Total Synthesis of (()-Terpestacin
LiI (1.12 g, 8.37 mmol), cooled to -78 °C in 18 mL of THF over
2× with H
2×, and the combined organic extracts were washed with brine,
dried over Na SO , and concentrated. The crude product was
purified by flash chromatography on silica gel (5-35% EtOAc in
hexanes) to provide 24 (141 mg, 70% yield) as a white powder:
2
O. The combined aqueous layer was back extracted
4
Å molecular sieves, was added rapidly by cannula. The solution
was warmed to 0 °C and stirred for 2 h and then quenched with
ice cold satd NaHCO O. The combined
and extracted 3× with Et
organic extracts were washed with brine, dried over Na SO , and
concentrated. The crude product was frozen in 50 mL of benzene
2
4
3
2
2
4
decomp 155-161 °C (some decolorization 105-155 °C); R
f
) 0.50
3
2
1
containing Et
3
N (∼ 150 µL) and was stored overnight. Evaporation
(50% EtOAc in hexanes); H NMR (500 MHz, C D ) δ 6.44 (t, J
6 6
followed by purification by flash chromatography on silica gel (10
) 6.5 Hz, 1H), 5.02-494 (m, 2H), 3.71-3.61 (m, 2H), 2.68 (ddd,
J ) 13.5, 8.0, 5.0 Hz, 1H) 2.50-2.34 (m, 4H), 2.18-2.06 (m, 3H),
2.06-1.80 (m, 6H), 1.73 (s, 3H), 1.57 (ddd, J ) 16.0, 11.5, 8.0
Hz, 1H), 1.7 (s, 3H), 1.51 (s, 3H), 1.43 (s, 3H), 1.404 (s, 3H),
to 50% EtOAc in hexanes) provided 21 (1.55 g, 65% yield) as a
3
3
yellow oil and as a mixture of diastereomers:
R
f
) 0.43 (50%
1
EtOAc in hexanes); H NMR (300 MHz, C D ) δ 5.40-5.20 (m
6 6
including triplet at 5.34, J ) 6.3 Hz, 2H), 4.33-4.18 (m, 1H), 4.10-
1.395 (s, 3H), 1.05 (s, 3H); 13C NMR (75 MHz, C
6 6
D ) δ 205.8,
3
2
.86 (m, 4H), 3.80-3.58 (m, 4H), 2.62 (dd, J ) 7.8, 4.2 Hz, 1H),
.50-1.94 (m including doublet of doublets at 2.43, J ) 14.4, 6.3
200.2, 153.3, 147.9, 140.2, 138.3, 137.6, 134.1, 122.5, 120.8, 107.0,
58.5, 50.2, 48.2, 40.3, 39.7, 35.1, 34.5, 33.0, 31.0, 25.6, 25.5, 24.1,
17.0, 16.6, 15.7, 12.0; IR (neat) 2972, 2916, 1712, 1661, 1645,
Hz, 12H), 1.90-1.75 (m, 1H), 1.70 (m including singlets at 1.70,
-
1
+
1
9
0
0
.64, 1.61, 8H), 1.44-1.25 (m, including singlets at 1.41, 1.40,
1377 cm ; EIMS m/z 426 (M , 63), 368 (62); HREIMS calcd for
426.2770, found 426.2767.
Keto Alcohol 25. An aluminate solution was prepared by adding
t-BuLi (3.2 mL, 1.67 M, 5.34 mmol) to DIBAL (1.0 mL, 798 mg,
5.61 mmol) in 6.5 mL of THF at -98 °C (N /MeOH). To a solution
H), 1.14-0.94 (m including singlets at 1.03, 0.98, 0.96, 39H),
27 38 4
C H O
-
.21- 0.05 (m including singlets at 0.20, 0.16, 0.14, 0.13, 0.10,
-
1
.06, -0.03, 6H); IR (neat) 2944, 1716, 1644, 1463, 1249 cm
.
Diol 22. To a solution of 21 (1.40 g, 1.64 mmol) and Et
mL, 5.7 g, 57 mmol) in 8 mL of CH Cl at rt was added TREAT‚
HF (8.0 mL, 7.92 g, 49.1 mmol). The solution was heated to
5 °C for 36 h then cooled and diluted with CH Cl . The reaction
mixture was washed 3× with H O, and the combined aqueous layers
were back extracted 3×. The combined organic extracts were
washed with brine, dried over Na SO , and concentrated. The crude
residue was purified by flash chromatography on silica gel (0 to
% MeOH in EtOAc) to provide 22 (801 mg, 83% yield) as a
yellow oil and as a mixture of diastereomers: R ) 0.25 (3% MeOH
) δ 5.38-5.22 (m, 2H), 4.18-
.06 (m, 1H), 4.00-3.70 (m, 5H), 3.70-3.46 (m, 3H), 2.80 (dd, J
3
N (7.9
2
2
2
of 24 (195 mg, 0.457 mmol) in 11 mL of THF at -98 °C was
added the aluminate (800 µL, 0.5M, 0.40 mmol). The reaction was
monitored carefully by TLC, and small aliquots (3-4 drops) of
aluminate were added until all starting material had been consumed.
The reaction was quenched with 500 µL of MeOH and warmed to
4
2
2
2
2
4
0 °C, and 5.0 mL of satd Na
suspension was filtered through a pad of Celite, rinsing with Et
and then subsequently washed 2× with H O. The combined aqueous
layer was back extracted 2×, and the combined organic extracts
2 4
SO was added. After 20 min, the
2
O
6
2
f
1
in EtOAc); H NMR (500 MHz, C
D
6 6
2 4
were washed with brine, dried over Na SO , and concentrated. The
4
crude residue (4:1, R/â by 1H NMR) was purified by flash
chromatography on silica gel (5-65% EtOAc in hexanes) to provide
)
9.0, 4.0 Hz, 0.33H), 2.74-2.65 (m, 0.66H), 2.50-2.00 (m
including 2 doublets of doublets at 2.47, J ) 14.0, 5.5 Hz and
C11r-25 (145 mg, 74% yield) as a foam: R
f
) 0.23 (40% EtOAc
1
2
.40, J ) 15.5, 6.0 Hz, 10H), 2.00-1.70 (m, 2H), 1.65-1.45 (m
in hexanes); H NMR (300 MHz, C D ) δ 5.28-5.14 (m, 3H), 4.02
6 6
including singlets at 1.62, 1.60, 1.60, 1.54, 8H), 1.44-1.38 (m
including singlets at 1.43, 1.42, 1.41, 1.40, 6H), 1.22-1.09 (m,
(dd, J ) 9.3, 4.2 Hz, 1H), 3.80-3.60 (m, 2H), 2.66 (dd, J ) 13.5,
10.8 Hz, 1H), 2.42-2.34 (d br, J ) 9.9 Hz, 1H), 2.30-1.58 (m
2
.5H), 1.09-0.97 (m, 8.5H); IR (neat) 3407, 2982, 2939, 1705,
including a triplet at 2.25, J ) 5.4 Hz, 13H), 1.54 (s, 3H), 1.49 (s,
-1
+
13
1
639, 1456, 1217 cm ; EIMS m/z 584 (M , 5), 526 (11); HREIMS
P 584.3478, found 584.3450.
Ketoaldehyde 23. To a solution of 22 (270 mg, 0.462 mmol)
and pyridine (220 µL, 220 mg, 2.77 mmol) in 5 mL of CH Cl at
3H), 1.46 (s, 3H), 1.44 (s, 3H), 1.41 (s, 3H), 1.08 (s, 3H);
C
calcd for C31
H O
53 8
6 6
NMR (75 MHz, C D ) δ 206.6, 155.0, 147.9, 137.8, 138.2, 133.0,
128.3, 124.3, 122.2, 106.8, 76.3, 58.5, 49.5, 48.7, 40.6, 39.4, 35.2,
33.0, 30.6. 28.9, 25.6, 25.4, 24.2, 16.7, 15.8, 15.2, 10.4; IR (neat)
2
2
-
1
+
rt was added the Dess-Martin periodinane (DMP; 591 mg, 1.40
mmol). The reaction was monitored by TLC, and after 3.5 h an
additional portion of DMP (100 mg, 0.237 mmol) was added. After
an additional 30 min, the reaction mixture was diluted with EtOAc
3400, 2935, 1704, 1642, 1450 cm ; EIMS m/z 428 (M , 27), 389
(5), 370 (7); HREIMS calcd for C27 428.2926 found 428.2921.
C11â-25 (39 mg, 20%) was also isolated as a foam: R ) 0.33
) δ 5.23 (t, J
40 4
H O
f
1
6 6
(40% EtOAc in hexanes); H NMR (300 MHz, C D
and washed with a 1:1 solution of satd Na
S O
2 2 3
and satd NaHCO
3
.
) 5.4 Hz, 1H), 5.31 (t, J ) 7.5 Hz, 1H), 5.26-5.16 (m, 1H), 4.06
(dd, J ) 9.0, 3.6 Hz, 1H), 3.75-3.58 (m, 2H), 2.45-2.34 (m, 2H),
2.28-1.94 (m, 8H), 1.94-1.62 (m, 6H), 1.56 (s, 3H), 1.50 (s, 3H),
1.44 (s, 3H), 1.43 (s, 3H), 1.42 (s, 3H), 1.22 (s, 3H); 13C (75 MHz,
The combined aqueous layer was back extracted 2× with EtOAc,
and the combined organic extracts were washed with brine, dried
2 4
over Na SO , and concentrated. The crude product was purified
by flash chromatography on silica gel (0 to 3% MeOH in EtOAc)
to provide 23 (220 mg, 82% yield) as a clear oil and as a mixture
6 6
C D ) δ 206.0, 154.9, 147.5, 136.9, 136.5, 134.2, 126.5, 125.6,
122.4, 106.9, 76.1, 58.4, 49.2, 47.8, 40.2, 38.8, 35.6, 33.0, 30.0,
28.3, 25.55, 25.46, 24.4, 17.3, 15.03, 14.99, 11.21; IR (neat) 3447,
1
of diastereomers: R
MHz, C
.80 (m, 4H), 3.74-3.54 (m, 2H), 3.40-2.90 (m, 3H), 2.60-2.45
f
) 0.40 (3% MeOH in EtOAc); H NMR (300
-
1
+
D
6
) δ 9.34-9.30 (m, 1H), 5.18 (at, J ) 6.6 Hz, 2H), 4.00-
2934, 1707, 1643, 1373 cm ; EIMS m/z 428 (M , 6), 410 (4),
6
3
370 (5) 352 (4); HREIMS calcd for C27
428.2914.
40 4
H O 428.2926, found
(
1
9
(
1
m, 1H), 2.45-2.25 (m, 4H), 2.15-1.75 (m, 8H), 1.62 (s, 3H),
.55 (s, 3H), 1.41-1.30 (m including doublet at 1.35, J ) 6.9 Hz,
H), 1.02 (dt, J ) 6.9, 2.1 Hz, 3H), 1.01 (t, J ) 6.9 Hz, 3H), 0.86
Ketone 26. To a solution of 25 (78 mg, 0.18 mmol) and Et
(175 µL, 128 mg, 1.30 mmol) in 2.0 mL of CH Cl at rt was added
TESCl (155 µL, 137 mg, 0.910 mmol) dropwise. The reaction was
monitored by TLC and after 1.5 h was diluted with CH Cl and
washed 3× with H O. The combined aqueous layer was back
extracted 3×, and the combined organic extracts were washed with
brine, dried over Na SO , and concentrated. The crude product was
purified by flash chromatography on silica gel (1 to 25% EtOAc
in hexanes) to provide 26 (83 mg, 84% yield) as a yellow oil: R
3
N
2
2
s, 1.5H), 0.85 (s, 1.5H); IR (neat) 2984, 2938, 1 713, 1642, 1455,
-
1
+
246, 1219 cm ; EIMS m/z 580 (M , 3), 522 (100); HREIMS
2
2
calcd for C31
H O
49 8
P 580.3165, found 580.3194.
2
Diketone 24. To a solution of 23 (274 mg, 0.472 mmol) and
LiCl (195 mg, 4.72 mmol) in 94 mL of acetonitrile at rt was added
diisopropylethylamine (820 µL, 610 mg, 4.72 mmol). After 45 h,
2
4
the reaction was concentrated, dissolved in CH
2
Cl
2
, and washed
f
1
)
5
0.34 (20% EtOAc in hexanes); H NMR (300 MHz, C
6 6
D ) δ
.36 (t, J ) 4.8 Hz, 1H), 5.28 (dd, J ) 10.6, 5.1 Hz, 1H), 5.21 (d,
(
32) It was noted that storage overnight in benzene containing Et3N
scavenged the excess allylic iodide, making the purification easier.
33) Complete stereoselectivity was achieved at C1, as indicated by the
formation of a single diastereomer from the macrocyclization.
J ) 8.4 Hz, 1H), 4.20 (dd, J ) 8.7, 4.5 Hz, 1H), 3.76-3.56 (m,
2H), 2.66 (dd, J ) 13.8, 10.6 Hz, 1H), 2.43-2.36 (m, 1H), 2.24-
1.66 (m, 13H), 1.59 (s, 3H), 1.55 (s, 3H), 1.49 (s, 3H), 1.42 (s,
(
J. Org. Chem, Vol. 72, No. 17, 2007 6479