Probing the SAR of dEpoB via Chemical Synthesis
reaction mixture was diluted with cold saturated NaHCO3 (80
mL) and extracted with Et2O (2 × 100 mL). The combined
extracts were dried over Na2SO4, filtered, and concentrated
to provide a mixture of silyl enol ether isomers (5.871 g) which
was used without further purification.
NMR (100 MHz, CDCl3) δ 164.6, 152.6, 141.3, 134.2, 119.1,
115.0, 107.1, 76.4, 60.4, 48.5, 43.4, 19.0, 14.3, 6.8, 4.7; HRMS
(EI+) calcd for C19H33INO2SSi (M + H)+ 494.1046, found
494.1032.
Com p ou n d 17. A solution of 16 (1.29 g, 2.62 mmol) and
pyridine (0.45 mL, 5.56 mmol) in CH2Cl2 (13 mL) at 0 °C was
treated with 2,2,2-trichloroethyl chloroformate (0.50 mL, 3.63
mmol). After 10 min at 0 °C, the reaction mixture was warmed
to room temperature and stirred for 1 h. The reaction mixture
was then washed with saturated NaHCO3 (2 × 15 mL), dried
over MgSO4, filtered, and concentrated. Purification by silica
gel chromatography (10:1 hex:EtOAc) provided 17 (1.52 g, 86%)
A homogeneous solution of K3Fe(CN)6 (13.18 g, 40.0 mmol),
K2CO3 (5.52 g, 39.9 mmol), MeSO2NH2 (1.39 g, 14.2 mmol),
(DHQ)2PHAL (0.524 g, 0.673 mmol), and OsO4 (2.5 wt % in
tert-butyl alcohol, 1.37 mL, 0.134 mmol) was cooled to 0 °C
and treated with the crude silyl enol ether. After 80 min, the
reaction mixture was quenched with saturated Na2SO3 (130
mL), warmed to room temperature, and stirred for 30 min.
The reaction mixture was extracted with EtOAc (3 × 150 mL).
The combined extracts were dried over MgSO4, filtered, and
concentrated The crude product was dissolved in 4:1 THF:H2O
(100 mL), treated with HOAc (2 mL), and allowed to stir
overnight. The reaction mixture was coevaporated with toluene
and the residue was purified by silica gel chromatography (1:1
hex:EtOAc) to provide a mixture of diol and MeSO2NH2 (3.155
g).
as a light yellow oil: [R]22 9.1° (c 1.00, CHCl3); IR (thin film)
D
2954, 2908, 2874, 1759, 1502, 1452, 1392, 1242, 1071, 1003
1
cm-1; H NMR (400 MHz, CDCl3) δ 6.93 (s, 1H), 6.47 (s, 1H),
5.69 (t, J ) 6.6 Hz, 1H), 4.73 (s, 2H), 4.31 (t, J ) 6.7 Hz, 2H),
4.21 (t, J ) 6.3 Hz, 1H), 2.86 (t, J ) 6.6 Hz, 2H), 2.69 (s, 3H),
2.46-2.36 (m, 2H), 2.00 (s, 3H), 0.92 (t, J ) 8.0 Hz, 9H), 0.58
(q, J ) 7.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 164.3, 153.7,
152.8, 141.3, 135.3, 118.9, 115.3, 102.4, 94.3, 76.6, 76.6, 67.4,
44.0, 43.6, 19.2, 14.1, 6.8, 4.7; HRMS (EI+) calcd for C22H34
-
The crude product and imidazole (3.03 g, 44.5 mmol) were
dissolved in DMF (20 mL) and treated with TESCl (5.6 mL,
33.3 mmol). The reaction mixture was stirred at room tem-
perature for 1 h and then poured into H2O (20 mL) and
extracted with EtOAc (3 × 25 mL). The combined extracts were
washed with H2O and then brine, dried over MgSO4, filtered,
and concentrated. The residue was purified by silica gel
chromatography (1:1 hex:EtOAc) to provide the bis-TES ether
Cl3INO4SSi (M + H)+ 668.0093, found 668.0095.
Com p ou n d 19. A solution of 18 (1.63 g, 2.57 mmol) in
degassed THF (5.0 mL) was added to a flask containing 9-BBN
dimer (0.477 g, 1.95 mmol) and stirred for 3 h, after which
time excess 9-BBN dimer was quenched by the addition of
degassed H2O (1.55 mL, 86.1 mmol). The reaction was stirred
for 20 min and then cannulated into a suspension of 17 (1.46
g, 2.18 mmol), Cs2CO3 (1.07 g, 3.28 mmol), AsPh3 (0.134 g,
0.44 mmol), and PdCl2(dppf)‚CH2Cl2 (0.182 g, 0.22 mmol) in
degassed DMF (12 mL) at 0 °C. After addition of the borane
solution, the reaction mixture was warmed to room temper-
ature and stirred for 5 h. Then additonal AsPh3 (0.131 g, 0.43
mmol) and PdCl2(dppf)‚CH2Cl2 (0.181 g, 0.22 mmol) were
added, and the reaction mixture was allowed to stir. After 15
h the reaction mixture was poured into Et2O (50 mL) and
washed with H2O (2 × 25 mL). The aqueous layer was back-
extracted with Et2O (2 × 25 mL). The combined Et2O extracts
were dried over MgSO4, filtered, and concentrated. Purification
by silica gel chromatography (10:1 hexanes:EtOAc) provided
a mixture of product (1.97 g) and borane impurities, which
was carried on to the next step without further purification.
13 (3.875 g, 50% overall) as a clear oil: [R]22 0.1° (c 0.90,
D
CHCl3); IR (thin film) 2954, 2910, 2876, 1718, 1457, 1417,
1352, 1239, 1104, 1006 cm-1 1H NMR (400 MHz, CDCl3) δ
;
5.59 (t, J ) 6.6 Hz, 1H), 4.08 (t, J ) 6.3 Hz, 1H), 3.70 (t, J )
6.7 Hz, 2H), 2.68 (t, J ) 6.6 Hz, 2H), 2.48-2.39 (m, 2H), 2.17
(s, 3H), 0.96-0.87 (m, 18H), 0.63-0.48 (m, 12H); 13C NMR (100
MHz, CDCl3) δ 210.8, 131.6, 107.0, 77.4, 61.8, 48.4, 41.8, 25.3,
6.7, 6.7, 4.7, 4.4; HRMS (EI+) calcd for C20H42IO3Si2 (M + H)+
513.1717, found 513.1700.
Com p ou n d 15. A solution of phosphine oxide 1418 (1.82 g,
5.82 mmol) in THF (70 mL) at -78 °C was treated with n-BuLi
(1.6 M, 3.6 mL, 5.8 mmol) dropwise and stirred for 30 min. A
solution of ketone 13 (2.00 g, 3.90 mmol) in THF (20 mL) was
added via cannula to the previously prepared red-orange
lithiated phosphine oxide solution and stirred at -78 °C. After
50 min, the reaction was warmed to room temperature, stirred
for an additional 50 min, and then quenched with saturated
NaHCO3 (50 mL). The reaction mixture was diluted with H2O
(50 mL) and extracted with EtOAc (3 × 100 mL). The combined
extracts were washed with brine, dried over MgSO4, filtered,
and concentrated. The residue was purified by silica gel
chromatography (10:1 hex:EtOAc) to provide 15 (2.04 g, 86%)
A solution of the crude product in CH2Cl2 (16 mL) at 0 °C
was treated with 2,6-lutidine (1.20 mL, 10.3 mmol) and then
TESOTf (1.10 mL, 4.86 mmol) and allowed to stir for 15 min,
after which the reaction was warmed to room temperature and
stirred for 21 h. Then, the reaction was washed with saturated
NaHCO3 (3 × 25 mL), dried over MgSO4, filtered, and
concentrated. 2,6-Lutidine was removed by repeated coevapo-
ration with toluene. A solution of the resulting syrup in THF
(16 mL) at 0 °C was treated with small portions of 0.12 N HCl
in MeOH over the course of 4 h (10.0 mL total) until starting
material was completely consumed, after which the reaction
was poured into saturated NaHCO3 (25 mL). The reaction was
then diluted with H2O (25 mL) and extracted with CHCl3 (3
× 25 mL). The combined extracts were dried over MgSO4,
filtered, and concentrated. Purification by silica gel chroma-
tography (1:1 f 3:1 EtOAc:hex) provided 19 (0.760 g, 35%
as a clear syrup: [R]22 9.43° (c 1.05, CHCl3); IR (thin film)
D
2953, 2910, 2874, 1506, 1457, 1413, 1377, 1238, 1182, 1094,
1005 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.91 (s, 1H), 6.46 (s,
1H), 5.58 (t, J ) 6.6 Hz, 1H), 4.20 (t, J ) 6.4 Hz, 1H), 3.68 (t,
J ) 7.0 Hz, 2H), 2.69-2.65 (m, 5H), 2.39-2.35 (m, 2H), 2.00
(s, 3H), 0.92 (t, J ) 3.9 Hz, 18H), 0.60-0.53 (m, 12H); 13C NMR
(100 MHz, CDCl3) δ 164.3, 153.0, 141.6, 133.7, 118.9, 115.2,
105.2, 77.0, 62.0, 48.4, 43.7, 19.2, 14.1, 6.8, 6.7, 4.8, 4.3; HRMS
(EI+) calcd for C25H47INO2SSi2 (M + H)+ 608.1911, found
608.1919.
overall) as a clear syrup: [R]22 -52.0° (c 1.10, CH2Cl2); IR
D
(thin film) 3420, 2957, 2865, 1756, 1700, 1652, 1456, 1385,
1
1249, 1062 cm-1; H NMR (400 MHz, CDCl3) δ 6.94 (s, 1H),
Com p ou n d 16. A solution of 15 (2.30 g, 3.79 mmol) in
MeOH (41 mL) at 0 °C was treated with HOAc (1.00 mL, 17.4
mmol.). After 11 h, the reaction mixture was quenched with
Et3N (2.7 mL, 19.4 mmol), warmed to room temperature, and
absorbed onto silica gel (10 g). Purification by silica gel
chromatography provided 16 (1.498 g, 80%) as a clear syrup:
6.70 (s, 1H), 5.20 (t, J ) 7.0 Hz, 1H), 4.90 (d, J ) 12.0 Hz,
1H), 4.73 (s, 2H), 4.68 (dd, J ) 2.6, 8.5 Hz, 1H), 4.64 (d, J )
12.0 Hz, 1H), 4.45-4.42 (m, 1H), 4.23 (t, J ) 7.0 Hz, 2H), 4.09
(dd, J ) 5.0, 7.5 Hz, 1H), 3.42-3.39 (m, 1H), 2.68 (s, 3H), 2.54
(dd, J ) 1.8, 16.9 Hz, 1H), 2.38-2.22 (m, 5H), 2.15-2.03 (m,
2H), 1.98-1.92 (m, 4H), 1.73-1.69 (m, 1H), 1.48-1.41 (m, 2H),
1.30-1.23 (m, 2H), 1.13 (s, 3H), 1.09-1.07 (m, 6H), 0.98 (d, J
[R]22 -7.9° (c 1.34, CHCl3); IR (thin film) 3342, 2952, 2910,
D
2874, 1502, 1460, 1414, 1376, 1239, 1184, 1070, 1006 cm-1
;
1H NMR (400 MHz, CDCl3) δ 6.89 (s, 1H), 6.42 (s, 1H), 5.65 (t,
J ) 6.8 Hz, 1H), 4.24 (t, J ) 6.2 Hz, 1H), 3.67 (m, 2H), 2.74-
2.63 (m, 5H), 2.56 (s br, 1H), 2.43 (t, J ) 6.7 Hz, 2H), 1.97 (s,
3H), 0.93 (t, J ) 8.0 Hz, 9H), 0.58 (q, J ) 7.8 Hz, 6H); 13C
) 6.2 Hz, 3H), 0.94 (t, J ) 7.9 Hz, 9H), 0.66-0.60 (m, 6H); 13
C
NMR (100 MHz, C6D6) δ 214.1, 175.2, 165.3, 154.9, 154.4,
153.1, 142.3, 137.0, 124.6, 118.9, 115.3, 95.5, 95.2, 81.1, 77.2,
76.8, 76.7, 73.3, 67.9, 55.1, 40.5, 40.3, 35.9, 35.0, 34.2, 32.3,
J . Org. Chem, Vol. 67, No. 22, 2002 7735