972 J. Am. Chem. Soc., Vol. 119, No. 5, 1997
Smith et al.
J ) 14.2 Hz, 1 H), 5.78 (d, J ) 11.1 Hz, 1 H), 4.70 (d, J ) 5.2 Hz,
1 H), 4.62 (br d, J ) 11.7 Hz, 1 H), 3.40 (dd, J ) 8.0, 4.9 Hz, 1 H),
2.93 (s, 3 H), 2.19 (br d, J ) 13.5 Hz, 1 H), 1.33 (d, J ) 1.0 Hz, 3 H),
1.01 (d, J ) 6.5 Hz, 3 H); 13C NMR (125 MHz, C6D6) major rotamer,
δ 198.0, 175.4, 167.7, 141.4, 138.6, 127.2, 102.6, 83.5, 79.9, 68.2, 55.9,
51.6, 44.6, 40.6, 36.9, 31.3, 27.0, 26.3, 24.8, 21.3, 16.3, 11.9, 7.5, 7.1;
minor rotamer, δ 198.1, 175.8, 166.5, 141.2, 138.3, 127.6, 102.6, 83.6,
80.1, 68.3, 55.8, 51.7, 41.1, 37.0, 31.5, 26.9, 24.6, 21.1, 16.4, 11.6,
7.5, 7.0; high-resolution mass spectrum (FAB, NBA) m/z 686.1971
[(M + Na)+; calcd for C28H46INO7SiNa, 686.1986].
206.1, 198.2, 170.0, 167.4, 139.5 (2 C),136.4, 132.5, 127.4, 127.2,
102.6, 87.1, 84.9, 83.6, 78.8, 75.9, 74.4, 68.1, 57.8, 57.3, 56.0, 51.8,
46.2, 44.3, 41.9, 41.4, 40.7, 40.6, 38.9, 37.2, 36.0, 35.9, 34.6, 34.5,
33.4, 32.2, 31.9, 30.7, 30.2, 27.1, 27.0, 26.1, 25.0, 22.2, 21.3, 18.5,
18.4, 16.4, 16.3, 16.0, 14.5, 14.0, 13.1, 11.1, 7.5, 7.0, -4.3, -4.5; high-
resolution mass spectrum (FAB, NBA) m/z 1320.8505 [(M + Na)+;
calcd for C72H127NO13Si3Na, 1320.8513].
10-O-TES-28-O-TBS-40-O-TIPS-27-demethoxyrapamycin [(-)-
73]. At ambient temperature a solution of iodo stannane (-)-72 (9
mg, 5 µmol) in THF and DMF (3:1, 2 mL) was treated with an aliquot
(1 mL) of a Pd catalyst stock solution, the latter freshly prepared by
addition of DIPEA (5 µL) to a solution of [(2-furyl)3P]2PdCl2 (3 mg,
4 µmol) in DMF (5 mL). The reaction mixture was stirred for 5 h and
then partitioned between ether and water (20 mL each). The organic
phase was washed with brine (10 mL), dried over MgSO4, filtered,
and concentrated. Flash chromatography (hexanes/ethyl acetate, 20:
1) afforded (-)-73 (5.0 mg, 74% yield) as a colorless oil: [R]2D3 -77°
(c 0.10, CHCl3); IR (CHCl3) 1740 (m), 1644 (m) cm-1; 1H NMR (500
MHz, C6D6) 4:1 mixture of rotamers, major rotamer, δ 6.26 (dd, J )
14.8, 11.0 Hz, 1 H), 6.08 (dd, J ) 14.8, 10.6 Hz, 1 H), 5.91 (d, J )
11.0 Hz, 1 H), 5.85 (dd, J ) 14.9, 10.6 Hz, 1 H), 5.55 (apparent q, J
) 5.0 Hz, 1 H), 5.43 (d, J ) 10.8 Hz, 1 H), 5.40 (d, J ) 5.1 Hz, 1 H),
5.33 (dd, J ) 14.9, 9.8 Hz, 1 H), 4.71 (d, J ) 8.5 Hz, 1 H), 4.38 (m,
1 H), 3.75 (m, 1 H), 3.68 (ddd, J ) 11.0, 8.3, 4.7 Hz, 1 H), 3.51 (dd,
J ) 11.4, 1.6 Hz, 1 H), 3.36-3.23 (m, 2 H), 3.32 (s, 3 H), 2.99 (s, 3
H), 2.91 (ddd, J ) 11.0, 8.1, 4.5 Hz, 1 H), 2.72-2.66 (m, 3 H), 2.34-
1.50 (m, 12 H), 1.71 (s, 3 H), 1.62 (s, 3 H), 1.46-1.08 (m, 44 H),
1.04-0.72 (m, 32 H), 0.19 (s, 3 H), 0.09 (s, 3 H); minor rotamer, δ
3.31 (s, 3 H), 3.08 (s, 3 H), 1.74 (s, 3 H), 1.65 (s, 3 H), 0.22 (s, 3 H),
0.10 (s, 3 H); 13C NMR (125 MHz, C6D6) mixture of rotamers, δ 209.6,
205.9, 197.8, 169.9, 167.5, 141.6, 141.1, 138.1, 133.4, 127.1, 124.0,
102.5, 84.8, 83.8, 75.8, 74.3, 72.3, 68.1, 57.1, 55.8, 52.1, 51.1, 46.5,
46.4, 44.3, 42.0, 41.2, 40.1, 39.9, 39.3, 37.2, 37.1, 35.9, 34.5, 34.1,
33.4, 31.9, 31.1, 30.1, 27.4, 26.7, 26.0, 24.9, 22.1, 21.2, 18.6, 18.4,
18.3, 17.8, 16.6, 16.4, 16.0, 15.6, 13.8, 13.0, 10.8, 7.5, 7.4, 7.1, 7.0,
-4.2, -4.3, -4.6, -4.7; high-resolution mass spectrum (FAB, NBA)
m/z 1290.8451 [(M + Na)+; calcd for C71H125NO12Si3Na, 1290.8407].
Rapamycin [(-)-1] via Hemiketal (-)-41. At 0 °C a solution of
synthetic tris(silyl ether) (-)-46 (7.5 mg, 6.0 µmol) in THF (1 mL)
was treated with an aliquot (5 drops) of a solution prepared by addition
of glacial AcOH (3 drops) to TBAF (1.0 M in THF, 0.5 mL). The
reaction mixture was stirred for 1 h and then partitioned between ether
and water (10 mL each). The organic phase was washed with water
and brine (10 mL each), dried over MgSO4, filtered, and concentrated.
Flash chromatography (hexanes/ethyl acetate, 10:1) gave (-)-41 (6.0
mg, 88% yield) as a colorless oil: [R]2D3 -83° (c 0.23, CHCl3); IR
(CHCl3) 3420 (br), 1720 (s), 1625 (s) cm-1; 1H NMR (500 MHz, C6D6)
4:1 mixture of rotamers, δ 6.45 (dd, J ) 12.0, 9.5 Hz, 2 H), 6.29 (d,
J ) 9.7 Hz, 1 H), 6.06 (dd, J ) 15.0, 9.7 Hz, 1 H), 5.47 (dd, J ) 15.0,
8.5 Hz, 1 H), 5.45-5.44 (m, 2 H), 5.40 (dt, J ) 7.3, 4.4 Hz, 1 H), 4.90
(s, 1 H), 4.42 (d, J ) 5.5 Hz, 1 H), 4.09 (m, 1 H), 3.89 (apparent t, J
) 7.8 Hz, 1 H), 3.83 (d, J ) 5.6 Hz, 1 H), 3.69-3.62 (m, 2 H), 3.43
(dd, J ) 13.3, 3.6 Hz, 1 H), 3.38 (dd, J ) 10.3, 6.7 Hz, 1 H), 3.30 (s,
3 H), 3.28 (s, 3 H), 3.09 (s, 3 H), 2.89 (ddd, J ) 11.0, 8.3, 4.4 Hz, 1
H), 2.77 (dd, J ) 16.3, 7.4 Hz, 1 H), 2.71 (m, 1 H), 2.63 (dd, J )
16.3, 4.5 Hz, 1 H), 2.23-2.07 (m, 5 H), 1.99-1.95 (m, 2 H), 1.77 (d,
J ) 0.8 Hz, 3 H), 1.71 (s, 3 H), 1.70-1.44 (m, 6 H), 1.41-1.21 (m,
8 H), 1.22-1.20 (m, 24 H), 1.11 (apparent t, J ) 6.8 Hz, 6 H), 1.06-
1.01 (m, 3 H), 0.96 (s, 9 H), 0.95 (overlapped d, 3 H), 0.90 (d, J ) 6.8
Hz, 3 H), 0.79 (q, J ) 12.2 Hz, 1 H), 0.17 (s, 3 H), 0.06 (s, 3 H);
minor rotamer, δ 6.11 (d, J ) 10.2 Hz, 1 H), 4.39 (d, J ) 7.4 Hz, 1
H), 3.17 (s, 3 H), 3.12 (s, 3 H), 0.13 (s, 3 H), 0.02 (s, 3 H); 13C NMR
(125 MHz, C6D6) mixture of rotamers, δ 209.2, 207.3, 194.1, 169.8,
167.0, 139.8, 137.9, 136.8, 133.5, 130.8, 99.2, 85.7, 84.8, 84.4, 79.2,
76.5, 75.8, 75.7, 67.4, 58.6, 57.1, 55.8, 51.8, 47.0, 44.3, 42.1, 42.0,
40.7, 38.7, 36.0, 35.5, 34.7, 34.5, 34.1, 33.4, 32.0, 31.6, 27.7, 26.9,
26.1, 25.2, 21.8, 20.7, 18.5, 16.5, 16.2, 15.6, 14.6, 13.1, 13.0, 10.5,
-4.5, -4.7; high-resolution mass spectrum (FAB, NBA) m/z 1206.7635
[(M + Na)+; calcd for C66H113NO13Si2Na, 1206.7648].
Rapamycin ABCDE Iodo Stannane (-)-71. A solution of ABC
alcohol (-)-3 (4.9 mg, 0.0050 mmol) and DE carboxylic acid (+)-5
(14 mg, 0.020 mmol) in dichloromethane (1 mL) was treated with a
mixture of EDC (4 mg, 0.020 mmol), DMAP (4 mg, 0.030 mmol),
and DMAP‚HCl (3 mg, 0.020 mmol) in one portion at ambient
temperature. The reaction mixture was stirred for 5 h and then
partitioned between ether (20 mL) and water (10 mL). The organic
phase was washed with 1 N HCl, water, and brine (10 mL each), dried
over MgSO4, filtered, and concentrated. Flash chromatography (hex-
anes/ethyl acetate, 10:1) furnished (-)-71 (4.8 mg, 58% yield) as a
viscous, colorless oil: [R]2D3 -32° (c 0.35, CHCl3); IR (CHCl3) 1730
(m), 1640 (m) cm-1 1H NMR (500 MHz, C6D6) 2:1 mixture of
;
rotamers, δ 7.18 (dd, J ) 14.1, 11.0 Hz, 1 H), 6.08 (d, J ) 18.9 Hz,
1 H), 6.08 (d, J ) 14.2 Hz, 1 H), 5.98 (dd, J ) 18.9, 7.3 Hz, 1 H),
5.76 (d, J ) 11.0 Hz, 1 H), 5.62 (dt, J ) 9.8, 3.0, 1 H), 5.34 (m, 2 H),
4.71-4.65 (m, 1 H), 4.50 (d, J ) 6.9 Hz, 1 H), 4.11 (m, 1 H), 4.01
(m, 1 H), 3.93 (d, J ) 7.2 Hz, 1 H), 3.66-3.54 (m, 3 H), 3.40-3.32
(m, 2 H), 3.31 (s, 3 H), 3.25 (s, 3 H), 2.93-2.85 (m, 3 H), 2.92 (s, 3
H), 2.70 (d, J ) 6.0 Hz, 1 H), 2.59 (dd, J ) 8.9, 2.7 Hz, 1 H), 2.45 (m,
1 H), 2.31 (m, 1 H), 2.25 (m, 1 H), 2.15-1.83 (m, 5 H), 1.80 (d, J )
1.2 Hz, 3 H), 1.76-1.55 (m, 12 H), 1.52-1.27 (m, 15 H), 1.26-1.12
(m, 48 H), 1.11-0.74 (m, 30 H), 0.11 (s, 3 H), 0.04 (s, 3 H); minor
rotamer, δ 7.24 (dd, J ) 14.1, 11.0 Hz, 1 H), 6.13 (d, J ) 14.2 Hz, 1
H), 5.92 (d, J ) 11.0 Hz, 1 H), 5.58 (m, 1 H), 4.70 (br s, 1 H), 3.31
(s, 3 H), 3.03 (s, 3 H), 1.81 (d, J ) 1.3 Hz, 3 H), 0.12 (s, 3 H), 0.06
(s, 3 H); 13C NMR (125 MHz, C6D6) mixture of rotamers, δ 211.2,
211.1, 207.5, 206.8, 198.4, 198.2, 169.9, 167.4, 166.6, 154.5 (2 C),
141.6, 141.3, 139.1, 138.3, 138.1, 127.5, 127.4, 102.8, 102.5, 85.3 (2
C), 84.9, 84.8, 83.6, 83.3, 80.1, 79.5, 78.7, 78.5 (2 C), 75.8, 75.3 (2
C), 68.7, 68.4, 58.0, 57.1, 57.0, 56.9, 56.0, 55.9, 51.9, 47.0, 46.9, 44.5,
42.9, 42.8, 41.9, 41.2, 40.7, 40.2, 40.1, 39.7, 39.3, 38.9, 37.0, 36.9,
36.2, 36.0, 34.6, 34.5, 34.1, 33.5 (2 C), 33.3, 31.6, 31.5, 30.2, 29.6,
27.9, 27.7, 26.1, 24.9, 23.1, 21.5, 21.1, 18.5, 18.4, 16.5, 16.4, 16.2,
15.6, 15.5, 15.2, 14.3, 14.0, 13.1, 12.4, 11.5, 9.9, 7.6, 7.5, 7.2, 7.1,
-4.3, -4.7; high-resolution mass spectrum (FAB, NBA) m/z 1738.8625
[(M + Na)+; calcd for C84H154INO13Si3SnNa, 1738.8693].
10-O-TES-28-O-TBS-40-O-TIPS-rapamycin (-)-46. B. From
(-)-71. A solution of iodo stannane (-)-71 (8.6 mg, 0.0050 mmol)
in THF and DMF (1:1, 0.6 mL) was treated with diisopropylethylamine
(1 µL) and [(2-furyl)3P]2PdCl2 (0.6 mg, 0.001 mmol)] at ambient
temperature. The reaction mixture was stirred for 7 h and then
partitioned between ether and water (10 mL each). The organic phase
was washed with brine (10 mL), dried over MgSO4, filtered, and
concentrated. Flash chromatography (hexanes/ethyl acetate, 10:1)
furnished (-)-46 (4.8 mg, 74% yield) as a colorless oil: [R]2D3 -86° (c
0.04, CHCl3); IR (CHCl3) 1730 (s), 1640 (s) cm-1; 1H NMR (500 MHz,
C6D6) 10:1 mixture of rotamers, δ 6.31 (dd, J ) 14.8, 11.0 Hz, 1 H),
6.17 (dd, J ) 14.8, 10.6 Hz, 1 H), 6.06 (d, J ) 11.0 Hz, 1 H), 5.92
(dd, J ) 15.0, 10.6 Hz, 1 H), 5.55 (d, J ) 10.2 Hz, 1 H), 5.47 (d, J )
4.6 Hz, 1 H), 5.25 (dd, J ) 15.0, 9.6 Hz, 1 H), 4.39 (d, J ) 3.0 Hz, 1
H), 4.36 (d, J ) 9.7 Hz, 1 H), 3.88 (d, J ) 4.0 Hz, 1 H), 3.74-3.68
(m, 2 H), 3.62 (d, J ) 10.0 Hz, 1 H), 3.52 (apparent t, J ) 12.3 Hz,
1 H), 3.34 (s, 3 H), 3.20 (dd, J ) 10.2, 6.6 Hz, 1 H), 3.17 (s, 3 H),
3.02 (s, 3 H), 2.93 (ddd, J )12.7, 8.3, 4.5 Hz, 1 H), 2.78 (ddd, J )
12.8, 7.5, 4.3 Hz, 1 H), 2.68 (dd, J ) 17.7, 3.9 Hz, 1 H), 2.55 (dd, J
) 17.7, 8.9 Hz, 1 H), 2.54 (m, 1 H), 2.35 (dt, J ) 13.9, 3.4 Hz, 1 H),
2.13-2.02 (m, 2 H), 1.99 (dq, J ) 12.9, 3.0 Hz, 1 H), 1.88 (d, J )
10.1 Hz, 1 H), 1.81 (dd, J ) 12.9, 3.0 Hz, 1 H), 1.76 (s, 3 H), 1.69-
1.59 (m, 2 H), 1.65 (s, 3 H), 1.50-1.26 (m, 6 H), 1.24-1.15 (series of
m, 9 H), 1.20 (s, 21 H), 1.09 (d, J ) 6.7 Hz, 3 H), 1.07 (d, J ) 6.5 Hz,
3 H), 1.02 (s, 9 H), 0.99-0.84 (series of m, 27 H), 0.25 (s, 3 H), 0.11
(s, 3 H); minor rotamer, δ 3.09 (s, 3 H), 3.05 (s, 3 H), 0.08 (s, 3 H),
0.06 (s, 3 H); 13C NMR (125 MHz, C6D6) mixture of rotamers, δ 208.7,
At 0 °C a solution of synthetic hemiketal (-)-41 (5.1 mg, 4.3 µmol)
in THF (0.5 mL) was treated with pyridine (0.5 mL) followed by
HF‚pyridine (0.5 mL). The reaction mixture was warmed to ambient
temperature, stirred for 48 h, and then partitioned between ether and