Total Synthesis of (+)-Aculeatin D
TES Protection of 17 Leading to 18. TESCl (1.68 mL, 10.0
mmol) was added dropwise to a solution of 17 (1.35 g, 5.00 mmol),
imidazole (1.68 g, 10.0 mmol), and activated 4 Å MS (1.5 g) in
dry THF (10 mL) stirred at ambient temperature. After 5 min of
stirring, TLC showed completion of the reaction. The mixture was
diluted with Et2O (200 mL) and filtered through Celite to remove
the white precipitates. The filtrate was concentrated on a rotary
evaporator to dryness. The residue was chromatographed (50:1 PE/
6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 154.2, 133.3, 129.5,
115.4, 69.2, 66.5, 51.9, 44.6, 43.3, 42.1, 37.5, 31.9, 29.7-29.6 (all
the remaining/unresolved alkyl carbons), 29.3, 26.4, 26.1, 25.8, 24.9,
22.7, 14.1; FT-IR (film) 3399, 3269, 2954, 2923, 2848, 2360, 2342,
1641, 1612, 1593, 1516, 1465, 1451, 1232, 829 cm-1; ESI-MS m/z
533.5 ([M + Na]+); ESI-HRMS calcd for C29H50O3S2Na ([M +
Na]+) 533.3094, found 533.3083.
Method B: A solution of 26 (100 mg, 0.18 mmol) in MeOH
(1.5 mL) containing aq. HCl (6 N, 0.1 mL) was stirred at ambient
temperature for 48 h. The mixture was concentrated to dryness on
a rotary evaporator. The residue was chromatographed (2:1 PE/
EtOAc) on silica gel to afford 27 as a white solid (86 mg, 0.168
mmol, 94%).
EtOAc) on silica gel to afford 18 as a colorless oil (1.865 g, 4.848
1
mmol, 97%): [R]25 -15.1 (c 1.01, CHCl3); H NMR (300 MHz,
D
CDCl3) δ 3.93-3.85 (m, 1H), 3.07-3.01 (m, 1H), 2.80 (dd, J )
3.9, 5.1 Hz, 1H), 2.49 (dd, J ) 2.5, 5.1 Hz, 1H), 1.71-1.56 (m,
2H), 1.46-1.54 (m, 2H), 1.30-1.24 (m, 20H), 0.97 (t, J ) 7.6
Hz, 9H), 0.88 (t, J ) 6.5 Hz, 3H), 0.62 (q, J ) 7.5 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 70.3, 49.9, 47.6, 40.4, 38.1, 31.9, 29.8,
29.70-29.65 (all the remaining/unresolved alkyl carbons), 29.61,
29.59, 29.4, 25.2, 22.7, 14.1, 6.9, 5.1; FT-IR (film) 3042, 2925,
2876, 2854, 1465, 1413, 1377, 1239, 1070, 1008, 742 cm-1; EI-
MS m/z (%) 355 (M+ + 1, 33), 300 (23), 299 (78), 143 (26), 115
(100), 103 (25), 87 (33), 69 (20); EI-HRMS calcd for C21H43O2Si
([M + H]+) 355.3032, found 355.3024.
Spirocyclization of 27 without Buffer (28). PIFA (42 mg, 0.098
mmol) was added to a solution of 27 (20 mg, 0.039 mmol) in
acetone-H2O (9:1 v/v, 0.5 mL) stirred at ambient temperature. The
mixture was stirred for another 20 min (when TLC showed full
disappearance of the starting 27). Aqueous sat. Na2SO3 was added
to quench the reaction. The mixture was diluted with Et2O, then
washed in turn with aq. sat. CuSO4 and aq. sat. Na2SO4 before
being dried over anhydrous Na2SO4. Removal of the solvent on a
rotary evaporator and chromatography (3:2 PE/EtOAc) on silica
Synthesis of 26 from 18 and 19b via 20b. n-BuLi (1.6 M, in
hexanes, 2.86 mL, 4.6 mmol) was added to a solution of 19b (1.300
g, 4.57 mmol) in dry THF (12 mL) stirred at -65 °C (EtOH-dry
ice bath) under N2. After completion of the addition, the mixture
was stirred at temperatures between -20 and -40 °C for 3 h. The
bath temperature was recooled to -65 °C. A solution of 18 (943
mg, 2.45 mmol) in dry THF (5 mL) and dry HMPA (3 mL) was
then introduced. The stirring was continued at -40 °C for 1 h,
when TLC showed completion of the reaction. The mixture was
partitioned between H2O and CH2Cl2. The phases were separated.
The organic layer was washed in turn with H2O and brine and dried
over anhydrous Na2SO4. Removal of the solvent and chromatog-
raphy (15:1 PE/EtOAc) on silica gel gave an inseparable mixture
of 20b and unreacted 19b, which was therefore used directly in
the following desilylation.
gel afforded 28 as a colorless oil (12 mg, 0.029 mmol, 74%): [R]25
D
+11.72 (c 0.60, CHCl3) (lit.2d [R]25 +5.7 (c 0.3, CHCl3); lit.2e
D
[R]26 +15.0 (c 1.0, CHCl3)); 1H NMR (300 MHz, C6D6) δ
D
6.72-6.68 (dd, J ) 2.9, 10.0 Hz, 1H), 6.17-6.01 (m, 3H),
4.05-3.95 (m, 1H), 3.80-3.70 (m, 1H), 2.04-1.84 (m, 3H),
1.76-1.71 (m, 1H), 1.61-1.32 (m, 28H), 0.92 (t, J ) 6.4 Hz, 3H);
13C NMR (75 MHz, C6D6) δ 184.7, 151.0, 149.0, 127.4, 126.7,
109.0, 79.1, 69.2, 65.1, 43.5, 41.2, 38.8, 36.4, 34.8, 32.3, 30.1-30.0
(all the remaining/unresolved alkyl carbons), 29.8, 26.0, 23.1, 14.3;
FT-IR (film) 3421, 2922, 2853, 1700, 1671, 1629, 1458, 1388, 1202,
1172, 1125, 1059, 990, 934, 877, 853. ESI-MS m/z 441.3 ([M +
Na]+); ESI-HRMS calcd for C26H42O4Na ([M + Na]+) 441.2975,
found 441.2990.
Synthesis of 1 (and 28). PIFA (42 mg, 0.098 mmol) was added
to a solution of 27 (20 mg, 0.039 mmol) in acetone-aqueous
Na2HPO4/citric acid buffer (5:1 v/v, 0.5 mL; with the buffer
stock solution prepared by mixing 63 mL of 0.2 M Na2HPO4
and 37 mL of 0.1 M citric acid according to the literature)19
stirred at 5 °C (ice-H2O bath). The mixture was stirred at the
same temperature for another 15 min (when TLC showed full
disappearance of the starting 27). Aqueous sat. Na2SO3 was
added to quench the reaction. The mixture was diluted with Et2O,
then washed in turn with aq. sat. CuSO4 and aq. sat. Na2SO4
before being dried over anhydrous Na2SO4. Removal of the
solvent on a rotary evaporator and chromatography (3:2 PE/
EtOAc) on silica gel gave 28 (the less polar component, 5 mg,
0.012 mmol, 31% yield) and 1 (the more polar component, 5
mg, 0.012 mmol, 31% yield) as colorless oils. Data for aculeatin
A solution of n-Bu4NF (1 M in THF, 5 mL, 5 mmol) was
added to a solution of the above obtained mixture of 20b and
19b in THF (4 mL) stirred at ambient temperature. The mixture
was stirred at the same temperature for 12 h before being
partitioned between H2O and CH2Cl2. The organic layer was
washed in turn with H2O and brine and dried over anhydrous
Na2SO4. Removal of the solvent and chromatography (4:1 PE/
EtOAc) on silica gel afforded 26 as a yellowish oil (1.051 g,
1
1.89 mmol, 77% from 18): [R25]D +3.66 (c 1.00, CHCl3); H
NMR (300 MHz, CDCl3) δ 7.12 (d, J ) 8.8 Hz, 2H), 6.96 (d,
J ) 8.8 Hz, 2H), 5.15 (s, 2H), 4.40-4.33 (m, 1H), 3.98-3.88
(m, 1H), 3.80 (br s, 1H, OH), 3.47 (s, 3H), 3.05-2.94 (m, 2H),
2.92-2.77 (m, 3H), 2.73-2.63 (m, 2H), 2.54-2.45 (dd, J )
9.8, 15.1 Hz, 1H), 2.33-2.10 (m, 2H), 2.07-1.91 (m, 3H),
1.26-1.69 (m, 28H), 0.88 (t, J ) 6.9 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 155.6, 134.9, 129.4, 116.5, 94.6, 69.0, 66.4,
55.9, 52.0, 44.8, 43.5, 42.1, 37.6, 31.9, 29.8, 29.7-29.5 (all the
remaining/unresolved alkyl carbons), 29.4, 26.4, 26.1, 25.8, 24.9,
22.7, 14.1; FT-IR (film) 3448, 2925, 2853, 1611, 1509, 1458,
1422, 1232, 1198, 1153, 1079, 1009, 923, 830 cm-1; ESI-MS
m/z 577.5 ([M + Na]+); ESI-HRMS calcd for C31H54O4S2Na
([M + Na]+) 577.3361, found 577.3344.
D 1: [R]25 +53.24 (c 0.57, CHCl3) (lit.1a [R]25 +46.5 (c 1.0,
D
D
CHCl3); lit.2e [R]26D +48.9 (c 1.0, CHCl3)); 1H NMR (300 MHz,
CDCl3) δ 7.00 (dd, J ) 2.8, 10.3 Hz, 1H), 6.80 (dd, J ) 3.1,
10.3 Hz, 1H), 6.16 (dd, J ) 2.0, 10.3 Hz, 1H), 6.13 (dd, J )
1.8, 10.2 Hz, 1H), 3.91-3.80 (m, 1H), 3.40-3.34 (m, 1H),
2.43-2.39 (m, 1H), 2.33-2.23 (m, 1H), 2.16-2.04 (m, 2H),
1.99-1.94 (m, 1H), 1.89-1.60 (m, 4H), 1.52-1.44 (m, 2H),
1.34-1.24 (m, 22H), 0.88 (t, J ) 6.7 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 185.5, 151.5, 148.8, 127.4, 127.2, 109.2, 78.1,
71.6, 66.8, 43.6, 40.8, 35.7, 34.9, 33.4, 31.9, 29.7-29.5 (all the
remaining/unresolved alkyl carbons), 29.4, 29.3, 25.9, 22.7, 14.1;
FT-IR (film) 3425, 2924, 2853, 1671, 1631, 1458, 1379, 1197,
1061, 1011, 953, 858 cm-1; ESI-MS m/z 441.2 ([M + Na]+);
ESI-HRMS calcd for C26H42O4Na ([M + Na]+) 441.2975, found
441.2980. Data for 6-epi-aculeatin D 28: see the above experi-
ment.
Removal of the MOM Group in 26 (27). Method A: A solution
of 26 (20 mg, 0.036 mmol) and Sc(OTf)3 (6.0 mg, 0.0018 mmol)
and HO(CH2)3OH (5.0 µL, 0.072 mmol) in CH2Cl2 (1 mL) was
heated to reflux for 3 h. After cooling to ambient temperature, the
mixture was chromatographed (3:1 PE/EtOAc) on silica gel to give
27 as a white solid (17 mg, 0.033 mmol, 92%): mp 76-77 °C;
[R25]D +5.67 (c 1.02, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.03
(d, J ) 8.1 Hz, 2H), 6.76 (d, J ) 8.1 Hz, 2H), 6.00-6.08 (m, 1H),
4.40-4.35 (m, 1H), 3.99 (br s, 2H, 2OH’s), 2.91-3.04 (m, 3H),
2.74-2.87 (m, 3H), 2.61-2.69 (m, 1H), 2.46-2.65 (dd, J ) 15.3
Hz, 1H), 1.92-2.30 (m, 5H), 1.25-1.78 (m, 26H), 0.88 (t, J )
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20372075, 20321202,
J. Org. Chem. Vol. 73, No. 18, 2008 7315