Synthesis of Acerogenin-Type Macrocycles
J . Org. Chem., Vol. 64, No. 3, 1999 921
7.16 (dd, J ) 10.8, 8.4 Hz, 1H, H18), 7.45 (ddd, J ) 2.2, 4.0,
8.4 Hz, H19), 7.86 (dd, J ) 2.2, 6.9 Hz, 1H, H15); 13C NMR
(CDCl3) δ 22.9, 27.9, 30.5, 34.4, 42.4, 42.9, 55.6, 110.2, 114.1,
117.8 (d, J ) 20.1 Hz), 119.2, 125.1, 125.7, 135.1 (d, J ) 11.3
Hz), 135.7 (d, J ) 8.9 Hz), 137.9, 144.3, 145.0, 153.5 (d, J )
260.6 Hz), 208.5; MS (EI) m/z 376.
2H, H13), 2.98 (t, J ) 6.5 Hz, 2H, H14), 5.60 (d, J ) 1.8 Hz,
1H, H20), 5.80 (s, 1H, OH), 6.58 (dd, J ) 1.8, 8.1 Hz, 1H, H6),
6.85 (d, J ) 8.1 Hz, 1H, H5), 6.95 (d, J ) 8.4 Hz, 2H, H17,
H18), 7.15 (d J ) 8.4 Hz, 2H, H16, H19); 13C NMR (CDCl3) δ
20.2, 27.2, 31.3, 32.0, 44.3, 46.1, 115.4, 116.9, 122.6, 123.3,
130.5, 132.7, 137.4, 143.1, 148.5, 156.7, 212.0; MS (EI) m/z 296.
Anal. Calcd for C19H20O3: C, 77.00; H, 6.80. Found: C, 76.69;
H, 6.91.
4-Me t h oxy-17-n it r o-2-oxa t r icyclo[13.2.2.13,7]e icosa -
1(18),3,5,7(20),15(19),16-h exa en -12-on e 19. To a solution of
compound 18 (0.80 g, 2.13 mmol) in DMF (213 mL) was added
CsF (1.62 g, 10. 66 mmol). After being stirred at room
temperature for 5 h, the reaction mixture was diluted with
EtOAc. The organic phase was washed with H2O and brine,
dried, and evaporated. Purification by flash chromatography
(SiO2, eluent: heptane/EtOAc ) 1/3) afforded product 19 (0.68
g, 90%): mp 75-77 °C IR (CHCl3) 2941, 2839, 1711, 1539,
1511, 1353, 1270, 1121 cm-1; 1H NMR (CDCl3, 250 MHz, TMS)
δ 0.95 (m, 1H, H10), 1.20 (m, 1H, H10), 1.40 (m, 2H, H9), 1.9-
2.1 (m, 2H, H11), 2.45 (t, J ) 6.0 Hz, 2H, H8), 2.5-2.7 (m,
2H, H13), 3.05 (m, 2H, H14), 3.95 (s, 3H, OMe), 5.61 (d, J )
1.9 Hz, 1H, H20), 6.72 (dd, J ) 1.9, 8.3 Hz, 1H, H6), 6.86 (d,
J ) 8.3 Hz, 1H, H5), 7.08 (d, J ) 8.4 Hz, 1H, H18), 7.35 (dd,
J ) 2.1, 8.4 Hz, 1H, H19), 7.85 (d, J ) 2.1 Hz, 1H, H16); 13C
NMR (CDCl3) δ 21.2, 28.1, 32.1, 32.2, 44.8, 46.6, 57.2, 113.8,
118.0, 124.2, 125.9, 127.5, 134.3, 136.4, 139.3, 144.7, 148.0,
150.3, 151.2, 211.5; MS (EI) m/z 355, 325.
Acer ogen in A (1). Sodium borohydride (75.0 mg, 2.0 mmol)
was added to a solution of acerogenin C (2) (60.0 mg, 0.2 mmol)
in MeOH (2.5 mL) cooled at 0 °C. After being stirred at room
temperature for 20 min, the reaction mixture was diluted with
water and extracted with EtOAc. The combined organic
extracts were washed with brine, dried over Na2SO4, and
evaporated. Purification of the crude product by preparative
TLC (SiO2, eluent: heptane/EtOAc ) 3/1) afforded acerogenin
A (1) (60 mg, quantitative): mp 147-149 °C [lit,4 mp 151-
152 °C]; IR (CHCl3) 4215, 3618, 3558, 3027, 2938, 2400, 1511,
1
1504, 1242, 1048, 929, 802, 735 cm-1; H NMR (CD3OD, 300
MHz) δ 0.90-1.25 (m, 4H), 1.27-1.48 (m, 1H), 1.50-1.52 (m,
1H) 1.53-1.59 (m, 1H), 1.58-2.10 (m, 1H), 2.4-2.55 (m, 2H),
2.76 (td, J ) 4.0, 12.8 Hz, 1H), 3.0 (dt, J ) 3.8, 13 Hz, 1H),
3.19 (q, J ) 4.8 Hz, 1H), 5.74 (d, J ) 1.8 Hz, 1H), 6.51 (dd, J
) 1.8, 8.1 Hz, 1H), 6.79 (d, J ) 8.1 Hz, 1H), 7.01 (dd, J ) 2.5,
8.2 Hz, 1H), 7.23 (dd, J ) 2.5, 8.2 Hz, 1H), 7.34 (dd, J ) 2.0,
8.2 Hz, 1H), 7.40 (dd, J ) 2.0, 8.2 Hz, 1H); 13C NMR (CD3OD)
δ 26.0, 29.4, 32.7, 33.4, 40.0, 41.4, 71.3, 117.0, 117.4, 123.1,
124.0, 125.2, 131.2, 132.8, 134.5, 140.6, 144.8, 151.2, 157.8;
MS (EI) m/z 298.
17-Am in e-4-m et h oxy-2-oxa t r icyclo[13.2.2.13,7]eicosa -
1(18),3,5,7(20),15(19),16-h exa en -12-on e 20. A solution of
compound 19 (270 mg, 0.76 mmol) in MeOH was hydrogenated
in the presence of Pd/C (10%) for 1 h. The reaction mixture
was filtered through a short pad of Celite. Evaporation of the
filtrate gave the analytically pure product 20 (quantitative):
mp 129-131 °C; IR (CHCl3) 3300, 3028, 2943, 1705, 1620,
P er ben zoa te of Acer osid e IV 22. To a solution of acero-
genin C (2) (11 mg, 0.037 mmol), R-D-glucopyranosyl bromide
(48 mg, 0.07 mmol) in CH2Cl2 (1 mL), and NaOH (1 N, 1 mL)
was added catalytic amount of tetrabutylammonium bromide.
After being stirred at room temperature for 5 h, the reaction
mixture was diluted by addition of aqueous HCl (2 N) and
extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried over Na2SO4, and evaporated.
Purification of crude product by preparative TLC (SiO2,
eluent: toluene/heptane/EtOAc ) 1/3/1) afforded product 22
(30.0 mg, 93%) as a white solid: mp 170-172 °C; [R]D ) +19.5
(c 0.5, CHCl3); IR (CHCl3) 3027, 2932, 1734, 1693, 1456, 1195,
1123 cm-1; 1H NMR (CDCl3) δ 1.01 (m, 2H, H10), 1.32 (m, 2H,
H9), 1.82 (m, 2H, H11), 2.40 (m, 2H, H8), 2.55 (brt, J ) 6.5
Hz, 2H, H13), 2.92 (brt, J ) 6.5 Hz, 2H, H14), 4.28 (m, 1H,
H5′), 4.55 (dd, J ) 5.8, 12.1 Hz, 1H, H6′), 4.65 (dd, J ) 3.3,
12.1 Hz, 1H, H6′), 5.41 (d, J ) 7.7 Hz, 1H, H1′), 5.56 (d, J )
1.9 Hz, 1H, H20), 5.75 (t, J ) 9.4 Hz, 1H, H4′), 5.86 (dd, J )
7.7, 9.4 Hz, 1H, H2′), 6.02 (t, J ) 9.4 Hz, 1H, H3′), 6.48 (dd, J
) 1.9, 8.3 Hz, 1H, H6), 6.60 (dd, J ) 2.5, 8.5 Hz, 1H, H18),
6.72 (dd, J ) 2.5, 8.5 Hz, 1H, H17), 7.0-8.0 (m, 23H, aromatic
protons); 13C NMR (CDCl3) δ 20.4, 27.2, 31.6, 32.4, 44.6, 46.3,
63.3, 69.9, 76.5, 77.3, 77.8, 102.2, 118.0, 121.3, 122.2, 123.2,
123.6, 128.2, 128.5, 128.9, 129.3, 129.5, 129.7, 129.9, 130.4,
133.0, 133.2, 133.3, 133.6, 137.0, 137.7, 143.8, 152.4, 156.7,
165.4, 166.4, 166.2, 188.7, 212.1; FABMS (LiCl) m/z 881 (M +
Li)+.
Acer osid e IV (3). To a suspension of compound 22 (14 mg,
0.016 mmol) in MeOH (4 mL) and water (1 mL) was added an
excess of NaOH. The reaction mixture was heated to 80 °C,
and the solution gradually became clear. After 12 h, the
reaction was diluted with water and extracted with EtOAc.
The combined organic extracts were washed with brine, dried
over Na2SO4, and evaporated. Purification by preparative TLC
(SiO2, eluent: CH2Cl2/MeOH ) 1/6) afforded aceroside IV (3)
(7.0 mg, 95%) as a white solid: [R]D ) -34 (c 0.5, MeOH) (lit.5c
[R]D -39.5, EtOH); mp 148-150 °C (lit.,5c mp 153 °C); 1H NMR
(CD3OD, 300 MHz, TMS) δ 0.8-1.0 (m, 2H, H10), 1.2-1.4 (m,
2H, H9), 1.9-2.0 (m, 2H, H11), 2.42 (brt, J ) 5.8 Hz, 2H, H8),
2.62 (m, 2H, H13), 2.95 (brt, J ) 6.5 Hz, 2H, H14), 3.4-3.6
(m, 4H, H2′,H3′, H4′, H5′), 3.71 (ddd, J ) 1.3, 3.7, 12.0 Hz,
1H, H6′), 3.88 (dd, J ) 1.3, 12.0 Hz, 1H, H6′), 5.00 (d, J ) 7.3
Hz, 1H, H1′), 5.73 (d, J ) 2.1 Hz, 1H, H20), 6.65 (dd, J ) 2.1,
8.3 Hz, 1H, H6), 6.98 (dd, J ) 2.1, 8.1 Hz, 1H, H17),7.03 (dd,
J ) 2.1, 8.1 Hz, 1H, H18), 7.08 (d, J ) 8.3 Hz, 1H, H5), 7.15
(dd, J ) 1.6, 8.1 Hz, 1H, H16), 7.22 (dd, J ) 1.6, 8.1 Hz, 1H,
1507, 1261, 1229, 1121 cm-1 1H NMR (CDCl3, 300 MHz) δ
;
1.15 (m, 2H, H10), 1.40 (m, 2H, H9), 1.97 (t, J ) 8.2 Hz, 2H,
H11), 2.46 (m, 2H, H8), 2.61 (m, 2H, H13), 2.88 (m, 2H, H14),
3.73 (brs, 2H, NH2), 3.94 (s, 3H, OMe), 5.91 (d, J ) 1.9 Hz,
1H, H20), 6.55 (m, 2H, H16, H19), 6.67 (dd, J ) 1.9, 8.2 Hz,
1H, H6), 6.82 (d, J ) 8.2 Hz, 1H, H5), 6.91 (d, J ) 8.6 Hz, 1H,
H18); 13C NMR (CDCl3) δ 20.2, 28.2, 31.7, 32.5, 44.4, 46.0, 56.2,
112.2, 116.7, 117.3, 119.3, 122.2, 124.1, 133.9, 138.3, 139.9,
143.1, 146.9, 148.6, 212.0; MS (EI) m/z 325.
4-Met h oxy-2-oxa t r icyclo[13.2.2.13,7]eicosa -1(18),3,5,7-
(20),15(19),16-h exa en -12-on e 21. To a solution of tert-bu-
tylnitrite (0.6 mmol, 79 µL) in dry DMF (2 mL), heated at 50
°C, was added a solution of amine 20 (130 mg, 0.4 mmol) in
DMF (1 mL) dropwise. After being stirred for 1 h, the reaction
mixture was cooled to room temperature, diluted with EtOAc
(100 mL), and washed with H2O and aqueous NH4Cl succes-
sively. The organic phase was dried and evaporated. Purifica-
tion by flash chromatography (SiO2, eluent: heptane/EtOAc
) 1/6) gave the product 21 (112 mg, 90%): mp 124-126 °C;
IR (CHCl3) 3012, 2934, 2833, 1703, 1519, 1261, 1117 cm-1; 1H
NMR (CDCl3, 200 MHz) δ 1.11 (m, 2H, H10), 1.37 (m, 2H, H9),
1.90 (m, 2H, H11), 2.45 (brt, J ) 6.0 Hz, 2H, H8), 2.61 (brt, J
) 7.0 Hz, 2H, H13), 2.99 (brt, J ) 7.0 Hz, 2H, H14), 3.95 (s,
3H, OMe), 5.64 (d, J ) 2.0 Hz, 1H, H20), 6.64 (dd, J ) 2.0, 8.2
Hz, 1H, H6), 6.82 (d, J ) 8.2 Hz, 1H, H5), 7.02, 7.20 (AB q, J
) 8.4 Hz, 4H, H16, H17, H18, H19); 13C NMR (CDCl3) δ 21.1,
28.2, 32.0, 32.9, 45.2, 46.8, 57.0, 113.1, 118.1, 122.6, 124.3,
131.2, 134.3, 137.8, 147.5, 151.6, 157.6, 212.6; MS (EI) m/z 310
(M+). Anal. Calcd for C20H22O3: C, 77.39; H, 7.14. Found: C,
77.59; H, 7.17.
Acer ogen in C (2). To a solution of compound 21 (120 mg,
0.38 mmol) in freshly redistilled CH2Cl2 (20 mL) was added
AlCl3 (257 mg, 1.93 mmol). The reaction mixture was heated
to reflux for 18 h. After being cooled to room tempearature,
the reaction was quenched by careful addition of water and
extracted with CH2Cl2. The combined organic extracts were
washed with brine, dried over Na2SO4, and evaporated.
Purification by flash chromatography (SiO2, eluent: heptane/
EtOAc ) 1/4) afforded acerogenin (2) (100 mg, 88%) as a white
solid: mp 114-115 °C [lit.,5c mp 116 °C]; IR (CHCl3) 3556,
3024, 2936, 1703, 1516, 1504, 1434, 1352, 1270 cm-1; 1H NMR
(CDCl3, 250 MHz) δ 1.00 (m, 2H, H10), 1.48 (m, 2H, H9), 1.95
(m, 2H, H11), 2.48 (t, J ) 5.8 Hz, 2H, H8), 2.62 (t, J ) 6.5 Hz,