Total Synthesis of (-)-FR901483
J. Am. Chem. Soc., Vol. 121, No. 34, 1999 7785
LAH (2.25 mL, 1.0 M in THF) was added to a solution of the 7:1
mixture of 40 and 41 (268 mg, 0.75 mmol) in dry THF (7.5 mL)
dropwise at -78 °C. The resulting mixture was warmed to 0 °C, stirred
at 0 °C for 15 min and at reflux for 2 h, and cooled to 0 °C. Excess
EtOAc was added to quench the LAH. Water (26 µL), 15% NaOH (26
µL), and water (78 µL) were added. The granular precipitate was
removed by filtration, and the filtrate was concentrated to give 223
mg of a crude 7:1 mixture of diols. The data for 42 were determined
from the mixture: 1H NMR 7.20 (d, 2, J ) 8.8), 6.81 (d, 2, J ) 8.8),
3.94 (ddd, 1, J ) 11.6, 6.8, 4.8), 3.77 (s, 3), 3.65 (m, 1), 3.53 (dd, 1,
J ) 9.2, 7.6, H3â), 3.46 (m, 1), 3.15 (m, 1, H2), 2.86 (dd, 1, J ) 13.2,
4.8), 2.76 (dd, 1, J ) 13.2, 10.0), 2.48 (dd, 1, J ) 9.2, 5.6, H3R), 2.34
(s, 3), 2.23 (m, 1, H9â), 2.17 (m, 1), 2.0-1.9 (m, 2), 1.84 (dd, 1, J )
12.8, 9.6), 1.70 (m, 1), 1.35 (m, 1), 1.34 (dd, 1, J ) 12.4, 2.8), 1.28
(dd, 1, J ) 12.8, 2.8).
(2S,5S,6S,7S,8R,10aS)-2-[[(Benzyloxy)carbonyl]methylamino]-
octahydro-5-[(4-methoxyphenyl)methyl]-1H-7,10a-methanopyrrolo-
[1,2-a]azocine-6,8-diol (43). Et3N (223 µL, 1.60 mmol) was added to
a solution of the diol 42 and the diastereomer (223 mg, 0.64 mmol)
and CBZCl (137 µL, 0.96 mmol) in 6 mL of CH2Cl2 at 25 °C. The
reaction mixture was stirred overnight. The solvent was evaporated,
and the residue was purified by flash chromatography on silica gel
(14:5:1 CH2Cl2/EtOAc/CH3OH) to give 163 mg (52% of 43 based on
the amount of 40 in the mixture) of pure diol 43. The 1H NMR spectrum
is very broad due to slow rotation about the CBZ group and proton
exchange. The only characteristic proton is a broad doublet at δ 1.15.
Some peaks become a little sharper when CD3OD is used as solvent
and when the temperature was raised to 40 °C.
(2S,5S,6S,7R,8R,10aS)-2-[[(Benzyloxy)carbonyl]methylamino]-
octahydro-6-hydroxy-5-[(4-methoxyphenyl)methyl]-1H-7,10a-meth-
anopyrrolo[1,2-a]azocin-8-yl (4-Nitrobenzene)sulfonate (44). Et3N
(121 µL, 0.87 mmol) was added to a solution of N-CBZ diol 43 (139
mg, 0.29 mmol), p-nitrobenzenesulfonyl chloride (96 mg, 0.44 mmol),
and DMAP (35 mg, 0.29 mmol) in CH2Cl2 (3 mL) at -20 °C. The
solution was stirred at 0 °C for 5 h and then diluted with 20 mL of
EtOAc. The solution was washed with 0.1 N HCl and water and dried
(Na2SO4). The solvent was evaporated, and the residue was purified
by flash chromatography on silica gel (1:1 hexane/EtOAc) to give 105
mg (65%) of nosylate 44: 1H NMR (CD3OD) 8.45 (d, 2, J ) 8.8),
8.10 (d, 2, J ) 8.8), 7.37 (m, 5), 7.24 (d, 2, J ) 8.8), 6.87 (d, 2, J )
8.8), 5.11 (s, 2), 5.04 (ddd, 1, J ) 11.2, 8.0, 5.6), 4.76 (m, 1), 3.81 (s,
1), 3.64-3.58 (m, 2), 3.58 (br s, 1), 2.97-2.84 (m, 3), 2.72 (s, 3), 2.36
(m, 1, H7), 2.29 (br d, 1, J ) 13.2), 2.14-1.94 (m, 3), 1.86 (dd, 1,
J ) 13.4, 9.8), 1.74 (m, 1), 1.50 (dd, 1, J ) 13.4, 7.0), 1.15 (dd, 1,
J ) 13.2, 2.0); 1H NMR (CDCl3) 8.32 (d, 2, J ) 9.2), 7.94 (d, 2, J )
9.2), 7.34 (m, 5), 7.14 (d, 2, J ) 8.8), 6.84 (d, 2, J ) 8.8), 5.09 (s, 2),
4.97 (ddd, 1, J ) 9.6, 8.8, 5.2), 4.74 (m, 1), 3.82 (s, 3), 3.51 (m, 1),
3.45 (m, 2), 3.86 (dd, 1, J ) 13.4, 6.2), 2.80-2.74 (m, 2), 2.75 (s, 3),
2.36 (m, 1), 2.16 (br d, 1, J ) 12.8), 2.06 (m, 3), 1.88 (dd, 1, J ) 13.6,
10.4), 1.68 (d, 1, J ) 6.4, OH), 1.57 (m, 1), 1.44 (dd, 1, J ) 13.6,
6.4), 1.16 (br d, 1, J ) 12.8); 13C NMR (CD3OD) 160.0, 157.8, 152.4,
144.3, 138.3, 132.8, 131.3 (2 C), 130.3 (2 C), 129.7 (2 C), 129.2, 129.0
(2 C), 125.8 (2 C), 114.8 (2 C), 84.5, 68.4, 66.0, 60.8, 59.2, 55.8, 54.9,
53.3, 52.5, 51.6, 43.3, 36.7, 34.9, 29.7, 28.0; 13C NMR (CDCl3) 158.0,
156.2, 150.5, 142.9, 136.7, 130.5, 129.8 (2 C), 128.6 (2 C), 128.4 (2
C), 127.9 (2 C), 127.8, 124.4 (2 C), 113.8 (2 C), 82.9, 67.1, 65.1, 63.6,
59.3, 57.6, 55.2, 51.8, 50.1, 41.9, 41.6, 35.7, 33.1, 29.0, 28.7; IR (neat)
3455, 1694, 1682, 1610, 1538, 1514; [R]D 22 (c 0.28, CHCl3); HRMS
(FAB) calcd for C34H40N3O9S (MH+) 666.2485, found 666.2466.
(2S,5S,6S,7R,8R,10aS)-2-[[(Benzyloxy)carbonyl]methylamino]-6-
(triethylsilyloxy)octahydro-5-[(4-methoxyphenyl)methyl]-1H-7,10a-
methanopyrrolo[1,2-a]azocin-8-yl (4-Nitrobenzene)sulfonate (45).
TESOTf (60 µL, 0.25 mmol) was added to a solution of nosylate 44
(83 mg, 0.125 mmol) and Et3N (73 µL, 0.50 mmol) in 2 mL of CH2-
Cl2 at -20 °C. The solution was stirred at 0 °C for 2 h, diluted with 10
mL of EtOAc, which was washed with 0.1 N HCl, water, and brine
and dried (Na2SO4). The solvent was removed, and the residue was
purified by flash chromatography on silica gel (2:1 hexane/EtOAc) to
give 93 mg (99%) of 45: 1H NMR 8.39 (d, 2, J ) 8.8), 8.09 (d, 2,
J ) 8.8), 7.35-7.29 (m, 5), 7.18 (d, 2, J ) 8.8), 6.80 (d, 2, J ) 8.8),
5.05 (s, 2), 4.97 (ddd, 1, J ) 12.4, 7.2, 4.8), 4.74 (m, 1), 3.84 (br s, 1),
3.77 (s, 3), 3.68 (m, 1), 3.62 (m, 1), 2.92 (dd, 1, J ) 15.2, 9.6), 2.82
(br d, 1, J ) 11.2), 2.73 (dd, 1, J ) 15.2, 4.8), 2.41 (s, 3), 2.37 (br s,
1), 2.35 (br d, 1, J ) 11.6), 2.23 (dddd, 1, J ) 13.6, 13.2, 11.6, 8.0),
2.02 (ddd, 1, J ) 14.4, 8.0, 8.0), 1.86-1.69 (m, 3), 1.34 (dd, 1, J )
12.8, 6.8), 0.93 (t, 9, J ) 8.0), 0.88 (br d, 1, J ) 11.6), 0.55 (q, 6,
J ) 8.0); 13C NMR 157.8, 156.2, 150.6, 142.8, 136.9, 131.3, 129.5
(2 C), 128.9 (2 C), 128.4 (2 C), 127.8 (2 C), 127.7, 124.4 (2 C), 113.6
(2 C), 83.3, 68.7, 66.8, 57.5, 57.2, 55.2, 51.3, 50.7, 42.9, 42.6, 35.7,
35.0, 28.6, 27.8, 25.4, 7.0 (3 C), 4.9 (3 C); IR (neat) 1694; [R]D 35
(c 0.06, CHCl3); HRMS (FAB) calcd for C40H54N3O9SSi (MH+)
780.3350, found 780.3362.
(2S,5S,6S,7S,8S,10aS)-2-[[(Benzyloxy)carbonyl]methylamino]-6-
(triethylsilyloxy)octahydro-5-[(4-methoxyphenyl)methyl]-1H-7,10a-
methanopyrrolo[1,2-a]azocin-8-yl Acetate (46). A solution of 45 (93
mg, 0.12 mmol), 18-crown-6 (34 mg, 0.13 mmol), and CsOAc (69
mg, 0.36 mmol) in benzene (2 mL) was stirred at 80 °C for 2 h. The
resulting mixture was diluted with 20 mL of CH2Cl2, washed with water
and brine, dried (Na2SO4), and concentrated. Flash chromatography of
the residue on silica gel (3:1 hexane/EtOAc) gave 14.5 mg (20%) of
elimination product 47, followed by 56 mg (70%) of acetate 46: 1H
NMR 7.37-7.27 (m, 5), 7.17 (d, 2, J ) 8.4), 6.81 (d, 2, J ) 8.4), 5.08
(s, 2), 4.88 (m, 1), 4.80 (m, 1), 3.78 (s, 3), 3.70 (m, 1), 3.59 (br s, 1),
3.52 (m, 1), 2.90 (dd, 1, J ) 14.4, 9.2), 2.82 (br d, 1, J ) 11.2), 2.73
(dd, 1, J ) 14.4, 6.0), 2.51 (s, 3), 2.23 (dddd, 1, J ) 13.6, 10.4, 7.2,
7.2), 2.12 (br s, 1), 2.06 (s, 3), 1.96 (m, 1), 1.86 (m, 1), 1.77-1.60 (m,
3), 1.39 (dd, 1, J ) 12.8, 6.0), 1.26 (dd, 1, J ) 12.4, 2.4), 0.96 (t, 9,
J ) 7.6), 0.60 (q, 6, J ) 7.6); 13C NMR 170.5, 157.8, 156.2, 137.0,
131.6, 129.6 (2 C), 128.4 (2 C), 127.8, 127.7 (2 C), 113.6 (2 C), 71.5,
70.3, 66.8, 58.0, 56.1, 55.3, 51.6, 50.6, 44.1, 42.8, 35.7, 31.7, 28.0,
26.8, 21.4, 21.1, 7.0 (3 C), 5.0 (3 C); IR (neat) 1732, 1694, 1613, 1514;
[R]D -6 (c 0.11, CHCl3); HRMS (FAB) calcd for C36H53N2O6Si (MH+)
637.3673, found 637.3683.
Data for (2S,5S,6S,7S,10aS)-2-[[(benzyloxy)carbonyl]methylamino]-
6-(triethylsilyloxy)-2,3,5,6,7,10-hexahydro-5-[(4-methoxyphenyl)methyl]-
1H-7,10a-methanopyrrolo[1,2-a]azocine (47): 1H NMR 7.37-7.27 (m,
5), 7.16 (d, 2, J ) 8.4), 6.79 (d, 2, J ) 8.4), 5.87 (ddd, 1, J ) 9.6, 3.2,
3.2), 5.37 (ddd, 1, J ) 9.6, 6.4, 6.4), 5.08 (s, 2), 4.81 (m, 1), 3.83 (m,
1), 3.77 (s, 3), 3.54 (ddd, 1, J ) 9,6, 6.0, 2.0), 3.40 (dd, 1, J ) 2.8,
2.0), 2.86 (dd, 1, J ) 14.4, 9.6), 2.78 (br d, 1, J ) 10.4), 2.65 (dd, 1,
J ) 14.4, 6.0), 2.50 (ddd, 1, J ) 6.0, 6.0, 2.8), 2.47 (s, 3), 2.37 (br d,
1, J ) 18.8), 2.22 (m, 1), 2.06 (br d, 1, J ) 18.8), 1.95 (m, 1), 1.40
(dd, 1, J ) 12.0, 5.0), 1.08 (dd, 1, J ) 12.0, 2.8), 0.98 (t, 9, J ) 8.0),
0.61 (q, 6, J ) 8.0); 13C NMR 157.7, 156.3, 137.1, 132.1, 130.8, 129.7
(2 C), 128.6, 128.4 (2 C), 127.8, 127.8 (2 C), 113.4 (2 C), 70.6, 66.8,
58.3, 55.3, 52.7, 51.7, 49.8, 43.3, 39.0, 38.3, 35.6, 28.0, 24.8, 7.1 (3
C), 5.1 (3 C); IR (neat) 1699, 1612, 1585, 1514; [R]D -77.1 (c 0.68,
CHCl3); HRMS (FAB) calcd for C34H49N2O4Si (MH+) 577.3462, found
577.3453.
(2S,5S,6S,7S,8S,10aS)-2-[[(Benzyloxy)carbonyl]methylamino]-6-
(triethylsilyloxy)octahydro-5-[(4-methoxyphenyl)methyl]-1H-7,10a-
methanopyrrolo[1,2-a]azocin-8-ol (48). A solution of acetate 46 (56
mg, 88 µmol) and 10 mg of K2CO3 in MeOH (1 mL) was stirred at 25
°C for 3 h. The solution was filtered, and the filtrate was concentrated
under the reduced pressure. The residue was dissolved in 10 mL of
EtOAc, which was washed with water and brine and dried (Na2SO4).
Removal of the solvent afforded 48 mg (92%) of alcohol 48: 1H NMR
7.37-7.27 (m, 5), 7.18 (d, 2, J ) 8.4), 6.81 (d, 2, J ) 8.4), 5.08 (s, 2),
4.82 (m, 1), 3.90 (m, 1), 3.77 (s, 3), 3.63 (m, 1), 3.57 (ddd, 1, J ) 9.2,
6.0, 2.4), 3.51 (dd, 1, J ) 2.4, 2.4), 2.90 (dd, 1, J ) 14.4, 9.2), 2.81
(dd, 1, J ) 11.2, 2.8), 2.73 (dd, 1, J ) 14.4, 6.0), 2.53 (s, 3), 2.26
(dddd, 1, J ) 14.4, 10.4, 6.8, 6.8), 2.11 (br s, 1), 2.03 (m, 1), 1.91 (m,
2), 1.70 (m, 1), 1.60 (m, 1), 1.39 (dd, 1, J ) 12.8, 6.8), 1.36 (dd, 1,
J ) 12.4, 2.8), 0.97 (t, 9, J ) 7.6), 0.61 (q, 6, J ) 7.6); 13C NMR
157.7, 137.0, 131.7, 129.6 (2 C), 128.4 (2 C), 127.8, 127.7 (2 C), 113.5
(2 C), 71.8, 67.5, 66.8, 58.4, 56.2, 55.2, 51.6, 50.7, 45.9, 44.0, 35.7,
31.6, 30.2, 28.1, 20.6, 7.1 (3 C), 5.1 (3 C), (CBZ carbonyl was not
observed); [R]D -19 (c 0.17, CHCl3).
(2S,5S,6S,7R,8S,10aS)-2-[[(Benzyloxy)carbonyl]methylamino]-6-
(triethylsilyloxy)octahydro-5-[(4-methoxyphenyl)methyl]-1H-7,10a-
methanopyrrolo[1,2-a]azocin-8-yl Dibenzyl Phosphate (49). A so-
lution of alcohol 48 (48 mg, 81 µmol), 1-H-tetrazole (13 mg, 0.19