A Total Synthesis of FK-506
J . Org. Chem., Vol. 61, No. 20, 1996 6867
) 1.8), 4.99 (d, 1H, J ) 8.7), 4.53 (d, 1H, J ) 12.0), 4.35-4.25
(m, 1H), 3.80-3.51 (m, 4H), 3.34 (s, 3H), 3.17-3.07 (m, 1H),
2.25-2.12 (m, 1H), 1.93-1.85 (m, 1H), 1.54 (s, 3H), 1.48 (s,
3H), 1.31 (s, 3H), 1.70-1.19 (m, 8H), 1.06 (s, 9H), 0.88 (s, 9H),
0.85 (s, 9H), 0.61 (d, 3H, J ) 6.9), 0.07 (s, 3H), 0.06 (s, 3H),
-0.02 (s, 3H), -0.11 (s, 3H); 13C NMR δ 136.5, 136.4, 135.6,
134.8, 134.2, 132.6, 131.4, 130.6, 129.8, 127.8, 99.4, 94.2, 84.7,
79.9, 76.2, 64.5, 63.8, 62.8, 57.8, 41.9, 38.1, 36.5, 35.2, 34.2,
31.4, 30.6, 27.5, 26.4, 26.2, 25.0, 19.8, 18.6, 18.5, 11.1, 10.0,
-3.6, -4.2, -4.3, -4.6. Anal. Calcd for C51H84O7Si3: C, 68.56;
H, 9.48. Found: C, 68.22; H, 9.39.
-0.01 (s, 3H), -0.03 (s, 3H); 13C NMR δ (toluene-d8 100 °C)
170.6, 155.3, 136.4, 136.3, 135.8, 135.3, 133.9, 133.5, 131.6,
129.5, 127.5, 99.4, 94.1, 84.4, 79.9, 79.3, 75.9, 65.6, 64.8, 64.0,
56.3, 54.8, 41.9, 40.2, 37.8, 36.0, 35.4, 33.9, 31.0, 30.6, 28.5,
27.4, 27.0, 25.9, 25.2, 24.2, 21.0, 19.4, 18.2, 13.0, 9.8, -4.6.
Anal. Calcd for C56H87NO10Si2: C, 67.91; H, 8.85; N, 1.41.
Found: C, 68.01; H, 8.95; N, 1.46.
Alcoh ol 29. To a solution of the silyl ether 28 (0.430 g,
0.43 mmol) in 50 mL of THF at 0 °C was added TBAF (0.480
mL of a 1.0 M solution in THF, 0.48 mmol). The reaction was
allowed to stir for 25 min and then was partitioned between
EtOAc/H2O. The organic layer was washed with H2O, dried
over K2CO3, and concentrated. Chromatography (5% to 25%
to 50% EtOAc/hexanes) afforded 0.327 g (84%) of the alcohol:
Alcoh ol 27b. To a solution of the bis-TBS ether 26b (0.116
g, 0.13 mmol) in 10 mL of THF at 0 °C was added TBAF (140
µL of a 1.0 M solution in THF, 0.14 mmol). The reaction was
allowed to stir for 1 h at which time H2O and EtOAc were
added. The layers were separated, and the aqueous layer was
extracted twice with EtOAc. The combined organic extracts
were washed with saturated NaCl, dried over Na2SO4, and
concentrated. Chromatography (25% EtOAc/hexanes) afforded
[R]23 -21.5 (c 0.70, CHCl3); IR 3420, 2940, 2860, 1730, 1690,
D
1370, 1250, 1150, 1100, 790 cm-1; 1H NMR δ (toluene-d8, 100
°C) 7.83-7.75 (m, 4H), 7.25-7.14 (m, 6H), 5.58 (d, 1H, J )
9.9), 5.40 (d, 1H, J ) 10.2), 5.35 (d, 1H, J ) 6.9), 5.26 (d, 1H,
J ) 8.7), 4.95-4.85 (m, 1H), 4.23-4.14 (m, 1H), 4.10-3.85 (m,
3H), 3.75-3.62 (m, 1H), 3.51 (d, 2H, J ) 8.1), 3.14 (s, 3H),
3.12-2.99 (m, 2H), 2.17-2.04 (m, 3H), 1.98-1.87 (m, 1H),
1.80-1.70 (m, 2H), 1.66 (s, 3H), 1.56 (s, 3H), 1.49 (s, 3H), 1.41
(s, 9H), 1.18 (s, 9H), 1.60-1.25 (m, 7H), 1.05 (d, 3H, J ) 6.6),
1.00-0.78 (m, 3H); 13C NMR (toluene-d8, 100 °C) δ 170.7,
155.4, 136.4, 136.3, 135.8, 135.3, 133.7, 133.0, 132.0, 131.4,
129.5, 127.6, 127.5, 99.4, 94.1, 84.4, 80.0, 79.4, 75.9, 65.6, 64.1,
63.4, 56.3, 54.9, 42.0, 40.1, 37.6, 36.0, 35.4, 33.9, 31.0, 30.6,
28.5, 27.4, 27.0, 25.2, 24.2, 20.9, 19.4, 13.0, 9.8. Anal. Calcd
for C50H73NO10Si: C, 68.54; H, 8.40; N, 1.60. Found: C, 68.36;
H, 8.43; N, 1.53.
0.055 g (54%) of the alcohol: [R]23 +12.4 (c 2.75, CHCl3); IR
D
3360 (b), 3040, 2910, 2840, 1450, 1420, 1370, 1250, 1100, 700
1
cm-1; H NMR δ 7.80-7.70 (m, 4H), 7.45-7.32 (m, 6H), 5.84
(d, 1H, J ) 10.2), 5.59 (dd, 1H, J ) 10.2, J ) 1.5), 5.01 (d, 1H,
J ) 8.7), 4.54 (d, 1H, J ) 11.7), 4.33-4.20 (m, 1H), 3.84-3.73
(m, 2H), 3.66-3.53 (m, 3H), 3.36 (s, 3H), 3.17-3.09 (m, 1H),
2.30-2.15 (m, 1H), 1.95-1.87 (m, 1H), 1.75-1.27 (m, 8H), 1.56
(s, 3H), 1.50 (s, 3H), 1.33 (s, 3H), 1.07 (s, 9H), 0.86 (s, 9H),
0.63 (d, 3H, J ) 6.9), 0.00 (s, 3H), -0.09 (s, 3H); 13C NMR δ
136.4, 135.8, 135.6, 134.8, 132.9, 132.7, 132.6, 129.8, 127.8,
99.6, 94.2, 84.7, 79.9, 76.2, 64.0, 63.9, 62.9, 57.9, 41.9, 37.7,
36.5, 35.2, 34.1, 31.4, 30.6, 27.5, 26.4, 25.0, 19.8, 18.6, 11.1,
10.0, -3.6, -4.7. Anal. Calcd for C45H70O7Si2: C, 69.36; H,
9.05. Found: C, 69.13; H, 9.13.
Sp ir oen on e 3. To a solution of the alcohol 29 (0.321 g, 0.37
mmol) in 10 mL of CH2Cl2 was added Dess-Martin periodi-
nane (0.233 g, 0.55 mmol). After stirring for 45 min, the
reaction mixture was diluted with Et2O. Saturated aqueous
Na2S2O3 and NaHCO3 were added, and the biphasic mixture
was vigorously stirred until the organic layer was clear. The
aqueous layer was extracted twice with Et2O, dried over K2-
CO3, and concentrated. Chromatography (25% EtOAc/hex-
anes) afforded 0.302 g (94%) of the enone: [R]23D -38.9 (c 1.70,
CHCl3); IR 3050, 2930, 2840, 1730, 1700, 1690, 1380, 1250,
Sp ir oen on e 16b. To a solution of the alcohol 27b (0.055
g, 0.07 mmol) in 2 mL of CH2Cl2 was added Dess-Martin
periodinane (0.045 g, 0.11 mmol). After stirring for 45 min,
the reaction mixture was diluted with Et2O. Saturated
aqueous Na2S2O3 and NaHCO3 were added, and the biphasic
mixture was vigorously stirred until the organic layer was
clear. The aqueous layer was extracted twice with Et2O, dried
over K2CO3, and concentrated. Chromatography (25% EtOAc/
1150, 1100, 780, 700 cm-1 1H NMR (toluene-d8, 100 °C) δ
;
hexanes) afforded 0.053 g (96%) of the enone: [R]23 -7.6 (c
7.83-7.78 (m, 4H), 7.21-7.19 (m, 6H), 6.20 (d, 1H, J ) 9.9),
5.74 (d, 1H, J ) 10.2), 5.34 (d, 1H, J ) 6.3), 5.24 (d, 1H, J )
9.0), 4.90-4.84 (bs, 1H), 4.18 (d, 1H, J ) 16.5), 4.20-4.09 (m,
1H), 4.05-3.93 (m, 1H), 3.81 (d, 1H, J ) 16.5), 3.71-3.61 (m,
1H), 3.15 (s, 3H), 3.13-2.97 (m, 2H), 2.23-2.03 (m, 3H), 1.97-
1.88 (m, 1H), 1.80-1.71 (m, 2H), 1.56 (s, 3H), 1.56-1.45 (m,
1H), 1.39 (s, 9H), 1.39 (s, 3H), 1.31 (s, 3H), 1.17 (s, 9H), 1.40-
1.09 (m, 7H), 1.01 (d, 3H, J ) 6.9), 0.89-0.75 (m, 2H); 13C
NMR (toluene-d8, 100 °C) δ 193.0, 170.7, 155.5, 148.0, 136.4,
136.3, 135.7, 135.3, 133.6, 131.4, 129.6, 127.6, 127.5, 126.9,
99.8, 93.7, 84.3, 79.4, 79.2, 75.9, 66.5, 65.9, 56.4, 54.8, 42.0,
40.0, 36.8, 36.0, 35.3, 33.8, 30.7, 30.6, 28.5, 27.4, 27.0, 25.2,
23.6, 20.9, 19.4, 13.1, 9.6. Anal. Calcd for C50H71NO10Si: C,
68.70; H, 8.19; N, 1.60. Found: C, 68.42; H, 8.14; N, 1.54.
[2S ,3R ,5S ,6R ]-2,5-Dim e t h oxy-6-(h yd r oxym e t h yl)-3-
m eth yltetr a h yd r op yr a n (33). To a solution of 7.58 g (43.0
mmol) of diol 32 in 75 mL of pyridine was added 18.0 g (64.6
mmol) of TrCl, and the solution was allowed to stir for 12 h at
room temperature. The reaction was diluted with ether and
washed with water, saturated CuSO4, and brine. The aqueous
washings were back extracted with ether, and the combined
organic layers were dried over MgSO4, filtered, and concen-
trated in vacuo. The crude trityl ether thus obtained was
dissolved in 150 mL of THF, and 3.9 g (130 mmol) of an 80%
dispersion of NaH was added in portions, followed by 8.0 mL
(129 mmol) of iodomethane. The reaction was stirred for 24
h and was then quenched by slow addition of water. The
reaction was filtered through Celite, and the THF was removed
in vacuo. The residue was diluted with ether and washed with
water and brine. The aqueous extracts were back extracted
with ether, and the combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The crude methyl
ether was then diluted with 200 mL of MeOH, and concd HCl
was added until pH ) 2. The reaction was stirred for 5 h,
solid NaHCO3 was added, and the reaction was filtered. The
D
2.65, CHCl3); IR 3050, 2920, 2840, 1695, 1375, 1250, 1100
1
cm-1; H NMR δ 7.78-7.70 (m, 4H), 7.40-7.32 (m, 6H), 6.64
(d, 1H, J ) 10.2), 6.04 (d, 1H, J ) 10.2), 5.01 (d, 1H, J ) 8.7),
4.57 (d, 1H, J ) 11.7), 4.40 (d, 1H, J ) 16.8), 4.05 (d, 1H, J )
16.8), 3.79 (d, 1H, J ) 9.0), 3.60-3.52 (m, 1H), 3.35 (s, 3H),
3.17-3.08 (m, 1H), 2.28-2.14 (m, 1H), 1.94-1.75 (m, 2H), 1.58
(s, 3H), 1.50 (s, 3H), 1.35 (s, 3H), 1.70-1.25 (m, 7H), 1.06 (s,
9H), 0.85 (s, 9H), 0.64 (d, 3H, J ) 6.9), -0.02 (s, 3H), -0.10
(s, 3H); 13C NMR δ 195.8, 149.3, 136.4, 135.6, 134.8, 132.8,
129.8, 129.7, 127.8, 127.3, 100.0, 93.9, 84.7, 79.9, 76.2, 66.6,
63.2, 57.9, 41.9, 37.5, 36.5, 35.2, 34.1, 31.1, 30.6, 27.5, 26.3,
24.4, 19.8, 18.6, 11.1, 10.0, -3.6, -4.7. Anal. Calcd for C45H68
O7Si2: C, 69.54; H, 8.82. Found: C, 69.28; H, 8.90.
-
P ip ecola te Ester 28. A flask containing the alcohol 24a
(4.0 g, 5.13 mmol) was dried under high vacuum for 1 h, and
then the flask was purged with argon. N-BOC-(L)-pipecolic
acid (20) (3.53 g, 15.4 mmol), DCC (3.50 g, 16.9 mmol), and
DMAP (0.125 g, 1.03 mmol) were then added to the flask, and
the contents were placed under high vacuum for 1 h. The flask
was then filled with argon and cooled to -20 °C, and 350 mL
of CH2Cl2 was added. After stirring for 10 min, the reaction
flask was placed in a -20 °C freezer for 48 h. The contents
were filtered and washed with hexanes, and the filtrate was
concentrated. Silica gel chromatography (5% EtOAc/hexanes)
gave 5.14 g (100%) of the pipecolate ester: [R]23D -15.6 (c 0.90,
CHCl3); IR 2920, 2850, 1730, 1690, 1390, 1360, 1250, 1150,
1100, 870, 780 cm-1 1H NMR δ (toluene-d8, 100 °C) 7.84-
;
7.75 (m, 4H), 7.24-7.15 (m, 6H), 5.70 (d, 1H, J ) 10.2), 5.42
(d, 1H, J ) 9.9), 5.34 (d, 1H, J ) 6.6), 5.25 (d, 1H, J ) 8.7),
4.90-4.83 (bs, 1H), 4.25-4.18 (m, 2H), 4.05-3.90 (m, 1H),
3.78-3.55 (m, 3H), 3.12 (s, 3H), 3.12-2.97 (m, 2H), 2.20-2.02
(m, 3H), 1.97-1.86 (m, 1H), 1.80-1.65 (m, 3H), 1.56 (s, 3H),
1.49 (s, 3H), 1.47-1.12 (m, 6H), 1.40 (s, 9H), 1.40 (s, 3H), 1.16
(s, 9H), 1.04 (d, 3H, J ) 6.9), 1.03-0.86 (m, 3H), 0.86 (s, 9H),