Total Synthesis of (+)-Deoxoprosopinine
(s, 9H), 1.31 (s, 3H), 1.25 (s, 3H), 1.07 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 155.4, 138.1, 135.9, 135.9, 134.2, 133.9, 129.5,
128.2, 127.4, 127.3, 108.9, 78.7, 78.1, 73.8, 72.9, 72.0, 65.4, 50.1,
29.2, 28.3, 28.1, 27.0, 26.2, 25.1, 19.4; MS (ESI) m/z 648 [M +
H]+, 670 [M + Na]+. Anal. Calcd for C38H53NO6Si: C, 70.44;
H, 8.25; N, 2.16; Found: C, 70.81; H, 8.41; N, 2.14.
(s, 9H), 0.88 (s, 9H), 0.061 (s, 3H), 0.051 (s, 3H); 13C NMR (62.5
MHz, CDCl3) δ 155.4, 138.1, 135.9, 133.5, 133.0, 129.9, 129.8,
128.3, 127.8, 127.6, 127.4, 84.9, 78.9, 73.0, 72.5, 71.9, 61.9, 50.1,
38.1, 28.9, 28.3, 27.0, 25.8, 19.4, 18.2, -5.5, -5.6; MS (ESI)
m/z 800 [M + H]+, 822 [M + Na]+, 838 [M + K]+; HRMS calcd
for C42H65NO8SSi2Na (M + Na) 822.3867, found 822.3836.
(2S,5S,6S)-1-Ben zyloxy-2-ter t-bu toxyca r bon yla m in o-5-
ter t-bu tyld ip h en ylsilyloxy-6,7-d ih yd r oxyh ep ta n e (14). A
solution of 13 (2.12 g, 3.28 mmol) in HOAc-water (4/1, 65 mL)
was stirred at rt overnight. The solvents were evaporated in
vacuo. The residue was purified by column chromatography
on silica gel (heptane/EtOAc ) 2/1) to give diol 14 (1.85 g,
93%): [R]D +20 (c 3.1, CHCl3); IR (CHCl3) 3568, 3442, 3073,
3013, 2960, 2934, 2892, 2861, 1705, 1503, 1473, 1455, 1428,
1393, 1368, 1240, 1219, 1170, 1112, 1074, 1028 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.71-7.66 (m, 4H), 7.46-7.25 (m, 11H),
4.57 (d, J ) 8.8 Hz, 1H), 4.45, 4.37 (AB q, J ) 12.0 Hz, 2H),
3.83 (m, 1H), 3.66-3.60 (m, 3H), 3.39-3.38 (m, 1H), 3.22 (dd,
J ) 4.0, 9.2 Hz, 1H), 3.13 (dd, J ) 2.9, 9.2 Hz, 1H), 2.67 (br s,
1H, OH), 2.26 (br s, 1H, OH), 1.69-1.61 (m, 1H), 1.48-1.20
(m, 3H), 1.41 (s, 9H), 1.07 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 155.6, 138.0, 135.8, 133.8, 133.2, 129.8, 129.7, 128.2, 127.7,
127.5, 127.5, 127.4, 79.0, 73.6, 73.5, 72.9, 71.7, 63.7, 60.2, 49.7,
29.3, 28.3, 27.8, 27.0, 19.4; MS (ESI) m/z 630 [M + Na]+, 646
[M + K]+; HRMS calcd for C35H49NO6SiNa (M + Na) 630.3227,
found 630.3200.
(2S,5S,6S)-1-Ben zyloxy-2-ter t-bu toxyca r bon yla m in o-7-
ter t-bu tyld im eth ylsilyloxy-5-ter t-bu tyld ip h en ylsilyloxy-
6-h yd r oxyh ep ta n e (15). To a solution of 14 (918 mg, 1.51
mmol) in dichloromethane (15 mL) at 0 °C were added
triethylamine (3.07 g, 4.2 mL, 30.2 mmol), DMAP (221 mg,
1.81 mmol), and TBDMSCl (2.28 g, 15.1 mmol) successively.
The reaction mixture was stirred at 0 °C for 2 h. Water was
added. The aqueous layer was extracted with dichloromethane.
The dichloromethane extracts were washed with 1 M HCl,
water, saturated sodium bicarbonate, and brine, dried, and
evaporated. Flash column chromatography on silica gel (hep-
tane/EtOAc ) 10/1 then 5/1) gave compound 15 (1.09 g,
100%): [R]D +12 (c 5.3, CHCl3); IR (CHCl3) 3562, 3443, 3072,
3053, 3019, 3011, 2956, 2931, 2895, 2886, 2859, 1705, 1501,
1472, 1463, 1454, 1428, 1391, 1367, 1256, 1170, 1112, 1085,
1027, 1006 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.68-7.65 (m,
4H), 7.43-7.23 (m, 11H), 4.45-4.36 (m, 1H), 4.43, 4.37 (AB q,
J ) 12.0 Hz, 2H), 3.86-3.84 (m, 1H), 3.64-3.61 (m, 2H), 3.58-
3.55 (m, 1H), 3.47-3.45 (m, 1H), 3.26-3.17 (m, 2H), 2.43 (d,
J ) 6.3 Hz, 1H, OH), 1.66-1.60 (m, 1H), 1.47-1.13 (m, 3H),
1.40 (s, 9H), 1.05 (s, 9H), 0.85 (s, 9H), 0.019, 0.013 (two s, 6H);
13C NMR (75 MHz, CDCl3) δ 155.5, 138.3, 136.0, 135.9, 134.1,
133.4, 129.8, 129.8, 128.4, 127.7, 127.6, 127.5, 79.0, 73.3, 73.2,
73.0, 71.9, 64.0, 50.2, 29.8, 28.4, 28.1, 27.1, 25.9, 19.6, 18.2,
-5.3, -5.3; MS (ESI) m/z 744 [M + Na]+, 760 [M + K]+; HRMS
calcd for C41H63NO6Si2Na (M + Na) 744.4091, found 744.4087.
(2S,5S,6S)-2-Am in o-1-ben zyloxy-7-ter t-bu tyld im eth yl-
silyloxy-5-ter t-b u t yld ip h en ylsilyloxy-6-m et h a n esu lfon -
yloxyh ep ta n e (17). To a solution of 16 (295 mg, 0.37 mmol)
in dichloromethane (10 mL) at rt were added 2,6-lutidine (86
µL, 0.74 mmol) and TBDMSOTf (146 mg, 127 µL, 0.55 mmol),
successively. The reaction mixture was then stirred at rt for 1
h. After evaporation of dichloromethane, a solution of 1% citric
acid in methanol was added, and the mixture was stirred at
rt overnight. The solvent was evaporated. The residue was
separated into diluted sodium bicarbonate and EtOAc. The
aqueous phase was extracted with EtOAc (5×). The organic
phases were dried and evaporated. Flash column chromatog-
raphy on silica gel (CH2Cl2/MeOH ) 50/1 then 20/1) afforded
amine 17 (257 mg, 99%): [R]D -4 (c 3.9, CHCl3); IR (CHCl3)
3376, 3073, 3032, 2956, 2932, 2886, 2859, 1589, 1472, 1463,
1428, 1360, 1259, 1214, 1175, 1112, 931, 910, 838, 822 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.67-7.64 (m, 4H), 7.44-7.24
(m, 11H), 4.59-4.54 (m, 1H), 4.39 (s, 2H), 4.24 (br s, 2H, NH2),
3.98-3.86 (m, 3H), 3.19 (dd, J ) 9.6, 3.5 Hz, 1H), 3.05 (dd, J
) 9.6, 7.5 Hz, 1H), 2.96 (s, 3H), 2.78-2.70 (m, 1H), 1.68-1.56
(m, 1H), 1.46-1.33 (m, 1H), 1.29-1.22 (m, 2H), 1.05 (s, 9H),
0.88 (s, 9H), 0.067 (s, 3H), 0.055 (s, 3H); 13C NMR (62.5 MHz,
CDCl3) δ 138.3, 135.9, 133.6, 133.1, 130.0, 129.9, 128.3, 127.8,
127.6, 84.9, 75.0, 73.1, 72.6, 62.0, 50.7, 38.2, 29.7, 28.6, 27.0,
25.9, 19.4, 18.2, -5.4, -5.5; MS (ESI) m/z 700 [M + H]+; HRMS
calcd for C37H58NO6SSi2 (M + H) 700.3523, found 700.3510.
(2R,3S,6S)-6-Ben zyloxym eth yl-2-(ter t-bu tyld im eth ylsi-
la n yloxym eth yl)-3-(ter t-bu tyld ip h en ylsila n yloxy)p ip er -
id in e (18). A solution of 17 (264 mg, 0.38 mmol) and
diisopropylethylamine (98 mg, 132 µL, 0.76 mmol) in methanol
(38 mL) was refluxed for 48 h. The solvent was evaporated.
The residue was purified by flash column chromatography on
silica gel (CH2Cl2/MeOH ) 100/1 then 50/1 then 30/1) afforded
amine 18 (209 mg, 92%): [R]D +17 (c 1.7, CHCl3); IR (CHCl3)
3072, 3020, 3016, 3010, 2931, 2858, 1471, 1462, 1428, 1361,
1
1257, 1221, 1215, 1210, 1111, 1027, 838 cm-1; H NMR (300
MHz, CDCl3) δ 7.68-7.64 (m, 4H), 7.43-7.28 (m, 11H), 4.58,
4.53 (AB q, J ) 12.1 Hz, 2H), 3.95 (dd, J ) 9.5, 4.3 Hz, 1H),
3.66 (t, J ) 8.8 Hz, 1H), 3.58-3.53 (m, 1H), 3.34 (dd, J ) 9.1,
4.9 Hz, 1H), 3.27 (t, J ) 9.0 Hz, 1H), 3.09-3.05 (m, 1H), 2.91
(dt, J ) 8.0, 4.3 Hz, 1H), 2.81 (br s, 1H, NH), 1.68-1.43 (m,
4H), 1.05 (s, 9H), 0.84 (s, 9H), -0.00012 (s, 3H), -0.014 (s,
3H); 13C NMR (62.5 MHz, CDCl3) δ 138.5, 135.9, 134.6, 133.9,
129.7, 129.6, 128.4, 127.7, 127.6, 127.5, 73.4, 70.5, 70.4, 64.7,
58.1, 50.3, 29.4, 27.1, 26.0, 24.5, 19.4, 18.3, -5.3; MS (ESI)
m/z 604 [M + H]+; HRMS calcd for C36H54NO3Si2 (M + H)
604.3636, found 604.3642.
(2R,3S,6S)-6-Ben zyloxym eth yl-2-(ter t-bu tyld im eth ylsi-
la n yloxym eth yl)-3-(ter t-bu tyld ip h en ylsila n yloxy)p ip er -
id in e-1-ca r boxylic Acid ter t-Bu tyl Ester (19). To a solution
of 18 (389 mg, 0.65 mmol) in DMF (2 mL) at 0 °C were added
triethylamine (135 µL, 0.97 mmol) and Boc2O (174 mg, 0.77
mmol) at rt. The reaction mixture was stirred at rt for 24 h.
Water was added. The mixture was extracted with ether. The
ether extracts were washed with 1 M HCl, water, saturated
sodium bicarbonate, and brine, dried, and evaporated. Flash
column chromatography on silica gel (heptane/EtOAc ) 50/1
then 30/1) gave compound 19 (436 mg, 96%): [R]D -19 (c 2.3,
CHCl3); IR (CHCl3) 3072, 3026, 3018, 3008, 2956, 2930, 2884,
2858, 1680, 1471, 1462, 1453, 1427, 1391, 1366, 1340, 1291,
1254, 1220, 1218, 1211, 1171, 1111, 1028, 1006 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.64-7.59 (m, 4H), 7.41-7.32 (m, 11H),
4.64-4.50 (m, 2H), 4.27-4.25 (m, 1H), 4.15-4.02 (m, 2H),
3.85-3.77 (m, 1H), 3.56 (dd, J ) 9.5, 4.5 Hz, 1H), 3.44 (t, J )
9.4 Hz, 1H), 2.08-2.04 (m, 1H), 1.79-1.61 (m, 3H), 1.44 (s,
9H), 1.04 (s, 9H), 0.72 (s, 9H), -0.12 (s, 6H); 13C NMR (62.5
(2S,5S,6S)-1-Ben zyloxy-2-ter t-bu toxyca r bon yla m in o-7-
ter t-bu tyld im eth ylsilyloxy-5-ter t-bu tyld ip h en ylsilyloxy-
6-m eth a n esu lfon yloxyh ep ta n e (16). To a solution of 15
(5.75 g, 7.97 mmol) in dichloromethane (160 mL) at -20 °C
were added triethylamine (1.61 g, 2.22 mL, 15.94 mmol),
DMAP (1.17 g, 9.56 mmol), and MsCl (1.37 g, 925 µL, 11.96
mmol) successively. The reaction mixture was then stirred at
0 °C for 2 h. Water was added. The aqueous layer was
extracted with dichloromethane. The dichloromethane extracts
were washed with 1 M HCl, water, saturated sodium bicar-
bonate, and brine, dried, and evaporated. Flash column
chromatography on silica gel (heptane/EtOAc ) 10/1 then 8/1)
gave compound 16 (6.33 g, 99%): [R]D -6.9 (c 2.7, CHCl3); IR
(CHCl3) 3442, 3022, 2957, 2932, 2859, 1705, 1500, 1361, 1264,
1215, 1174, 1112, 930, 910, 838 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 7.69-7.66 (m, 4H), 7.44-7.21 (m, 11H), 4.58-4.53
(m, 1H), 4.49 (d, J ) 9.0 Hz, 1H), 4.41, 4.36 (AB q, J ) 12.0
Hz, 2H), 4.00-3.95 (m, 2H), 3.87 (dd, J ) 11.2, 7.7 Hz, 1H),
3.48 (m, 1H), 3.27 (dd, J ) 9.2, 4.0 Hz, 1H), 3.20 (dd, J ) 9.3,
3.8 Hz, 1H), 2.93 (s, 3H), 1.69-1.16 (m, 4H), 1.42 (s, 9H), 1.06
J . Org. Chem, Vol. 69, No. 14, 2004 4771