1170 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 5
Gregson et al.
779, 758, 666, 649, 620 cm-1; MS (FAB) m/ z (relative intensity)
943 ([M + Na]+•, 15), 921 ([M + H]+•, 100), 863 (34), 789 (11),
690 (9), 346 (49); HRMS [M + H]+• calcd for C43H69N4O14Si2
m/ z 921.4349, found (FAB) m/ z 921.4312.
was dried (MgSO4), filtered, and evaporated under reduced
pressure to afford the product as a foam.
1,1′-[[(P r op a n e-1,3-d iyl)d ioxy]-bis[(2-a m in o-N-a llylox-
yca r bon yl-5-m eth oxy-1,4-p h en ylen e)ca r bon yl]]-bis[(2S,-
4R)-2-t-bu tyld im eth ylsilyloxym eth yl-4-h yd r oxyp yr r oli-
d in e] (17a ). Yield ) 1.83 g (84%); [R]2D0 ) -14° (c ) 0.25,
CHCl3); 1H NMR (270 MHz, CDCl3) δ 8.80 (s, 2H), 7.63 (s, 2H),
6.73 (s, 2H), 6.00-5.85 (m, 2H), 5.33 (dd, 2H, J ) 1.5, 17.2
Hz), 5.22 (dd, 2H, J ) 1.5, 10.4 Hz), 4.63-4.54 (m, 6H), 4.35-
4.27 (m, 2H), 4.26-4.13 (m, 8H), 3.77 (s, 6H), 3.63-3.52 (m,
6H), 2.36-2.03 (m, 6H), 0.89 (s, 18H), 0.00 (s, 12H); 13C NMR
(67.8 MHz, CDCl3) δ 169.5, 153.8, 150.3, 144.3, 132.5, 131.7,
118.1, 116.5, 111.6, 106.4, 70.5, 65.8, 65.3, 62.3, 59.9, 57.1, 56.3,
35.5, 29.2, 25.8, 18.1, -5.42/-5.52; IR (neat) 3351 (br), 2931,
2857, 1762, 1722, 1603, 1521, 1463, 1404, 1264, 1222, 1106,
1,1′-[[(Alk a n e-1,3-d iyl)d ioxy]-bis[(2-a m in o-5-m eth oxy-
1,4-p h en ylen e)ca r bon yl]]-bis[(2S,4R)-2-t-bu tyld im eth yl-
silyloxym eth yl-4-h yd r oxyp yr r olid in e] 16a ,b. A solution of
hydrazine hydrate (0.74 mL, 0.76 g, 23.7 mmol, 15a or 1.25
mL, 1.29 g, 40.2 mmol, 15b) in MeOH (12 mL, 15a or 20 mL,
15b) was added dropwise to a solution of the bis-nitro
compound (2.12 g, 2.38 mmol, 15a or 3.6 g, 3.91 mmol, 15b)
in MeOH (40 mL, 15a or 68 mL, 15b) gently refluxing over
Raney nickel (300 mg, 15a or 510 mg, 15b of a thick slurry).
After 5 min at reflux TLC (90:10 v/v CHCl3/MeOH) revealed
the incomplete consumption of starting material. The reaction
mixture was treated with additional Raney nickel (ca. 500 mg)
and hydrazine (0.74 mL, 15a or 1.25 mL, 15b) in MeOH (12
mL, 15a or 20 mL, 15b) resulting in complete consumption of
starting material. Excess Raney nickel was added to the
reaction mixture to decompose unreacted hydrazine hydrate,
and the reaction mixture was then allowed to cool. The reaction
mixture was filtered through celite to remove excess Raney
nickel, and the filter pad was washed with additional MeOH
(Caution! Raney nickel is pyrophoric; do not allow filter pad
to dry; use conc. HCl to destroy nickel). The combined filtrate
was evaporated by rotary evaporation under reduced pressure,
and the residue was redissolved in CH2Cl2. The CH2Cl2
solution was dried (MgSO4), filtered, and evaporated to afford
the product as a foam.
1053, 1015, 936, 872, 837, 775, 629 cm-1
.
1,1′-[[(P en ta n e-1,5-d iyl)d ioxy]-bis[(2-a m in o-N-a llyloxy-
ca r b on yl-5-m et h oxy-1,4-p h en ylen e)ca r b on yl]]-b is[(2S,-
4R)-2-t-bu tyld im eth ylsilyloxym eth yl-4-h yd r oxyp yr r oli-
d in e] (17b). Yield ) 4.89 g (92%); [R]2D0 ) -68.7° (c ) 0.46,
1
CHCl3); H NMR (250 MHz, CDCl3) δ 8.89 (br s, 2H), 7.65 (s,
2H), 6.77 (s, 2H), 6.05-5.85 (m, 2H), 5.40-5.19 (m, 4H), 4.70-
4.52 (m, 6H), 4.37 (br s, 2H), 4.20-4.00 (m, 4H), 3.77 (s, 6H),
3.70-3.40 (m, 8H), 2.70-2.53 (bs, 2H), 2.27-2.22 (m, 2H),
2.06-1.90 (m, 6H), 1.67-1.64 (m, 2H), 0.88 (s, 18H), 0.03 (s,
12H); 13C NMR (67.8 MHz, CDCl3) δ 169.5, 153.9, 150.5, 144.1,
132.5, 131.9, 118.0, 116.1, 111.6, 105.9, 70.4, 68.6, 65.8, 62.2,
59.8, 57.1, 56.4, 35.5, 28.6, 25.8, 22.4, 18.1, -5.44/-5.54; IR
(CHCl3) 3422 (br), 3020, 2955, 1620, 1524, 1465, 1411, 1260,
1215, 1121, 1051, 928, 837, 669, cm-1; MS (FAB) m/ z (relative
intensity) 1051 ([M + Na]+•, 38), 1029 ([M + H]+•, 77), 971
(49), 946 (16), 798 (62), 740 (30), 714 (21), 509 (100), 469 (59),
372 (71), 318 (33); HRMS [M + H]+• calcd for C51H81N4O14Si2
m/ z 1029.5288, found (FAB) m/ z 1029.5247.
1,1′-[[(P r opan e-1,3-diyl)dioxy]-bis[(2-am in o-5-m eth oxy-
1,4-p h en ylen e)ca r bon yl]]-bis[(2S,4R)-2-t-bu tyld im eth yl-
silyloxym eth yl-4-h yd r oxyp yr r olid in e] (16a ). Yield ) 1.84
g (93%); [R]2D4 ) -94° (c ) 0.25, CHCl3); H NMR (270 MHz,
1
CDCl3) δ 6.65 (s, 2H), 6.21 (s, 2H), 4.52 (bs, 2H), 4.35-4.30 (m,
4H), 4.20-4.16 (m, 4H), 3.75 (s, 6H), 3.61-3.35 (m, 12H), 2.30-
2.10 (m, 4H), 2.06-1.95 (m, 2H), 0.89-0.84 (m, 18H), 0.04 to
-0.01 (m, 12H); 13C NMR (67.8 MHz, CDCl3) δ 170.2, 150.6,
141.1, 140.3, 112.8, 112.6, 102.2, 70.1, 63.8, 62.3, 59.6, 56.8,
56.7, 35.2, 29.8, 25.9, 18.1, -5.41/-5.51; IR (neat) 3359 (br),
2929, 2856, 1621, 1591, 1469, 1433, 1406, 1358, 1346, 1261,
1232, 1175, 1117, 1056, 1006, 866, 835, 776 cm-1; MS (FAB)
m/ z (relative intensity) 833 ([M + H]+•, 18), 773 (9), 602 (13),
399 (7), 371 (34), 232 (9), 206 (22), 192 (14), 176 (13), 166 (44),
150 (8), 100 (10), 73 (100).
1,1′-[[(Alk a n e-1,3-d iyl)d ioxy]-bis[(2-a m in o-N-a llyloxy-
ca r bon yl-5-m eth oxy-1,4-p h en ylen e)ca r bon yl]]-bis[(2S)-
2-t-bu tyldim eth ylsilyloxym eth yl-4-oxo-pyr r olidin e] 18a,b.
A solution of dimethyl sulphoxide (1.12 mL, 1.24 g, 15.84
mmol, 17a or 2.0 mL, 2.2 g, 28.02 mmol, 17b) in dry CH2Cl2
(24 mL, 17a or 43 mL, 17b) was added dropwise over 50 min
to a stirred solution of oxalyl chloride (3.96 mL of a 2 M
solution in CH2Cl2, 7.92 mmol, 17a or 7.0 mL, 14.0 mmol, 17b)
at -60 °C under a N2 atmosphere. After the sample was stirred
at -50 °C for 25 min, a solution of the bis-alcohol (2.64 g, 2.64
mmol, 17a or 4.80 g, 4.67 mmol, 17b) in CH2Cl2 (40 mL, 17a
or 72 mL, 17b) was added dropwise over a period of 70 min.
The reaction mixture was allowed to stir at -55 °C for 30 min
prior to the dropwise addition of a solution of Et3N (3.63 g,
5.00 mL, 35.9 mmol, 17a or 6.54 g, 9.0 mL, 63.48 mmol, 17b)
in CH2Cl2 (20 mL, 17a or 37 mL, 17b). Stirring was continued
at -55 °C for 45 min and then allowed to warm to 0 °C. The
reaction mixture was diluted with CH2Cl2 (20 mL, 17a ,b)
washed with cold 1 M HCl (2 × 60 mL, 17a or 2 × 100 mL,
17b) and brine (60 mL, 17a or 100 mL, 17b), and then dried
(MgSO4). Removal of excess solvent afforded the crude product
which was purified by flash column chromatography (50:50
v/v EtOAc/40-60° petroleum ether) to yield the pure bis-ketone
as a colourless foam (18a ) or a pale yellow foam (18b).
1,1′-[[(P en ta n e-1,5-diyl)d ioxy]-bis[(2-a m in o-5-m eth oxy-
1,4-p h en ylen e)ca r bon yl]]-bis[(2S,4R)-2-t-bu tyld im eth yl-
silyloxym eth yl-4-h yd r oxyp yr r olid in e] (16b). Yield ) 3.37
g (91%); [R]2D0 ) -100° (c ) 0.19, CHCl3); 1H NMR (270 MHz,
CDCl3) δ 6.69 (s, 2H), 6.24 (s, 2H), 4.40-3.40 (m, 28H), 2.40-
1.60 (m, 10H), 0.88 (s, 18H), 0.03 (s, 12H); 13C NMR (67.8 MHz,
CDCl3) δ 170.2, 151.0, 141.4, 140.6, 112.8, 112.3, 102.4, 70.3,
68.4, 62.6, 59.6, 56.8, 35.6, 28.4, 25.9, 22.3, 18.2, -5.39/-5.49;
IR (nujol) 3351 (br), 2922, 1713, 1592, 1556, 1515, 1463, 1378,
1260, 1177, 1117, 1058, 1001, 938, 916, 835, 774, 723, 669
cm-1; MS (FAB) m/ z (relative intensity) 861 ([M + H]+., 20),
803 (7), 630 (12), 399 (100), 346 (32); HRMS [M + H]+• calcd
for C43H73N4O10Si2 m/ z 861.4865, found (FAB) m/ z 861.4833.
1,1′-[[(Alk a n e-1,3-d iyl)d ioxy]-bis[(2-a m in o-N-a llyloxy-
ca r b on yl-5-m et h oxy-1,4-p h en ylen e)ca r b on yl]]-b is[(2S,-
4R)-2-t-bu tyld im eth ylsilyloxym eth yl-4-h yd r oxyp yr r oli-
d in e] 17a ,b. A solution of allyl chloroformate (0.463 mL, 0.526
g, 4.36 mmol, 16a or 1.10 mL, 1.25 g, 10.4 mmol, 16b) in dry
CH2Cl2 (36 mL, 16a or 86 mL, 16b) was added dropwise to a
solution of the bis-aniline (1.817 g, 2.18 mmol, 16a or 4.47 g,
5.28 mmol, 16b) and pyridine (0.72 g, 0.74 mL, 9.16 mmol,
16a or 1.72 g, 1.76 mL, 21.7 mmol, 16b) in CH2Cl2 (71 mL,
16a or 175 mL, 16b) at 0 °C under a N2 atmosphere. The
reaction mixture was allowed to warm to room temperature
and to stir for 3.5 h. At which time TLC (90:10 v/v CHCl3/
MeOH) revealed the reaction to be complete. The reaction
mixture was diluted with CH2Cl2 (20 mL, 16a or 50 mL, 16b)
and washed with saturated aqueous CuSO4 (2 × 70 mL, 16a
or 2 × 180 mL, 16b), water (60 mL, 16a or 160 mL, 16b), and
then brine (60 mL, 16a or 160 mL, 16b). The organic phase
1,1′-[[(P r op a n e-1,3-d iyl)d ioxy]-bis[(2-a m in o-N-a llylox-
yca r bon yl-5-m eth oxy-1,4-p h en ylen e)ca r bon yl]]-bis[(2S)-
2-t-bu tyldim eth ylsilyloxym eth yl-4-oxo-pyr r olidin e] (18a).
Yield ) 1.56 g (59%); 1H NMR (270 MHz, CDCl3) δ 8.64 (s,
2H), 7.80 (s, 2H), 6.75 (s, 2H), 6.03-5.89 (m, 2H), 5.35 (dd,
2H, J ) 1.5, 17.2 Hz), 5.25 (dd, 2H, J ) 1.3, 10.4 Hz), 4.64-
4.61 (m, 4H), 4.29 (t, 4H, J ) 6.1 Hz), 4.13-3.83 (m, 8H), 3.80
(s, 6H), 3.66-3.62 (m, 2H), 2.73 (dd, 2H, J ) 9.4, 17.9 Hz),
2.51 (d, 2H, J ) 17.4 Hz), 2.44-2.38 (m, 2H), 0.87 (s, 18H),
0.00 (s, 12H); 13C NMR (67.8 MHz, CDCl3) δ 208.9, 169.1,
153.5, 150.8, 144.3, 132.4, 118.2, 115.1, 110.9, 106.0, 66.1, 65.8,
65.4, 56.5, 55.0, 39.6, 28.9, 25.7, 18.1, -5.68/-5.77; IR (neat)
3308 (br), 2931, 2856, 1765, 1730, 1624, 1602, 1522, 1468,
1407, 1332, 1259, 1204, 1105, 1053, 1010, 937, 870, 837, 808,
778, 674, 657 cm-1
1,1′-[[(P en ta n e-1,5-d iyl)d ioxy]-bis[(2-a m in o-N-a llyloxy-
.