Total synthesis of (±)-glyflavanone by a rigid quaternary ammonium salt

Article abstract of DOI:10.1002/jccs.200700119

Total synthesis of (±)-glyflavanones and glychalcones was accomplished starting from the known 1-(5-hydroxy-7-methoxy-2,2-dimethyl-2H- chromen-6-yl)ethanone (6). A new approach to synthesis of flavanones, based on a high yielding N-benzylcinchoninium salt

Full text of DOI:10.1002/jccs.200700119

Journal of the Chinese Chemical Society, 2007, 54, 817-822
817
Note
Total Synthesis of ( )-Glyflavanone by a Rigid Quaternary Ammonium Salt
Yu-Ting Fang (
Huan-Ting Wu (
Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan, R.O.C.
), Chia-Ning Lin (
),
) and Yean-Jang Lee* (
)
Total synthesis of (±)-glyflavanones and glychalcones was accomplished starting from the known
1-(5-hydroxy-7-methoxy-2,2-dimethyl-2H-chromen-6-yl)ethanone (6). A new approach to synthesis of
flavanones, based on a high yielding N-benzylcinchoninium salt catalyzed chromane ring forming enantio-
selective cyclization process, is described. Also, synthesis of (+)-glyflavanone 1, the natural enantiomer,
was achieved through optical resolution of a key intermediate in racemic synthesis.
Keywords: Enantioselectve; Glyflavanones; N-benzylcinchoninium salt.
Studies on the constituents of plants of Glycosmis
ered to be an advanced synthetic intermediate for 1. For the
construction of the trans-a,b-unsaturated ketone in 3, we
anticipated that an aldol condensation of 6 and the corre-
sponding benzaldehyde would proceed thermodynamically
for the construction of a trans-geometry in 3. First, we sub-
jected the known5 2-hydroxy ketone 6 to aldol reaction
with 4-methoxybenzaldehyde to produce the correspond-
ing glychalcone as the trans-geometry 3 in high 94% yield
(Scheme I). The trans-geometry isomer of 3 was assigned
by use of the X-ray crystallographic method.6 To investi-
gate the scope of the N-benzylcinchoninium salt catalyzed
enantioselective cyclization process, we examined reac-
tions of various starting materials, including simple chal-
cones. The results are summarized in Table 1. Flavanones,
bearing substituents in the 5,7,4¢-positions (entries 1-4),
are prepared by use of this method in high yields. 4,6-Di-
methoxy-4¢-methoxy chalcone also reacts under these con-
ditions to afford the desired product (entries 5-8). How-
ever, the enantioselective cyclization of glychalcones, cat-
alyzed by N-benzylcinchoninium salts, requires high tem-
perature and leads to generation of only 55% ee glyflavones
in > 90% yield (entries 9-12). On the other hand, it is worth
noting that NaOH was dissolved in H2O and Adogen 464
for an efficient route to racemic 1 in Scheme I.
citrifolia (Willd), which are used in traditional herbal medi-
cines in areas of China, show cell growth inhibition of hu-
man promyelocytic leukaemic cells (HL-60) and also in-
hibit macromolecular synthesis.1 (+)-Glyflavanones and
glychalcones were isolated from the leaves of this plant
collected in Taiwan by Wu et al. in 1995.2 The structures of
(+)-glyflavanones and glychalcones were elucidated as 1-4
by examination of optical rotation, IR, UV, NMR, and high-
resolution mass spectra. To date, no (+)-glyflavanones has
been synthesized. In addition, phase-transfer catalyzed re-
action systems are one of the most useful methodologies in
organic syntheses.3 Recently, Corey et al. reported the de-
velopment of the chiral quaternary cinchonidium cation as
a superior catalyst for enantioselective reactions, including
Michael, alkylation, aldol, nitroaldol, and epoxidation re-
actions.4 Moreover, due to the medicinal imperatives and
the intact structure of interest, the scarcity of (+)-1 and the
clear need for a reliable supply, we undertook the synthesis
of one member of this family-(+)-glyflavanone 1-to con-
firm the overall structure assignment.
Having established an efficient route to racemic 1 and
2, we next focused our attention on the synthesis of an opti-
cally active 1. For separation, the reduction of racemic
ketone 1 with NaBH4 was smoothly converted to generate
the desired diastereomer chromanol 8 in 93% yield. How-
ever, attempts to separate diastereomers 8 were unsuccess-
ful. It is worth noting that chromanol 8 underwent the dehy-
Perhaps the easiest route to optically active 1 would
have been to employ the enantioselective cyclization of the
glychalcone 3. Thus, the trans-glychalcone 3 was consid-

818 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Fang et al.
Scheme I
Scheme II
dration reaction at various weak acid conditions as well as
standing on chloroform or silica gel. Alternately, when
racemic (±)-1 was treated with BBr3, the racemic (±)-9 was
produced in excellent yield (96%). Followed by alkylation
of the racemic 5-hydroxyflavanone 9 with (-)-chlorometh-
yl menthyl ether, the desired diastereomers 10 were ob-
tained in quantitative yield. However, attempts to separate
diastereomers 10 were unsuccessful. Consequently, 10
were further transformed by reduction with NaBH4, and
readily separable diastereomers 11a, 11b, and 11c were
isolated (Scheme II). The structure of diastereomers, 11a,
11b, and 11c, was assigned by use of COSY (1H-1H) and
HSQC (1H-13C) NMR experimental analysis. Both COSY
and HSQC spectra of 11a, 11b, and 11c were shown on the
supporting material. Subsequently MnO2 oxidation of 11a
and 11b produced optically pure 10a and 10b, respectively.
Finally, enantiomerically pure 10a or 10b was eventually
converted into (+)-glyflavanone or (-)-glyflavanone using

Total Synthesis of ( )-Glyflavanones
J. Chin. Chem. Soc., Vol. 54, No. 3, 2007 819
Table 1. Asymmetric synthesis of flavanones with various n-benzylcinchoninium salts
Product/
Entry
Chalcones
Conditions
Yield (%)a ee%b
flavanones
cat. 7a X=H
7b X=Br
7c X=I
OH
O
(10 mol%)
R
R
R
3
2
1
1
2
R1=R3=H, R2=OMe
R1=R3=H, R2=OMe
R1=R3=H, R2=OMe
R1=R3=H, R2=OMe
R1=R3=R2=OMe
R1=R3=R2=OMe
R1=R3=R2=OMe
R1=R3=R2=OMe
3
7b, Et3N, 0 °C
99
98
99
98
18
56
34
70
90
95
93
92
31
33
30
28
4
7c, Et3N, 0 °C
3
7c, NaOH, 0 °C
7c, Dabco, 0 °C
7b, Et3N, 0 °C
4
5
6
7b, Et3N, 60 °C
7c, NaOH, 60 °C
7c, NaOH, Adogen 464, 60 °C
7a, Et3N, 60 °C
8
7
5
8
9
9
0
10
11
12
3
7b, Et3N, 60 °C
7c, Et3N, 60 °C
13
15
55
3
3
7c, NaOH, 60 °C
a Isolated yield; b Determined by HPLC analysis using a chiral column.
a deprotection and methylation reaction sequence. The syn-
thesized optically active (+)-1 had a consistent specific ro-
tation with that of natural (+)-1 {[a]D +15 (c 0.06, CHCl3)
for synthetic, lit.2 [a]D +13.5 (c 0.065, CHCl3) for natural}.
In addition, 1H, 13C NMR, and high-resolution mass spectra
of the synthetic product are in agreement with those re-
ported for the naturally derived material.2 Although 1H and
13C NMR spectroscopic analysis of these substances
showed that they contained the desired glyflavanone ring
system, the data were not sufficient to enable unambiguous
assignments of the structures. Thus, 1 was subjected to X-
ray crystallographic analysis,6 which provided the struc-
ture.
EXPERIMENTAL SECTION7
1-(5-Hydroxy-7-methoxy-2,2-dimethyl-2H-chromen-6-
yl)ethanone (6)
This compound was prepared as a yellow solid from
phloroglucinol dihydrate (Acros) according to the litera-
ture8 (Scheme I). The mp, 1H and 13C NMR spectra are in
agreement with those reported.9
1-(5-Hydroxy-7-methoxy-2,2-dimethyl-2H-chromen-6-
yl)-3-(4-methoxyphenyl)propenone (3)
A mixture of 6 (0.50 g, 2.0 mmol) and 4-methoxy-
benzaldehyde (0.41 g, 3.0 mmol) in 25 mL ethanol was in-
troduced into 10 mL KOH (1.20 g in H2O/ethanol 1:1) un-
der a nitrogen atmosphere at 0 °C. The suspension was then
stirred and maintained at room temperature for 8 h. A dark
brown suspension was neutralized with HCl until pH = 4
and then followed by extraction with CH2Cl2 (3 ´ 100 mL).
The organic layer was concentrated and the crude product
was subjected to column chromatography (SiO2, Hexane/
EA 10/1) to yield glychalcone 3 (0.69 g, 94%) as a red
In summary, we have proposed the versatility of the
N-benzylcinchoninium salt catalyzed chromane ring form-
ing enantioselective cyclization process. We have achieved
the total synthesis of (±)-glyflavanones in 7 steps in an
overall yield 48% starting with commercially available
phloroglucinol dihydrate. In addition, optical resolution of
the key intermediates 11a and 11b led to the syntheses of
natural (+)- and unnatural (-)-glyflavanone. However, the
mechanistic issues uncovered in the enantioselective cy-
clization process as well as the scope and generality of this
new synthetic method will be probed in detail in our con-
tinuing studies in this area. Further syntheses of (+)-gly-
flavanones are currently underway to employ this strategy
for supplying biological assays.
solid: mp 115-117 °C (lit.2 mp 112-114 °C); H NMR
1
[(CD3)2CO] d 1.41 (s, 6H), 3.84 and 3.98 (s, 6H), 5.55 (d, J
= 10.0 Hz, 1H), 6.01 (s, 1H), 6.60 (d, J = 10.0 Hz, 1H), 6.99
and 7.68 (d, J = 8.8 Hz, 4H), 7.95 and 8.10 (d, J = 15.4 Hz,
2H); 13C NMR [(CD3)2CO] d 28.7, 55.9, 56.7, 79.0, 92.6,
103.6, 106.7, 115.5, 116.7, 125.9, 126.5, 129.1, 131.3,

820 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Fang et al.
143.5, 161.4, 162.8, 163.4, 163.9, 193.6; HRMS (EI) calcd
for C22H22O5 (M+) 366.1467, found 366.1461; Anal. Calcd
for C22H22O5: C, 72.12; H, 6.05; O, 21.83. Found: C, 72.26;
H, 5.89; O, 21.92.
procedure, from 4 (0.40 g, 1.0 mmol) and benzylcincho-
ninium salt (0.047 g, 10 mol %) using base NaOH (0.061 g,
1.5 mmol) in 6 mL of H2O and Adogen 464 (1:1) for 2 h.
The product was isolated in 91% yield (0.36 g, 0.91 mmol)
after flash chromatography (SiO2, cyclohexane/EA 5/1) as
a light yellow solid: mp 148-150 °C; 1H NMR [(CD3)2CO]
d 1.39 and 1.41 (s, 6H), 2.64 (dd, J = 16.4, 3.1 Hz, 1H),
3.00 (dd, J = 16.4,12.5 Hz, 1H), 3.81 and 3.83 (s, 6H), 5.42
(dd, J = 12.5,3.1 Hz, 1H), 5.55 (d, J = 10.0 Hz, 1H), 6.07 (s,
1H), 6.54 (d, J = 10.0 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H),
3-(3,4-Dimethoxyphenyl)-1-(5-hydroxy-7-methoxy-2,2-
dimethyl-2H-chromen-6-yl)propenone (4)
This unsaturated ketone 4 was prepared, using the
above procedure, from 6 (0.50 g, 2.0 mmol) and 3,4-di-
methoxybenzaldehyde (0.50 g, 3.0 mmol) using base KOH
(1.3 g) in ethanol (25 mL) for 8 h. The product was isolated
in 96% yield (0.77 g, 1.9 mmol) after flash chromatography
(SiO2, hexane/EA 10/1) as a yellow solid: mp 130-132 oC;
1H NMR [(CD3)2CO] d 1.42 (s, 6H), 3.85, 3.89, and 3.99 (s,
9H), 5.55 (d, J = 10.0 Hz, 1H), 6.01 (s, 1H), 6.60 (d, J =
10.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 4H), 7.27 (dd, J = 8.0, 1.9
Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.72 and 7.88 (d, J = 15.4
Hz, 2H); 13C NMR [(CD3)2CO] d 28.7, 56.2, 56.3, 56.7,
79.0, 92.6, 103.6, 106.7, 111.8, 112.7, 116.7, 123.9, 126.1,
126.6, 129.3, 143.9, 150.7, 152.9, 163.4, 163.9, 193.6.
7.06 (dd, J = 8.3,1.9 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H); 13
C
NMR [(CD3)2CO] d 28.2, 28.9, 46.7, 56.8, 56.9, 79.1, 80.6,
95.1, 104.0, 107.2, 111.8, 113.2, 117.3, 120.3, 127.9,
133.4, 151.1, 151.2, 160.2, 160.9, 163.7, 188.8.
5-Methoxy-2-(4-methoxyphenyl)-8,8-dimethyl-2,3-di-
hydro-8H-pyrano[2,3-j]chroman-4-ol (8)
In a solution of racemic 1 (0.31 g, 0.85 mmol) in 30
mL THF was cooled down to 0 °C and then followed by ad-
dition of NaBH4 (0.080 g, 2.1 mmol). The mixture was
stirred and maintained at room temperature for 2 h. After
quenching with methanol, the resulting solution was ex-
tracted with CH2Cl2 (3 ´ 100 mL). The solvent was re-
moved in vacuo, and the residue was subjected to short col-
umn chromatography (SiO2, cyclohexane:EA 10:1) to pro-
vide chromanol 8 (0.29 g, 93%) as a yellow solid: mp 138-
140 °C; 1H NMR [(CD3)2CO] d 1.34 and 1.37 (s, 6H), 2.04
(ddd, J = 13.4,11.9,1.8 Hz, 1H), 2.42 (ddd, J = 13.4, 7.4,
1.8 Hz, 1H), 3.79 and 3.85 (s, 6H), 4.00 (s, OH), 4.98 (dd, J
= 11.9, 1.8 Hz, 1H), 5.16 (t, J = 7.4 Hz, 1H), 5.44 (d, J = 9.9
Hz, 1H), 6.06 (s, 1H), 6.46 (d, J = 9.9 Hz, 1H), 6.94 and
7.41 (d, J = 8.6 Hz, 4H); 13C NMR [(CD3)2CO] d 28.4, 28.6,
40.0, 56.2, 56.7, 64.2, 77.5, 78.3, 94.3, 104.8, 109.4, 115.3,
118.1, 127.5, 129.0, 134.5, 153.0, 155.4, 160.9, 161.1.
5-Methoxy-2-(4-methoxyphenyl)-8,8-dimethyl-2,3-di-
hydro-8H-pyrano[2,3-j]chromen-4-one (1)
Ketone 3 (0.44 g, 1.2 mmol) and freshly prepared
benzylcinchoninium salt10 (0.056 g, 10 mol %) were dis-
solved in 25 mL of H2O/CH2Cl2 (1:1). To NaOH (0.072 g,
1.8 mmol) in 3 mL of distilled H2O was added one portion
at 0 oC followed by 3 mL of Adogen 464. The reaction mix-
ture was heated to 60 °C (oil bath) under reflux for 2 h. Af-
ter cooling, the organic and aqueous phase was separated,
and the aqueous layer was extracted with CH2Cl2 (3 ´ 100
mL). The combined organic phase and organic extracts
were dried over anhydrous MgSO4 and evaporated in vacuo.
The residue was subjected to flash column chromatography
(SiO2, cyclohexane/EA 5/1) to give 1 (0.40 g, 90%) as light
o
o
1
yellow solid: mp 114-115 C (lit.2 mp 112-114 C); H
NMR [(CD3)2CO] d 1.39 and 1.41 (s, 6H), 2.63 (dd, J =
16.4, 3.0 Hz, 1H), 2.97 (dd, J = 16.4,12.5 Hz, 1H), 3.81 (s,
3H), 5.44 (dd, J = 12.5,3.0 Hz, 1H), 5.55 (d, J = 10.0 Hz, 1H),
6.08 (s, 1H), 6.52 (d, J = 10.0 Hz, 1H), 6.97 and 7.47 (d, J =
8.6 Hz, 4H); 13C NMR [(CD3)2CO] d 27.1, 27.4, 44.8, 54.4,
55.0, 77.2, 78.4, 93.2, 102.1, 105.2, 113.5, 115.5, 126.0,
127.4, 131.0, 158.3, 159.0, 159.6, 161.8, 186.9; HRMS
(EI) calcd for C22H22O5 (M+) 366.1467, found 366.1462.
5-Hydroxy-2-(4-methoxyphenyl)-8,8-dimethyl-2,3-di-
hydro-8H-pyrano[2,3-j]chromen-4-one (9)
Racemic 1 (0.25 g, 0.68 mmol) was dissolved in an-
hydrous CH2Cl2 (10 mL) and cooled down to -23 °C under
a nitrogen atmosphere. To the solution was added BBr3 (1.2
eq. 1 M 0.82 mL) for 5 h at -23 °C; the resulting solution
was quenched with MeOH and subjected to flash chroma-
tography (SiO2, cyclohexane/EA 10/1) to provide the de-
sired phenol 9 (0.23 g, 96%) as a white solid: mp 156-158
°C; 1H NMR (CDCl3) d 1.42 and 1.44 (s, 6H), 2.78 (dd, J =
17.1, 3.2 Hz, 1H), 3.06 (dd, J = 17.1, 12.8 Hz, 1H), 3.83 (s,
3H), 5.36 (dd, J = 12.8, 3.2 Hz, 1H), 5.45 (d, J = 10.0 Hz,
2-(3,4-Dimethoxyphenyl)-5-methoxy-8,8-dimethyl-2,3-
dihydro-8H-pyrano[2,3-j]chromen-4-one (2)
The glyflavanone 2 was prepared, using the previous

Total Synthesis of ( )-Glyflavanones
J. Chin. Chem. Soc., Vol. 54, No. 3, 2007 821
1H), 5.99 (s, 1H), 6.52 (d, J = 10.0 Hz, 1H), 6.95 and 7.38
(d, J = 8.7 Hz, 4H); 13C NMR (CDCl3) d 28.2, 28.4, 43.0,
55.3, 78.0, 78.8, 97.5, 101.9, 102.8, 114.1, 115.5, 126.3,
127.5, 130.4, 156.8, 159.8, 162.1, 163.7, 195.9.
(d, J = 6.6 Hz, 3H), 1.21-1.27 (m, 1H), 1.33 and 1.38 (s,
6H), 1.34-1.42 (m, 2H), 1.59-1.65 (m, 2H), 2.02-2.08 (m,
1H), 2.17-2.20 (m, 2H), 2.42 (ddd, J = 9.6, 7.8, 2.4 Hz,
1H), 3.56 (ddd, J = 15.0, 10.8, 4.2 Hz, 1H), 3.79 (s, 3H),
4.04 (d, J = 2.4 Hz, 1H), 4.98 (dd, J = 12.0, 1.2 Hz, 1H),
5.18 (ddd, J = 9.0, 7.8, 2.4 Hz, 1H), 5.32 (d, J = 7.2 Hz,
1H), 5.46 (d, J = 9.6 Hz, 1H), 5.47 (d, J = 7.2 Hz, 1H), 6.26
(s, 1H), 6.47 (d, J = 9.6 Hz, 1H), 6.95 and 7.41 (d, J = 8.4
Hz, 4H); 13C NMR [(CD3)2CO] d 16.1, 21.4, 22.6, 23.6,
26.0, 27.4, 28.3, 32.1, 35.0, 39.3, 41.8, 49.0, 55.5, 63.7,
76.6, 77.6, 78.8, 92.1, 96.5, 104.7, 109.2, 114.5, 117.4,
127.2, 128.3, 133.8, 152.2, 154.4, 157.9, 160.4.
11b: [a]D = -114° [acetone; c 0.8]; 1H NMR [(CD3)2CO]
d 0.63 and 0.81 (d, J = 7.2 Hz, 6H), 0.64-1.02 (m, 2H), 0.89
(d, J = 6.6 Hz, 3H), 1.19-1.26 (m, 1H), 1.34 and 1.35 (s,
6H), 1.32-1.39 (m, 2H), 1.59-1.65 (m, 2H), 2.02-2.12 (m,
2H), 2.17-2.20 (m, 1H), 2.42 (ddd, J = 9.0, 7.2, 1.2 Hz,
1H), 3.56 (ddd, J = 15.0, 10.8, 4.2 Hz, 1H), 3.79 (s, 3H),
4.03 (d, J = 2.4 Hz, 1H), 4.97 (dd, J = 12.0, 1.2 Hz, 1H),
5.17 (ddd, J = 9.6, 7.2, 2.4 Hz, 1H), 5.35 (d, J = 7.2 Hz,
1H), 5.46 (d, J = 9.6 Hz, 1H), 5.44 (d, J = 7.2 Hz, 1H), 6.24
(s, 1H), 6.48 (d, J = 9.6 Hz, 1H), 6.94 and 7.41 (d, J = 8.4
Hz, 4H); 13C NMR [(CD3)2CO] d 16.0, 21.3, 22.6, 23.6,
26.0, 27.4, 27.8, 27.9, 32.2, 35.0, 39.3, 41.8, 48.9, 55.5,
63.6, 76.7, 77.6, 78.8, 91.8, 96.4, 104.7, 109.2, 114.5,
117.5, 127.2, 128.3, 133.8, 152.2, 154.3, 157.8, 160.3.
11c: [a]D = -105° [acetone; c 0.3]; 1H NMR [(CD3)2CO]
d 0.58 and 0.80 (d, J = 6.6 Hz, 6H), 0.81-1.02 (m, 2H), 0.89
(d, J = 7.2 Hz, 3H), 1.18-1.23 (m, 1H), 1.34 and 1.37 (s,
6H), 1.34-1.40 (m, 2H), 1.58-1.65 (m, 2H), 1.89-1.94 (m,
1H), 2.10-2.13 (m, 2H), 2.20-2.23 (m, 1H), 3.53 (ddd, J =
15.0, 10.8, 4.2 Hz, 1H), 3.80 (s, 3H), 4.94 (ddd, J = 9.0, 7.2,
4.2 Hz, 1H), 5.18 (dd, J = 12.0, 1.2 Hz, 1H), 5.31 and 5.35
(d, J = 7.2 Hz, 1H), 5.46 (d, J = 10.2 Hz, 1H), 6.21 (s, 1H),
6.51 (d, J = 10.2 Hz, 1H), 6.96 and 7.41 (d, J = 9.0 Hz, 4H);
13C NMR [(CD3)2CO] d 15.9, 21.3, 22.6, 23.6, 25.9, 27.5,
28.2, 32.1, 35.1, 38.8, 41.7, 48.9, 55.5, 59.1, 73.7, 76.6,
78.3, 91.5, 95.9, 104.4, 107.8, 114.6, 117.5, 126.8, 128.4,
134.3, 151.8, 154.8, 157.7, 160.3.
5-[(-)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy-
methoxy]-2-(4-methoxyphenyl)-8,8-dimethyl-2,3-di-
hydro-8H-pyrano[2,3-j]chromen-4-one (10)
Phenol 9 (0.21 g, 0.59 mmol) was dissolved in 30 mL
of distilled CH2Cl2. NaOH (0.036 g, 0.89 mmol) in 0.50 mL
of distilled water was added in one portion at 0 °C (ice bath)
followed by 0.50 mL of Adogen 464. The reaction mixture
was allowed to stir for 30 min at room temperature and was
then cooled to 0 °C. (-)-Chloromethy menthyl ether (0.13 g,
0.66 mmol) was then added dropwise over 0.5 h until reac-
tion was complete. The organic and aqueous phases were
separated, and the aqueous layer was extracted with CH2Cl2
(3 ´ 50 mL). The combined organic phase and organic ex-
tracts were dried over anhydrous MgSO4 and evaporated in
vacuo. Purification by flash column chromatography (SiO2,
cyclohexane/EA 10/1) afforded the desired ketone 10 (0.31
1
g, 100%) as a white solid: mp 116-118 °C; H NMR
[(CD3)2CO] d 0.55 and 0.62 (d, J = 6.6 Hz, 6H), 0.81 and
0.89 (d, J = 7.2 Hz, 12H), 0.89-1.27 (m, 6H), 1.34-1.40 (m,
4H), 1.37, 1.39, 1.40 and 1.42 (s, 12H), 1.60-1.62 (m, 4H),
2.01-2.05 (m, 4H), 2.65 (dd, J = 16.3, 3.1 Hz, 2H), 2.93
(dd, J = 12.5, 4.2, 2H), 3.51 (m, 2H), 3.80 (s, 6H), 5.29 (dd,
J = 7.2, 2.4 Hz, 2H), 5.35-5.48 (m, 6H), 5.57 (d, J = 10.0
Hz, 2H), 6.25 (s, 2H), 6.53 (d, J = 10.0 Hz, 2H), 6.97 and
7.47 (d, J = 9.0 Hz, 8H); 13C NMR (CDCl3) d 15.4, 15.5,
21.0, 22.3, 22.9, 25.2, 25.3, 27.7, 28.1, 28.2, 28.5, 31.4,
34.4, 40.8, 45.6, 48.1, 55.3, 77.9, 78.0, 78.6, 90.9, 91.0,
97.2, 103.5, 106.1, 114.0, 116.1, 126.6, 127.5, 131.0,
158.5, 159.6, 159.7, 189.2.
5-[(-)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy-
methoxy]-2-(4-methoxyphenyl)-8,8-dimethyl-2,3-dihy-
dro-8H-pyrano[2,3-j]chroman-4-ol (11)
These diastereomers 11 were prepared, using the
above procedure, from 10 (0.20 g, 0.38 mmol) and NaBH4
(0.036 g, 0.96 mmol) in THF (25 mL) for 4 h. The benzyl
alcohols were separated by column chromatography (SiO2,
cyclohexane, cyclohexane/EA 10/1) to afford 11a, 11b, and
11c in 40, 44, 16% yield (0.080, 0.088, 0.032 g), respec-
tively.
5-[(-)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy-
methoxy]-2-(4-methoxyphenyl)-8,8-dimethyl-2,3-dihy-
dro-8H-pyrano[2,3-j]chromen-4-one (10a)
To a solution of benzyl alcohol 11a (0.080 g, 0.15
mmol) in 10 mL of ether and EA (1:1) was added MnO2
(0.033 g, 0.38 mmol) at room temperature and stirred for 1
h. To the suspension was added the other portion of MnO2
11a: [a]D = -74.5° [acetone; c 0.8]; 1H NMR [(CD3)2CO]
d 0.62-1.02 (m, 2H), 0.66 and 0.85 (d, J = 7.2 Hz, 6H), 0.88

822 J. Chin. Chem. Soc., Vol. 54, No. 3, 2007
Fang et al.
(0.033 g, 0.38 mmol) and then it was allowed to stir 1 h. Af-
ter filtering with celite, the filtrate was subjected to column
chromatography (SiO2, cyclohexane/EA 5/1) to produce
optically pure ketone 10a (0.080 g, 100%) as a white solid:
mp 115-117 °C; [a]D = -64.2° [acetone; c 0.8].
90-2113-M-018-008 and NSC 91-2113-M018-003). We
also acknowledge with appreciation the NSC-supported
High Resolution Mass and 500 MHz NMR spectrometry
facility (Department of Chemistry, National Chung Tsing
University) for providing high-resolution Mass and 2-D
NMR spectra.
5-[(-)-(1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy-
methoxy]-2-(4-methoxyphenyl)-8,8-dimethyl-2,3-dihy-
dro-8H-pyrano[2,3-j]chromen-4-one (10b)
Supporting Information Available
Spectroscopic characterization and copies of 1H and
13C NMR spectra of the compounds described in the text,
and tables giving all of the crystallographic details and the
structure refinement information for 1 and 3, and including
COSY (1H-1H) and HSQC (1H-13C) of 11a, 11b, and 11c are
available free of charge via the Internet at http://www.ccs.
sinica.edu.tw/publish33.asp.
This optically pure 10b was prepared, using the above
procedure, from 11b (0.088 g, 0.17 mmol) and MnO2
(0.074 g, 0.84 mmol) in ether/EA (10 mL) for 2 h. Column
chromatography (SiO2, cyclohexane/EA 5/1) provided op-
tically pure ketone 10b (0.089 g, 100%) as a white solid:
mp 115-116 °C; [a]D = -54.5° [acetone; c 0.8].
(+)-5-Methoxy-2-(4-methoxyphenyl)-8,8-dimethyl-2,3-
dihydro-8H-pyrano[2,3-j]chromen-4-one (1)
Received November 21, 2006.
A solution of 10a (0.050 g, 0.096 mmol) in 5 mL
CH2Cl2 was treated with diluted HCl (0.1 mL conc. HCl in
1 mL CH2Cl2) at 0 °C for 10 min. The resulting solution
was subjected to column chromatography (SiO2, cyclohex-
ane/EA 4/1) to give phenol 9 (0.034 g, 0.096 mmol), which
is then transformed to the methylation reaction. To a mix-
ture of phenol 9 and K2CO3 (0.066 g, 0.48 mmol) in 5 mL
acetone was heated to reflux at 70 °C (oil bath), followed
by addition of Me2SO4 (0.024 g, 0.19 mmol) and main-
tained for 2 h. After cooling, the resulting suspension was
extracted with CH2Cl2 (3 ´ 10 mL). The combined organic
phase and organic extracts were dried over anhydrous
MgSO4 and evaporated in vacuo. The residue was sub-
jected to flash column chromatography (SiO2, cyclohex-
ane/EA 5/1) to give (+)-1 (0.033 g, 94%) as a light yellow
solid: mp 114-115 °C; [a]D = +18.5° [acetone; c 0.33].
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ACKNOWLEDGEMENTS
We thank the National Science Council of the Repub-
lic of China for financial support (Research Grant NSC