Synthesis of Homochiral Aculeatins
32.6, 38.5, 90.2, 119.8, 129.2, 134.7, 153.1, 158.8; IR νmax (neat)
2959, 1511, 1253, 1100, 919, 846 cm-1; UV (MeOH) 279, 224,
207 nm; MS (DCI, NH3 + isobutane) m/z (%) 309 [M + H]+ (39),
293 (25), 179 (100).
(MeOH) 280, 225, 206 nm; MS (ESI+) m/z (%) 443 [M + Na]+
(100), 421 [M + H]+ (1), 107 (94); HRMS (ESI+) m/z calcd for
C26H44O4Na 443.3137, found 443.3141.
(+)-(2S,4R,6R)-2-[2-(4-Hydroxyphenyl)ethyl]-2-methoxy-6-
tridecyltetrahydropyran-4-ol (12). The (-)-3,5-syn-diol ketone
1 (50 mg, 0.10 mmol) was solubilized in 5 mL of anhydrous MeOH.
The reaction mixture was refluxed 16 h and then concentrated in
vacuo. The crude product was purified by flash chromatography
on silica gel (cyclohexane/ether 6:4) to afford (+)-12 (32.5 mg,
0.05 mmol, 63%) as a colorless oil; Rf ) 0.15 (cyclohexane/ether
(-)-(5R,7R)-Dihydroxy-1-(4-hydroxyphenyl)icosan-3-one (1)
and (+)-(2S,4S,6R)-2-[2-(4-hydroxyphenyl)ethyl]-6-tetrahydro-
pyran-2,4-diol (11). To a stirred solution of aldehyde 3e (19 mg,
0.04 mmol) in dry CH2Cl2 (0.7 mL) was added dropwise BF3‚OEt2
(10 µL) at -78 °C. After stirring for 2 min, enolsilane 4 (19 mg,
0.06 mmol) in dry CH2Cl2 (0.2 mL) was added. After stirring for
1.5 h at -78 °C, the reaction was quenched by a addition of
saturated aqueous solution of NaHCO3 (1 mL) and the mixture was
warmed to rt. The product was extracted with CH2Cl2, and the
organic layer was dried over MgSO4 and concentrated in vacuo.
The crude products were then dissolved in THF (8 mL) and treated
with TBAF (1 M in THF, 0.08 mL) at 0 °C. After stirring for 1 h
at rt, a saturated aqueous solution of NH4Cl (6 mL) was added.
The mixture was extracted with EtOAc, and the combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography on silica
gel (cyclohexane/ EtOAc 4:1 then 3:2) to afford the (-)-3,5-syn-
diol ketone 1 (8.2 mg, 0.02 mmol, 51%) and the (+)-tetrahydro-
pyran-hemiketal 11 (3.4 mg, 0.01 mmol, 21%).
27
1
6:4); [R]D + 41.1 (c 0.4, EtOH); H NMR (400 MHz, CD3OD)
δ 0.90 (t, J ) 7.0 Hz, 3H), 1.25-1.56 (m, 25H), 1.66-1.76 (m,
3H), 1.89-2.02 (m, 2H), 2.43-2.60 (m, 2H), 3.23 (s, 3H), 3.86-
3.94 (m, 1H), 4.03-4.07 (m, 1H), 6.69 (d, J ) 8.4 Hz, 2H), 7.00
(d, J ) 8.4 Hz, 2H); 13C NMR (100 MHz, CD3OD) δ 14.7, 23.9,
26.8, 30.1, 30.7-31.0, 33.3, 37.2, 38.7, 39.0, 39.9, 47.9, 65.9, 102.4,
116.3, 130.2, 134.1, 156.6; IR νmax (thin film, CH2Cl2) 3347, 2980,
1590, 1261, 723 cm-1; UV (MeOH) 280, 224, 206 nm; MS (ESI+)
m/z (%) 473 [M + K]+ (4), 457 [M + Na]+ (100), 425 [MCH3OH
+ Na]+ (74); HRMS (ESI+) m/z calcd for C27H46O4Na 457.3294,
found 457.3283.
(-)-(2R,4R,6R)-4-Hydroxy-2-tridecyl-1,7-dioxadispiro[5.1.5.2]-
pentadeca-9,12-dien-11-one [(-)-aculeatin A] and (+)-(2R,4R,6S)-
4-Hydroxy-2-tridecyl-1,7-dioxadispiro[5.1.5.2]pentadeca-9,12-
dien-11-one [(+)-aculeatin B]. To a stirred solution of (-)-3,5-
syn-diol ketone 1 (75 mg, 0.18 mmol) in acetone/H2O (4.4 mL of
a 10:1 v/v solution) were added TFA (5 µL, 0.07 mmol) and PIFA
(86 mg, 0.20 mmol) in one portion at rt in darkness. After 15 min,
a saturated aqueous solution of NaHCO3 (5 mL) was added, and
the products were extracted with EtOAc. The combined organic
layers were dried over MgSO4, filtered, and concentrated in vacuo.
The crude products were purified by flash chromatography on silica
gel (cyclohexane/EtOAc 4:1) to afford (-)-aculeatin A (36 mg, 86
µmol, 48%) and (+)-aculeatin B (25 mg, 60 µmol, 34%).
(-)-1. Rf ) 0.45 (cyclohexane/EtOAc 1:1); [R]D25 - 3.2 (c 1.0,
CHCl3); 1H NMR (400 MHz, CD3OD) δ 0.91 (t, J ) 6.8 Hz, 3H),
1.26-1.38 (m, 22H), 1.38-1.50 (m, 3H), 1.53-1.58 (m, 1H), 2.58
(d, J ) 6.4 Hz, 2H), 2.73-2.82 (m, 4H), 3.67-3.77 (m, 1H), 4.19-
4.29 (m, 1H), 6.69 (d, J ) 8.6 Hz, 2H), 7.01 (d, J ) 8.6 Hz, 2H);
13C NMR (100 MHz, CD3OD) δ 14.6, 23.9, 26.7, 29.9, 30.6-30.9,
33.2, 38.8, 44.9, 46.6, 51.3, 68.0, 71.2, 116.3, 130.4, 133.4, 156.8,
211.9; IR νmax (thin film, CH2Cl2) 3477, 3388, 2918, 2848, 1703,
1682, 1518, 1470, 1120, 815 cm-1; UV (MeOH) 280, 225, 204
nm; MS (ESI+) m/z (%) 443 [M + Na]+ (100), 421 [M + H]+
(4), 107 (56); HRMS (ESI+) m/z calcd for C26H44O4Na 443.3137,
found 443.3134.
25
(+)-11: Rf ) 0.30 (cyclohexane/EtOAc 1:1); [R]D + 6.7 (c
Acknowledgment. We thank the MENRT for doctoral
fellowship (M.P.) and the CNRS for financial assistance.
1
1.0, EtOH); H NMR (400 MHz, CD3OD) δ 0.90 (t, J ) 6.8 Hz,
3H), 1.03-1.13 (m, 1H), 1.24-1.38 (m, 23H), 1.39-1.58 (m, 2H),
1.82-1.89 (m, 2H), 1.89-1.96 (m, 1H), 2.01-2.08 (m, 1H), 2.61-
2.68 (m, 2H), 3.85-3.93 (m, 1H), 3.99-4.09 (m, 1H), 6.69 (d, J
) 8.2 Hz, 2H), 7.01 (d, J ) 8.2 Hz, 2H); 13C NMR (100 MHz,
CD3OD) δ 14.6, 23.9, 26.8, 30.2, 30.6-30.9, 33.2, 37.2, 42.1, 43.6,
46.6, 65.9, 69.9, 99.0, 116.3, 130.4, 134.6, 156.5; IR νmax (thin
film, CH2Cl2) 3349, 2849, 1516, 1468, 1451, 1247, 823 cm-1; UV
Supporting Information Available: Experimental procedures,
characterization data, and NMR spectra for 1, 3a-d, 4, 7, 8a-d,
13, and aculeatins. This material is available free of charge via the
JO0707986
J. Org. Chem, Vol. 72, No. 14, 2007 5379