Syntheses of (-)-Oleocanthal
1
2H), 2.72 (m, 2H), 2.65 (m, 1H), 2.08 (d, J ) 7.1 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 200.4, 195.1, 171.9, 154.3, 154.2, 143.4,
129.5, 130.1, 115.4, 65.2, 46.3, 36.9, 34.2, 27.3 15.2; IR (neat)
3351, 2924, 1723, 1675, 1516, 1226 cm-1; HRMS (ES+) m/z
327.1217 [(M + Na)+; calcd for C17H20O5Na 327.1208]. For
cm-1; H NMR (500 MHz, CDCl3) δ 9.65 (s, 1H), 9.24 (d, J )
2.0 Hz, 1H), 7.19 (d, J ) 8.4 Hz, 2H), 6.80 (d, J ) 8.3 Hz, 2H),
6.61 (q, J ) 7.1 Hz, 1H), 5.04 (br s, 1H), 4.97 (s, 2H), 3.63-3.66
(m, 1H), 3.00 (ddd, J ) 1.3, 8.6, 18.4 Hz, 1H), 2.72-2.80 (m,
2H), 2.65 (dd, J ) 6.4, 15.9 Hz, 1H), 2.01 (d, J ) 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 200.3, 195.0, 171.8, 155.7, 154.4,
143.0, 130.3, 127.9, 115.4, 115.3, 66.0, 46.2, 36.8, 27.3, 15.2;
HRMS (ES+) m/z 313.1057 [(M + Na)+; calcd for C16H18O5Na
313.1052].
unnatural (+)-1: [R]20 +0.73 (c ) 0.55, CHCl3); all other data
D
were the same.
(3S,4E)-4-Formyl-3-(2-oxoethyl)hex-4-enoic acid phenethyl
ester, (-)-37. Isolated as a colorless oil: [R]20 -0.84 (c ) 0.9,
D
CHCl3); IR (neat) 3058, 3029, 2945, 2722, 1733, 1681, 1640 cm-1
;
(3S,4E)-4-Formyl-3-(2-oxoethyl)hex-4-enoic acid pentyl ester,
1H NMR (500 MHz, CDCl3) δ 9.63 (s, 1H), 9.23 (d, J ) 1.9 Hz,
1H), 7.19-7.31 (m, 5H), 6.62 (q, J ) 7.1 Hz, 1H), 4.23-4.29 (m,
2H), 3.60-3.62 (m, 1H), 2.98 (dd, J ) 8.6, 18.3 Hz, 1H), 2.91 (t,
J ) 7.0 Hz, 2H), 2.74 (dd, J ) 5.5, 18.3 Hz, 1H), 2.61-2.69 (m,
2H), 2.07 (d, J ) 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
200.3, 195.0, 171.8, 154.1, 143.2, 137.6, 128.8, 128.4, 126.5, 64.9,
46.1, 36.8, 35.0, 27.2, 15.2; HRMS (ES+) m/z 311.1257 [(M +
Na)+; calcd for C17H20O4Na 311.1259].
(-)-43. Isolated as a colorless oil: [R]20 -16.0 (c ) 0.05,
D
CH2Cl2); IR (neat) 2956, 2836, 2724, 1731, 1681, 1640 cm-1; H
1
NMR (500 MHz, CDCl3) δ 9.67 (s, 1H), 9.27 (d, J ) 1.9 Hz, 1H),
6.68 (q, J ) 7.1 Hz, 1H), 4.00 (t, J ) 6.8 Hz, 2H), 3.63-3.66 (m,
1H), 2.98 (ddd, J ) 1.1, 8.7, 18.3 Hz, 1H), 2.80 (dd, J ) 5.7, 18.3
Hz, 1H), 2.71 (dd, J ) 8.6, 16.0 Hz, 1H), 2.62 (dd, J ) 6.4, 16.1
Hz, 1H), 2.11 (d, J ) 7.1 Hz, 3H), 1.57 (pentet, J ) 7.2 Hz, 2H),
1.24-1.33 (m, 4H), 0.88 (t, J ) 7.2 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 200.3, 195.5, 172.0, 154.1, 143.4, 64.6, 46.2, 36.8, 28.2,
28.0, 27.2, 22.2, 15.2, 13.8; HRMS (ES+) m/z 277.1402 [(M +
Na)+; calcd for C14H22O4Na 277.1416].
(3S,4E)-4-Formyl-3-(2-oxoethyl)hex-4-enoic acid 2-(4-fluo-
rophenyl)ethyl ester, (-)-38. Isolated as a colorless oil: [R]20
D
-6.5 (c ) 0.23, CH2Cl2); IR (neat) 2957, 2832, 2723, 1729, 1679,
1
1602, 1511 cm-1; H NMR (500 MHz, CDCl3) δ 9.64 (s, 1H),
(3S,4E)-4-Formyl-3-(2-oxoethyl)hex-4-enoic acid methyl ester,
9.24 (d, J ) 1.9 Hz, 1H), 7.13-7.15 (m, 2H), 6.96-7.00 (m, 2H),
6.62 (q, J ) 6.1 Hz, 1H), 4.17-4.25 (m, 2H), 3.59-3.62 (m, 1H),
2.93 (dd, J ) 0.9, 8.5 Hz, 1H), 2.87 (t, J ) 6.9 Hz, 2H), 2.72 (dd,
J ) 5.7, 18.3 Hz, 1H), 2.68 (dd, J ) 8.6, 16.0 Hz, 1H), 2.61 (dd,
J ) 6.4, 16.1 Hz, 1H), 2.07 (d, J ) 6.0 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 200.2, 195.0, 171.8, 154.1, 130.3, 130.2, 115.3,
115.1, 64.7, 46.2, 36.7, 34.2, 27.1, 15.1; HRMS (ES+) m/z
329.1178 [(M + Na)+; calcd for C17H19FO4Na 329.1165].
(-)-44. Isolated as a colorless oil: [R]20 -50.0 (c ) 0.05,
D
CH2Cl2); IR (neat) 2954, 2836, 2723, 1730, 1681, 1639, 1437 cm-1
;
1H NMR (500 MHz, CDCl3) δ 9.66 (s, 1H), 9.28 (d, J ) 2.0 Hz,
1H), 6.69 (q, J ) 7.1 Hz, 1H), 3.62-2.66 (m, 1H), 6.61 (s, 3H),
2.98 (ddd, J ) 1.1, 8.4, 18.3 Hz, 1H), 2.80 (dd, J ) 5.7, 18.3 Hz,
1H), 2.71 (dd, J ) 8.6, 16.0 Hz, 1H), 2.62 (dd, J ) 6.4, 16.1 Hz,
1H), 2.11 (d, J ) 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
200.3, 195.0, 172.3, 154.2, 143.3, 51.5, 46.2, 36.6, 27.2, 15.2;
HRMS (ES+) m/z 221.0791 [(M + Na)+; calcd for C10H14O4Na
221.0790].
(3S,4E)-4-Formyl-3-(2-oxoethyl)hex-4-enoic acid 2-(3-hydroxy-
phenyl)ethyl ester, (-)-39. Isolated as a colorless oil: [R]20D -0.77
(c ) 1.0, CHCl3); IR (neat) 3443, 2957, 2727, 1731, 1681, 1453
(-)-Deacetoxy-Oleuropein Aglycone, (-)-8. Isolated as a
1
cm-1; H NMR (500 MHz, CDCl3) δ 9.64 (s, 1H), 9.22 (d, J )
colorless oil: [R]20 -70.0 (c ) 0.05, CHCl3); IR (neat) 3355,
D
2920, 1723, 1677, 1516, 1226 cm-1; 1H NMR (500 MHz, CDCl3)
δ 9.65 (s, 1H), 9.21 (d, J ) 2.0 Hz, 1H), 6.79 (d, J ) 8.0 Hz, 1H),
6.72 (d, J ) 1.9 Hz, 1H), 6.65 (q, J ) 7.1 Hz, 1H), 6.61 (dd, J )
2.0, 8.1 Hz, 1H), 4.14-4.24 (m, 2H), 3.61-3.66 (m, 1H), 2.93
(dd, J ) 1.0, 8.5 Hz, 1H), 2.79-2.81 (m, 3H), 2.77 (dd, J ) 6.4,
16.1 Hz, 1H), 2.70 (dd, J ) 6.6, 16.8 Hz, 1H), 1.25 (d, J ) 7.1
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 200.8, 195.6, 171.7, 155.0,
143.2, 143.1, 142.6, 130.6, 121.3, 116.2, 115.2, 65.1, 46.2, 36.9,
34.1, 27.1, 15.2; HRMS (ES+) m/z 343.1162 [(M + Na)+; calcd
for C17H20O6Na 343.1158].
1.9 Hz, 1H), 7.15 (t, J ) 7.8 Hz, 1H), 7.08 (d, J ) 7.5 Hz, 1H),
6.68-6.72 (m, 3H), 6.63 (q, J ) 7.1 Hz, 1H), 5.63 (s, 1H), 4.19-
4.28 (m, 2H), 3.60-3.63 (m, 1H), 2.93 (dd, J ) 0.9, 8.1 Hz, 1H),
2.84 (t, J ) 7.0, 2H), 2.80 (dd, J ) 5.7, 18.2 Hz, 1H), 2.61 (dd, J
) 6.5, 15.8 Hz, 1H), 2.05 (d, J ) 7.0 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 200.6, 195.4, 171.8, 155.8, 154.7, 143.2, 139.6,
129.7, 121.0, 116.0, 113.6, 64.8, 46.2, 36.9, 34.7, 27.1, 15.2; HRMS
(ES+) m/z 327.1217 [(M + Na)+; calcd for C17H20O5Na 327.1208].
(3S,4E)-4-Formyl-3-(2-oxoethyl)hex-4-enoic acid 2-(2-hydroxy-
phenyl)ethyl ester, (-)-40. Isolated as a colorless oil: [R]20D -0.72
(c ) 0.90, CHCl3); IR (neat) 3443, 2957, 2727, 1731, 1681 cm-1
;
(3S,4E)-3-(2-Hydroxyethyl)-4-hydroxymethylhex-4-enoic acid
2-(4-hydroxyphenyl)ethyl ester, (-)-45. A solution of (-)-oleo-
canthal (1) (45 mg, 0.148 mmol) in 1.0 mL of MeOH was cooled
to 0 °C, and NaBH4 (5.6 mg, 0.148 mmol) was added in one portion.
The reaction was stirred at 0 °C for 30 min. The solution was
reduced to half the original volume and placed directly onto a silica
gel column. Elution with 4:1 ethyl acetate/hexanes provided 44 mg
1H NMR (500 MHz, CDCl3) δ 9.64 (s, 1H), 9.25 (d, J ) 2.0 Hz,
1H), 7.12 (t, J ) 7.9 Hz, 1H), 7.08 (d, J ) 7.5 Hz, 1H), 6.86 (t, J
) 6.4 Hz, 1H), 6.80 (t, J ) 7.9 Hz, 1H), 6.64 (q, J ) 7.1 Hz, 1H),
5.73 (s, 1H), 4.21-4.27 (m, 2H), 3.62-3.64 (m, 1H), 2.95 (dd, J
) 0.7, 8.2 Hz, 1H), 2.92 (t, J ) 6.9 Hz, 2H), 2.79 (dd, J ) 5.6,
18.2 Hz, 1H), 2.62-2.74 (m, 2H), 2.07 (d, J ) 7.0 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 200.5, 195.1, 172.3, 154.3, 143.2, 130.8,
128.2, 123.6, 120.7, 115.8, 64.4, 46.2, 36.8, 29.9, 27.1, 15.2; HRMS
(ES+) m/z 327.1196 [(M + Na)+; calcd for C17H20O5Na 327.1208].
(3S,4E)-4-Formyl-3-(2-oxoethyl)hex-4-enoic acid 3-(4-hydroxy-
(97%) as a colorless oil: [R]20 -10.9 (c ) 0.055, CH2Cl2); IR
D
1
(neat) 3386, 2865, 2359, 2340, 1713, 1614, 1596 cm-1; H NMR
(500 MHz, CDCl3) δ 7.09 (d, J ) 8.3 Hz, 2H), 6.75 (d, J ) 8.5
Hz, 2H), 6.28 (br s, 1H), 5.62 (q, J ) 7.1 Hz, 1H), 4.19-4.29 (m,
2H), 3.99 (s, 2H), 3.58 (t, J ) 7.2 Hz, 2H), 3.13-3.30 (m, 1H),
2.78 (t, J ) 7.0 Hz, 2H), 2.48-2.69 (m, 3H), 1.71-1.85 (m, 3H),
1.68 (d, J ) 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 173.1,
154.7, 139.2, 129.9, 129.4, 126.3, 115.4, 65.8, 65.1, 60.8, 39.2,
35.9, 34.1, 32.7, 13.3; HRMS (ES+) m/z 331.1534 [(M + Na)+;
calcd for C17H24O5Na 331.1521].
(3S,4E)-4-Formyl-3-(2-hydroxyethyl)hex-4-enoic acid 2-(4-
hydroxyphenyl)ethyl ester, (-)-46. To a solution of diol (-)-45
(41 mg, 0.13 mmol, 1.0 equiv) in 1.0 mL of THF was added MnO2
(70 mg, 0.80 mmol, 6 equiv) at 23 °C. The reaction was stirred for
48 h and filtered through a plug of Celite and purified by flash
column chromatography with 2:1 hexanes/ethyl acetate to provide
(-)-46 (21 mg, 52%, 88% BORSM) as a colorless oil: [R]20D -12.0
(c ) 0.075, CH2Cl2); IR (neat) 3353, 2954, 2359, 2342, 1698, 1518
phenyl)propyl ester, (-)-41. Isolated as a colorless oil: [R]20
D
-0.79 (c ) 1.0, CHCl3); IR (neat) 3353, 2954, 2359, 2341, 1682,
1
1637, 1518 cm-1; H NMR (500 MHz, CDCl3) δ 9.64 (s, 1H),
9.29 (d, J ) 2.0 Hz, 1H), 7.02 (d, J ) 8.5 Hz, 2H), 6.75 (d, J )
8.4 Hz, 2H), 6.69 (q, J ) 7.0 Hz, 1H), 4.90 (s, 1H), 4.03 (t, J )
6.6 Hz, 2H), 3.65 (m, 1H), 2.98 (dd, J ) 1.1, 8.6 Hz, 1H), 2.79
(dd, J ) 1.1, 5.6 Hz, 1H), 2.60-2.74 (m, 2H), 2.58 (t, J ) 7.8 Hz,
2H), 2.12 (d, J ) 7.0 Hz, 3H), 1.85-1.90 (m, 2H); 13C NMR (125
MHz, CDCl3) δ 200.3, 195.1, 172.0, 154.3, 143.3, 133.1, 129.3,
115.2, 63.8, 46.2, 36.7, 31.2, 30.2, 27.2, 15.3; HRMS (ES+) m/z
341.1380 [(M + Na)+; calcd for C18H22O5Na 341.1365].
(3S,4E)-4-Formyl-3-(2-oxoethyl)hex-4-enoic acid 4-hydroxy-
benzyl ester, (-)-42. Isolated as a colorless oil: [R]20 -12.5 (c
D
) 0.15, CH2Cl2); IR (neat) 3353, 2921, 1721, 1676, 1516, 1226
J. Org. Chem, Vol. 72, No. 18, 2007 6899