1908 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 9
Wipf et al.
SiO2 (hexanes/EtOAc, 4:1) to give (2S)-3-(tert-butyldimethyl-
trated, and chromatographed on SiO2 (hexanes/EtOAc, 3:2) to
give (1R,2Z,6E,8E,12R)-N-(1-hydroxymethyl-12-methoxy-9-
methylpentadeca-2,6,8,14-tetraenyl)-2,2-dimethylpropiona-
mide (31 mg, 0.082 mmol, 82%) as an oil. 1H NMR: δ 6.24
(dd, 1 H, J ) 15.1, 10.8 Hz), 5.87-5.73 (m, 3 H), 5.65-5.48
(m, 2 H), 5.37-5.30 (m, 1 H), 5.11-5.04 (m, 2 H), 4.75-4.70
(m, 1 H), 3.67-3.55 (m, 2 H), 3.34 (s, 3 H), 3.19 (p, 1 H, J )
5.8 Hz), 3.11 (t, 1 H, J ) 5.6 Hz), 2.30-1.98 (m, 8 H), 1.72 (s,
3 H), 1.66-1.55 (m, 2 H), 1.20 (s, 9 H).
silanyloxy)-2-(2,2-dimethylpropionylamino)propionic acid meth-
1
yl ester (8.41 g, 26.5 mmol, 89%) as an oil. H NMR: δ 6.49
(br d, 1 H, J ) 7.1 Hz), 4.62 (dt, 1 H, J ) 8.1, 2.8 Hz), 4.05
(dd, 1 H, J ) 10.0, 2.5 Hz), 3.81 (dd, 1 H, J ) 10.0, 3.1 Hz),
3.74 (s, 3 H), 1.22 (s, 9 H), 0.85 (s, 9 H), 0.03 (s, 3 H), 0.01 (s,
3 H).
(2R)-N-[2-(ter t-Bu tyld im eth ylsila n yloxy)-1-h yd r oxym -
eth yleth yl]-2,2-d im eth ylp r op ion a m id e (31). A solution of
(2S)-3-(tert-butyldimethylsilanyloxy)-2-(2,2-dimethylpropiony-
lamino)propionic acid methyl ester (5.21 g, 16.4 mmol) in THF
(30 mL) was treated with LiCl (1.39 g, 32.8 mmol), NaBH4
(1.25 g, 32.8 mmol), and EtOH (60 mL). The reaction mixture
was stirred at room temperature overnight, cooled with ice
water, adjusted to pH 4 by gradual addition of 10% aqueous
citric acid solution, and concentrated. H2O was added, and the
solution was extracted with CH2Cl2. The organic layer was
washed with saturated NaHCO3, dried (MgSO4), concentrated,
and chromatographed on SiO2 (hexanes/EtOAc, 1:1) to give 31
(3.37 g, 11.7 mmol, 71%) as an oil; [R]D +11.9 (c 1.2, CHCl3).
IR (neat): 3450, 3366, 2954, 2859, 1644, 1513, 1469, 1255,
1101, 840 cm-1. 1H NMR: δ 6.34 (br d, 1 H, J ) 6.9 Hz), 3.93-
3.85 (m, 1 H), 3.79-3.66 (m, 3 H), 3.62-3.53 (m, 2 H), 1.16 (s,
9 H), 0.85 (s, 9 H), 0.03 (2s, 6 H). 13C NMR: δ 179.1, 63.5,
63.1, 51.9, 38.8, 27.5, 25.8, 18.1, -5.5, -5.6. MS (EI) m/z
(relative intensity): 289 (M+, 1), 232 (35), 84 (100). HRMS (EI)
calcd for C14H31NO3Si, 289.2073; found, 289.2071.
(2S)-N-[2-(ter t-Bu tyldim eth ylsilan yloxy)-1-for m yleth yl]-
2,2-d im eth ylp r op ion a m id e (32). A solution of oxalyl chlo-
ride (0.45 mL, 5.2 mmol) in CH2Cl2 (5 mL) was treated at -60
°C with dimethyl sulfoxide (DMSO; 0.49 mL, 6.9 mmol)
followed by a solution of alcohol 31 (1.01 g, 3.46 mmol) in CH2-
Cl2 (10 mL). After 15 min at -60 °C, Et3N (1.9 mL, 13.8 mmol)
was added dropwise. The reaction mixture was allowed to
warm over 20 min, quenched with H2O, diluted with hexanes,
washed with saturated KHSO4 solution, dried (MgSO4), con-
centrated, and chromatographed on SiO2 (hexanes/EtOAc, 4:1)
to give 32 (775 mg, 2.70 mmol, 78%) as an oil. 1H NMR: δ
9.62 (s, 1 H), 6.60-6.50 (br, 1 H), 4.50 (ddd, 1 H, J ) 9.9, 4.2,
3.0 Hz), 4.21 (dd, 1 H, J ) 10.4, 3.0 Hz), 3.85 (dd, 1 H, J )
10.4, 4.2 Hz), 1.24 (s, 9 H), 0.86 (s, 9 H), 0.04 (s, 6 H).
(4R)-2-ter t-Bu t yl-4-[(1Z,5E,7E,11R)-11-m et h oxy-8-m e-
th yltetr a d eca -1,5,7,13-tetr a en yl]-4,5-d ih yd r ooxa zole (26).
A solution of (1R,2Z,6E,8E,12R)-N-(1-hydroxymethyl-12-meth-
oxy-9-methylpentadeca-2,6,8,14-tetraenyl)-2,2-dimethylpropi-
onamide (31 mg, 0.082 mmol) in CH2Cl2 (3 mL) was treated
dropwise at -25 °C with Deoxo-Fluor (50 µL, 0.54 mmol). After
25 min at -20 °C, the reaction mixture was quenched with
saturated NaHCO3 solution and extracted with CH2Cl2. The
organic extract was dried (MgSO4), concentrated, and chro-
matographed on SiO2 (hexanes/EtOAc, 19:1) to give 26 (26.8
mg, 0.0747 mmol, 91%) as an oil; [R]D +9.9 (c 0.61, CHCl3). IR
1
(neat): 2974, 2922, 1651, 1137, 1097, 962 cm-1. H NMR: δ
6.23 (dd, 1 H, J ) 14.9, 10.8 Hz), 5.87-5.74 (m, 2 H), 5.58-
5.48 (m, 2 H), 5.33 (t, 1 H, J ) 9.3 Hz), 5.11-5.04 (m, 2 H),
4.84 (q, 1 H, J ) 9.3 Hz), 4.34 (dd, 1 H, J ) 9.5, 8.2 Hz), 3.76
(t, 1 H, J ) 8.2 Hz), 3.34 (s, 3 H), 3.19 (p, 1 H, J ) 5.9 Hz),
2.29-2.02 (m, 8 H), 1.72 (s, 3 H), 1.62-1.55 (m, 2 H), 1.22 (s,
9 H). 13C NMR: δ 136.7, 134.7, 131.4, 131.1, 130.9, 127.3,
124.6, 117.0, 79.8, 72.9, 63.0, 56.5, 37.6, 35.3, 32.8, 31.6, 27.8,
16.5. MS (EI) m/z (relative intensity): 359 (M+, 100), 318 (75).
HRMS (EI) calcd for C23H37NO2, 359.2824; found, 359.2825.
HPLC analysis: (C18, MeCN, ELSD) tR ) 5.58 min, 99.9%; (C18
MeOH/H2O (9:1), ELSD) tR ) 7.62 min, 100%.
,
2-ter t-Bu tyl-4-[(1Z,5E,7E,11R)-11-m eth oxy-8-m eth yltet-
r a d eca -1,5,7,13-tetr a en yl]oxa zole (27). A solution of 26 (22
mg, 0.061 mmol) in hexanes (8 mL) was treated with 85%
MnO2 (605 mg, 6.95 mmol). The reaction mixture was stirred
at room temperature for 50 h and filtered through a short pad
of SiO2, and the filtrate was concentrated and chromato-
graphed on SiO2 (hexanes/EtOAc, 24:1) to give 27 (9.8 mg,
0.027 mmol, 45%) as an oil; [R]D -6.9 (c 0.23, CHCl3). IR (neat)
2974, 2927, 1640, 1572, 1461, 1362, 1105, 962 cm-1. 1H NMR:
δ 7.46 (s, 1 H), 6.32-6.10 (m, 2 H), 5.87-5.66 (m, 3 H), 5.60
(dt, 1 H, J ) 14.2, 6.9 Hz), 5.11-5.03 (m, 2 H), 3.33 (s, 3 H),
3.19 (p, 1 H, J ) 5.9 Hz), 2.49-2.41 (m, 2 H), 2.32-2.22 (m, 4
H), 2.15-1.99 (m, 2 H), 1.72 (s, 3 H), 1.62-1.55 (m, 2 H), 1.37
(s, 9 H). 13C NMR δ 170.4, 137.3, 136.6, 134.9, 134.7, 133.0,
131.3, 127.2, 124.6, 119.1, 116.9, 79.8, 56.5, 37.6, 35.3, 33.5,
32.5, 31.5, 29.5, 28.5, 16.5. MS (EI) m/z (relative intensity):
357 (M+, 8), 284 (15). HRMS (EI) calcd for C23H35NO2,
357.2668; found, 357.2674. HPLC analysis: (C18, MeCN,
ELSD) tR ) 6.11 min, 100%; (C18, MeOH/H2O (9:1), ELSD) tR
) 11.16 min, 100%.
(1R ,2Z,6E ,8E ,12R )-N -[1-(t er t -Bu t yld im e t h ylsila n yl-
oxym eth yl)-12-m eth oxy-9-m eth ylp en ta d eca -2,6,8,14-tet-
r aen yl]-2,2-dim eth ylth iopr opion am ide. A solution of amide
34 (120 mg, 0.244 mmol) in toluene (4 mL) was treated with
Lawesson’s reagent (59.0 mg, 0.146 mmol). The reaction
mixture was heated at 70 °C for 2.5 h, cooled to room
temperature, concentrated, and chromatographed on SiO2
(hexanes/EtOAc, 97:3) to give (1R,2Z,6E,8E,12R)-N-[1-(tert-
butyldimethylsilanyloxymethyl)-12-methoxy-9-methylpentadeca-
2,6,8,14-tetraenyl]-2,2-dimethyl-thiopropionamide (22 mg, 0.043
mmol, 18%) as an oil. 1H NMR: δ 7.75 (br d, 1 H, J ) 5.8 Hz),
6.25 (dd, 1 H, J ) 15.0, 10.8 Hz), 5.88-5.74 (m, 2 H), 5.66-
5.35 (m, 4 H), 5.12-5.04 (m, 2 H), 3.89-3.84 (m, 1 H), 3.65-
3.60 (m, 1 H), 3.34 (s, 3 H), 3.23-3.16 (m, 1 H), 2.37-2.00 (m,
8 H), 1.73 (bs, 3 H), 1.60-1.54 (m, 2 H), 1.33 (s, 9 H), 0.90 (s,
9 H), 0.06 (s, 3 H), 0.05 (s, 3 H).
(1R,2Z,6E,8E,12R)-N-[1-(ter t-Bu tyldim eth ylsilan yloxym -
eth yl)-12-m eth oxy-9-m eth ylpen tadeca-2,6,8,14-tetr aen yl]-
2,2-d im eth ylp r op ion a m id e (34). A solution of phosphonium
salt 33 (494 mg, 0.810 mmol) in THF (7 mL) was treated
dropwise at -78 °C with 2 M solution of NaHMDS in THF
(0.50 mL, 1.0 mmol). The reaction mixture was stirred for 45
min at -78 °C and then treated with a solution of aldehyde
32 (459 mg, 1.60 mmol) in THF (3 mL). The reaction mixture
was allowed to warm to room temperature overnight, quenched
with H2O, and extracted with Et2O. The organic extract was
dried (MgSO4), concentrated, and chromatographed on SiO2
(hexanes/EtOAc, 19:1) to give 34 (150 mg, 0.305 mmol, 38%)
as an oil; [R]D +7.5 (c 1.8, CHCl3). IR (neat): 3358, 3366, 2931,
1
1640, 1501, 1255, 1097, 836 cm-1. H NMR: δ 6.23 (dd, 1 H,
J ) 15.1, 10.8 Hz), 6.02 (br d, 1 H, J ) 7.3 Hz), 5.88-5.74 (m,
2 H), 5.60-5.39 (m, 3 H), 5.12-5.04 (m, 2 H), 4.73-4.64 (m, 1
H), 3.67 (dd, 1 H, J ) 9.8, 3.9 Hz), 3.55 (dd, 1 H, J ) 9.8, 3.7
Hz), 3.34 (s 3 H), 3.19 (p, 1 H, J ) 8.2 Hz), 2.32-2.23 (m, 4
H), 2.21-2.01 (m, 4 H), 1.72 (s, 3 H), 1.62-1.55 (m, 2 H), 1.18
(s, 9 H), 0.90 (s, 9 H), 0.05 (s, 6 H). 13C NMR: δ 177.4, 136.4,
134.8, 132.5, 131.3, 127.9, 127.3, 124.8, 116.9, 79.9, 77.2, 65.4,
56.5, 48.0, 38.7, 37.7, 35.4, 32.9, 31.6, 27.8, 27.6, 25.8, 18.2,
16.5, -5.5. MS (EI) m/z (relative intensity): 491 (M+, 14), 434
(62). HRMS (EI) calcd for C29H53NO3Si, 491.3795; found,
491.3794.
(1R,2Z,6E,8E,12R)-N-(1-Hyd r oxym eth yl-12-m eth oxy-9-
m eth ylp en ta d eca -2,6,8,14-tetr a en yl)-2,2-d im eth ylp r op i-
on a m id e. A solution of 34 (49 mg, 0.10 mmol) in THF (10
mL) was treated at 0 °C with HF‚pyridine complex (0.28 mL).
The reaction mixture was stirred at 0 °C for 30 min and then
at room temperature for 14 h. The solution was diluted with
Et2O, poured into saturated aqueous NaHCO3, and extracted
with EtOAc. The organic extract was dried (MgSO4), concen-
(1R,2Z,6E,8E,12R)-N-(1-Hyd r oxym eth yl-12-m eth oxy-9-
m et h ylp en t a d eca -2,6,8,14-t et r a en yl)-2,2-d im et h ylt h io-
p r op ion a m id e. A solution of (1R,2Z,6E,8E,12R)-N-[1-(tert-
butyldimethylsilanyloxymethyl)-12-methoxy-9-methylpentadeca-
2,6,8,14-tetraenyl]-2,2-dimethylthiopropionamide (22 mg, 0.043
mmol) in THF (9 mL) was treated at 0 °C with HF‚pyridine