4.3. 17b-Acetoxy-1a-azido-5a-androstan-3b-ol (4) and -3a-ol (5)
and 64.0 (C-1 and C-3), 82.4 (C-17), 122.3 (C-5¢), 125.8 (2C, C-2¢¢
and C-6¢¢), 128.3 (C-4¢¢), 128.9 (2C, C-3¢¢ and C-5¢¢), 130.2 (C-1¢¢),
146.7 (C-4¢), 170.9 (Ac-CO); ESI-MS: 478 [M+H]+; Anal. Calcd
for C29H39N3O3 C, 72.92; H, 8.23; N, 8.80. Found: C, 73.03; H,
8.39; N, 8.98%.
Compound 3 (7.0 g, 18.7 mmol) was dissolved in MeOH (100 mL),
and KBH4 (5.0 g, 89.1 mmol) was added in small portions. To
maintain pH 6–8, the solution was repeatedly acidified as needed
with MeOH/AcOH (1 : 1), using bromothymol blue as indicator.
The mixture was stirred for 3 h, and after completion of the
reaction, diluted with water and acidified with dilute HCl. The
precipitate that formed was filtered off, washed with water and
dried. The resulting epimeric azidoalcohols could be separated
by column chromatography with 1% EtOAc/CH2Cl2 as eluent,
yielding 4 (4.53 g, 68%) and 5 (2.14 g, 27%). (4): mp 145–147 ◦C,
Rf 0.55 (ss C); 1H NMR (500 MHz, CDCl3): dH = 0.80 (s, 3H, 18-
H3), 0.83 (s, 3H, 19-H3), 0.88-0.96 (m, 1H), 1.09–1.50 (m, 11H),
1.61–1.75 (m, 4H), 1.88–1.93 (m, 1H), 2.02 (s, 3H, Ac-CH3), 2.08
(m, 1H), 2.12–2.19 (m, 1H), 2.90 (d, 1H, J = 9.4 Hz), 3.67 (bs, 1H,
1-H), 3.94 (m, 1H, 3-H), 4.60 (t, 1H, J = 8.4 Hz, 17-H); 13C NMR
(125 MHz, CDCl3): dC = 12.2 (C-18), 12.5 (C-19), 19.9 (CH2), 21.1
(Ac-CH3), 23.4 (CH2), 27.5 (CH2), 28.1 (CH2), 31.0 (CH2), 32.1
(CH2), 32.5 (CH), 35.3 (CH), 35.8 (CH2), 36.5 (CH2), 40.1 (C-10),
42.6 (C-13), 48.1 (CH), 50.7 (CH), 65.0 and 66.5 (C-1 and C-3),
82.6 (C-17), 171.1 (Ac-CO); Anal. Calcd for C21H33N3O3 C, 67.17;
H, 8.86; ◦N, 11.19. Found: C, 67.05; H, 9.05; N, 11.36%. (5): mp
141–143 C, Rf 0.35 (ss C); 1H NMR (500 MHz, CDCl3): dH = 0.77
(s, 3H, 18-H3), 0.85 (s, 3H, 19-H3), 0.87–0.92 (m, 1H), 1.06–1.39
(m, 8H), 1.42–1.50 (m, 3H), 1.58–1.64 (m, 3H), 1.67–1.74 (m, 3H),
2.02 (s, 3H, Ac-CH3), 2.10–2.19 (m, 2H), 3.70 (bs, 1H, 1-H), 3.91
(m, 1H, 3-H), 4.58 (t, 1H, J = 8.4 Hz, 17-H); 13C NMR (125 MHz,
CDCl3): dC = 12.1 (C-18), 13.2 (C-19), 20.1 (CH2), 21.1 (Ac-CH3),
23.5 (CH2), 27.5 (CH2), 28.3 (CH2), 31.0 (CH2), 34.6 (CH2), 35.2
(CH), 36.5 (CH2), 37.7 (CH2), 37.8 (CH), 39.2 (C-10), 42.6 (C-13),
47.7 (CH), 50.5 (CH), 65.6 and 66.2 (C-1 and C-3), 82.7 (C-17),
171.1 (Ac-CO); Anal. Calcd for C21H33N3O3 C, 67.17; H, 8.86; N,
11.19. Found: C, 67.03; H, 9.02; N, 11.40%.
4.5. 3a,17b-Diacetoxy-1a-azido-5a-androstane (9)
Compound 5 (1.0 g, 2.7 mmol) was dissolved in a mixture of
pyridine (30 mL) and Ac2O (15 mL), and the solution was stirred at
room temperature for 4 h. It was then poured onto a mixture of ice
and H2SO4 (25 mL), diluted with water and extracted with CH2Cl2
(3 ¥ 50 mL). The combined organic layers were washed with water,
dried over Na2SO4 and evaporated in vacuo. The resulting crude
product was purified by flash chromatography with CH2Cl2 as
eluent to give 9 (978 mg, 88%), mp 88–91 ◦C, Rf 0.23 (ss A);
1H NMR (500 MHz, CDCl3): dH = 0.77 (s, 3H, 18-H3), 0.87 (s,
3H, 19-H3), 0.88–0.93 (m, 1H), 1.06–1.12 (m, 1H), 1.17–1.69 (m,
14H), 1.73 (m, 1H), 1.78–1.83 (m, 1H), 2.01 (s, 3H, Ac-CH3), 2.02
(s, 3H, Ac-CH3), 2.11–2.20 (m, 2H), 3.72 (bs, 1H, 1-H), 4.59 (t,
1H, J = 8.4 Hz, 17-H), 4.96 (m, 1H, 3-H); 13C NMR (125 MHz,
CDCl3): dC = 12.1 (C-18), 13.2 (C-19), 20.1 (CH2), 21.1 (Ac-CH3),
21.3 (Ac-CH3), 23.5 (CH2), 27.5 (CH2), 28.2 (CH2), 30.9 (CH2),
31.2 (CH2), 33.5 (CH2), 35.2 (CH), 36.5 (CH2), 37.5 (CH), 39.3
(C-10), 42.6 (C-13), 47.6 (CH), 50.5 (CH), 65.4 and 69.1 (C-1 and
C-3), 82.7 (C-17), 170.3 (Ac-CO), 171.1 (Ac-CO); Anal. Calcd for
C23H35N3O4 C, 66.16; H, 8.45; N, 10.06. Found: C, 66.37; H, 8.29;
N, 10.19%.
4.6. General procedure for the preparation of triazoles 8a, 8h,
10a and 10h
To
a solution of 17b-acetoxy-1a-azido-5a-androstan-3a-ol
(5) (300 mg, 0.79 mmol) or 3a,17b-diacetoxy-1a-azido-5a-
androstane (9) (300 mg, 0.72 mmol) in toluene (10 mL) were added
Ph3P (41 mg, 0.16 mmol), CuI (15 mg, 0.08 mmol) and DIPEA
(0.40 mL, 2.4 mmol). Finally, the appropriate terminal alkyne (6a
or 6h, 1.1 eq) was added to the reaction mixture, which was then
refluxed for 5 h, allowed to cool and evaporated in vacuo. The
resulting crude product was purified by column chromatography.
4.4. General procedure for the preparation of triazoles 7a–g
To a solution of 17b-acetoxy-1a-azido-5a-androstan-3b-ol (4)
(300 mg, 0.79 mmol) in toluene (10 mL) were added Ph3P (41
mg, 0.16 mmol), CuI (15 mg, 0.08 mmol) and DIPEA (0.40 mL,
2.4 mmol). Finally the appropriate terminal alkyne (6a–g, 1.1 eq)
was added to the reaction mixture, which was then refluxed for 3
h, allowed to cool and evaporated in vacuo. The resulting crude
product was purified by column chromatography.
17b-Acetoxy-1a-[4¢-phenyl-1¢H-1¢,2¢,3¢-triazol-1¢-yl]-5a-andro-
stan-3a-ol (8a). Substrate: 5, alkyne: phenylacetylene (6a, 0.09
mL). After purification with CH2Cl2/EtOAc (80 : 20) as eluent, 8a
was obtained as a white solid (233 mg, 61%), mp 182–184 ◦C, Rf
0.29 (ss E); 1H NMR (500 MHz, CDCl3): dH = 0.37 (m, 1H), 0.75
(s, 3H, 18-H3), 0.80–0.91 (m, 3H), 1.11 (s, 3H, 19-H3), 1.18–1.33
(m, 2H), 1.34–1.47 (m, 5H), 1.49–1.62 (m, 4H), 1.94 (m, 1H), 1.97
(s, 3H, Ac-CH3), 1.99–2.01 (m, 3H), 2.47 (m, 1H), 4.42 (t, 1H, J =
8.3 Hz, 17-H), 4.60-4.65 (m, 2H, 1-H and 3-H), 7.32 (t, 1H, J =
7.3 Hz, 4¢¢-H), 7.41 (t, 2H, J = 7.3 Hz, 3¢¢-H and 5¢¢-H), 7.71 (s,
1H, 5¢-H), 7.78 (d, 2H, J = 7.3 Hz, 2¢¢-H and 6¢¢-H); 13C NMR
(125 MHz, CDCl3): dC = 12.3 (C-18), 13.9 (C-19), 21.1 (Ac-CH3),
21.3 (CH2), 23.3 (CH2), 27.4 (CH2), 28.8 (CH2), 30.6 (CH2), 35.7
(CH), 36.4 (2C, 2 ¥ CH2), 37.8 (CH2), 38.0 (CH), 40.1 (C-10),
42.6 (C-13), 47.4 (CH), 50.3 (CH), 65.5 and 65.7 (C-1 and C-3),
82.4 (C-17), 121.4 (C-5¢), 125.5 (2C, C-2¢¢ and C-6¢¢), 128.2 (C-4¢¢),
128.9 (2C, C-3¢¢ and C-5¢¢), 130.2 (C-1¢¢), 146.0 (C-4¢), 171.0 (Ac-
CO); ESI-MS: 478 [M+H]+; Anal. Calcd for C29H39N3O3 C, 72.92;
H, 8.23; N, 8.80. Found: C, 73.06; H, 8.10; N, 8.93%.
17b-Acetoxy-1a-[4¢-phenyl-1¢H-1¢,2¢,3¢-triazol-1¢-yl]-5a-andro-
stan-3b-ol (7a). Alkyne: phenylacetylene (6a, 0.09 mL). After
purification with CH2Cl2/EtOAc (90 : 10) as eluent, 7a was
obtained as a white solid (355 mg, 93%), mp 266–268 ◦C, Rf 0.32
1
(ss D); H NMR (500 MHz, CDCl3): dH = 0.22 (m, 1H), 0.76 (s,
3H, 18-H3), 0.82–0.89 (m, 3H), 1.06 (s, 3H, 19-H3), 1.19–1.29 (m,
2H), 1.34–1.44 (m, 4H), 1.49–1.80 (m, 6H), 1.98 (s, 3H, Ac-CH3),
2.05 (m, 2H), 2.34–2.42 (m, 2H), 4.01 (bs, 1H, 3-H), 4.43 (t, 1H,
J = 8.4 Hz, 17-H), 4.58 (d, 1H, J = 5.2 Hz, 1-H), 5.19 (bs, 1H,
3-OH), 7.34 (t, 1H, J = 7.3 Hz, 4¢¢-H), 7.43 (t, 2H, J = 7.3 Hz,
3¢¢-H and 5¢¢-H), 7.80 (d, 2H, J = 7.3 Hz, 2¢¢-H and 6¢¢-H), 7.91 (s,
1H, 5¢-H); 13C NMR (125 MHz, CDCl3): dC = 12.4 (C-18), 13.4
(C-19), 21.1 (Ac-CH3), 21.3 (CH2), 23.3 (CH2), 27.4 (CH2), 28.7
(CH2), 30.4 (CH2), 32.9 (CH), 33.2 (CH2), 35.8 (CH), 36.3 (2C,
2 ¥ CH2), 40.4 (C-10), 42.6 (C-13), 47.5 (CH), 50.5 (CH), 63.8
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 8051–8057 | 8055
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