Total Syntheses of Pumiliotoxins A and B
J. Am. Chem. Soc., Vol. 118, No. 38, 1996 9071
1
1023 cm-1; H NMR (500 MHz, CDCl3) δ 6.19 (d, 1H, J ) 9.4 Hz),
of saturated aqueous NH4Cl (3 mL), water (1 mL), and Rochelle’s salt
(0.5 g) and then was stirred vigorously for 1 h. The organic layer was
separated, the aqueous layer was extracted with CH2Cl2 (3 × 10 mL),
and the combined extracts were dried (MgSO4) and concentrated.
Purification of the resulting oil on silica gel (7:3-1:1 hexanes-ether)
gave recovered alkyne 54 (164 mg, 98% of theory) and adduct 56 (294
mg, 95%) as a colorless oil whose 1H NMR spectrum showed the
presence of a mixture of carbamate rotamers: [R]20D -19 [R]405 -68,
[R]435 -58, [R]546 -41 (c 2.0, CHCl3); IR (film) 3369, 2981, 2977,
5.44 (t, 1H, J ) 7.1 Hz), 3.78 (m, 1H), 3.73 (m, 1H), 2.54 (m, 1H),
2.37 (br s, 1H), 2.10 (app t, 2H, J ) 7.2 Hz), 1.62 (s, 3H), 1.11 (d, 3H,
J ) 6.3 Hz), 1.02 (d, 3H, J ) 6.8 Hz); 13C NMR (125 MHz, CDCl3)
143.4, 136.4, 126.0, 87.8, 82.7, 68.9, 38.5, 33.6, 18.9, 18.8, 12.1 ppm.
(3R,5E,7R,8R)-1,1-Dibromo-3,6-dimethyl-7,8-O-isopropylidene-
1,5-nonadiene (53). A solution of diol 52 (335 mg, 0.98 mmol),
acetone (14 mL), and TsOH (38 mg, 0.20 mmol) was maintained at
room temperature for 30 h. Concentration followed by purification of
the residue on silica gel (20:1 hexane-EtOAc) gave acetonide 53 (313
1
2246, 1677, 1356 cm-1; H NMR (500 MHz, CDCl3) δ 7.4-7.3 (m,
mg, 84%) as a colorless oil: [R]23 +1.7, [R]577 +1.4, [R]546 +1.7,
5H), 5.61 (brs, 1H), 5.34 (brs, 1H), 5.15 (app s, 2H), 4.19 (brs, 1H),
3.85 (m, 2H), 3.74 (brs, 1H), 3.29 (m, 1H), 2.51 (m, 1H), 2.40 (AB,
1H, J ) 17.3 Hz), 2.32 (AB, 1H, J ) 17.3 Hz), 2.29-2.10 (m, 3H),
1.90 (brs, 1H), 1.75 (m, 2H), 1.66 (s, 3H), 1.42 (s, 3H), 1.41 (s, 3H),
D
[R]435 +5.9, [R]405 +9.5 (c 4.5, CHCl3); IR (film) 2985, 1613, 1455,
1379, 1240, 1037 cm-1; 1H NMR (300 MHz, CDCl3) δ 6.20 (d, 1H, J
) 9.4 Hz), 5.49 (t, 1H, J ) 7.3 Hz), 3.88 (m, 2H), 2.54 (m, 1H), 2.12
(app t, 2H, J ) 7.2 Hz), 1.66 (br s, 3H), 1.43 (app s, 6H), 1.24 (d, 3H,
J ) 5.5 Hz), 1.02 (d, 3H, J ) 6.7 Hz); 13C NMR (75.5 MHz, CDCl3)
143.4, 133.1, 126.4, 108.0, 88.3, 87.8, 74.6, 38.4, 33.7, 27.5, 26.9, 18.7,
17.1, 11.8 ppm; MS (isobutane CI) m/e 383, 325, 323, 267, 217; HRMS
(EI) m/e 383.0032 (383.0044 calcd for C14H23Br79Br81O2, M). Anal.
calcd for C14H23Br2O2: C, 43.89; H, 6.05; Br, 41.71. Found: C, 44.11;
H, 5.80; Br, 41.69.
1.22 (d, 3H, J ) 6.0 Hz), 1.15 (bd, 3H, J ) 7.0 Hz), 1.12 (s, 3H); 13
C
NMR (125 MHz, CDCl3) 136.3, 132.3, 128.5, 128.0, 127.9, 127.6,
107.8, 88.5, 74.9, 74.3, 67.5, 65.7, 48.0, 35.1, 31.3, 28.1, 27.5, 27.4,
26.9, 26.8, 26.0, 24.3, 20.7, 17.0, 17.0, 11.6 ppm; HRMS (CI, isobutane)
m/e 484.3002 (484.3062 calcd for C29H42NO5, MH).
(S)-2-[(1S,5R,7E,9R,10R)-1-Hydroxy-9,10-O-isopropylidene-1,5,8-
trimethyl-7-undecen-3-ynyl]pyrrolidene (57). A mixture of Ba-
(OH)2‚H2O (1.34 g, 4.24 mmol), carbamate 56 (294 mg, 0.609 mmol),
and 21 mL of 1,4-dioxane-H2O (1.5:1) was placed in a preheated 100
°C oil bath and heated without stirring for 14 h. The reaction mixture
was allowed to cool to room temperature and then was partitioned
between a mixture of brine (50 mL), saturated aqueous NH4Cl (20 mL),
and EtOAc (60 mL). The aqueous layer was extracted with EtOAc (3
× 50 mL), and the combined organic extracts were dried (K2CO3) and
concentrated. Purification of the resulting oil on silica gel (1:1
hexanes-EtOAc and then 8:1:0.1 CHCl3-MeOH-12 M NH4OH) gave
57 as a clear oil (164 mg, 77%): [R]20D -20, [R]405 -199, [R]435 -231,
(3R,5E,7R,8R)-3,6-Dimethyl-7,8-O-isopropylidene-5-nonen-1-
yne (54). A solution of 53 (93 mg, 0.24 mmol) and THF (4.6 mL)
was cooled to -78 °C. A hexane solution of n-BuLi (260 µL, 2.4 M
in hexane, 0.62 mmol) was added dropwise, and the resulting mixture
was stirred at -78 °C for 1.5 h. The reaction was quenched by the
addition of saturated aqueous NH4Cl (1 mL) and allowed to warm to
rt. This mixture was extracted with EtOAc (5 x 2 mL), and the organic
phase was dried (Na2SO4) and concentrated; the residue was purified
on silica gel (20:1 hexane-EtOAc) to give alkyne 54 (50 mg, 94%) as
a colorless oil: [R]23D -10.1, [R]577 -11.0, [R]546 -12.3, [R]435 -20.3,
1
1
[R]546 -16, [R]577 -13 (c 0.37, CHCl3); H NMR (500 MHz, CDCl3)
[R]40 -22.9 (c 2.1, CHCl3); H NMR (300 MHz, CDCl3) δ 5.60 (t,
δ 5.57 (t, 1H, J ) 7.0 Hz), 4.05 (br m, 1H), 3.88 (m, 2H), 3.44 (t, 1H,
J ) 8.0 Hz), 3.11 (m, 1H), 3.04 (m, 1H), 2.49 (m, 1H), 2.40 (m, 2H),
2.20 (m, 3H), 1.9-1.7 (m, 4H), 1.65 (s, 3H), 1.42 (s, 6H), 1.23 (s,
3H), 1.21 (d, 3H, J ) 5.5 Hz), 1.14 (d, 3H, J ) 7.0 Hz); 13C NMR
(125 MHz, CDCl3) 132.5, 127.5, 108.0, 88.6, 87.0, 74.4, 71.8, 64.4,
46.7, 35.2, 32.3, 27.5, 26.9, 26.1, 26.0, 25.8, 23.1, 20.8, 17.0 ppm; IR
(film) 3351, 2980, 2932, 1455, 1378, 1240 cm-1; MS (CI, isobutane)
m/e 350.2666 (350.2695 calcd for C21H36NO3, MH).
1H, J ) 7.1 Hz), 3.89 (m, 2H), 2.51 (m, 1H), 2.24 (m, 2H), 2.04 (d,
1H, J ) 2.3 Hz), 1.66 (br s, 3H), 1.42 (app s, 6H), 1.22 (d, 3H, J )
5.6 Hz), 1.17 (d, 3H, J ) 6.9 Hz); 13C NMR (125 MHz, CDCl3) 133.0,
126.7, 108.0, 88.4, 88.4, 74.5, 68.4, 34.5, 27.5, 26.9, 25.7, 20.3, 17.0,
11.7 ppm; IR (film) 3311, 2985, 2145, 1456, 1379, 1239, 1037 cm-1
;
MS (EI) m/e 222 (M), 207, 183; HRMS (CI, isobutane) m/e 223.1723
(223.1698 calcd for C14H23O2, MH). Anal. calcd for C14H22O2: C,
75.68; H, 9.91. Found: C, 75.64; H, 9.95.
(R)-2-(tert-Butyldiphenylsiloxy)-4-(triphenylphosphoranylidene)-
3-pentanone (44). Triethylamine (0.71 mL) was added dropwise to a
solution of acid 5514 (1.53 g, 4.66 mmol) and THF (45 mL) at -77 °C
(internal temperature). Pivaloyl chloride (0.55 mL, 4.5 mmol) was
added dropwise, and the resulting solution was allowed to warm to 0
°C over 2 h and then was maintained at 0° for 1 h.
(+)-Pumiliotoxin B (3). Due to the sensitivity of vinyl iodide 58
to room light, the following manipulations were done in glassware
wrapped with aluminum foil. A mixture of alkynylamine 57 (523 mg,
1.50 mmol), NaI (2.2 g, 15 mmol), paraformaldehyde (220 mg, 7.5
mmol), pyridinium p-toluenesulfonate (1.13 g, 4.50 mmol), and H2O
(50 mL) contained in a 60 mL Fisher-Porter pressure bottle was placed
in a 105 °C oil bath and stirred for 2 h. The reaction mixture was
allowed to cool to room temperature and then was partitioned between
EtOAc and 1:1 1 M aqueous Na2CO3-brine. The layers were
separated, the aqueous phase was saturated with NaCl and extracted
with EtOAc (3 × 40 mL), and the combined organic layers were dried
(K2CO3) and concentrated. Purification of the residue on silica gel
(20:1:0.1 CHCl3-MeOH-12 M NH4OH) provided 58 (344 mg, 51%)
as a clear oil, which was immediately deiodinated. Yields as high as
68% were realized in this step in smaller scale runs. Characterization
data for 58: IR (film) 3405, 2971, 2930, 2798, 1702, 1450, 1423, 1372,
A solution of PhLi (7.6 mL of a 2.0 M solution in 7:3 cyclohexane-
Et2O, 15.2 mmol) was added slowly to a stirred suspension of
ethyltriphenylphosphonium bromide (5.65g, 15.2 mmol) and THF (45
mL) at 0 °C, producing an orange solution. After being stirred at 0 °C
for 0.5 h, the ylide solution was added dropwise by syringe to the crude
mixed anhydride solution, which had been recooled to -78 °C. The
rate of addition was controlled so that the internal temperature was
maintained below -70 °C throughout the addition. The reaction was
maintained at -78 °C for 1 h, allowed to warm to room temperature
over 2 h, and then was quenched by the addition of saturated aqueous
NH4Cl (100 mL). The ylide was extracted into EtOAc (3 × 50 mL),
and the organic phase was washed sequentially with saturated aqueous
NaHCO3 (2 × 50 mL) and brine (2 × 50 mL) and dried (Na2SO4).
Concentration gave an orange oil, which was purified on silica gel (2:3
hexane-EtOAc) to give the known14 ylide 44 as a light yellow
amorphous solid (1.66 g, 62%).
(S)-2-[(1S,5R,7E,9R,10R)-1-Hydroxy-9,10-O-isopropylidene-1,5,8-
trimethyl-7-undecen-3-ynyl]-1-(carbobenzyloxy)pyrrolidine (56). To
a solution of alkyne 54 (310 mg, 1.40 mmol) and toluene (2.1 mL) at
0 °C was added n-BuLi (0.53 mL, 2.40 M in hexanes), and the resulting
solution was maintained at 0 °C for 15 min. Diethylaluminum chloride
(1.27 mL, 1.0 M in hexanes) was added dropwise, and the heteroge-
neous reaction mixture was stirred at 0 °C for 1 h. A solution of
epoxide 7 (168 mg, 0.642 mmol, azeotropically dried with toluene)
and 0.7 mL toluene was added dropwise, and the resulting mixture
was stirred at 0 °C for 2 h. The reaction was quenched by the addition
1
1128, 732 cm-1; H NMR (500 MHz, CDCl3) δ 5.29 (t, J ) 6.0 Hz,
1H), 4.07 (dd, 1H, J ) 12.2, 1.0 Hz), 3.75 (m, 1H), 3.69 (d, 1H, J )
6.5 Hz), 3.04 (m, 1H), 2.99 (app d, 1H, J ) 15 Hz), 2.55 (brs, 1H),
2.48 (bd, 1H, J ) 12.0 Hz), 2.3-1.9 (m, 6H), 1.8-1.6 (m, 6H), 1.64
(s, 3H), 1.17 (s, 3H, Me), 1.12 (d, 3H, J ) 6.5 Hz), 1.06 (d, 3H, J )
6.0 Hz); 13C NMR (125 MHz, CDCl3) 136.0, 125.8, 82.0, 71.7, 69.1,
68.7, 54.8, 54.0, 53.9, 39.3, 35.9, 24.5, 23.1, 22.5, 21.5, 18.9, 13.0
ppm.
To a solution of the crude vinyl iodide 58 (344 mg, ∼0.75 mmol)
and THF (13.5 mL) cooled in a -78 °C bath was added dropwise a
solution of tert-butyllithium (2.8 mL, 1.5 M in pentane). After 15 min
at -78 °C, the stirring yellow solution was quenched by cautious
addition of degassed saturated aqueous NH4Cl (5 mL). The resulting
colorless mixture was allowed to warm to room temperature with
vigorous stirring and then was partitioned between brine (50 mL) and
EtOAc (50 mL); the aqueous layer was saturated with NaCl and