4456 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 22
Fujita et al.
79.46, 64.33, 63.97, 37.09, 33.73, 33.12, 30.82, 30.67, 30.55,
30.51, 30.33, 23.77, 14.67; MS (FAB) m/z 370 (M + H)+; HRMS
(FAB) obsd 370.2953, calcd for C21H40NO4 370.2959.
14.12; MS (FAB) m/z 584 (M + H)+; 606 (M + Na)+; HRMS
(FAB) obsd 584.3806, calcd for C31H54NO9 584.3801.
A solution of 19 (1.031 g, 1.72 mmol) in MeOH (68.6 mL)
containing 1 N NaOH (17.2 mL) was refluxed for 6 h and then
concentrated. The residue was washed with water and dis-
solved in MeOH. The solution was acidified with concentrated
HCl and concentrated to afford 12 (621 mg, 85.7%): mp 111.0-
113.5 °C; IR (KBr) 3300, 2930, 2850, 1580, 1510, 1480, 1390,
(3R,4R)-(E)-2-Am in o-2-(h yd r oxym et h yl)eicos-6-en e-
1,3,4,14-tetr ol Hyd r och lor id e (11). Lithium aluminum
hydride (800 mg, 21.05 mmol) was added to a stirred solution
of 813 (2.00 g, 5.22 mmol) in anhydrous tetrahydrofuran (66
mL) under ice cooling. The reaction mixture was stirred at
room temperature for 45 min. Water (1.6 mL) was added
dropwise at 0 °C, and the whole was stirred at room temper-
ature for 10 min and then evaporated to dryness. Acetic
anhydride (88 mL) and pyridine (80 mL) were added to the
residue. The mixture was kept standing overnight, then
poured into ice water, and extracted with EtOAc. The organic
solution was successively washed with aqueous 1 N HCl,
saturated aqueous NaHCO3, and saturated brine and dried.
The organic solvent was removed, and the residue was
chromatographed on silica gel with n-hexane/EtOAc (6:5) to
give the crude acetate (1.667 g). This (650 mg) was purified
by preparative HPLC to give the pure acetate 18 (475 mg) as
1080, 1060, 1030 cm-1 1H NMR (300 MHz, CD3OD) δ 5.57
;
(1H, dtt-like, J ) 15.2 and 6.5 Hz, 6-H), 5.43 (1H, dtt-like, J
) 15.3 and 6.9 Hz, 7-H), 3.88-3.73 (5H, m, HOCH2 × 2, 4-H),
3.67 (1H, d, J ) 0.9 Hz, 3-H), 2.31 (2H, t, J ) 6.7 Hz, 5-H2),
2.01 (2H, q, J ) 6.6 Hz, 8-H2), 1.28 (22H, br s, CH2 × 11), 0.90
(3H, t, J ) 6.7 Hz, 20-H3); 13C NMR (67.5 MHz, CD3OD) δ
135.02, 126.83, 71.93, 69.68, 64.96, 61.13, 60.25, 38.54, 33.80,
33.08, 30.82, 30.67, 30.62, 30.49, 30.35, 23.76, 14.47; MS (FAB)
m/z 374 (M + H)+; HRMS (FAB) obsd 374.3282, calcd for
C21H44NO4 374.3272. Anal. (C21H43NO4HCl) C, H, N, Cl.
(3R,4R)-2-Am in o-2-(h yd r oxym eth yl)eicosa n e-1,3,4,14-
tetr ol Hyd r och lor id e (13). A solution of 18 (244 mg, 0.381
mmol) in MeOH (10 mL) was subjected to hydrogenation over
5% palladium carbon (25 mg). The catalyst was filtered off,
and the solvent was evaporated to give the dihydro derivative
20 as an oil (167 mg, 68.2%): IR (KBr) 2930, 2860, 1740, 1380,
1240, 1040 cm-1; 1H NMR (200 MHz, CDCl3) δ 6.37 (1H, br s,
NH), 5.63 (1H, d, J ) 2.7 Hz, 3-H), 5.12 (1H, ddd, J ) 7.9, 5.5
and 2.4 Hz, 4-H), 4.85 (1H, qui, J ) 6.1 Hz, 14-H), 4.59 (1H,
d, J ) 11.5 Hz, HOCHa), 4.53 (1H, d, J ) 11.7 Hz, HOCHc),
4.50 (1H, d, J ) 11.7 Hz, HOCHb), 4.38 (1H, d, J ) 11.7 Hz,
HOCHd), 2.15 (3H, s, Ac), 2.13 (3H, s, Ac), 2.06 (3H, s, Ac),
2.04 (3H, s, Ac), 2.04 (3H, s, Ac), 1.98 (3H, s, Ac), 1.50 (4H, q,
J ) 6.1 Hz, 13- and 15-H2), 1.26 and 1.24 (24H, s, CH2 × 12),
0.88 (3H, t, J ) 6.5 Hz, 20-H3); 13C NMR (67.5 MHz, CDCl3) δ
170.98, 170.81, 170.55, 170.44, 170.13, 169.52, 74.45, 72.31,
72.06, 63.74, 63.47, 59.87, 34.14, 32.40, 31.75, 29.49, 29.34,
29.22, 25.34, 25.28, 23.85, 22.59, 21.31, 21.22, 20.75, 20.65,
14.09; MS (FAB) m/z 644 (M + H)+, 666 (M + Na)+; HRMS
(FAB) obsd 644.4005, calcd for C33H58NO11 644.4012.
an oil: IR (KBr) 2930, 2860, 1740, 1380, 1240, 1040, 970 cm-1
;
1H NMR (200 MHz, CDCl3) δ 6.31 (1H, br s, NH), 5.62 (1H, d,
J ) 2.4 Hz, 3-H), 5.48 (1H, dtt-like, J ) 15.4 and 6.4 Hz, 6-H),
5.26 (1H, dtt-like, J ) 15.1 and 7.1 Hz, 7-H), 5.13 (1H, dt, J )
7.3 and 2.2 Hz, 4-H), 4.85 (1H, q, J ) 6.1 Hz, 14-H), 4.59 (1H,
d, J ) 11.7 Hz, HOCH2), 4.53 (1H, d, J ) 11.7 Hz, HOCH2),
4.48 (1H, d, J ) 11.8 Hz, HOCH2), 4.35 (1H, d, J ) 11.9 Hz,
HOCH2), 2.24 (4H, m, 5- and 8-H2), 2.16 (3H, Ac), 2.11 (3H,
Ac), 2.05 (3H, Ac), 2.04 (3H, Ac), 2.04 (3H, Ac), 1.97 (3H, Ac),
1.52-1.49 (4H, m, 13- and 15-H2), 1.26 (16H, br s, CH2 × 8),
0.88 (3H, t, J ) 6.5 Hz, 20-H3); 13C NMR (75 MHz, CDCl3) δ
170.94, 170.72, 170.35, 170.17, 170.14, 169.43, 135.15, 123.50,
74.42, 72.13, 71.58, 63.65, 63.41, 60.01, 35.68, 34.15, 32.55,
31.75, 29.40, 29.26, 29.20, 29.09, 25.29, 23.84, 22.58, 21.29,
21.18, 20.73, 20.68, 14.06; MS (FAB) m/z 642 (M + H)+; HRMS
(FAB) obsd 642.3869, calcd for C33H56NO11 642.3856.
A solution of 18 (209 mg, 0.326 mmol) in MeOH (15.6 mL)
containing 1 N NaOH (3.9 mL) was refluxed for 6 h. The
solution was concentrated, and the residue was dissolved in
water. The solution was applied to a SEP-PAK Cartridge C18
(Millipore Co.) and eluted with water and MeOH. The MeOH
eluate was acidified with concentrated HCl and concentrated
to give compound 11 (104 mg, 75.0%): mp 97.0-98.0 °C; IR
(KBr) 3250, 2930, 2850, 1580, 1480, 1080, 1030, 980 cm-1; 1H
NMR (300 MHz, CD3OD) δ 5.57 (1H, dt, J ) 15.3 and 6.6 Hz,
6-H), 5.43 (1H, dt, J ) 15.3 and 6.9 Hz, 7-H), 3.85 (1H, dt, J
) 6.9 and 1.0 Hz, 4-H), 3.90-3.73 (5H, m), 3.67 (1H, d, J )
1.0 Hz, 3-H), 2.31 (2H, t, J ) 6.7 Hz, 5-H2), 2.02 (2H, q, J )
6.4 Hz, 8-H2), 1.42-1.31 (20H, m, CH2 × 10), 0.90 (3H, t, J )
6.8 Hz, 20-H3); 13C NMR (75 MHz, CD3OD) δ 134.99, 126.93,
72.49, 71.95, 69.94, 64.78, 61.38, 60.55, 38.57, 38.49, 38.44,
33.76, 33.08, 30.74, 30.57, 30.56, 30.30, 26.81, 23.72, 14.45;
MS (FAB) m/z 390 (M + H)+, 412 (M + Na)+; HRMS (FAB)
A solution of 20 (100 mg, 0.156 mmol) in MeOH (7.5 mL)
containing 1 N NaOH (1.87 mL) was refluxed for 6 h. The
reaction mixture was treated in a manner similar to that used
for the preparation of 11 to give 13 (48 mg, 72.2%): mp 105.5-
107.5 °C; IR (KBr) 3250, 2930, 2850, 1580, 1470, 1060 cm-1
;
1H NMR (270 MHz, CD3OD) δ 3.86-3.74 (5H, m, 4-H and
HOCH2 × 2), 3.62 (1H, br s, 3-H), 3.55-3.47 (1H, m, 14-H),
1.60 (2H, m, CH2), 1.42 and 1.31 (26H, each br s, CH2 × 13),
0.90 (3H, t, J ) 6.9 Hz, 20-H3); 13C NMR (67.5 MHz, CD3OD)
δ 72.13, 71.41, 69.88, 64.47, 60.79, 59.89, 38.01, 37.97, 34.81,
32.63, 30.48, 30.37, 30.17, 26.38, 23.32, 14.30; MS (FAB) m/z
392 (M + H)+, 414 (M + Na)+; HRMS (FAB) obsd 392.3369,
calcd for C21H46NO5 392.3378. Anal. (C21H45NO5HCl) H, N,
Cl; C: calcd, 58.93; found 58.25.
(3R ,4R )-2-Am in o-2-(h yd r oxym e t h yl)e icosa n e -1,3,4-
tr iol Hyd r och lor id e (14). A solution of 19 (621 mg, 1.07
mmol) in MeOH (23 mL) was prepared in the same manner
as that used for the preparation of 20 to give the dihydro
derivative 21 (290 mg, 46.5%): mp 92.0-93.0 °C; IR (KBr)
3400, 2930, 2850, 1740, 1230, 1040 cm-1; 1H NMR (270 MHz,
CDCl3) δ 6.38 (1H, br s, NH), 5.62 (1H, d, J ) 2.6 Hz, 3-H),
5.12 (1H, ddd, J ) 8.2, 5.6, and 2.6 Hz, 4-H), 4.60 (1H, d, J )
11.9 Hz, HOCaHa), 4.54 (1H, d, J ) 11.9 Hz, HOCbHa), 4.51
(1H, d, J ) 11.9 Hz, HOCaHb), 4.38 (1H, d, J ) 11.9 Hz,
HOCbHb), 2.15 (3H, s, Ac), 2.13 (3H, s, Ac), 2.06 (3H, s, Ac),
2.05 (3H, s, Ac), 1.98 (3H, s, Ac), 1.56-1.43 (2H, m, 5-H2), 1.25
and 1.24 (28H, s, CH2 × 14), 0.88 (3H, t, J ) 6.6 Hz, 20-H3);
13C NMR (67.5 MHz, CDCl3) δ 170.78, 170.55, 170.40, 170.11,
169.49, 72.29, 72.04, 63.72, 63.45, 59.86, 32.40, 31.91, 29.69,
29.65, 29.61, 29.54, 29.40, 29.36, 25.35, 23.83, 22.70, 21.20,
20.74, 20.63, 14.12; MS (FAB) m/z 586 (M + H)+. HRMS (FAB)
obsd 586.3963, calcd for C31H56NO9 586.3957.
obsd 390.3210, calcd for C21H44NO5 390.3221. Anal. (C21H43
NO5HCl) C, H, N.
-
(3R,4R)-(E)-2-Am in o-2-(h ydr oxym eth yl)eicos-6-en e-1,3,4-
tr iol Hyd r och lor id e (12). Lithium aluminum hydride (1.850
g, 48.68 mmol) was added to a stirred solution of 9 (4.492 g,
12.17 mmol) in anhydrous tetrahydrofuran (150 mL) under
ice cooling. The reaction mixture was treated in a similar
manner to that used for the preparation of 18 to afford the
crude triacetate, which was recrystallized from n-hexane to
give the acetate 19 (3.643 g, 51.3%): mp 80.5-81.5 °C; IR
(KBr) 3400, 2930, 2850, 1740, 1680, 1380, 1220, 1040, 970
1
cm-1; H NMR (270 MHz, CDCl3) δ 6.30 (1H, br s, NH), 5.61
(1H, d, J ) 2.3 Hz, 3-H), 5.48 (1H, dtt-like, J ) 15.2 and 6.6
Hz, 6-H), 5.27 (1H, dtt-like, J ) 15.2 and 7.3 Hz, 7-H), 5.13
(1H, ddd, J ) 7.6, 5.9 and 2.3 Hz, 4-H), 4.60 (1H, d, J ) 11.9
Hz, HOCH2), 4.53 (1H, d, J ) 11.9 Hz, HOCH2), 4.49 (1H, d,
J ) 11.9 Hz, HOCH2), 4.37 (1H, d, J ) 11.9 Hz, HOCH2), 2.25-
2.18 (4H, m, 5- and 8-H2), 2.16 (3H, s, Ac), 2.11 (3H, s, Ac),
2.05 (3H, s, Ac), 2.04 (3H, s, Ac), 1.97 (3H, s, Ac), 1.25 (22H,
br s, CH2 × 11), 0.88 (3H, t, J ) 6.8 Hz, 20-H3); 13C NMR (67.5
MHz, CDCl3) δ 170.73, 170.31, 170.19, 170.15, 169.41, 135.31,
123.34, 72.07, 71.55, 63.61, 63.36, 59.91, 35.69, 32.60, 31.91,
29.69, 29.51, 29.36, 29.22, 23.85, 22.70, 21.19, 20.75, 20.68,
A solution of 21 (200 mg, 0.342 mmol) in MeOH (14 mL)
containing 1 N NaOH (3.42 mL) was refluxed for 6 h and then
treated in a manner similar to that used for the preparation
of 12 to give 14 (94 mg, 66.7%): mp 119.0-121.5 °C; IR (KBr)
3270, 2920, 2850, 1470, 1080, 1040 cm-1; 1H NMR (270 MHz,
CD3OD) δ 3.86-3.74 (5H, m, 4-H and HOCH2 × 2), 3.62 (1H,