First total synthesis of (±)-latifolin and its antioxidant mechanism

Article abstract of DOI:10.1002/cjoc.201500505

The first total synthesis of (±)-latifolin has been accomplished in six steps and 47.8% overall yield. To understand the relative importance of phenolic O-H and benzhydryl C-H hydrogen on the antioxidant activity of latifolin, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and density functional theory (DFT) studies were carried out. On scavenging DPPH radical in ethanol, the activity of latifolin (1) bearing phenolic hydrogen is remarkably higher than analogue 10 bearing no phenolic hydrogen. Therefore, Phenolic hydrogen is responsible for latifolin's antioxidant activity rather than benzhydryl C-H hydrogen. Furthermore, the 5-OH BDE is lower than 2′-OH and 7-CH BDEs by a DFT calculation, respectively. Based on theoretical results it is definitely concluded that the phenolic 5-OH plays a major role in the antioxidant activity of latifolin. The first total synthesis of (±)-latifolin has been accomplished in six steps and 47.8% overall yield. Based on DPPH-scavenging assay and density functional theory (DFT) studies, the H-atom abstraction of latifolin should take place in the phenolic 5-OH rather than benzhydryl 7-CH.

Full text of DOI:10.1002/cjoc.201500505

FULL PAPER
DOI: 10.1002/cjoc.201500505
First Total Synthesis of (±)-Latifolin and Its Antioxidant
Mechanism
Yihua Dai,a Qiaoling Liu,a Zhifang Li,a Weifeng Chen,*,a and Zhongli Liub
a Key Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou
Normal University, Hangzhou, Zhejiang 310012, China
b National Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, Gansu 730000, China
The first total synthesis of (±)-latifolin has been accomplished in six steps and 47.8% overall yield. To under-
stand the relative importance of phenolic O－H and benzhydryl C－H hydrogen on the antioxidant activity of lati-
folin, 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and density functional theory (DFT) studies
were carried out. On scavenging DPPH radical in ethanol, the activity of latifolin (1) bearing phenolic hydrogen is
remarkably higher than analogue 10 bearing no phenolic hydrogen. Therefore, Phenolic hydrogen is responsible for
latifolin’s antioxidant activity rather than benzhydryl C－H hydrogen. Furthermore, the 5-OH BDE is lower than
2'-OH and 7-CH BDEs by a DFT calculation, respectively. Based on theoretical results it is definitely concluded
that the phenolic 5-OH plays a major role in the antioxidant activity of latifolin.
Keywords total synthesis, latifolin, antioxidant, DPPH-scavenging, density functional theory
Introduction
oxybenzene and o-methoxycinnamyl cation,[19] no total
synthesis of latifolin has been reported. We have been
interested in the synthesis of benzhydryl natural prod-
ucts, such as cassumunin C.[20] In order to study the rel-
ative importance of the phenolic O－H and the benzhy-
dryl C－H hydrogen on the antioxidant activity of lati-
folin, we describe here the first total synthesis of
(±)-latifolin.
Latifolin (1), a naturally occurring phenolic com-
pound, was first isolated from the heartwood of Dalber-
gia latifolia in 1962.[1] It has been reported to deliver a
variety of biological and pharmacological activities,
including inhibition of β-amyloid production,[2] anti-
fungal,[3,4] anticarcinogenic[5] and antioxidant activity.[6]
It is obvious that benzhydryl C－H bond (Figure 1,
highlighted in 1) on latifolin is very weak due to delo-
calization of the π electrons on the adjacent phenyl or
alkenyl group. Thus, the free radical scavenging activity
of latifolin can arise from the highly activated benzhy-
dryl C－H hydrogen. On the other hand, latifolin also
contains two phenolic hydrogens, which are usually
responsible for antioxidant properties of plant phenolic
compound.[7-9] Having a very similar antioxidant struc-
ture as curcumin, latifolin contains acidic protons in the
benzhydryl carbon and phenolic group. Contradictory
opinions have been proposed to explain the radical-at-
tacking sites in curcumin. The main argument was
whether the phenolic hydrogen or the central methylenic
hydrogen in the heptadienone moiety is responsible for
its antioxidant activity.[10-14] Focusing on kinetics and
mechanisms of curcumin and its synthetic analogues,
our previous work has showed that the phenolic group is
responsible for its antioxidant activity.[15-18] In addition,
although the synthesis of (±)-latifolin dimethyl ether
has been reported by Kumari et al. from 1,2,4-trimeth-
3
2
MeO
HO
OMe
4
9
5
8
1CH 7
6
1'
OH
6'
5'
2'
3'
4'
latifolin (1)
O
O
MeO
HO
OMe
OH
H H
curcumin
Figure 1 Structures of latifolin and curcumin.
Experimental
Oxygen- and moisture-sensitive reactions were car-
ried out under an argon atmosphere. Solvents were puri-
fied and dried by standard methods prior to use. All
commercially available reagents were used without fur-
*
E-mail: chenwf@hznu.edu.cn
Received July 17, 2015; accepted September 1, 2015; published online September 29, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500505 or from the author.
Chin. J. Chem. 2015, 33, 1287—1292
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Dai et al.
FULL PAPER
ther purification, unless otherwise noted. Column chro-
7.12 (d, J＝8.2 Hz, 1H), 7.05 (t, J＝7.5 Hz, 1H), 5.73 (s,
1H), 5.24 (ABq, J＝6.7 Hz, 2H), 3.50 (s, 3H), 3.29 (br s,
1H), 0.21 (s, 9H); 13C NMR (101 MHz, CDCl3) δ: 154.4,
129.6, 129.5, 128.0, 122.1, 114.5, 105.1, 94.5, 90.3,
61.1, 56.2, −0.1. ESI-HRMS [M＋Na]＋ calcd for
C14H20NaO3Si: 287.1079, found 287.1106.
matography was carried out on silica gel (200－300
1
mesh). H (400 MHz) and 13C (100 MHz) spectra were
recorded with TMS as an internal standard on a Bruker
AV-400 MHZ instrument. The EIMS were recorded on
a Trance 2000 DSQ mass spectrometer. The ESI-MS
were recorded with an LCQ advantage mass spectrome-
ter. High-resolution MS were recorded on a Thermo
Scientific LTQ Orbitrap XL spectrometer. IR spectra
were recorded on a Nicolet 5700 spectrometer. Melting
points are uncorrected. 2,4-Dimethoxyphenol was pre-
pared according to a literature procedure.[21] All calcula-
tions were performed with the Gaussian09 suites of
programs.[22] The DFT calculations employed the
B3LYP functional using the standard 6-31G(d,p) basis
set.
Synthesis of 2,4-dimethoxy-5-(1-(2-(methoxy-
methoxy)phenyl)-3-(trimethylsilyl)prop-2-ynyl)phe-
nol (6) and 5-(1-(2-hydroxyphenyl)-3-(trimethyl-
silyl)prop-2-ynyl)-2,4-dimethoxyphenol (7)
To a solution of compound 4 (187 mg, 0.71 mmol)
and 5 (111 mg, 0.72 mmol) in dry acetonitrile (4.0 mL)
was added iodine (11 mg, 0.04 mmol) at −10 ℃. The
reaction was allowed to warm to r.t. and stirred for 0.5 h.
The mixture was diluted with EtOAc. The organic phase
was washed with saturated Na2S2O3, water and brine,
dried over anhydrous Na2SO4. The crude material was
purified by column chromatography on silica gel col-
umn [V(hexane)∶V(EtOAc)＝4∶1] to give 6 (199 mg,
0.50 mmol, yield 70%) as a white solid and 7 (24 mg,
0.07 mmol, yield 10%) as a yellow oil.
Synthesis of 2-(methoxymethoxy)benzaldehyde (3)[23]
To a suspension of NaH (60% in oil, 1.58 g, 39.50
mmol) in dry THF (5.0 mL) was added dropwise a solu-
tion of 2-hydroxybenzaldehyde (4.00 g, 32.75 mmol) in
DMF (4.5 mL) at 0 ℃. After stirring for 30 min, a so-
lution of methoxymethyl chloride (3.00 mL, 39.50
mmol) in THF (10.0 mL) was added dropwise to the
reaction mixture at 0 ℃. After stirring for 2 h, the reac-
tion mixture was diluted with hexane. The organic
phase was washed with NaOH (aq., 20%) and H2O,
dried over anhydrous Na2SO4, and evaporated under
reduced pressure. The crude material was purified by
column chromatography on silica gel column
[V(hexane)∶V(EtOAc)＝30∶1] to give 3 (5.03 g,
Compound 6 m.p. 136－138 ℃ after crystal-
1
lization from hexane and EtOAc; H NMR (400 MHz,
CDCl3) δ: 7.41 (d, J＝7.6 Hz, 1H), 7.18 (t, J＝8.4 Hz,
1H), 7.03 (d, J＝8.2 Hz, 1H), 7.01 (s, 1H), 6.97 (t, J＝
7.5 Hz, 1H), 6.47 (s, 1H), 5.70 (s, 1H), 5.34 (br s, 1H),
5.15 (ABq, J＝6.7 Hz, 2H), 3.84 (s, 3H), 3.73 (s, 3H),
3.39 (s, 3H), 0.17 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ: 154.1, 150.2, 145.7, 139.4, 130.5, 129.1, 127.8, 122.5,
121.7, 115.4, 114.2, 107.5, 97.5, 94.2, 86.4, 57.1, 56.1,
55.8, 31.3, 0.2; IR (neat film) ν: 3574, 2956, 2172, 1515,
1
30.27 mmol) as a light yellow liquid, yield 92%. H
1207, 1152, 1099, 1035, 995, 843, 748 cm−1.
NMR (400 MHz, CDCl3) δ: 10.49 (s, 1H) 7.83 (d, J＝
7.7 Hz, 1H), 7.52 (t, J＝7.5 Hz, 1H), 7.19 (d, J＝8.4 Hz,
1H), 7.06 (t, J＝7.5 Hz, 1H), 5.29 (s, 2H), 3.51 (s, 3H);
13C NMR (101 MHz, CDCl3) δ: 189.8, 159.7, 135.9,
128.3, 125.4, 121.8, 115.0, 94.6, 56.5; MS (70 eV, EI)
m/z: 166 (M＋, 79), 135 (54), 121(100).
＋
ESI-HRMS [M ＋ Na]
calcd for C22H28NaO5Si:
423.1604, found 423.1617.
Compound 7 1H NMR (400 MHz, CDCl3) δ: 7.55
(dd, J＝7.7, 1.5 Hz, 1H), 7.15 (s, 1H), 7.11 (td, J＝7.9,
1.6 Hz, 1H), 6.99 (br s, 1H), 6.90 (td, J＝7.6, 1.1 Hz,
1H), 6.83 (dd, J＝8.0, 1.1 Hz, 1H), 6.46 (s, 1H), 5.46 (s,
1H), 5.31 (br s, 1H), 3.90 (s, 3H), 3.84 (s, 3H), 0.21 (s,
9H); 13C NMR (101 MHz, CDCl3) δ: 153.4, 148.0,
146.1, 140.6, 128.5, 128.3, 127.2, 121.5, 120.8, 116.9,
114.9, 106.3, 96.7, 88.4, 57.1, 56.2, 31.2, 0; IR (neat
film) ν: 3578, 3490, 2958, 2167, 1514, 1455, 1200,
1030, 846, 750 cm−1; ESI-HRMS [M＋Na]＋ calcd for
C20H24NaO4Si: 379.1342, found 379.1342.
Synthesis of 1-(2-(methoxymethoxy)phenyl)-3-(tri-
methylsilyl)prop-2-yn-1-ol (4)
To a solution of trimethylsilylacetylene (0.60 mL,
4.25 mmol) in dry THF (20.0 mL) was added dropwise
n-BuLi (1.40 mL, 2.5 mol/L in hexane, 3.50 mmol) at
−78 ℃. The reaction was stirred at this temperature for
20 min then r.t. for 1 h. After cooling to −78 ℃, alde-
hyde 3 (0.54 g, 3.25 mmol) was added dropwise to the
mixture. The solution was allowed to warm to r.t.
gradually and stirred for an additional hour before
quenched with aqueous NH4Cl. The mixture was ex-
tracted with EtOAc, and the organic phases were
washed with water and brine, dried over anhydrous
Na2SO4. The crude material was purified by column
chromatography on silica gel column [V(hexane)∶
V(EtOAc)＝15∶1] to give 4 (794 mg, 3.00 mmol) as a
colorless liquid, yield 92%. 1H NMR (400 MHz, CDCl3)
δ: 7.60 (dd, J＝7.6, 1.3 Hz, 1H), 7.33－7.25 (m, 1H),
Synthesis of compound 7 from 6
To a solution of compound 6 (92 mg, 0.23 mmol) in
MeOH (25.0 mL) was added 4 mol/L HCl (5.0 mL) at
r.t. The mixture was stirred at 50 ℃ for 12 h. After
removal of most of the solvent, the crude product was
extracted with EtOAc. The organic layer was washed
with water and brine, dried over anhydrous Na2SO4. The
crude material was purified by column chromatography
over a silica gel column [V(hexane)∶V(EtOAc)＝4∶1]
to give 7 (77 mg, 0.21 mmol) as a yellow oil, yield 91%.
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First Total Synthesis of (±)-Latifolin and Its Antioxidant Mechanism
Synthesis of 5-(1-(2-hydroxyphenyl)prop-2-ynyl)-2,4-
dimethoxyphenol (8)
(s, 3H), 2.05－2.12 (m, 2H), 0.88 (t, J＝7.2 Hz, 3H);
13C NMR (101 MHz, CDCl3) δ: 154.1, 148.9, 145.0,
140.6, 130.6, 127.2, 126.2, 124.8, 120.6, 116.3, 113.2,
96.7, 57.2, 56.1, 36.2, 26.8, 12.6. ESI-HRMS [M＋Na]＋
calcd for C17H20NaO4: 311.1259, found 311.1263.
To a solution of compound 7 (66 mg, 0.19 mmol) in
THF (2.0 mL) was added TBAF in THF (0.24 mL, 1
mol/L, 0.20 mmol) at 0 ℃. After stirring for 30 min,
the reaction mixture was quenched with 10% HCl (0.54
mL), extracted with EtOAc, washed with water and
brine, dried over anhydrous Na2SO4. The crude material
was purified by column chromatography over a silica
gel column [V(hexane)∶V(EtOAc)＝2∶1] to give 8
Synthesis of 3,3-diphenylpropene (10)
To a mixture of t-BuOK (0.62 g, 5.50 mmol) and
methyltriphenyl phosphonium bromide (1.79 g, 5.00
mmol) was added dry THF (20.0 mL) at 0 ℃. The re-
action mixture was stirred for 2 h at r.t. After cooling to
0 ℃, a solution of 2,2-diphenylacetaldehyde (0.98 mL,
5.00 mmol) was added to the reaction mixture slowly
and the mixture was stirred for 24 h at r.t. The mixture
was diluted with EtOAc and filtered. The filtrate was
washed with water and brine, dried over anhydrous
Na2SO4. The crude material was purified by column
chromatography over a silica gel column [V(hexane)∶
V(EtOAc)＝50∶1] to give 10 (738 mg, 3.80 mmol) as
1
(50 mg, 0.18 mmol) as a yellow oil, yield 94%. H
NMR (400 MHz, CDCl3) δ: 7.62 (dd, J＝7.7, 1.6 Hz,
1H), 7.16 (s, 1H), 7.12 (td, J＝7.8, 1.7 Hz, 1H), 6.92 (td,
J＝7.6, 1.1 Hz, 1H), 6.83 (dd, J＝8.0, 1.1 Hz, 1H), 6.46
(s, 1H), 5.48 (d, J＝2.6 Hz, 1H), 3.90 (s, 3H), 3.83 (s,
3H), 2.43 (d, J＝2.6 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ: 153.1, 147.9, 146.2, 140.6, 128.5, 128.4,
127.0, 121.1, 120.9, 116.9, 114.8, 96.6, 84.3, 71.9, 57.2,
56.2, 29.9; IR (neat film) ν: 3396, 3287, 2937, 2482,
1600, 1505, 1456, 1200, 1030, 878, 756 cm−1.
ESI-HRMS [M＋Na]＋ calcd for C17H16NaO4: 307.0946,
found 307.0947.
1
a colorless liquid, yield 76%. H NMR (400 MHz,
CDCl3) δ: 7.42－7.38 (m, 4H), 7.33－7.30 (m, 6H),
6.42 (ddd, J＝17.1, 10.0, 7.2 Hz, 1H), 5.32 (d, J＝9.3,
1H), 5.11 (dd, J＝17.1, 1.2 Hz, 1H), 4.85 (d, J＝6.9 Hz,
1H); 13C NMR (101 MHz, CDCl3) δ: 143.4, 140.7,
128.7, 128.5, 126.5, 116.5, 55.1; MS (70 eV, EI) m/z
(%): 194 (M＋, 100), 179 (44), 165 (40), 115 (71).
Synthesis of latifolin
To a solution of alkyne 8 (50 mg, 0.18 mmol) in
EtOAc (2.0 mL) was added quinoline (6 mg, 46.45
μmol) and 5% palladium on barium sulfate (6 mg, 2.82
μmol). The mixture was hydrogenated at r.t. and at-
mospheric pressure for 12 h. The mixture was filtered
through celite, concentrated, and purified by column
chromatography over a silica gel column [V(hexane)∶
V(EtOAc)＝2∶1] to give latifolin (47 mg, 0.17 mmol)
DPPH assay
The DPPH-scavenging assay[16] was carried out by
monitoring the absorbance of an ethanolic solution of
DPPH (100 μmol/L) at 517 nm at r.t. in the presence
and absence of latifolin and its analogues. IC0.20 repre-
sents the concentration of the test compound at which
absorbance decreased by 0.20 of a unit during a 30-min
observation and was taken as the free radical scavenging
potency.
1
as a light brown oil, yield 94%. H NMR (400 MHz,
CDCl3) δ: 7.18 (d, J＝7.6 Hz, 1H), 7.11 (t, J＝7.6 Hz,
1H), 6.92－6.80 (m, 2H), 6.76 (s, 1H), 6.52 (s, 1H),
6.33 (ddd, J＝16.9, 10.2, 5.8 Hz, 1H), 6.02 (br s, 1H),
5.27 (d, J＝10.2 Hz, 1H), 5.23 (br s, 1H), 5.19 (d, J＝
5.8 Hz, 1H), 5.05 (dd, J＝17.1, 1.1 Hz, 1H), 3.87 (s,
3H), 3.85 (s, 3H); 13C NMR (101 MHz, CDCl3) δ: 153.7,
149.5, 145.5, 140.1, 139.0, 129.4, 128.5, 127.7, 122.6,
120.6, 116.7, 116.3, 115.2, 97.1, 57.2, 56.2, 40.1; IR
(neat film) ν: 3432, 2859, 2172, 1602, 1489, 1457, 1251,
1154, 1040, 843, 758 cm−1. ESI-HRMS [M＋Na]＋
calcd for C17H18NaO4: 309.1103, found 309.1112.
Results and Discussion
Our synthesis of latifolin is outlined in Scheme 1.
2-Hydroxybenzaldehyde (2) was protected with a
methoxymethyl group under basic condition to give 3
(92%). Treatment of trimethylsilylacetylene with
n-butyllithium followed by addition of 3 afforded the
expected propargyl alcohol 4 (92%). Aromatic propar-
gylation[20,24] of 4 with 2,4-dimethoxyphenol 5 using
iodine as the catalyst in acetonitrile for 30 min gave
alkyne 6 (70%) and deprotecting compound 7 (10%).
Compounds 6 and 7 were easily separated using silica
gel column chromatography, and 6 can be further con-
verted into 7 (91%) in the presence of a concentrated
HCl solution in methanol. The structure of 6 was unam-
biguously confirmed by X-ray crystallographic analysis
(Figure 2). With key intermediate 7 in hand, removal of
the TMS group with tetrabutylammonium fluoride
(TBAF) gave 8 (94%). Catalytic hydrogenation in the
presence of Pd/BaSO4 and quinoline afforded
Synthesis of dihydrolatifolin (9)
To a mixture of compound 8 (30 mg, 0.11 mmol) in
EtOAc (1.0 mL) was added Pd/C (20% w/w, 30 mg,
0.06 mmol). The mixture was hydrogenated at r.t. and
atmospheric pressure for 12 h. The mixture was filtered
through celite, concentrated, and purified by column
chromatography over a silica gel column [V(hexane)∶
V(EtOAc)＝2∶1] to give 9 (29 mg, 0.10 mmol) as a
light brown oil, yield 91%. 1H NMR (400 MHz, CDCl3)
δ: 7.28 (dd, J＝7.7, 1.3 Hz, 1H), 7.06 (td, J＝7.6, 1.5
Hz, 1H), 6.88 (dd, J＝7.6, 0.8 Hz, 1H), 6.87 (s, 1H),
6.83 (dd, J＝7.9, 0.8 Hz, 1H), 6.82 (s, 1H), 6.48 (s, 1H),
5.26 (s, 1H), 4.26 (t, J＝7.7 Hz, 1H), 3.91 (s, 3H), 3.84
1
(±)-latifolin (1) (94%). The H and 13C NMR spectra
were in good agreement with the reported data of
Chin. J. Chem. 2015, 33, 1287—1292
© 2015 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Scheme 1 Synthesis of (±)-latifolin
O
O
OH
MOMCl
TMS
H
H
TMS
NaH, DMF
n-BuLi, THF
OH
OMOM
3, 92%
OMOM
2
4, 92%
OMe
OMe
MeO
HO
HO
HO
OMe
OMe
OMe
5
+
5% I2, MeCN
TMS
TMS
OMOM
6, 70%
OH
7, 10%
4 mol/L HCl, MeOH
91%
OMe
MeO
HO
OMe
HO
TBAF
THF
H2, Pd/BaSO4
quinoline
OMe
7
OH
OH
(±)-latifolin(1), 94%
8, 94%
Scheme 2 Synthesis of analogues 9 and 10
OMe
MeO
OMe
HO
HO
OMe
Pd/C
OH
H2
OH
9, 91%
8
CHO
+
-
Ph3PCH3Br
t-BuOK/THF
2,2-diphenylacetaldehyde
10, 76%
assay. The capacity of antioxidant to scavenge the
DPPH radical, can be expressed as its magnitude of an-
tioxidation ability.[27,28] Table 1 showed the scavenging
activities of the tested compounds expressed as IC0.2
value. Compared with vitamin C that has an IC0.2 value
of 9.53 μmol/L, latifolin and analogue 9 were consid-
ered as strong DPPH-scavengers with IC0.2 value of 8.19
μmol/L and 8.63 μmol/L, respectively. While the activ-
ity of 10 which bears no phenolic hydrogen was negli-
gible (~6200 times less than latifolin). In our previous
work, the antioxidant effects of curcumin and synthetic
analogues were studied in micelles, human low density
lipoprotein (LDL), human red blood cell (RBC) and rat
liver mitochondria.[15-18] We found that the antioxidative
activities of analogues which bear no phenolic group are
also inactive. Therefore, phenolic hydrogen is responsi-
ble for latifolin’s antioxidant activity, which agrees well
Figure 2 ORTEP view of the crystal structure of 6.
natural latifolin.[4]
Analogues 9 and 10 were also synthesized to study
the antioxidant mechanism of latifolin. As shown in
Scheme 2, Pd/C-catalyzed hydrogenation of 8 gave the
dihydrolatifolin (9) (91%). The synthesis of 3,3-diphe-
nylpropene 10 from 2,2-diphenylacetaldehyde was re-
ported in low yield (33%－46%) using n-butyllithium as
a base.[25,26] We modified the Wittig reaction using po-
tassium tert-butoxide as a base to afford 10 in a satisfied
yield (76%).
Antioxidant mechanism
Herein, we investigated the antioxidant effect of lati-
folin (1) and analogues 9, 10 on the DPPH-scavenging
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Chin. J. Chem. 2015, 33, 1287—1292

First Total Synthesis of (±)-Latifolin and Its Antioxidant Mechanism
with the conclusion from our previous work on the rad-
ical-scavenging mechanism of curcumin.[15-18] In addi-
tion, there was no significant difference between latifo-
lin and analogue 9 in the DPPH-scavenging activities,
suggesting that the teminal double bond has limited in-
fluence on antioxidant activity of latifolin.
Scheme 3 Antioxidant mechanism of latifolin
MeO
OMe
HO
OH
latifolin
Table 1
analoguesa
DPPH-scavenging activities of latifolin and its
Compound
IC0.20/(μmol•L−1)
8.19±0.16
Latifolin (1)
MeO
HO
OMe
MeO
O
OMe
9
8.63±0.25
(5.14±0.11)×104
10
OH
Vc
9.53±0.19
OH
a The DPPH-scavenging assay was carried out by monitoring the
absorbance of an ethanolic solution of DPPH (100 μmol/L) at 517
nm in the presence and absence of the test compounds at r.t. The
concentration (IC0.20) of the test compounds at which absorbance
decreased by 0.20 of a unit during a 30-min observation was tak-
en as the free radical scavenging potency.
Conclusions
The first concise and efficient total synthesis of lati-
folin has been accomplished in six steps and 47.8%
overall yield. This synthetic process should be able to
pave the way for further biological and pharmacological
studies of latifolin and analogues. Latifolin (1) and di-
hydrolatifolin (9) that bear phenolic hydrogen were con-
sidered as strong DPPH-scavengers, and they are better
antioxidants than 10 possessing no phenolic hydrogen.
Therefore, Phenolic hydrogen is responsible for latifo-
lin’s antioxidant activity rather than benzhydryl C-H
hydrogen. Furthermore, the 5-OH BDE is lower than
2'-OH and 7-CH BDEs by a DFT calculation, respec-
tively. Based on theoretical results it is definitely con-
cluded that the phenolic 5-OH plays a major role in the
antioxidant activity of latifolin.
In antioxidant mechanism, the evaluation of the an-
tioxidant activity is also usually done by determining the
bond dissociation enthalpy (BDE). In fact, low values of
BDE suggest an easier dissociation or proton abstraction,
a better interaction with the free radicals and conse-
quently a higher antioxidant activity of the compound.
To elucidate the antioxidant activity-structure relation-
ship of latifolin, the BDE of the phenolic O－H bonds
and benzhydryl C － H bond was calculated at
B3LYP/6-31G* level of theory (Table 2). The results
show that not only 5-OH BDE (ca. 271 kJ•mol−1) but
also 2'-OH BDE (ca. 279 kJ•mol−1) is lower than ben-
zhydryl 7-CH BDE (ca. 280 kJ•mol−1), indicating that
the phenolic OH plays a major role in the activity of
latifolin. On the other hand, the 5-OH BDE is lower by
7.37 and 9.27 kJ•mol−1 than 2'-OH and 7-CH BDEs,
respectively. This is due to the electron-rich phenol ring
containing both ortho- and para-MeO groups. It has
been proved that the ortho-methoxyl group can form
intramolecular hydrogen bond with the phenolic hydro-
gen, making the H-atom abstraction from the ortho-
methoxyphenols surprisingly easy.[29] Thus, the first
H-atom abstraction of latifolin should take place in the
phenolic 5-OH rather than benzhydryl 7-CH (Scheme
3).
Acknowledgement
This work was supported by the National Natural
Science Foundation of China (Nos. 21202031,
21472032) and Zhejiang Provincial Natural Science
Foundation of China (No. Y4110297).
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