2
M. Mizuno et al. / Bioorganic & Medicinal Chemistry Letters xxx (2017) xxx–xxx
Previously, we synthesized a catechin analogue known as ‘pla-
catechin molecules in octa-O-benzyl procyanidin B3 (9), while
the second method involves the same reaction with only one cate-
chin molecule in compound 12, the synthesis of which was accom-
nar catechin,’ in which the geometry of (+)-catechin is constrained
in a planar orientation by a bridge between the 3-hydroxyl group
and C’6 on the C-ring (Fig. 1).17 Compared with (+)-catechin, planar
catechin was found to exhibit not only more potent antioxidative
activity, but also demonstrated additional bioactivities, such as ɑ-
glucosidase inhibition, and both anti-tumor and anti-virus activi-
plished via
a condensation reaction between the catechin
derivative 5 and the planar catechin derivative 7.
The first method utilized octa-O-benzyl procyanidin B3 (9) as an
intermediate in the synthesis of 2. As shown in Scheme 1, the four
phenolic hydroxyl groups of (+)-catechin were protected as benzy-
loxy moieties by reaction with benzyl bromide to yield 3, and the
alcohol hydroxyl group was subsequently protected by acetic
anhydride. The desired product (4) formed in quantitative yield
was then oxidized with DDQ in the presence of ethylene glycol
to yield a C4-activated electrophile (5) with high stereoselectivity.
Reaction between the nucleophilic compound 3 and the elec-
trophilic derivative 5 in the presence of TMSOTf as a Lewis acid fur-
nished the catechin dimer 8, with a stereochemical preference for a
3,4-trans isomer in high yield. After removing the acetyl group
1
7,18
ties.
Planar catechin, in particular, exhibits potent glucosidase
inhibitory activity, suggesting a structural similarity to the gluco-
sidic linkage that is hydrolyzed by ɑ-glycosidase. That is, planar
catechin is also expected to adopt a structure that facilitates affin-
ity for the lectin-like domain of LOX-1.
In the context of prevention of cerebrovascular diseases, we
focused on procyanidin B3, a dimer of (+)-catechin, which is likely
to be capable of readily crossing the blood-brain barrier. When the
geometries of one or both catechin molecules in procyanidin B3 are
constrained to a planar orientation, the enhanced antioxidative
activities are further improved, thus decreasing the formation of
OxLDL. Introduction of a planar structure into the procyanidin B3
framework may also increase the LOX-1 inhibitory activity because
of the expected high affinity for the C-type lectin-like recognition
domain of LOX-1. Moreover, introduction of an alkyl moiety to
allow for construction of such planar structures should further
enhance the lipophilicity, allowing for the ability to more easily
cross the blood-brain barrier.
2 3
with K CO , the geometries of both catechin molecules in 9 were
constrained to planar orientations via the Oxa-Pictet–Spengler
reaction using acetone in the presence of TMSOTf, to give 10 at a
yield of 80%.
The second method employed for the synthesis of 2 used com-
pound 12 as an intermediate, in which the geometry of one cate-
chin molecule was constrained in a planar orientation. Synthesis
of the unit of the planar catechin derivative (7) was readily accom-
plished via the Oxa-Pictet–Spengler reaction, in which (+)-catechin
and acetone were treated with TMSOTf in THF, and the four hydro-
xyl groups were subsequently protected by benzyl bromide. The
electrophilic catechin derivative 5 and the nucleophilic planar cat-
echin 7 were then condensed using TMSOTf, resulting in the highly
stereoselective formation of the 3,4-trans isomer (11) in high yield.
The condensed product (11) was subjected to hydrolysis of the
To this end, we recently synthesized proanthocyanidin ana-
logue 1, in which the geometry of one catechin molecule was con-
strained to a planar orientation. The radical scavenging activity of 1
and procyanidin B3 (Cat-Cat) were evaluated in a non-aqueous sys-
tem using galvinoxyl radical (GOÅ) as an oxyl radical species.
Results demonstrated that the activity of 1 was 1.9-fold higher
1
9
than that of Cat-Cat. This finding led us to hypothesize that intro-
duction of planar structures into catechin oligomers with a lower
degree of polymerization may improve the antioxidative and
LOX-1 inhibitory activities, leading to the development of chemo-
preventive agents for cerebrovascular diseases. In this study, we
designed another novel proanthocyanidin derivative (2), in which
the geometry of both catechin molecules in the catechin dimer
were constrained to planar orientations, with the aim of further
enhancing the potent antioxidative activity and binding affinity
for LOX-1.
2 3
acetyl group with K CO in methanol-toluene solvent, to yield
12. The geometry of one catechin molecule was then constrained
to a planar orientation via the Oxa-Pictet–Spengler reaction, in
which 12 and acetone were treated with TMSOTf in THF, at a yield
of 60% (10). Finally, 10 was subjected to deprotection of the benzyl
groups by Pd(OH) -catalyzed hydrogenation, to yield the desired
2
proanthocyanidin analogue 2 at a yield of 70%.
The radical scavenging activity of 2 was evaluated in a non-
20
aqueous system using GOÅ as the 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 electrons taken up.
The procyanidin B3 analogue 2, in which the geometry of the
two catechin molecules in procyanidin B3 are constrained to pla-
nar orientations, was synthesized by two different methods. The
first method involves the Oxa-Pictet–Spengler reaction with both
Fig. 1. Structures of (+)-catechin, planar catechin, procyanidin B3 (Cat-Cat), and procyanidin B3 derivatives 1 (Cat-PCat) and 2 (PCat-PCat).