A. Pietraszek et al. / Steroids 78 (2013) 1003–1014
1005
67.40, 67.70, 67.75, 113.56, 113.72, 128.31, 128.35, 128.55, 128.57,
130.90, 131.04, 131.08, 131.22, 131.65, 131.68, 138.86, 139.10. MS
(relative intensity) m/z: 593 ([M + Na]+/100), 594/39, 571
([M + H]+/25), 1163([2 M + Na]+/23), 307/20, 1164/18, 595/10,
595/10, 572/7 1142 ([2 M + H]+/7), 1165/8, 1167/5, 308/5; HRMS
115.38, 123.18, 131.73, 132.85, 135.07, 135.17, 136.59, 142.35;
MS (relative intensity) m/z: 451 ([M + Na]+/100), 411/36, 519/34,
452/32, 495/23, 520/12, 880/9, 587/8, 881/6, 581/6. HRMS (ESI):
calcd for C28H4403Na [M + Na]+: 451.3188, found 451.3185; XRPD
(2h), [°]: 3.35, 3.67, 3.84, 4.09, 4.37, 4.64, 4.82, 4.89, 5.12, 5.33,
5.57, 6.32, 6.69, 8.35, 9 64, 16.68.
(ESI): calcd for
593.3032.
C
32H5103NaSi2P [M + Na]+: 593.3012, found
2.1.6. (1R,3R,7E,22E,24E)-24a,26,27-trihomo-19-nor-9,10-
2.1.4. (7E)-(1R,3R)-24-phenylsulfonyl-1,3-bis(tert-
secoergosta-5,7,22.24-tetraen-1,3,25-triol (PRI-5202, 2)
butyldimethylsililoxy)-9,10-seco-19,22,23-trinor-chola-5,7-dien (15)
The solution of the sulfone 8 (0.11 g, 0.33 mmol) in THF (0.7 mL)
was added drop-wise to the phosphine oxide solution 14 (0.33 g,
0.58 mmol) in THF (0.7 mL) at ꢁ60 °C and stirred at ꢁ40 °C for
2 h. The resulting mixture was extracted with hexane–ethyl ace-
tate and purified by silica gel chromatography to give the sulfone
15 as foam (0.18 g, 0.26 mmol, 79%); mp 184.3–186.1 °C; UV kmax
n-BuLi (1.6 M in hexane, 2.4 mL, 3.8 mmol) was added to the
solution of diisopropylamine (0.8 mL, 5.5 mmol) in tetrahydrofu-
ran (2 mL) at ꢁ60 °C. The solution of sulfone 15 (2.2 g, 3.2 mmol)
in tetrahydrofuran (10 mL) was added to this mixture. The stirring
continued for 15 min and the freshly destilled ethyl 3-methyl-4-
oxobut-2-enoate 16 (0.7 g, 4.9 mmol) was added. The mixture
was stirred at ꢁ60 °C for 1 h and extracted with tetrahydrofuran.
The solvent was replaced with ethyl ether (3.0 mL) and ethyl mag-
nesium bromide (3 M, 2.0 mL, 6.0 mmol) was added to the result-
ing crude ester 17. The mixture was stirred for 30 min and
extracted with t-butyl methyl ether to give the crude alcohol 19.
The saturated methanolic solution of Na2HPO4 (15 mL) and sodium
amalgam (10%, 12 g) were added and the mixture was stirred at
room temperature for 2 h. The mixture was extracted with t-butyl
methyl ether to give the crude silylated alcohol 21. This was dis-
solved in tetrahydrofuran (3 mL) and tetrabutylammonium fluo-
ride (1 M, 4.0 ml, 4.0 mmol) was added. The solution was stirred
at 76 °C for 2 h and extracted with tetrahydrofuran. The product
was purified by silica gel chromatography and crystallized from
ethyl acetate to give the analog 2 (0.64 g, 1.4 mmol, 44% from
243.6, 251.8, 261.6 nm; IR (KBr,
m
(cmꢁ1)): 2923, 2855, 1732,
1674, 1620, 1587, 1471, 1447, 1379, 1361, 1306, 1252, 1149,
1086, 1051, 1026, 1006, 961, 921, 836, 774; 1H NMR (200 MHz,
CDCl3) d: 0.05 (s, 6H, 2xSiCH3), 0.52 (s, 3H, 18-CH3), 0.86 (m,
18H, 2xSiC(CH3)3), 1.23 (d, 3J = 6,6 Hz, 3H, 21-CH3), 3.95–4.18 (m,
2H, 24-CH2), 5.79 (d, 3J = 11 Hz, 1H, 6-CH), 6.18 (d, 3J = 11 Hz, 1H,
7-CH), 7.50–7.94 (m, 5H, Ar–H); 13C NMR (200 MHz, CDCl3) d:
ꢁ4.89, ꢁ4.69, ꢁ4.78, 11.88, 18.09, 20.26, 22.08, 23.17, 25.84,
27.48, 28.49, 29.69, 32.57, 36.77, 40.29, 43.66, 45.68, 45.99,
55.76, 56.13, 62.04, 67.91, 68.06, 116.54, 121.50, 127.86, 129.24,
133.49, 134.19, 139.77, 140.38; MS (relative intensity) m/z: 709
([M + Na]+/100), 710/47, 711/18, 1397 [2 M + Na]+/13), 1399/8,
712/5. HRMS (ESI): calcd for C39H6604NaSi2S [M + Na]+: 709.4118,
found 709.4112. The analytical sample of 15 was crystallized from
ethyl acetate. The crystals were dried in the vacuum drier
(10 mbar, 40 °C). XRPD (2h), [°]: 10.42, 15.30, 15.72, 17.16, 18.04,
19.71, 20.79, 21.94, 22.61, 23.97, 24.93, 25.86, 27.59, 29.39.
15); mp 71.6–74.7 °C; UV kmax 242.8, 251.6, 261.6 nm; IR (KBr,
m
(cmꢁ1)): 3384, 2930, 2874, 1725, 1618, 1457, 1374, 1257, 1135,
1047, 964, 965; 1H NMR (600 MHz, CDCl3) d: 0.57 (s, 3H, 18-
CH3), 0.89 (m, 6H, 28-CH3, 29-CH3), 1.06 (d, 3J = 6.6 Hz, 3H, 21-
CH3), 1.63 (q, 3J = 7.2 Hz, 4H, 26-CH2, 27-CH2), 1.96 (d, 3J = 1.2 Hz,
3H, 30-CH3), 4.04 (m, 1H, 1-CH), 4.11 (m, 1H, 3-CH), 5.31 (s, 1H,
24a-CH), 5.50 (dd, 3J = 8.6 Hz, 3J = 8.6 Hz, 1H, 22-CH), 5.85 (d,
3J = 11.2 Hz, 1H, 7-CH), 5.96 (d, 3J = 15.6 Hz, 1H, 23-CH), 6.30 (d,
3J = 11.2 Hz, 1H, 6-CH); 13C NMR (600 MHz, CDCl3) d: 8.16, 8.18,
13.35, 20.71, 22.21, 23.45, 27.73, 28.89, 33.91, 33.95, 37.13,
40.32, 40.33, 42.12, 44.59, 45.76, 56.31, 56.52, 67.13, 67.36,
76.38, 115.33, 123.71, 131.28, 133.28, 134.48, 134.54, 136.05,
142.83; MS (relative intensity) m/z: 479 ([M + Na]+]/100), 480/33,
936 [2 M + Na]+/22, 937/19, 137/19, 1393/13, 697/10, 1394/5;
HRMS (ESI): calcd for C30H4803Na [M + Na]+: 479.3501, found
479.3499.
2.1.5. (1R,3R,7E,22E,24E)-24a-homo-19-nor-9,10-secoergosta-
5,7,22,24-tetraen-1,3,25-triol (PRI-5201, 1)
n-BuLi (1.6 M in hexane, 2.2 mL, 3.5 mmol) was added to the
solution of diisopropylamine (0.7 mL, 5.0 mmol) in tetrahydrofu-
ran (2 mL) at ꢁ60 °C. The solution of the sulfone 15 (2.0 g,
2.9 mmol) in tetrahydrofuran (8 mL) was added to the mixture.
The stirring continued for 15 min and the freshly destilled ethyl
3-methyl-4-oxobut-2-enoate 16 (0.6 g, 4.2 mmol) was added. The
mixture was stirred at ꢁ60 °C for 1 h and extracted with tetrahy-
drofuran. The solvent was replaced with ethyl ether (2.5 mL) and
methyl magnesium bromide (3 M, 1.8 mL, 5.4 mmol) was added
to the resulting crude ester 17. The mixture was stirred for
30 min and extracted with t-butyl methyl ether to give the crude
alcohol 18. The saturated methanolic solution of Na2HPO4
(15 mL) and sodium amalgam (10%, 10 g) were added and the mix-
ture was stirred at room temperature for 2 h. The mixture was ex-
tracted with t-butyl methyl ether to give the crude silylated
alcohol 20. This was dissolved in tetrahydrofuran (3 mL) and tetra-
butylammonium fluoride (1 M, 3.8 ml) was added. The solution
was stirred at 74 °C for 2 h and extracted with tetrahydrofuran.
The product was purified by silica gel chromatography and crystal-
lized from ethyl acetate to give the analog 1 (0.55 g, 1.3 mmol, 45%
from 15); mp 93.2–96.4 °C UV kmax 242.6, 251.2, 261.6 nm; IR (KBr,
2.1.7. (R)-3-hydroxy-2,3-dimethylbutanal (24a)
The solution of methyl (S)-(+)-3-hydroxy-2-methylpropionate
22a (15.0 g, 127.1 mmol) in tetrahydrofuran (40 mL) was added
to the solution of methyl magnesium bromide (3 M, 160 mL,
480.0 mmol) cooled to ꢁ10 °C. The mixture was stirred for 3 h un-
der argon and extracted with t-butyl methyl ether. The residue was
distilled under reduced pressure (1 mmHg/73–75 °C) to give the
crude diol 23a as oil (11.9 g, 100.8 mmol, 79%). Dess-Martin peri-
odinane (40.0 g, 94.3 mmol) was added to the solution of the diol
23a (6.8 g, 57.6 mmol) in dichloromethane (150 mL) which was
then stirred at room temperature for 1 h. The mixture was ex-
tracted with dichloromethane and distilled under reduced pressure
(1 mmHg/43–45 °C) to give the aldehyde 24a as oil (4.8 g,
m
(cmꢁ1)): 3320, 2970, 2941, 2869, 1614, 1454, 1444, 1376, 1363,
1350, 1217, 1185, 1086, 1056; 1H NMR (600 MHz, CDCl3); d 0.57 (s,
3H, 18-CH3), 1,05 (d, 3J = 6.6 Hz, 3H, 21-CH3), 1,40 (s, 6H, 26-CH3,
27-CH3), 1,94 (s, 3H, 28-CH3), 4,01 (m, 1H, 1-CH), 4,09 (m, 1H, 3-
CH), 5,50 (s, 1H, 24a-CH), 5,52 (m, 1H, 22-CH), 5,85 (d,
3J = 11.2 Hz, 1H, 7-CH), 5,93 (d, 3J = 15.6 Hz, 1H, 23-CH), 6,28 (d,
3J = 11.2 Hz, 1H, 6-CH); 3C NMR (600 MHz, CDCl3) d: 12.17, 13.07,
20.61, 22.08, 23.33, 27.66, 28.75, 30.94, 31.05, 36.70, 40.25,
40.31, 41.72, 44.27, 45.64, 56.20, 56.37, 66.70, 66.99, 70.87,
41.4 mmol, 72% from 23a). IR (film,
m
(cmꢁ1)): 3427, 2975, 2942,
2882, 2736, 1712, 1460, 1371, 1272, 1158, 954; 1H NMR
(200 MHz, CDCl3) d: 1.14 (d, 3J = 7.2 Hz, 3H, 2-CH3), 1.25 (s, 3H,
3-CH3), 1.30 (s, 3H, 4-CH3), 2.46 (dq, 3J = 7.3 Hz, 3J = 1.8 Hz, 1H, 2-
H), 2.74 (bs, 1H, 3-OH), 9.83 (d, 3J = 1.8 Hz, 1H, 1-CHO); 13C NMR
(200 MHz, CDCl3) d: 9.28, 26.21, 28.42, 55.64, 71.75, 205.98; HRMS
calcd for C6H1202Na [M + Na]+: 139.0735, found 139.0733.