Synthesis of Subunits of the Aplyronines
J . Org. Chem., Vol. 65, No. 5, 2000 1507
3 H), 1.83 (m, 1 H), 1.72-1.60 (m, 4 H), 1.50 (m, 1 H), 1.14
(m, 1 H), 0.89 (s, 9 H), 0.89 (d, J ) 7.0 Hz, 3 H), 0.84 (d, J )
6.5 Hz, 3 H), 0.04 (s, 6 H); 13C NMR (125 MHz, CDCl3) δ
141.18, 114.62, 98.34, 83.08, 73.62, 65.91, 55.94, 37.47, 35.88,
34.66, 28.25, 25.91, 18.23, 16.24, 10.88, -5.35, -5.42.
(S)-O-Meth yl Ma n d ela te of Alcoh ol 12. To a solution of
alcohol 12 (14 mg, 0.03 mmol) in CH2Cl2 (2 mL) were added
dicyclohexylcarbodiimide (12 mg, 0.06 mmol), (S)-(+)-R-(meth-
oxy)phenylacetic acid (9.5 mg, 0.06 mmol), and a catalytic
amount of DMAP. After 30 min, the mixture was concentrated
in vacuo and purified by flash chromatography (4:1 hexanes-
EtOAc) to provide the (S)-R-(methoxy)phenyl acetate [(S)-MPA]
derivative of 12 (19 mg, 99%) as a clear oil: Rf 0.66 (4:1
hexanes-EtOAc); 1H NMR (500 MHz, CDCl3) δ 7.45-7.43 (m,
2 H), 7.37-7.31 (m 3 H), 5.63 (ddd, J ) 17.5, 10.5, 6.0 Hz, 1
H), 5.27 (apparent q, J ) 6.0 Hz, 1 H), 4.99 (d, J ) 10.5 Hz, 1
H), 4.92 (d, J ) 17.5 Hz, 1 H), 4.76 (s, 1 H), 4.64 (d, J ) 6.5
Hz, 1 H), 4.59 (d, J ) 6.5 Hz, 1 H), 3.47 (dd, J ) 9.5, 8.0 Hz,
1 H), 3.42 (dd, J ) 9.5, 6.0 Hz, 1 H), 3.41 (s, 3 H), 3.37 (s, 3
H), 3.37 (m, 1 H), 1.79 (m, 1 H), 1.74-1.53 (m, 4 H), 1.07 (m,
1 H), 0.89 (s, 9 H), 0.85 (d, J ) 7.0 Hz, 3 H), 0.83 (d, J ) 7.5
Hz, 3 H), 0.04 (s, 6 H).
(R)-O-Meth yl Ma n d ela te of Alcoh ol 12. Alcohol 12 (7.0
mg, 0.014 mmol), DCC (6 mg, 0.028 mmol), (R)-(-)-R-(meth-
oxy)phenylacetic acid (5 mg, 0.028 mmol), and DMAP were
combined for 5 min as previously described to provide the (R)-
MPA derivative of 12 (9 mg, 99%) as a clear oil: Rf 0.66 (4:1
hexanes-EtOAc); 1H NMR (500 MHz CDCl3) δ 7.46-7.44 (m,
2 H), 7.37-7.30 (m, 3 H), 5.77 (ddd, J ) 17.0, 10.5, 6.5 Hz, 1
H), 5.27 (apparent q, J ) 6.5 Hz, 1 H), 5.22 (d, J ) 17.0, 1 H),
5.15 (d, J ) 10.5 Hz, 1 H), 4.75 (s, 1 H), 4.57 (d, J ) 6.5 Hz,
1 H), 4.53 (d, J ) 6.5 Hz, 1 H), 3.43 (dd, J ) 10.0, 7.5 Hz, 1
H), 3.41 (s, 3 H), 3.38 (dd, J ) 10.0, 6.5 Hz, 1 H), 3.37 (s, 3 H),
3.28 (dd, J ) 7.0, 3.0 Hz, 1 H), 1.69 (m, 1H), 1.61 (m, 1 H),
1.53 (m, 1 H), 1.46 (m, 1 H), 1.33 (m, 1 H), 0.89 (s, 9 H), 0.84
(m, 1 H), 0.79 (d, J ) 7.0 Hz, 3 H), 0.72 (d, J ) 6.5, 3 H), 0.03
(s, 6 H).
(2R,3R,4R,7S)-1-(ter t-Bu t yld im et h ylsilyloxy)-2,4-d i-
m eth yl-7-m eth oxy-3-(m eth oxym eth oxy)-8-n on en e (13).
To a cold (0 °C) solution of alcohol 12 (1.35 g, 3.75 mmol) in
THF (40 mL) was added NaH (135 mg, 5.62 mmol) in small
portions. Iodomethane (1.15 mL, 18.7 mmol) was added
dropwise followed by 15-crown-5 (0.07 mL, 0.38 mmol). The
resultant mixture was allowed to warm to room temperature
and stirred for 3 h. The solution was then cooled to 0 °C and
quenched by the dropwise addition of saturated aqueous NH4-
Cl (Ca u tion : vigor ou s evolu tion of H2 m a y r esu lt). The
organic layer was washed with brine. The aqueous layer was
extracted with Et2O, and the combined extracts were dried
over Na2SO4. Filtration and concentration followed by flash
chromatography (14:1 hexanes-EtOAc with 1% triethylamine)
provided methyl ether 13 (1.39 g, 99%) as a clear oil: Rf 0.88
(4:1 hexanes-EtOAc); [R]20D - 5.3 (c 1.7, CHCl3); 1H NMR (500
MHz, CDCl3) δ 5.64 (ddd, J ) 17.5, 10.5, 7.0 Hz, 1 H), 5.19 (d,
J ) 10.5 Hz, 1 H), 5.18 (d, J ) 17.5 Hz, 1 H), 4.65 (d, J ) 6.5
Hz, 1 H), 4.61 (d, J ) 6.5 Hz, 1 H), 3.48 (dd, J ) 10.0, 7.5 Hz,
1 H), 3.47 (m, 1 H), 3.43 (dd, J ) 10.0, 6.5 Hz, 1 H), 3.38 (s, 3
H), 3.38 (m, 1 H), 3.26 (s, 3 H), 1.83 (m, 1 H), 1.71-1.49 (m, 4
H), 1.08 (m, 1 H), 0.89 (s, 9 H), 0.88 (d, J ) 6.5 Hz, 3 H), 0.85
(d, J ) 7.0 Hz, 3 H), 0.03 (s, 6 H); 13C NMR (125 MHz, CDCl3)
δ 138.82, 117.12, 98.18, 83.51, 83.05, 65.99, 56.09, 55.92, 37.44,
36.03, 33.07, 28.29, 25.91, 18.23, 16.12, 11.08, -5.37, -5.44.
Anal. Calcd for C20H42O4Si: C, 64.12; H, 11.30. Found: C,
64.29; H, 11.39.
(2R ,3R ,4R ,7S )-2,4-Dim e t h yl-7-m e t h oxy-3-(m e t h oxy-
m eth oxy)-8-n on en -1-ol (14). To a cold (0 °C) solution of silyl
ether 13 (1.39 g, 3.71 mmol) in THF (37 mL) was added TBAF
(5.56 mL, 1.0 M in THF, 5.56 mmol) dropwise. The reaction
mixture was allowed to warm to room temperature and stirred
for 15 h. Saturated aqueous NH4Cl was added followed by
Et2O. The organic layer was washed with brine. The aqueous
layer was extracted with Et2O, and the combined extracts were
dried over Na2SO4. Filtration and concentration followed by
flash chromatography (2:1 to 1:1 hexanes-EtOAc with 1%
triethylamine) provided alcohol 14 (932 mg, 97%) as a clear
oil: Rf 0.27 (2:1 hexanes-EtOAc); [R]20 -68.3 (c 3.6 CHCl3);
D
IR (film) 3453, 1038 cm-1; H NMR (300 MHz, CDCl3) δ 5.63
1
(ddd, J ) 18.0, 10.5, 7.5 Hz, 1 H), 5.22-5.14 (m, 2 H), 4.66 (s,
2 H), 3.51-3.46 (m, 3 H), 3.42 (s, 3 H), 3.39 (m, 1 H), 3.26 (s,
3 H), 3.00 (t, J ) 6.6 Hz, 1 H), 1.94 (m, 1 H), 1.74-1.45 (m, 4
H), 1.02 (m, 1 H), 0.84 (d, J ) 6.6 Hz, 3 H), 0.78 (d, J ) 6.9
Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 138.67, 117.25, 98.94,
83.70, 83.36, 65.09, 56.18, 56.10, 36.63, 35.96, 32.76, 28.30,
15.71, 9.86. Anal. Calcd for C14H28O4: C, 64.58; H, 10.84.
Found: C, 64.55; H, 10.77.
(2S ,3R ,4R ,7S )-2,4-Dim e t h yl-7-m e t h oxy-3-(m e t h oxy-
m eth oxy)-8-n on en a l (15). To a solution of alcohol 14 (932
mg, 3.58 mmol) in CH2Cl2 (36 mL) were added solid NaHCO3
(3.00 g, 35.8 mmol) and the Dess-Martin periodinane reagent
(1.82 g, 4.30 mmol).9 The resultant solution was stirred for
1.25 h and then quenched by the simultaneous addition of
saturated aqueous Na2S2O3 and saturated aqueous NaHCO3.
Diethyl ether was added, and the biphasic mixture was stirred
vigorously for 1 h at which time both layers had cleared. The
organic layer was washed with brine, the aqueous layer was
extracted with Et2O, and the combined extracts were dried
over Na2SO4. Filtration and removal of solvent in vacuo
provided aldehyde 15 (831 mg, 90%) as a clear oil. This
material was used immediately without further purification:
1
Rf 0.69 (2:1 hexanes-EtOAc); H NMR (300 MHz, CDCl3) δ
9.72 (d, J ) 0.6 Hz, 1 H), 5.64 (ddd, J ) 18.0, 10.5, 7.5 Hz, 1
H), 5.23-5.16 (m, 2 H), 4.63 (d, J ) 6.9 Hz, 1 H), 4.57 (d, J )
6.9 Hz, 1 H), 3.80 (dd, J ) 7.5, 3.0 Hz, 1 H), 3.48 (m, 1 H),
3.27 (s, 3 H), 3.26 (s, 3 H), 2.53 (qd, J ) 7.2, 3.0 Hz, 1 H),
1.77-1.49 (m, 4 H), 1.13 (d, J ) 7.2 Hz, 3 H), 1.12 (m, 1 H),
0.92 (d, J ) 6.9 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 204.15,
138.55, 117.35, 97.68, 83.22, 81.82, 56.09, 55.80, 48.81, 35.99,
32.75, 28.04, 15.92, 7.57.
Eth yl (2E,4R,5R,6R,9S)-4,6-Dim eth yl-9-m eth oxy-5-(m e-
th oxym eth oxy)-2,10-u n d eca d ien oa te (16). To a solution of
aldehyde 15 (831 mg, 3.22 mmol) in CH2Cl2 (32 mL) was added
(carbethoxymethylene)triphenylphosphorane (3.36 g 9.66 mmol)
in one portion. The solution was heated to reflux for 20 h. The
mixture was cooled to room temperature, concentrated in
vacuo, and subjected to flash chromatography (8:1 to 4:1
hexanes-EtOAc with 1% triethylamine) to provide R,â-
unsaturated ester 16 (909 mg, 86%) as a clear oil: Rf 0.37 (4:1
hexanes-EtOAc); [R]20 +25.3 (c, 2.5, CHCl3); IR (film) 1718,
D
1
1652, 1035 cm-1; H NMR (300 MHz, CDCl3) δ 6.95 (dd, J )
15.6, 7.8 Hz, 1 H), 5.80 (dd, J ) 15.6, 1.2 Hz, 1 H), 5.61 (ddd,
J ) 16.8, 10.5, 7.8 Hz, 1 H), 5.18 (d, J ) 10.5 Hz, 1 H), 5.15
(d, J ) 16.8 Hz, 1 H), 4.61 (d, J ) 6.9 Hz, 1 H), 4.58 (d, J )
6.9 Hz, 1 H), 4.17 (q, J ) 7.2 Hz, 2 H), 3.43 (m, 1 H), 3.36 (s,
3 H), 3.24 (s, 3 H), 3.23 (m, 1 H), 2.59 (m, 1 H), 1.68-1.41 (m,
4 H), 1.27 (t, J ) 7.2 Hz, 3 H), 1.07 (d, J ) 6.9 Hz, 3 H), 1.07
(m, 1 H), 0.91 (d, J ) 6.6 Hz, 3 H); 13C NMR (75 MHz, CDCl3)
δ 166.59, 152.08, 138.63, 120.51, 117.26, 97.94, 86.21, 83.30,
60.16, 56.04, 39.08, 35.84, 32.93, 27.09, 16.57, 14.71, 14.22.
Anal. Calcd for C18H32O5: C, 65.82; H, 9.82. Found: C, 65.88;
H, 9.91.
(2E ,4R ,5R ,6R ,9S )-2,4-Dim e t h yl-9-m e t h oxy-5-(m e t h -
oxym eth oxy)-2,10-u n d eca d ien -1-ol (17). To a cold (-78 °C)
solution of ester 16 (909 mg, 2.77 mmol) in CH2Cl2 (35 mL)
was added diisobutylaluminum hydride (6.92 mL, 1.0 M in
hexane, 6.92 mmol) dropwise with a syringe pump. The
reaction was stirred at -78 °C for 1.5 h and then poured into
a vigorously stirred solution of saturated aqueous sodium
potassium tartrate (Rochelle’s salt) and Et2O. The biphasic
mixture was stirred vigorously for 1 h, at which time both
layers had cleared. The organic layer was washed with brine.
The aqueous layer was extracted with Et2O, and the combined
extracts were dried over Na2SO4. Filtration and concentration
followed by flash chromatography (2:1 to 1:1 hexanes-EtOAc)
provided allylic alcohol 17 (774 mg, 98%) as a clear oil: Rf 0.25
(2:1 hexanes-EtOAc); [R]20 +15.0 (c 2.5, CHCl3); IR (film)
D
1
3446 (broad), 1039 cm-1; H NMR (300 MHz, CDCl3) δ 5.75-
5.57 (m, 3 H), 5.18 (d, J ) 10.5 Hz, 1 H), 5.17 (d, J ) 16.5 Hz,
1 H), 4.65 (d, J ) 6.9 Hz, 1 H), 4.62 (d, J ) 6.9 Hz, 1 H), 4.08
(apparent t, J ) 5.4 Hz, 2 H), 3.44 (m, 1 H), 3.38 (s, 3 H), 3.25