Dias and Meira
over four steps) as a pale yellow oil: Rf 0.72 (5% EtOAc/
hexane); IR νmax (film, cm-1) 3075, 2988, 2930, 1108; 1H NMR
(300 MHz, CDCl3) δ 0.04 (s, 3H), 0.05 (s, 3H), 0.15 (s, 9H),
0.71 (d, 3H, J 6.9 Hz), 0.82 (t, 3H, J 6.9 Hz), 0.87 (d, 3H, J 7.3
Hz), 0.89 (s, 9H), 0.97 (d, 3H, J 6.9 Hz), 1.00-1.18 (m, 1H),
1.37 (m, 1H), 1.42-1.62 (m, 2H), 1.71 (s, 3H), 2.66-2.54 (m,
1H), 3.45 (dd, 1H, J 8.2, 2.2 Hz), 3.63 (ap t, 1H, J 3.4 Hz),
5.64 (d, 1H, J 9.5 Hz), 6.10 (d, 1H, J 14.6 Hz), 7.04 (d, 1H, J
14.6 Hz); 13C NMR (75 MHz, CDCl3) δ -3.4, -3.1, 1.3, 12.1,
12.3, 12.6, 13.8, 18.6, 19.3, 26.1, 26.2, 35.1, 41.5, 41.6, 72.5,
76.0, 79.4, 132.9, 136.0, 150.0; HRMS calcd for C24H49IO2Si2
[M+] 552.2316, found 552.2308.
2H), 6.58 (d, 1H, J 15.8 Hz); 13C NMR (125 MHz, CDCl3) δ
-3.6, -3.3, 1.5, 12.4, 12.9, 13.7, 13.8, 18.7, 19.7, 20.9, 22.2,
24.0, 24.3, 24.5, 26.3, 26.5, 31.0, 32.4, 35.5, 41.2, 41.7, 41.9,
67.3, 69.9, 76.1, 80.3, 93.6, 125.2, 126.5, 127.6, 128.7, 128.8,
132.3, 132.4, 135.9, 136.1, 137.0. HRMS calcd for C38H69O4Si2
[(M - C3H7)+] 645.4734, found 645.4722.
The same experimental procedure was used for the coupling
of (E)-vinyl iodide 39 with alkyl iodide 2, providing coupled
product 41 in 67% isolated yield.
(2R,6R)-6-((1E,3Z,5R,7E,9E,11R,12R,13R,14R,15S)-14-
(tert-Butyldimethylsilyloxy)-3-ethyl-12-hydroxy-5,9,11,-
13,15-pentamethylheptadeca-1,3,7,9-tetraenyl)-5,6-dihy-
dro-2H-pyran-2-ol (42). To the mixture containing lactols 40
and 41 as well as aldehyde 43 obtained before in anhydrous
THF (1 mL) at ambient temperature was added water (0.17
mL) and glacial AcOH (0.17 mL), and the resulting solution
was stirred for 4 days. The reaction was quenched by the slow
addition of saturated aqueous NaHCO3 (10 mL), and the
phases were separated. The aqueous layer was extracted with
EtOAc (3 × 5 mL), and the combined organic layers were
washed with brine (5 mL), dried with MgSO4, and concentrated
in vacuo to give lactol 42 (0.020 g, 38%, over two steps) and
R,â-unsaturated aldehyde 43 (0.013 g, 25%, over two steps)
as colorless oils.
(1E,3E,5R,6R,7R,8R,9S)-8-(tert-Butyldimethylsilyloxy)-
1-iodo-3,5,7,9-tetramethylundeca-1,3-dien-6-ol (39).4f To
a solution of (E)-vinyl iodide 3 (0.187 g, 0.34 mmol) in
anhydrous ethanol (3 mL) at ambient temperature was added
camphor sulfonic acid (CSA, 0.015 g). The reaction mixture
was stirred at ambient temperature for 12 h before it was
concentrated in vacuo. The remaining organic residue was
purified by flash chromatography on silica gel (5% EtOAc/
hexane, deactivated with Et3N) to provide the desired product
39 (0.156 g, 96%) as a viscous yellow oil: Rf 0.61 (15% EtOAc/
hexane); [R]20D +41.2 (c 1.17, CHCl3); IR νmax (film, cm-1) 3473,
1
3080, 2980, 1110; H NMR (300 MHz, CDCl3) δ 0.06 (s, 3H),
0.10 (s, 3H), 0.70 (d, 3H, J 6.8 Hz), 0.88 (t, 3H, J 7.2 Hz), 0.93
(s, 9H), 0.98 (d, 3H, J 6.8 Hz), 1.05 (d, 3H, J 6.8 Hz), 1.20-
1.37 (m, 3H), 1.70 (m, 1H), 1.73 (d, 3H, J 1.1 Hz), 2.54 (m,
1H), 3.63 (m, 2H), 4.2 (br s, 1H), 5.7 (d, 1H, J 10.3 Hz), 6.14
(d, 1H, J 14.5 Hz), 7.00 (d, 1H, J 14.5 Hz); 13C NMR (75 MHz,
CDCl3) δ -4.8, -4.2, 11.9, 12.1, 13.7, 15.4, 17.5, 18.0, 25.8,
26.0, 29.0, 35.6, 41.5, 72.8, 77.3, 80.4, 134.0, 135.2, 150.0;
HRMS calcd for C21H41IO2Si [M+] 480.1921, found 480.1916.
(R)-6-((1E,3Z,5R,7E,9E,11R,12R,13R,14R,15S)-14-(tert-
Butyldimethylsilyloxy)-3-ethyl-12-hydroxy-5,9,11,13,15-
pentamethylheptadeca-1,3,7,9-tetraenyl)-5,6-dihydropy-
ran-2-one (44). To a solution of lactol 42 (0.011 g) in freshly
distilled CH2Cl2 (3 mL) was added activated manganese(IV)
oxide (0.024 g, 0.2 mmol). The resulting mixture was stirred
at ambient temperature for 20 h, filtered through Celite, and
concentrated in vacuo to give (C17)-hydroxy lactone 44 (0.0079
(2R,6R)-2-((1E,3Z,5R,7E,9E,11R,12R,13S,14R,15S)-14-
(tert-Butyldimethylsilyloxy)-3-ethyl-5,9,11,13,15-pen-
tamethyl-12-(trimethylsilyloxy)heptadeca-1,3,7,9-
tetraenyl)-6-isopropoxy-3,6-dihydro-2H-pyran (40) and
(3S,4R,5R,6R,7R,8E,10E,13R,14Z,16E)-4-(tert-Butyldi-
methylsilyloxy)-15-ethyl-17-((2R,6R)-6-isopropoxy-3,6-di-
hydro-2H-pyran-2-yl)-3,5,7,9,13-pentamethylheptadeca-
8,10,14,16-tetraen-6-ol (41). To a solution of alkyl iodide 2
(0.055 g, 0.14 mmol) in anhydrous Et2O (2 mL) at ambient
temperature was added 9-MeO-9-BBN (0.37 mL, 1.0 M in
hexanes). The mixture was cooled to -78 °C, and t-BuLi (0.19
mL, 1.7 M in pentane) was added rapidly. The resulting
mixture was stirred for 10 min; THF (2.0 mL) was added, and
the mixture was warmed to ambient temperature and stirred
for an additional 1 h. In a separate flask, vinyl iodide 3 (0.051
g, 0.092 mmol) was dissolved in DMF (1.5 mL), and Pd(dppf)-
Cl2 (0.0034 g, 0.0046 mmol), AsPh3 (0.0042 g, 0.014 mmol),
CsCO3 (0.12 g, 0.37 mmol), and water (0.040 mL, 2.2 mmol)
were added. The ethereal solution of alkyl boronate prepared
before was then cannulated into the DMF solution, and the
resulting mixture was stirred for 15 h at ambient temperature.
The reaction mixture was partitioned between Et2O and H2O,
the organic layer extracted with Et2O (3 × 10 mL), and then
the organic layer was washed with brine, dried over anhydrous
MgSO4, filtered, and evaporated to give a 34:66 mixture of
lactols 40 and 41, respectively, together with R,â-unsaturated
aldehyde 43. This mixture was carried on without further
purification, although an analytical sample of lactol 40 was
obtained for purposes of comparison with that described by
Lautens and Stammers.4g Lactol 40: Rf 0.38 (5% EtOAc/
hexane); [R]20D +55.3 (c 2.15, CHCl3); IR νmax (film, cm-1) 2965,
g, 72%) as a viscous oil: Rf 0.12 (30% EtOAc/hexanes); [R]20
D
+51.4 (c 0.27, CHCl3); IR νmax (film, cm-1) 3485, 2975, 1725,
1468, 1250; 1H NMR (500 MHz, CDCl3) δ 0.67 (s, 3H), 0.08 (s,
3H), 0.71 (d, 3H, J 7.0 Hz), 0.90 (t, 3H, J 7.3 Hz), 0.91 (s, 9H),
0.95 (d, 3H, J 7.1 Hz), 0.98 (d, 3H, J 7.0 Hz), 1.03 (t, 3H, J 6.9
Hz), 1.07 (d, 3H, J 6.9 Hz), 1.20 (m, 1H), 1.35 (m, 1H), 1.57
(m, 1H), 1.72 (d, 3H, J 0.9 Hz), 1.75 (m, 1H), 2.10 (t, 2H, J 6.9
Hz), 2.18 (q, 1H, J 7.3 Hz), 2.20 (q, 1H, J 7.1 Hz), 2.46 (m,
2H), 2.57 (m, 1H), 2.64 (m, 1H), 3.63 (d, 1H, J 9.7 Hz), 3.67 (t,
1H, J 0.8 Hz), 4.08 (br s, 1H), 4.97 (q, 1H, J 7.1 Hz), 5.3 (d,
1H, J 9.3 Hz), 5.3 (dt, 1H, J 15.5, 7.5 Hz), 5.6 (d, 1H, J 9.9
Hz), 5.8 (dd, 1 H, J 15.7, 6.7 Hz), 6.00 (m, 2H), 6.67 (d, 1H, J
15.7 Hz), 6.87 (dt, 1H, J 9.9, 4.0 Hz); 13C NMR (125 MHz,
CDCl3) δ -4.6, -4.0, 12.1, 12.9, 13.6, 14.0, 15.7, 18.2, 20.7,
26.1, 26.5, 29.1, 30.1, 30.4, 32.7, 35.8, 36.1, 41.2, 41.5, 78.1,
79.2, 80.9, 122.1, 125.0, 125.2, 130.3, 131.4, 133.4, 135.5, 137.1,
137.6, 145.1, 164.5. HRMS calcd for C36H64O4Si [M+] 588.4574,
found 588.4563.
(R)-6-((1E,3Z,5R,7E,9E,11R,13S,14R,15S)-14-(tert-Bu-
tyldimethylsilyloxy)-3-ethyl-5,9,11,13,15-pentamethyl-12-
oxoheptadeca-1,3,7,9-tetraenyl)-5,6-dihydropyran-2-
one (45). To a solution of (C17)-hydroxy lactone 44 (0.0056 g,
0.010 mmol) in freshly distilled CH2Cl2 (1 mL) was added
Dess-Martin periodinane (0.012 g, 0.02 mmol). The resulting
mixture was stirred at ambient temperature for 1 h, filtered
through Celite, and concentrated in vacuo. Purification by
silica gel flash column chromatography (5% EtOAc/hexane)
gave ketolactone 45 (C19-TBS callystatin A) (0.0044 g, 81%)
as a colorless oil: Rf 0.32 (30% EtOAc/hexane); [R]20D -81.1 (c
0.045, CH2Cl2); IR νmax (film, cm-1) 3032, 2930, 2857, 1733,
1712, 1460; 1H NMR (500 MHz, CDCl3) δ 0.03 (s, 3H), 0.04 (s,
3H), 0.73 (d, 3H, J 6.6 Hz), 0.82 (t, 3H, J 7.2 Hz), 0.90 (s, 9H),
0.95 (d, 3H, J 6.5 Hz), 1.05 (t, 3H, J 7.3 Hz), 1.08 (d, 3H, J 7.1
Hz), 1.12 (d, 3H, J 7.0 Hz), 1.80 (d, 3H, J 1.1 Hz), 2.07 (m,
3H), 2.18 (m, 2H), 2.34 (m, 1H), 2.46 (m, 2H), 2.65 (m, 1H),
2.82 (m, 1H), 3.64 (m, 1H), 3.86 (dd, 1H, J 7.7, 1.9 Hz), 5.01
(m 1H), 5.18 (d, 1H, J 9.7 Hz), 5.25 (d, 1H, J 9.7 Hz), 5.7 (dt,
1H, J 15.6, 7.0 Hz), 5.8 (dd, 1H, J 15.9, 6.8 Hz), 6.02 (d, 1H,
J 15.7 Hz), 6.04 (dt, 1H, J 9.9, 1.6 Hz), 6.62 (d, 1H, J 15.7
Hz), 6.91 (dt, 1H, J 9.4, 4.2 Hz); 13C NMR (125 MHz, CDCl3)
1
2930, 2880, 1465, 1182, 1100; H NMR (500 MHz, CDCl3) δ
0.03 (s, 3H), 0.05 (s, 3H), 0.15 (s, 9H), 0.72 (d, 3H, J 7.0 Hz),
0.83 (d, 3H, J 6.9 Hz), 0.85 (t, 3H, J 7.3 Hz), 0.89 (s, 9H), 0.96
(m, 6H), 1.04 (t, 3H, J 7.3 Hz), 1.05 (m, 1H), 1.16 (d, 3H, J 6.3
Hz), 1.25 (d, 3H, J 6.2 Hz), 1.37 (m, 1H), 1.65 (m, 1H), 1.70 (d,
3H J 0.8 Hz), 2.08 (m, 4H), 2.20 (m, 2H), 2.39 (m, 1H), 2.66
(m, 2H), 2.77 (m, 1H), 3.48 (dd, 1H, J 7.7, 2.1 Hz), 3.65 (t, 1H,
J 3.6 Hz), 4.01 (hept, 1H, J 6.1 Hz), 4.50 (m, 1H), 5.12 (s, 1H),
5.21 (d, 1H, J 9.4 Hz), 5.47 (m, 2H), 5.73 (m, 2H), 6.04 (m,
4772 J. Org. Chem., Vol. 70, No. 12, 2005