6964
H. Wilhelm, L. A. Wessjohann / Tetrahedron 62 (2006) 6961–6966
flash chromatography silica gel 60 (0.040–0.063 mm) was
used. Xanthohumol was obtained from hop-industry (special
thanks to Dr. Martin Biendl).
1H, J¼17.0 Hz, J¼3.1 Hz), 3.04 (dd, 1H, J¼17.0 Hz,
J¼13.2 Hz), 5.32 (dd, 1H, J¼13.2 Hz, J¼3.1 Hz), 5.97 (s,
1H), 6.89 (d, 2H, J¼8.6 Hz), 7.34 (d,ꢀ2H, J¼8.2 Hz), 11.76
(s, 1H); ESI-MS: m/z 339.3 [MꢀH ]; 4,20-dihydroxy-60-
methoxy-600,600-dimethyl-400,500-dihydropyrano-[200,300:30,40]-
chalkone (8),27,28 tR¼26.3 min, 2 mg, 4% as yellow powder,
3.1.1. Isoxanthohumol (2). Xanthohumol (500 mg,
1.4 mmol) was dissolved in 500 ml 1% NaOH solution and
stirred at 0 ꢁC for 2 h. Acidification with 50% H2SO4 gives
a light yellow precipitate. After filtration and careful wash-
ing with water the dried product (100%) can be used for
most processes. If further purification is required the mate-
rial is dissolved in methanol, filtered again, water is added
to the solution for precipitation, and evaporated to further
drive precipitation. Lyophylization of the filtered product
gives 2 as a light yellow powder of at least 95% purity (usu-
ally >99.9%). 2: UV: lmax 288 nm; 1H NMR: d 1.60 (s, 3H),
1.61 (s, 3H), 2.62 (dd, 1H, J¼16.3 Hz, J¼2.9 Hz), 2.93 (dd,
1H, J¼16.3 Hz, J¼12.6 Hz), 3.26 (d, 1H, J¼7.1 Hz), 3.73
(s, 3H), 5.20 (t, 1H, J¼7.1 Hz), 5.36 (dd, 1H, J¼12.6 Hz,
J¼2.9 Hz), 6.22 (s, 1H), 6.89 (d, 2H, J¼8.6 Hz), 7.39 (d,
1H, J¼8.6 Hz); 13C NMR: d 17.87, 22.50, 25.87, 46.12,
55.73, 79.37, 93.49, 106.04, 108.79, 115.85, 123.63,
128.45, 130.83, 131.31, 158.10, 160.84, 161.81, 162.57,
188.49; ESI-MS: 353.3 [MꢀHꢀ].
1
UV: lmax 371 nm; H NMR: d 1.36 (s, 6H), 1.81 (t, 2H,
J¼6.7 Hz), 2.63 (t, 2H, J¼6.7 Hz), 3.88 (s, 3H), 5.88 (s,
1H), 6.86 (d, 2H, J¼8.5 Hz), 7.51 (d, 2H, J¼8.7 Hz), 7.74
(d, 1H, J¼15.6 Hz), 7.83 (d, 1H, J¼15.6 Hz), 14.79 (s,
1H); ESI-MS: m/z 353.3 [MꢀHꢀ]; 8-(300-hydroxyisoamyl)-
naringenin (9),33 tR¼7.6 min, 3 mg, 6% as white powder,
1
UV: lmax 214, 293 nm; H NMR: d 1.18 (s, 6H), 1.64 (m,
2H), 2.64 (t, 2H, J¼8.1 Hz), 2.80 (dd, 1H, J¼17.0 Hz,
J¼3.1 Hz), 3.11 (dd, 1H, J¼17.0 Hz, J¼12.6 Hz), 5.47 (dd,
1H, J¼12.6 Hz, J¼3.1 Hz), 6.01 (s, 1H), 6.90 (d, 2H,
J¼8.6 Hz), 7.43 (d, 1H, J¼8.4 Hz), 12.11 (s, 1H); ESI-MS:
357.3 [MꢀHꢀ]; 8-(300-hydroxyisoamyl)-7,40-dihydroxy-5-
methoxyflavanone (10),28 tR¼4.0 min, 0.5 mg, 1% as light
yellow powder, UV: lmax 287 nm; 1H NMR: d 1.18 (s, 6H),
1.66 (m, 2H), 2.64 (dd, 1H, J¼16.3 Hz, J¼2.9 Hz), 2.67 (t,
2H, J¼8.1 Hz), 2.99 (dd, 1H, J¼16.3 Hz, J¼12.6 Hz), 3.74
(s, 3H), 5.37 (dd, 1H, J¼12.6 Hz, J¼2.9 Hz), 6.19 (s, 1H),
6.88 (d, 2H, J¼8.6 Hz), 7.41 (d, 1H, J¼8.4 Hz); ESI-MS:
m/z 371.2 [MꢀHꢀ].
3.1.2. Demethylation of isoxanthohumol (2) with AlBr3.
To a stirred suspension of isoxanthohumol (2) (50 mg,
0.14 mmol) in 4 ml CH2Cl2 sym. collidine is slowly added
until 2 is completely dissolved (ca. 100 mg, 0.83 mmol).
AlBr3 solution (0.28 ml, 1 M in CH2Br2) is added dropwise
at rt. The mixture is stirred overnight and filtered. The orange
precipitate is dried in vacuo and dissolved in 10 ml 0.5 M
NaOH. After the solution is stirred for 1.5 h at 0 ꢁC (to con-
vert reformed 1 back to 2) it is acidified with 50% H2SO4. The
yellow precipitate is filtered off, washed carefully with water,
and dried. The mixture is dissolved in methanol and sepa-
rated by HPLC with a gradient of 40–70% acetonitrile in
water within 20 min: 1, tR¼21.1 min, 2, tR¼9.6 min, 4,
tR¼14.4 min. Lyophylization gives 1 (0.5 mg, 1%) as yellow
powder, 2 (27 mg, 54%), and 4 (12 mg, 25%, 60%
based on recovered starting material) as white powders.
3.1.4. Demethylation of isoxanthohumol (2) with
CH3AlCl2. This was conducted as described in procedure
3.1.2 with AlBr3 exchanged for CH3AlCl2. Conditions were
altered as given in Table 1, entries 4 and 5.
3.1.5. Demethylation of isoxanthohumol (2) with LiI. A
solution of 2 (53 mg, 0.150 mmol) in 1.2 ml pyridine is
added to LiI (30 mg, 0.224 mmol) and stirred for 12 h at
120 ꢁC. After addition of 10 ml 0.5% HCl the solution is ex-
tracted with ethyl acetate (2ꢂ30 ml). The combined organic
layers are washed with aqueous NH4Cl solution and water
and dried over Na2SO4. The solvent is evaporated, and the
residue was dissolved in methanol and subjected to HPLC
with a gradient of 40–70% acetonitrile in water within
20 min. Lyophylization gives 1, tR¼20.1 min, 5 mg, 9%; 2,
tR¼9.5 min, 6 mg, 11%; 4, tR¼14.1 min, 4 mg, 8%; 6-prenyl-
naringenin (5), tR¼18.3 min, 5 mg, 9% as off-white powder,
UV: lmax 292, 334 nm; 1H NMR: d 1.64 (s, 3H), 1.75 (s, 3H),
2.72 (dd, 1H, J¼17.0 Hz, J¼3.0 Hz), 3.17 (dd, 1H, J¼
17.0 Hz, J¼12.9 Hz), 3.34 (d, 2H, J¼7.3 Hz), 5.23 (t, 1H,
J¼1.4 Hz), 5.42 (dd, 1H, J¼13.0 Hz, J¼2.9 Hz), 6.03 (s,
1H), 6.89 (d, 2H, J¼8.6 Hz), 7.39 (d, 1H, J¼8.6 Hz), 12.47
(s, 1H); ESI-MS: m/z 339.3 [MꢀHꢀ]; 5-hydroxy-10-
prenyl-4,8-di-(4-hydroxyphenyl)-3,4,7,8-tetrahydro-pyrano-
[3,2-g]chromene-2,6-dione (12) mixture of diastereomers,
tR¼17.6 min, 5 mg, 7% as off-white powder; 1H NMR:
d 1.63, (s, 6H), 2.92 (m, 2H), 3.26 (m, 2H), 3.31 (dd, 2H),
4.60 (m, 1H), 5.19 (m, 1H), 5.58 (m, 1H), 6.76 (dd, 2H,
J¼8.6 Hz), 6.92 (d, 2H, J¼8.4 Hz), 7.01 (dd, 2H,
J¼8.4 Hz), 7.44 (dd, 2H, J¼8.6 Hz), 12.37 (s, 1H) (most
peaks are doubled because of the two diastereomers); 13C
NMR (acetone-d6): d 17.89, 22.33, 22.36, 25.86, 33.92,
33.97, 37.25, 37.33, 43.31, 43.62, 80.06, 80.17, 105.52,
105.62, 106.99, 107.02, 109.40, 109.43, 116.18, 116.33,
122.61, 122.64, 128.62, 128.94, 128.98, 130.45, 130.52,
132.27, 132.29, 132.99, 133.06, 157.33, 157.35, 157.54,
157.58, 158.40, 158.45, 158.74, 159.88, 159.99, 166.92,
1
8-Prenylnaringenin (4): UV: lmax 293, 335 nm; H NMR:
d 1.60 (s, 3H), 1.61 (s, 3H), 2.76 (dd, 1H, J¼17.2 Hz,
J¼3.1 Hz), 3.14 (dd, 1H, J¼17.2 Hz, J¼12.8 Hz), 3.22 (d,
2H, J¼7.3 Hz), 5.19 (t, 1H, J¼7.3 Hz), 5.45 (dd, 1H,
J¼12.8 Hz, J¼3.1 Hz), 6.03 (s, 1H), 6.90 (d, 2H, J¼
8.6 Hz), 7.41 (d, 2H, J¼8.6 Hz), 12.14 (s, 1H); 13C NMR
(CDCl3): d 17.93, 21.88, 25.91, 43.17, 78.69, 96.80,
103.11, 106.01, 115.46, 121.42, 127.62, 130.78, 134.96,
155.72, 159.51, 162.03, 163.50, 196.19; ESI-MS: 339.3
[MꢀHꢀ].
3.1.3. Demethylation of isoxanthohumol (2) with BBr3.
To a stirred suspension of isoxanthohumol (2) (50 mg,
0.14 mmol) in 4 ml CH2Cl2 sym. collidine is slowly added
until 2 is completely dissolved (ca. 100 mg, 0.83 mmol).
BBr3 solution (0.5 ml) (1 M in CH2Cl2) is added dropwise
at ꢀ80 ꢁC. The mixture is stirred for 3 h at ꢀ80 ꢁC and fil-
tered. For work up see above. Six fractions are separated by
HPLC: 2, tR¼9.8 min, 9 mg, 18%; 4, tR¼14.6 min, 9 mg,
18%; 5,40-dihydroxy-600,600-dimethyl-400,500-dihydropyrano-
[200,300:7,8]flavanone (6),11 tR¼20.7 min, 5 mg, 10% as white
1
powder, UV: lmax 218, 295 nm; H NMR (CDCl3): d 1.33
(s, 3H), 1.35 (s, 3H), 1.76 (m, 2H), 2.58 (m, 2H), 2.78 (dd,