1H), 1.36−1.30 (m, 6H), 1.13−
0.81 (m, 28H). 13C NMR (126 MHz, CDCl3) δ 164.3, 155.8, 134.2,
133.0, 132.0, 131.1, 130.8, 127.0, 125.1, 117.7, 102.3, 99.8, 93.2, 80.6,
74.5, 73.3, 73.0, 69.9, 68.4, 65.7, 50.1, 33.3, 32.2, 17.8, 17.8, 17.6, 17.5,
17.5, 17.5, 17.4, 17.3, 14.3, 14.2, 13.2, 12.7, 9.0, 8.9, 0.8. HRMS: [M +
Na]+ calcd for C40H61NO10Si2Na 794.37317; found 794.3749.
7-[2-Deoxy-3,4-tetraisopropyldisiloxyl-α-L-fucopyranosyl-(1 →
4)-3-N-allyloxycarbonyl-2,3-dideoxy-α-L-fucopyranoside]-14-O-
tert-butyldimethylsilyl-doxorubicinone (22). Prepared according to
General Procedure C from donor 21 (722 mg, 1.00 mmol) and 14-O-
tert-butyldimethylsilyl-doxorubicinone 16 (793 mg, 1.50 mmol, 1.5
equiv) to give after column chromatography (5:95−20:80 EtOAc/
pentane−4:96 acetone/toluene) the title compound as a red solid (714
mg, 0.640 mmol, 64%). 1H NMR (500 MHz, chloroform-d) δ 13.83 (s,
1H), 13.09 (s, 1H), 7.93 (dd, J = 7.7, 1.0 Hz, 1H), 7.72 (t, J = 8.1 Hz,
1H), 7.43−7.32 (m, 1H), 6.07 (d, J = 7.8 Hz, 1H), 5.91−5.78 (m, 1H),
5.50 (d, J = 3.8 Hz, 1H), 5.27−5.18 (m, 2H), 5.13 (dq, J = 10.5, 1.4 Hz,
1H), 4.98−4.86 (m, 3H), 4.61−4.37 (m, 4H), 4.13 (q, J = 6.5 Hz, 1H),
4.05 (d, J = 24.2 Hz, 6H), 3.90−3.77 (m, 1H), 3.55 (s, 1H), 3.09 (dd, J
= 18.8, 2.0 Hz, 1H), 2.81 (d, J = 18.7 Hz, 1H), 2.29 (d, J = 14.6 Hz, 1H),
2.22−2.05 (m, 2H), 2.05−1.95 (m, 1H), 1.92 (dd, J = 13.1, 4.5 Hz,
1H), 1.78 (td, J = 12.9, 4.0 Hz, 1H), 1.30 (dd, J = 16.4, 6.4 Hz, 6H),
1.16−0.82 (m, 37H), 0.15 (d, J = 2.7 Hz, 6H). 13C NMR (126 MHz,
CDCl3) δ 211.4, 186.8, 186.4, 161.0, 156.3, 155.7, 135.7, 135.3, 134.0,
133.9, 132.9, 120.7, 119.8, 118.5, 117.5, 111.3, 111.2, 101.9, 101.0, 81.0,
73.2, 69.9, 69.7, 68.2, 68.0, 66.7, 65.5, 56.7, 46.6, 35.7, 34.0, 33.3, 31.3,
26.0, 18.7, 17.8, 17.7, 17.6, 17.5, 17.5, 17.5, 17.4, 17.3, 17.2, 14.3, 14.1,
13.1, 12.6, −5.2, −5.3. HRMS: [M + Na]+ calcd for C55H83NO17Si3Na
1136.48665; found 1136.4866.
7-[2-Deoxy-3,4-tetraisopropyldisiloxyl-α-L-fucopyranosyl-(1 →
4)-3-amino-2,3-dideoxy-α-L-fucopyranoside]-14-O-tert-butyldime-
thylsilyl-doxorubicinone (23). A solution of 22 (704 mg, 0.631 mmol)
and N,N-dimethylbarbituric acid (440 mg, 2.84 mmol, 4.5 equiv) in
DCM (63 mL) was degassed for 5 min. Then, Pd(PPh3)4 (36.5 mg,
0.032 mmol, 0.05 equiv) was added and the mixture was allowed to stir
for 20 min. It was then directly subjected to column chromatography
(pentane, then 0:100−50:50 acetone/toluene) to give the title
1
compound as a red solid (650 mg, 0.631 mmol, 100%). H NMR
(500 MHz, chloroform-d) δ 7.93 (dd, J = 7.8, 1.0 Hz, 1H), 7.73 (t, J =
8.1 Hz, 1H), 7.42−7.33 (m, 1H), 5.53−5.41 (m, 1H), 5.21 (dd, J = 4.1,
2.2 Hz, 1H), 4.98 (d, J = 3.7 Hz, 1H), 4.96−4.81 (m, 2H), 4.65 (s, 1H),
4.42 (ddd, J = 12.1, 4.6, 2.5 Hz, 1H), 4.15 (q, J = 6.5 Hz, 1H), 4.10−3.93
(m, 5H), 3.53 (s, 1H), 3.40−3.20 (m, 3H), 3.18−3.00 (m, 2H), 2.82 (d,
J = 18.7 Hz, 1H), 2.29 (dt, J = 14.8, 2.2 Hz, 1H), 2.21−2.09 (m, 2H),
2.05−1.93 (m, 1H), 1.76 (ddd, J = 27.6, 14.0, 4.2 Hz, 1H), 1.29 (d, J =
6.5 Hz, 3H), 1.23 (d, J = 6.5 Hz, 3H), 1.13−0.75 (m, 36H), 0.15 (d, J =
1.4 Hz, 6H). 13C NMR (126 MHz, CDCl3) δ 211.2, 186.7, 186.4, 161.0,
156.3, 155.6, 135.7, 135.3, 134.0, 132.1, 132.1, 128.6, 120.7, 119.7,
118.5, 111.3, 101.3, 101.1, 81.5, 73.3, 70.1, 69.6, 68.3, 67.8, 66.6, 56.7,
46.8, 35.6, 33.8, 33.4, 25.9, 18.7, 17.7, 17.7, 17.6, 17.6, 17.5, 17.5, 17.4,
17.3, 17.2, 14.2, 14.1, 13.1, 12.6. HRMS: [M + H]+ calcd for
C51H80NO15Si3 1030.48358; found 1030.4855.
155.9, 155.3, 135.9, 135.4, 133.8, 133.5, 120.8, 119.8, 118.6, 111.6,
111.4, 100.9, 99.2, 73.6, 71.0, 69.2, 68.6, 66.6, 65.4, 65.2, 61.7, 56.6,
43.0, 35.5, 33.8, 32.3, 28.7, 17.9, 16.6. HRMS: [M + H]+ calcd for
C35H44NO14 702.27619; found 702.2769.
7-[2-Deoxy-3,4-tetraisopropyldisiloxyl-α-L-fucopyranosyl-(1 →
4)-3-amino-2,3-dideoxy-α-L-fucopyranoside]-aklavinone (24). Pre-
pared according to General Procedure C from donor 21 (623 mg, 0.806
mmol) and aklavinone 14 (665 mg, 1.61 mmol, 2.00 equiv) at −20 °C
to give after column chromatography (10:90 EtOAc/pentane and then
2:98−10:90 acetone/toluene) of the residue an inseparable mixture of
J
J. Med. Chem. XXXX, XXX, XXX−XXX