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by benzyl protection of the hydroxyl groups of catechol 6, were per-
formed using the crude reaction products. The resulting compound
7 was subjected to Knoevenagel condensation with monoethyl mal-
onate in pyridine containing a catalytic amount of piperidine to
produce
a,b-unsaturated ester 8. Reduction of 8 with LAH/AlCl3
gave the corresponding cinnamyl alcohol 2.
Phenol 3, obtained by the method of Lehmann and Jahr,16 was
subjected to Friedel–Crafts alkylation with 2 using H2SO4/SiO2 as
catalyst in CS2/CH2Cl2 to furnish the coupled product 9 as shown
in Scheme 2. Oxidation of 9 with NMO in the presence of a catalytic
amount of OsO4 gave the cis-diol product 10, which was converted
into ortho-ester 11 with triethyl orthoformate and a catalytic
amount of pyridinium p-toluenesulfonate (PPTS) at room temper-
ature. The reaction was continued with heating at 60 °C to form
the flavan framework as intermediate formate ester 12. De-esteri-
fication of 12 with K2CO3 in 1,2-dimethoxyethane/methanol and
debenzylation using Pd(OH)2 and H2 in THF/methanol afforded 1
(Fig. 1).
Figure 1. Structures of catechin, resveratrol, and their analogues.
The radical scavenging activity of 1 was evaluated in a non-
aqueous system using galvinoxyl radical (GOÅ) as an oxyl radical
species. Because of its odd electron, GOÅ exhibits a strong absorption
band at 428 nm, and a solution of GOÅ appears yellow in color. As
the electron is paired, the absorption vanishes, and the resulting
decolorization is stoichiometric with respect to the number of elec-
trons taken up. Taking advantage of the color change of GOÅ in the
presence of an antioxidant, the rate of radical scavenging of 1
toward galvinoxyl was measured. As shown in Figure 2, the decay
rate of the absorbance at 428 nm followed pseudo first-order kinet-
ics when the concentration of 1 was maintained at more than 10-
fold excess to the GOÅ concentration. The pseudo first-order rate
constant (kobs) exhibited first-order dependence with respect to
the concentration of 1 as shown in Figure 3. From the linear plot
of kobs versus [1], the second-order rate constant (k) for the radical
scavenging of 1 toward GOÅ was determined to be 1.07 Â 103
molÀ1 dm3 sÀ1. The k value for (+)-catechin was determined in the
there is a role for the antioxidant chemistry of phenols via a radical
scavenging mechanism that is accelerated by electron-donating
substituents.
There are numerous methods for construction of the flavonoid
skeleton using a biomimetic strategy.14,15 The synthetic strategy
employed here is an efficient and general approach to access the
flavan framework of 1. This process consisted of a solid acid cata-
lyzed Friedel–Crafts coupling of cinnamyl alcohol derivative 2, that
included an embedded dimethylcatechol moiety, with 3,5-diben-
zyloxyphenol 3, followed by hydroxylation and cyclization to give
the corresponding dimethyl catechin derivative.
The synthesis of 2 is outlined in Scheme 1. Introduction of
methyl groups at both ortho positions of the catechol could be read-
ily accomplished by Mannich reaction of catechol using morpholine
and formamide to afford 4. Palladium catalyzed hydrogenation of 4
was carried out with heating at 70 °C under a high pressure of
hydrogen gas to give dimethylcatechol 5. Since 5 was highly sensi-
tive, the subsequent reactions, formylation with CH(OEt)3 followed
Scheme 1. Reagents and conditions: (a) morpholine, formaldehyde, EtOH, rt, 61%;
(b) H2, 10% Pd/C, THF, 5 atm, 70 °C; (c) CH(OEt)3, AlCl3, toluene, rt; (d) BnBr, K2CO3,
KI, acetone, rt, 3.2% (total yield from 4); (e) monoethyl malonate, piperidine,
pyridine, reflux, 87%; (f) LAH, AlCl3, THF, rt, 48%.
Scheme 2. Reagents and conditions: (a) H2SO4/SiO2, CH2Cl2, rt, (b) NMO, OsO4,
acetone, H2O, rt, 37% (total yield from 2); (c) CH(OEt)3, PPTS, EDC, rt; (d) CH(OEt)3,
PPTS, EDC, 60 °C; (e) K2CO3, MeOH, DMF, rt, 89% (a total yield from 10); (f) H2,
Pd(OH)2, MeOH, THF, rt, 56%.
Imai, Kohei
