P. Seneci et al. / Bioorg. Med. Chem. 17 (2009) 5834–5856
5849
pressure, and the crude product was purified by flash
chromatography.
1H), 4.73 (d, J = 7.6, 1H), 4.67 (t, J = 8.4, 1H), 4.06 (m, 1H), 4.01
(m, 2H), 3.87 (dd, J = 17.6, 8.8 Hz, 1H), 2.44 (m, 1H), 2.26 (m, 1H),
2.06 (s, 3H), 1.88 (m, 4H), 1.80–1.60 (m, 3H), 1.55 (m, 1H), 1.47
(s, 9H), 1.22–1.10 (m, 1H), 0.97 (t, 7.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d: 172.1, 171.7, 170.6, 169.5, 142.1, 141.2,
128.7, 128.6, 127.4, 127.3, 127.2, 65.4, 61.0, 58.7, 56.7, 56.3, 52.9,
39.1, 34.3, 33.4, 31.5, 28.3, 25.6, 20.9, 10.8. ESI-MS: m/z 635.0
[M+H]+, 657.0 [M+Na]+.
4.1.4.1. Compound 8a. Compound 8a was synthesized by gen-
eral procedure C, starting from alcohol 7a (1.18 g, 2.0 mmol). Elu-
ant mixture: petroleum ether/EtOAc 30:70. Yield 51% (635 mg,
MW 617.74, 1.02 mmol) of pure 8a as an amorphous white solid.
Analytical characterization:
½
a 2D0
¼ À109:9 (c 0.62, MeOH); 1H
NMR (400 MHz, CDCl3): d: 7.82 (d, J = 8.8 Hz, 1H), 7.30–7.13 (m,
10H), 7.21 (d, J = 6.4 Hz, 2H), 7.11 (d, J = 6.8 Hz, 1H), 6.14 (d,
J = 8.8 Hz, 1H), 4.92 (br d, J = 7.2 Hz, 1H), 4.64 (d, J = 7.6 Hz, 1H),
4.50 (dd, J = 10.0 Hz, 8.0, 1H), 3.96 (dd, J = 13.6, 7.2 Hz, 1H), 3.76
(dd, J = 17.6, 9.2 Hz, 1H), 3.45 (dd, J = 12.4, 3.6 Hz, 1H), 3.06 (dd,
J = 12.4, 9.2 Hz, 1H), 2.36 (dd, J = 12.4, 6.8 Hz, 1H), 2.18 (m, 1H),
1.95 (m, 1H), 1.82–1.44 (m, 6H), 1.39 (s, 9H), 1.30–1.1 (m, 2H),
0.89 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d: 172.4,
171.3, 169.4, 155.8, 142.0, 141.1, 128.7, 128.6, 127.3, 127.2, 80.3,
61.0, 58.9, 56.8, 56.4, 53.6, 53.5, 40.0, 34.2, 33.3, 32.0, 28.3, 25.5,
21.0, 10.2. ESI-MS: m/z 618.1 [M+H]+, 640.1 [M+Na]+.
Full analytical characterization of compound 11b is reported in
the Supplementary data.
4.1.6.2. Synthesis of 13a. A 0.9 M water solution of sodium
ascorbate (45
Cu(OAc)2 (65
solutions of compound 8a (62 mg, 0.10 mmol) and of 1-pentynyl-
3-ol (8.6 L).
L, 0.10 mmol) in a 1:1 mixture of H2O/tBuOH (300
lL, 0.4 mmol) and
a 0.3 M water solution of
lL, 0.02 mmol) were sequentially added to stirred
l
l
The reaction mixture was stirred overnight at room temperature
and then the solvent was removed under reduced pressure. The
crude product was purified by BiotageTM. BiotageTM eluant condi-
tions: 1% of MeOH and 99% of CH2Cl2 to 10% of MeOH and 90% of
CH2Cl2. Yield 58% (41 mg, MW 701.85, 0.058 mmol) of pure 13a
as an amorphous white solid. Analytical characterization:
Full analytical characterization of compound 8b is reported in
the Supplementary data.
4.1.5. General procedure D—synthesis of compounds 9
A 1 N solution of (CH3)3P in toluene (1.5 equiv) was added to a
stirred solution of azide 8 (1.0 equiv) in dry CH2Cl2 (0.67 M concen-
tration for 8) under argon atmosphere at room temperature. After
2 h, an excess of 1 N aqueous HCl was added to the reaction mix-
ture, which was stirred at room temperature for further 10–
20 min. After reaction completion, the reaction mixture was ex-
tracted with CH2Cl2 (3 times), the organic layers were combined
and dried over Na2SO4, and the solvent was removed under re-
duced pressure. The crude product was used without further
purification.
½
a 2D0
¼ À50:0 (c 0.88, CHCl3); 1H NMR (400 MHz, CDCl3): 7.75
(dd, J = 8.4, 2.8 Hz, 1H), 7.35–7.00 (m, 11H), 6.11 (d, J = 8.4 Hz,
1H), 4.99 (d, J = 6.4 Hz, 1H), 4.76 (br s, 1H), 4.63 (m, 2H), 4.43 (m,
1H), 4.08 (m, 1H), 3.92 (m, 1H), 2.71 (m, 1H), 2.32 (m, 1H), 2.12
(m ,1H), 2.05 (m, 1H), 1.95–1.45 (m, 10H), 1.32 (s, 9H), 1.18 (s,
3H), 1.15–1.05 (m, 1H), 1.00–0.85 (m, 6H); 13C NMR (100 MHz,
CDCl3): 172.9, 170.7, 169.3, 141.8, 141.3, 128.7, 127.5, 127.3,
127.1, 80.3, 68.4, 61.2, 58.8, 56.8, 56.3, 54.0, 52.2, 40.3, 33.8,
33.3, 31.7, 30.3, 29.7, 28.3, 25.7, 10.2, 9.8. ESI-MS: m/z 702.5
[M+H]+, 724.5 [M+Na]+.
4.1.6.3. Synthesis of 15a. N,N’-Bis-Boc-1-guanylpyrazole (47 mg,
0.15 mmol) in a mixture of THF (1 mL) and water (0.2 mL), a 1 M
aqueous LiOH solution (0.2 mL, 0.2 mmol) and triphenylphosphine
(79 mg, 0.30 mmol) were sequentially added to a stirred solution
of compound 8a (62 mg, 0.10 mmol). The reaction mixture was
stirred at room temperature for 48 h and then THF was removed
under reduced pressure. The residue was partitioned between
aqueous 10% citric acid and EtOAc. The aqueous layer was ex-
tracted with EtOAc (3 times) and then the organic layers were
combined, washed once with brine and dried over Na2SO4. Finally,
the crude product was purified by chromatography on a C18 re-
verse phase semi-preparative HPLC column. HPLC eluant condi-
tions: from 45% of H2O (0.1% TFA) and 55% of CH3CN to 30% of
H2O (0.1% TFA) and 70% of CH3CN, flow rate 20 mL/min, 10 min
runs. Yield 31% (26 mg, MW 834.01, 0.031 mmol) of pure trifluoro-
acetate salt of 15a as an amorphous white solid. Analytical charac-
4.1.5.1. Compound 9a. Compound 9a was synthesized by gen-
eral procedure D, starting from azide 8a (617 mg, 1.0 mmol). Yield
92% (578 mg, MW 628.20, 0.92 mmol) of pure hydrochloride salt of
9a as an amorphous white solid. Analytical characterization:
½
a 2D0
¼ À68:5 (c 1.31, MeOH); 1H NMR (400 MHz, CDCl3): d: 8.39
(br s, 3H), 8.04 (br s, J = 7.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.40–
7.20 (m, 10H), 6.18 (d, J = 8.4 Hz, 1H), 5.12 (d, J = 6.4 Hz, 1H),
4.71 (d, J = 7.2 Hz, 1H), 4.49 (t, J = 8.0 Hz, 1H), 4.05 (q, J = 7.2 Hz,
1H); 3.74 (q, J = 8.4 Hz, 1H); 2.90 (br s, 2H); 2.40 (m, 1H), 2.21
(m, 1H), 2.05–1.55 (m, 7H), 1.47 (s, 9H), 1.33 (m, 1H), 1.22 (m,
1H), 0.99 (t, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3): d: 175.9,
170.1, 169.4, 142.2, 141.1, 128.7, 127.5, 127.4, 127.3, 80.3, 61.3,
58.7, 57.1, 53.8, 42.8, 38.1, 34.0, 33.3, 32.0, 29.0, 28.3, 25.8, 25.0,
10.4. ESI-MS: m/z 592.1 [M+H]+, 614.1 [M+Na]+.
Full analytical characterization of compound 9b is reported in
the Supplementary data.
terization:
½
a 2D0
¼ À84:2 (c 0.65, MeOH); 1H NMR (400 MHz,
CDCl3): d: 7.60 (m, 2H), 7.50 (m, 1H), 7.30–7.08 (m, 11H), 6.12
(d, J = 8.4 Hz, 1H), 4.94 (m, 1H), 4.64 (d, J = 7.2 Hz, 1H), 4.54 (m,
1H), 3.77 (m, 2H), 3.54 (m, 1H), 2.87 (m, 1H), 2.34 (m, 1H), 2.30–
1.51 (m, 9H), 1.47 (s, 9H), 1.34 (s, 9H), 1.20 (s, 9H), 1.10 (m, 1H),
0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): d: 172.4,
171.3, 169.4, 158.1, 156.0, 154.0, 149.0, 142.0, 141.1, 128.7,
128.6, 127.3, 127.2, 126.9, 80.3, 79.5, 79.2, 61.0, 58.9, 56.8, 56.4,
53.6, 53.5, 40.0, 34.2, 33.3, 32.0, 31.2, 28.3, 27.9, 25.5, 21.0, 10.2.
ESI-MS: m/z 834.2 [M+H]+.
4.1.6. General procedure E—synthesis of compounds 11
Pyridine (81 lL, 1.0 mmol), a carboxylic acid chloride RCOCl
(0.10 mmol) and DMAP (12 mg, 0.02 mmol) were sequentially
added to a stirred solution of 7a (59 mg, 0.10 mmol) in dry CH2Cl2
(2 mL). The reaction mixture was stirred at room temperature
overnight, the solvent was removed under reduced pressure and
the crude product was purified by BiotageTM.
4.1.6.1. Compound 11a. Compound 11a was synthesized by gen-
eral procedure E. BiotageTM eluant conditions: from 1% of MeOH and
99% of CH2Cl2 to 10% of MeOH and 90% of CH2Cl2. Yield 92% (58 mg,
MW 634.74, 0.092 mmol) of pure 11a as an amorphous white solid.
4.1.7. General procedure F—synthesis of compounds 17
NaBH(OAc)3 (26 mg, 0.13 mmol) was added to a stirred solution
of compound 9a (0.10 mmol) and of
a carbonyl compound
Analytical characterization: ½a D20
¼ À105:0 (c 1.28, MeOH); 1H NMR
(0.11 mmol) in dry CH2Cl2 (2 mL) under nitrogen atmosphere.
The reaction mixture was stirred overnight at room temperature,
and then the solvent was removed under reduced pressure. The
(400 MHz, CDCl3): d: 7.93 (d, J = 8.8 Hz, 1H), 7.38–7.19 (m, 10H),
7.10 (d, J = 8.4, 1H), 6.23 (d, J = 8.8 Hz, 1H), 5.01 (d, J = 6.8 Hz,