Synthesis of deuterium-labeled flavanones

Article abstract of DOI:10.1248/cpb.52.953

Deuterium incorporation at the C-3 position of flavanones was achieved by treatment of flavanones and 2′-hydroxychalcones with D₃PO ₄ and AcOD. We propose that the deuteration reaction mechanism for 2′-hydroxychalcones substrates is

Full text of DOI:10.1248/cpb.52.953

August 2004
Chem. Pharm. Bull. 52(8) 953—956 (2004)
953
Synthesis of Deuterium-Labeled Flavanones
,a
a
a
b
a
Hitoshi KAGAWA,* Tetsuya TAKAHASHI, Mariko UNO, Shigeru OHTA, and Yoshihiro HARIGAYA
a
Department of Organic Synthesis, School of Pharmaceutical Sciences, Kitasato University; 5–9–1, Shirokane, Minato-ku,
b
Tokyo 108–8641, Japan: and Graduate School of Biomedical Sciences, Hiroshima University; 1–2–3 Kasumi, Minami-ku,
Hiroshima 734–8551, Japan. Received February 26, 2004; accepted June 2, 2004; published online June 3, 2004
Deuterium incorporation at the C-3 position of flavanones was achieved by treatment of flavanones and 2ꢀ-
hydroxychalcones with D PO and AcOD. We propose that the deuteration reaction mechanism for 2ꢀ-hydroxy-
3
4
chalcones substrates is as follows. In the first step, 2ꢀ-hydroxychalcones cyclize to the corresponding flavanones
by an intramolecular Michael-type reaction. Then deuteriums are incorporated into the flavanones via enoliza-
tion.
Key words deuteration; flavanone; chalcone; metabolism; flavonoid
Flavonoids are polyphenolic compounds that are diverse in
Since D PO and AcOD are commercially available and
3 4
both chemical structure and chemical properties. Since easily handled, these reagents are useful deuterating reagents
flavonoids are naturally present in fruits, vegetables and tea, and have been used for the experiments reported here. The
1)
they are an integral part of the human diet. Ingested method results in high yields of flavanone dideuteration and
flavonoids are absorbed by the gastrointestinal tract and have requires only short reaction times. Our experiments also
been found in body fluids and tissues. It is generally accepted allow us to suggest a reaction mechanism for the cyclization
that dietary flavonoids have important biological effects, such and the deuteration of 2ꢀ-hydroxychalcones.
2)
as decreasing the risk of death from coronary heart disease.
Other known biological properties of flavonoids include: an- Results and Discussion
3
)
4)
tioxidant activity, antiallergic activity, and modulation of
As shown in Chart 1, monodeuterated chalcone 2 was syn-
5,6)
14)
monooxygenase activity. Recently two interesting proper- thesized from 4ꢀ-methoxychalcone 1 using Silva’s method
ties of flavonoids have been reported. 1) Apparently, certain (chemical yield, 71.7%; deuteration yield, 94%). Compound
flavonoids can pass the blood–brain barrier because they 2 was converted to the dideuterated flavanone 3 by deutera-
7)
were found to accumulate in rat brains. 2) Certain tion with D PO and AcOD (chemical yield, 74.4%;
3
4
flavonoids inhibit the cellular excretion of some drugs—a dideuteration yield, 90%). In an attempt to synthesize mon-
8,9)
process mediated by P-glycoprotein.
Dietary flavonoids odeuterated flavanone 5, monodeuterated chalcone 2 was
are probably ingested at sufficient levels to have significant treated with H PO and AcOH. Instead, the non-deuterated
3
4
pharmaceutical effects. Therefore, to understand the diverse 4ꢀ-methoxyflavanone 4 was generated in good yield (73.2%).
pharmacological properties of flavonoids, their metabolism As the deuterium of monodeuterated chalcone 2 was ex-
must be understood.
changed for a hydrogen when the reaction was run in the
We have studied the metabolism of flavanones by cy- presence of non-deuterated H PO and AcOH, deuteriums
3
4
tochrome P450. This enzyme mediates the formation of may be incorporated via enolization.
flavones, flavanonols and isoflavones from the corresponding
Given these results and the proposed reaction mechanism,
flavanones. We postulated that cytochrome P450 abstracts a we predicted that dideuterated flavanones could be readily
hydrogen radical from the C-2 or 3 position of the flavanone synthesized from non-labeled 2ꢀ-hydroxychalcones or from
10)
skeleton. In plants, cytochrome P450 also participates in flavanones. Non-labeled 2ꢀ-hydroxychalcones (6, 1) or fla-
11)
isoflavone biosynthesis. For example, Hakamatsuka et al.
vanones (7, 4) were converted to the corresponding dideuter-
reported that the formation of daidzein (isoflavone) from ated flavanones (10, 3, 11) by treatment with D PO and
3
4
liquiritigenin (flavanone) was dependent on isoflavone syn- AcOD at 100 °C (Chart 2 and Table 1). Chemical yields were
thase (cytochrome P450). It appears that a hydrogen radical determined as isolation yields. The structures and deuteration
abstraction from flavanones, as mediated by cytochrome yields of the monodeuterated chalcones (8, 2), the poly-
P450, is a relatively general reaction in flavonoid metabolism deuterated chalcone 9, the dideuterated flavanones (10, 3)
and biosynthesis. To further clarify these reaction mecha- and the polydeuterated flavanone 11 were characterized by
1
nisms, regio-selective deuterated flavanones would be useful
tools.
Rasku et al.
H-NMR spectroscopy. When the a position of the chalcones
1
was deuterated, the H-NMR signals of the a-H disappeared
12,13)
reported the synthesis of polydeuterium- and the b-H signals became broad singlets, rather than dou-
labeled, polyhydroxylated flavones, flavonols and iso- blets. For flavanones after deuteration, the signals of C-3-H
2
flavonoids with D PO ·BF /D O as the deuteration reagent. disappeared and those of C-2-H became broad singlets,
3
4
3
2
Because polydeuteration might cause significant and undesir- rather than doublet of doublets. To determine deuteration
able changes to the flavanones’ cytochrome P450 binding yields of flavanones, the signal of C-5-H was used as the
properties and/or the cytochrome P450 catalytic activities— standard. In the case of chalcones, the signal of b-H and C-
in comparison to the non-deuterated flavanones—a regio-se- 3ꢀ-H were used as the standard for 6 and 1, respectively. The
lective deuteration is needed. Therefore, we developed a new chemical and deuteration yields of the products are given in
method for specific deuteration of the C-3 position of Table 1.
flavanones.
For the reaction of non-labeled 2ꢀ-hydroxychalcone 6 with
*
To whom correspondence should be addressed. e-mail: kagawah@pharm.kitasato-u.ac.jp
© 2004 Pharmaceutical Society of Japan

9
54
Vol. 52, No. 8
Chart 1. Acid-Catalyzed Deuteration of 2ꢀ-Hydroxy[a-d ]4-methoxychalcone 2
1
Chart 2. Deuteration Reactions of Non-labeled Chalcones and Flavanones
D PO and AcOD, the deuteration yield of dideuterated fla- Table 1. Chemical and Deuteration Yields of Flavanones and 2ꢀ-Hydroxy-
3
4
chalcones with D PO and AcOD
vanone 10 was large whether the reaction was run for 10 or
0 min. However, for the 10 min reaction time, the chemical
3
4
6
Time
Chemical
yield (%)
Deuteration
yield (%)
yield of 10 was less satisfactory (16.7%), and large amounts
of unreacted 6 remained (82.8%). With non-labeled 2ꢀ-hy-
droxy-4-methoxychalcone 1 as the substrate, high levels of
deuterium were incorporated at the C-3 position of the fla-
vanone products (3, 11). Additionally, chemical yields of
flavanones, with 1 as the substrate, were greater than with 6
as the substrate, no matter the reaction time. However, the
quantity of polydeuterated flavanone 11 also increased signif-
icantly as the reaction time increased with 1 as the substrate.
Substrate
Product
(min)
6
6
1
1
7
10
10
6
10
8
3
2
11
9
10
8
7
10
6
10
8
3
2
11
9
16.7
82.8
67.9
19.2
72.0
20.7
70.3
18.0
91.6
6.2
88.9
91.3
3.5
87.1
7.3
90
—
95
9
92
72
60
10
a)
60
93(46)
99(96)
a)
1
10
89
76
—
61
—
85
94
91
87
Analysis of the H-NMR spectrum of 11 proved that deutera-
tion occurred at the C-3 position and at the carbons ortho to
the methoxy group. In comparison with 2ꢀ-hydroxychalcone
b)
7
7
10
10
c)
6
, the deuteration yield at the a position of 2ꢀ-hydroxy-4-
7
4
4
60
10
60
methoxychalcone 1 increased. Therefore, the 4-methoxy
group, which is an electron-donating group, enhances deuter-
ation at both the a position and at the ortho positions as well
as increasing the extent of cyclization of the chalcone. There-
fore, our method is also applicable when polydeuteration of
flavonoids is desired.
79.1
16.2
77.6
15.0
a)
95(26)
94(59)
a)
a) Deuteration yield at R1. b) With only AcOD as the deuteration reagent.
c) Reagents were AcOH and D PO .
Reaction of the non-labeled flavanone 7 with D PO and
3
4
3
4
AcOD gave good deuteration yields for both reaction times,
as predicted by the proposed reaction mechanism. In com- ated flavanone 10 was not formed and non-deuterated fla-
parison with substrate 6, monodeuterated 2ꢀ-hydroxychal- vanone 7 was recovered. If only D PO was used as the
3
4
cone 8 was obtained from 7 at high deuteration yields even deuteration reagent, little, if any, deuteration occurred (data
after the shorter reaction time. Thus, the formation of com- not shown), because non-deuterated flavanone 7 is insoluble
pound 8 may have occurred by a retro-Michael-type reaction in D PO . When non-deuterated acetic acid (AcOH) was pre-
3
4
of the dideuterated flavanone 10. When non-labeled fla- sent and D PO used as the deuteration reagent, the deutera-
3
4
vanone 7 was reacted only with AcOD, the desired dideuter- tion yield at the C-3 position of 10 decreased because of hy-

August 2004
955
1
drogen-deuterium exchange between D PO and AcOH. uncorrected. H-NMR spectra were recorded using a Varian VXR-300 or a
3
4
1
3
XL-400 spectrometer. C-NMR spectra were recorded using a Varian XL-
00 spectrometer. Mass spectra were obtained using a JEOL-JMX-DX 300
Thus, deuteriums from D PO were incorporated into the fla-
vanones, while AcOD served as the solvent. Therefore
D PO and AcOD were necessary for the high incorporation
3
4
4
or a JEOL-JMS-AX505 HA mass spectrometer. Microanalyses were
recorded using a Yanaco CHN corder MT-5. Thin-layer chromatography and
preparative chromatography were run using silica gel 60 PF254 (Merck)
3
4
rate of deuteriums.
Starting with 4ꢀ-methoxyflavanone 4, the deuteration yield with benzene as the mobile solvent. 2ꢀ-Hydroxychalcone 6 and flavanone 7
were purchased from Tokyo Kasei Kogyo Co., Ltd. (Tokyo, Japan) and
Wako Pure Chemical Industries, Ltd. (Osaka, Japan) respectively.
General Procedure for Deuteration of Flavonoids To individual solu-
tions of non-labeled chalcones (6 or 1) and of non-labeled flavanones (7 or
at the C-3 position of 4 was large for both reaction times.
But, as for deuteration of 1, an extension of the reaction time
increased the deuteration at the carbons ortho to the 4ꢀ-
methoxy group. We propose that deuteration at the positions 4)—all at quantities of 50 mg—in AcOD (0.5 ml, 98 atom% D, Sigma-
ortho to the methoxy group is caused by resonance involving Aldrich Japan K. K.), D
PO (0.5 ml, 99 atom% D, Sigma-Aldrich Japan K.
3 4
K.) was added. The reaction mixtures were stirred at 100 °C for 10 or 60 min
under argon. After each reaction was finished, the mixture was treated with
an ion-exchange resin (AMBERLYST® A-21 from ORGANO Co.), ex-
tracted with benzene, evaporated, and then purified by preparative TLC.
Preparation of 2ꢀ-Hydroxy-4-methoxychalcone (1) A mixture of
the electron-donating group itself. Thus, for many flavonoids,
with one or more electron-donating groups associated with
the A and/or B-ring of the flavonoid skeleton, polydeutera-
tion may be a general result when our method is used. In-
deed, in a preliminary report, we showed that polydeuteration
of 5-methoxyflavanone occurs at the carbons ortho (C-6) and
para (C-8) to the methoxy group, as well as at the C-3 posi-
2
7
ꢀ-hydroxyacetophenone (1.00 g, 7.35 mmol), p-anisaldehyde (1.01 g,
.43 mmol), and KOH (4.17 g, 74.3 mmol) in ethanol (100 ml) was stirred at
room temperature for 20 h. The reaction mixture was neutralized with acetic
acid (10% ethanolic solution) and evaporated. The residue was extracted
with ethyl acetate and brine. The organic phase was dried over Na SO . The
15)
16)
tion. Mazur et al. reported that isoflavonoids from plant-
2
4
derived foods could be quantified using isotope dilution gas organic layer was then evaporated, and the residue was purified using col-
umn chromatography (silica gel, benzene : n-hexaneꢁ1 : 10) to give 1 as yel-
chromatographic-mass spectroscopy with polydeuterated
isoflavonoids as internal standards. We expect that poly-
deuterated flavonoids, prepared by our method, can be used
lowish needles (1.47 g; yield, 78.9%). Rfꢁ0.37 (benzene : n-hexaneꢁ1 : 1),
17)
ꢂ1
1
mp: 95—96 °C (EtOH) (lit., 95 °C); IR (CHCl ) cm : 1640 (CꢁO); H-
3
NMR (400 MHz, CDCl ) d: 12.933 (1H, s, OH), 7.925 (1H, dd, Jꢁ1.5,
3
for identification and quantification of non-deuterated 7.8 Hz, 6ꢀ-H), 7.912 (1H, d, Jꢁ15.0 Hz, b-H), 7.636 (2H, d, Jꢁ8.7 Hz, 2,6-
flavonoids derived from biological sources.
Hs), 7.547 (1H, d, Jꢁ15.0 Hz, a-H), 7.492 (1H, ddd, Jꢁ8.2, 8.5, 1.5 Hz, 4ꢀ-
H), 7.025 (1H, dd, Jꢁ8.2, 1.0 Hz, 3ꢀ-H), 6.956 (2H, d, Jꢁ8.7 Hz, 3,5-Hs),
6
.943 (1H, ddd, Jꢁ1.0, 8.5, 7.8 Hz, 5ꢀ-H), 3.869 (3H, s, 4-OMe); HR-EI-
Conclusion
MS m/z: 254.0944 (Calcd. for C H O : 254.0943 ); Anal. Calcd. for
C H O : C, 75.57, H, 5.55; Found: C, 75.32, H, 5.61.
1
6
14
3
We report a new method for deuteration of non-deuterated
chalcones and flavanones. We show that dideuterated fla-
1
6
14
3
Preparation of (ꢁ)-4ꢀ-Methoxyflavanone (4) To a solution of 2ꢀ-hy-
vanones and monodeuterated chalcones are readily prepared droxy-4-methoxychalcone 1 (97.5 mg, 0.38 mmol) in acetic acid (1 ml), 1 ml
of phosphoric acid was added. The stirred reaction mixture was placed in a
using D PO and AcOD. Our results suggest a reaction
mechanism for deuteration of 2ꢀ-hydroxychalcones. In the
first step, 2ꢀ-hydroxychalcones cyclize to the corresponding
3
4
boiling water bath for 10 min. The mixture was then poured into water and
the precipitate was extracted with ethyl acetate. The organic layer was dried
over Na SO and evaporated to give an orange oil that was then purified by
2
4
flavanones by an intramolecular Michael-type reaction. Then, preparative TLC. These procedures gave 4 as colorless needles (70.7 mg;
1
8)
yield, 72.5%). Rfꢁ0.30 (benzene), mp: 93—94 °C (EtOH) (lit., 96—
9
7
in a second step, deuteriums are incorporated at the C-3 posi-
tion of flavanones via enolization. In our study of flavanone
metabolism by cytochrome P450, we probed the reaction
mechanism using C-3 deuterium-labeled flavanones. An in-
ꢂ1
1
8 °C); IR (CHCl ) cm : 1690 (CꢁO); H-NMR (400 MHz, CDCl ) d:
3
3
.934 (1H, dd, Jꢁ8.2, 1.9 Hz, 5-H), 7.505 (1H, ddd, Jꢁ1.9, 8.2, 8.8 Hz, 7-
H), 7.416 (2H, d, Jꢁ8.8 Hz, 2ꢀ,6ꢀ-Hs), 7.048 (1H, ddd, Jꢁ8.2, 8.2, 1.0 Hz,
-H), 7.038 (1H, dd, Jꢁ1.0, 8.8 Hz, 8-H), 6.964 (2H, d, Jꢁ8.8 Hz, 3ꢀ,5ꢀ-
6
termolecular isotope effect was observed for the metabolism Hs), 5.436 (1H, dd, Jꢁ13.2, 2.9 Hz, 2-H), 3.114 (1H, dd, Jꢁ13.2, 16.8 Hz,
3
-H ax), 2.866 (1H, dd, Jꢁ2.9, 16.8 Hz, 3-H eq), 3.836 (3H, s, 4ꢀ-OCH3);
of dideuterated flavanones (3, 10) and non-labeled flavanones
4, 7) to the corresponding 2,3-trans-flavanonols by cy-
tochrome P450. Therefore, these dideuterated flavanones
are useful reagents for metabolic study of flavonoids.
In summary, we achieved a regio-selective deuteration at
the C-3 position of flavanones, and we proposed a reaction
mechanism for the cyclization and the deuteration of 2ꢀ-hy-
1
3
C-NMR (100 MHz, CDCl ) d: 192.182 (C-4), 161.607 (C-9), 159.953 (C-
3
(
4
1
ꢀ), 136.115 (C-7), 130.751 (C-1ꢀ), 127.701 (C-2ꢀ,6ꢀ), 127.003 (C-5),
21.487 (C-6), 120.895 (C-10), 118.103 (C-8), 114.181 (C-3ꢀ,5ꢀ), 79.319
10)
(C-2), 55.231 (4ꢀ-OMe), 44.426 (C-3); HR-EI-MS m/z: 254.0938 (Calcd. for
: 254.0943); Anal. Calcd. for C16 : C, 75.57, H, 5.55; Found:
C, 75.33, H, 5.59
ꢀ-Hydroxy-4-methoxy[a-D ]chalcone (2) Yellow solid, mp: 94—
C
H
O
H O
14 3
16
14
3
2
1
1
9
5 °C; H-NMR (300 MHz, CDCl ) d: 12.931 (1H, s, 2ꢀ-OH), 7.918 (1H, dd,
3
droxychalcones. The deuteration reagents, D PO and AcOD,
3
4
Jꢁ1.5, 8.0 Hz, 6ꢀ-H), 7.903 (1H, s, b-H), 7.633 (2H, d, Jꢁ8.5 Hz, 2,6-Hs),
are commercially available and easily handled. Although ap- 7.490 (1H, ddd, Jꢁ1.5, 7.8, 8.5 Hz, 4ꢀ-H), 7.025 (1H, dd, Jꢁ1.0, 8.2 Hz, 3ꢀ-
plied only to chalcones and flavanones in this report, the H), 6.957 (2H, d, Jꢁ8.5 Hz, 3,5-Hs), 6.942 (1H, ddd, Jꢁ1.0, 7.8, 8.0 Hz, 5ꢀ-
H), 3.869 (3H, s, 4-OMe); HR-FAB-MS (mNBA) m/z: 255.0998 (Calcd. for
method may be a general procedure for the introduction of
deuteriums at positions a to ketones in other natural prod-
ucts. Additionally, in the case of these compounds with one
C H O D : 255.1006 ).
1
6
13
3
1
1
4
ꢀ-Methoxy[3,3-D ]flavanone (3) Colorless solid, mp: 87—88 °C; H-
2
NMR (300 MHz, CDCl ) d: 7.930 (1H, dd, Jꢁ1.8, 8.2 Hz, 5-H), 7.504 (1H,
3
or more electron-donating groups with aromatic rings in their ddd, Jꢁ1.8, 7.5, 8.0 Hz, 7-H), 7.415 (2H, d, Jꢁ8.5 Hz, 2ꢀ,6ꢀ-Hs), 7.053 (1H,
ddd, Jꢁ1.0, 7.5, 8.2 Hz, 6-H), 7.036 (1H, dd, Jꢁ1.0, 8.0 Hz, 8-H), 6.963
structures, deuteration at the carbons ortho and/or para to the
(2H, d, Jꢁ8.5 Hz, 3ꢀ,5ꢀ-Hs), 5.430 (1H, s, 2-H), 3.836 (3H, s, 4ꢀ-OMe); HR-
electron-donating groups may also occur when the reaction
time is extended. Therefore, our deuteration method is also
useful for polydeuteration of natural products with one or
more electron-donating groups and/or ketones.
EI-MS m/z: 256.1078 (Calcd. for C H O D : 256.1068 ).
1
6
12
3
2
1
2
ꢀ-Hydroxy[a-D ]chalcone (8) Pale yellow solid, mp: 78—79 °C; H-
1
NMR (400 MHz, CDCl ) d: 12.820 (1H, s, 2ꢀ-OH), 7.935 (1H, dd, Jꢁ1.5,
3
8.0 Hz, 6ꢀ-H), 7.932 (1H, s, b-H), 7.695—7.664 (2H, m, Ar-H), 7.512 (1H,
ddd, Jꢁ1.5, 7.5, 8.5 Hz, 4ꢀ-H), 7.475—7.425 (3H, m, Ar-H), 7.040 (1H, dd,
Jꢁ0.5, 8.5 Hz, 3ꢀ-H), 6.957 (1H, ddd, Jꢁ0.5, 7.5, 8.0 Hz, 5ꢀ-H); HR-EI-MS
m/z: 225.0885 (Calcd. for C H O D : 225.0900 ).
Experimental
Melting points were taken using a Yanagimoto hot-stage apparatus and are
1
5
11
2
1

9
56
Vol. 52, No. 8
2
ꢀ-Hydroxy-4-methoxy[a,3,5-D ]chalcone (9) Yellow solid, mp: 89—
7) Datla K. P., Christidou M., Widmer W. W., Rooprai H. K., Dexter D.
T., NeuroReport, 12, 3871—3875 (2001).
8) Takanaga H., Ohnishi A., Yamada S., Matsuo H., Morimoto S.,
Shoyama Y., Ohtani H., Sawada Y., J. Pharmacol. Exp. Ther., 293,
230—236 (2000).
9) Choi C. H., Sun K. H., An C. S., Yoo J. C., Hahm K. S., Lee I. H.,
Sohng J. K., Kim Y. C., Biochem. Biophys. Res. Commun., 295, 832—
840 (2002).
3
1
9
0 °C; H-NMR (300 MHz, CDCl ) d: 12.933 (1H, s, 2ꢀ-OH), 7.920 (1H, dd,
3
Jꢁ1.8, 8.0 Hz, 6ꢀ-H), 7.905 (1H, s, b-H), 7.636 (2H, s, 2,6-Hs), 7.493 (1H,
ddd, Jꢁ1.8, 7.5, 8.5 Hz, 4ꢀ-H), 7.025 (1H, dd, Jꢁ1.0, 8.5 Hz, 3ꢀ-H), 6.944
(
2
1H, ddd, Jꢁ1.0, 7.5, 8.0 Hz, 5ꢀ-H), 3.871 (3H, s, 4-OMe); HR-EI-MS m/z:
57.1127 (Calcd. for C H O D : 257.1131 ).
1
6
11
3
3
1
[
3,3-D ]Flavanone (10) Colorless solid, mp: 78—78.5 °C; H-NMR
2
(
(
400 MHz, CDCl ) d: 7.870 (1H, dd, Jꢁ1.8, 8.0 Hz, 5-H), 7.545—7.362
3
6H, m, Ar-H), 7.090—7.035 (2H, m, Ar-H), 5.488 (1H, s, 2-H); HR-EI-MS 10) Kagawa H., Kimura R., Konda Y., Takeda K., Sakabe C., Nakagawa
m/z: 226.0959 (Calcd. for C H O D : 226.0963 ).
A., Sato N., Harigaya Y., Ohta S., Hirobe M., Sixth North American
ISSX Meeting, Raleigh, USA, International society for the study of
xenobiotics proceedings, 6, p. 142 (1994).
1
5
10
2
2
4
ꢀ-Methoxy[3,3,3ꢀ,5ꢀ-D ]flavanone (11) Colorless solid, mp: 84—
4
1
8
7
5 °C; H-NMR (300 MHz, CDCl ) d: 7.930 (1H, dd, Jꢁ1.8, 8.0 Hz, 5-H),
.505 (1H, ddd, Jꢁ1.8, 7.5, 8.0 Hz, 7-H), 7.415 (2H, s, 2ꢀ,6ꢀ-Hs), 7.050
3
11) Hakamatsuka T., Hashim M. F., Ebizuka Y., Sankawa U., Tetrahedron
47, 5969—5978 (1991).
(
1H, ddd, Jꢁ1.0, 7.5, 8.0 Hz, 6-H), 7.035 (1H, dd, Jꢁ1.0, 8.0 Hz, 8-H),
5
.430 (1H, s, 2-H), 3.830 (3H, s, 4ꢀ-OMe); HR-EI-MS m/z: 258.1195 12) Rasku S., Wähälä K., Koskimies J., Hase T., Tetrahedron, 55, 3445—
(
Calcd. for C H O D : 258.1194 ).
3454 (1999).
16
10
3
4
1
3) Rasku S., Wähälä K., Tetrahedron, 56, 913—916 (2000).
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)
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