Total synthesis of kaempferol and methylated kaempferol derivatives

Article abstract of DOI:10.1002/jccs.200100033

Kaempferol (1), a natural product from various plants, was synthesized in which the longest linear sequence is only seven steps in overall yields of 47% from commercially available 1,3,5-trimethoxybenzene (10). The methylated kaempferols 2-5 were also prepared by use of this concise synthetic methodology. The key transformations in this synthesis involved the I₂ oxidative-promoting-cyclization and DDO oxidative hydroxylation. Several strategies to achieve 1 are provided.

Full text of DOI:10.1002/jccs.200100033

JournaloftheChineseChemicalSociety, 2001, 48, 201-206
201
Total SynthesisofKaempferolandMethylatedKaempferolDerivatives
Yean-Jang Lee* (
) and Tsao-Dong Wu (
)
DepartmentofChemistry,NationalChanghuaUniversityofEducation,Changhua,Taiwan
Kaempferol (1), a nat u ral prod uct from var i ous plants, was syn the sized in which the lon gest lin ear se-
quence is only seven steps in over all yields of 47% from com mer cially avail able 1,3,5-trimethoxybenzene
(10). The meth yl ated kaempferols 2-5 were also pre pared by use of this con cise syn thetic meth od ol ogy. The
key trans for ma tions in this syn the sis in volved the I2 oxidative-promoting-cyclizationandDDOoxidative
hydroxylation. Severalstrategiestoachieve1 are pro vided.
INTRODUCTION
The flavone nu cleus is part of a large num ber of nat u ral
thesisincludecrossaldolcondensation,I2 oxidativepromot-
ing-cyclization re ac tion, and C-3 hydroxylation of flavone
with dimethyldioxirane (DDO).29
productsandmedicinalcompounds.1 Kaempferol (1)2 and
other flavonoids are known as po ten tial antitumor agents and
humanimmunodeficiencyvirus(HIV)type1integraseinhib-
itors.3 Kaempferol and its 3-O-glycosidederivativeshave
beenidentifiedinvariousplants, vegetables, fruits, andbev-
erages such as Taiwan Bauhinia,4 Phyllanthus virgatus,5
Chamaecyparis formosensis,6 Inula britannica,7 French
beans,8 on ions,9 asparagus,10 blueberries,11 red raspberry
juice,12 grape fruit juice,13 teas,14 and honey.15 Possessing
tyrosinaseinhibitoryactivity,16 kaempferol was ob served to
inhibittheoxidationofL-3,4-dihydroxyphenylalaninecata-
lyzed by mush room tyrosinase with an ID50 of 67 g/mL
(0.23 mM). In ad di tion, kaempferol was as sayed in mouse
skin carcinogensis to show an antitumor-promoting ef fect17
andtheinhibitoryactivityofHIVprotease.18 Ourprevious
investigationindicatedthattheflavonoidanaloguesarether-
a peu ti cally use ful in anal ogy to the struc tural fea tures of
CAPE. 19 We ex tend this as sump tion that kaempferol or other
flavonoids per form in hib i tory ac tiv ity against HIV-1 inte-
grase and tu mors. On the other hand, meth yl ated kaemperols
2-5 were iso lated from Alpinia,20 Zingiber,21 and Amomum
Koenigii.22 Amomum K., a mem ber of the Zingiberaceae, and
many spe cies of this fam ily in clud ing gin ger, tur meric, and
car da mom have been used as tra di tional Chi nese, Jap a nese
andIndianmedicines.23 Duetothemedicinalimperatives,the
scar city of kaempferol and the clear need for a re li able sup-
ply, we are stim u lated to syn the size these flavonoids. There
are semisynthetic stud ies in the lit er a ture.24,25 The re ported
results26 and our pre lim i nary study show that the fla vones can
be syn the sized from o-hydroxy-ketones or chalcones us ing
the Allan-Robinson27 or Algar-Flym-Oyamada28 reaction,
butinpooryields. Hereinwereportthesynthesesofkaempferol
(1) and meth yl ated kaempferols2-5. High lights of the syn-
OR
O
O
3
OR
1
R O
4
OR
2
kaempferol 1
R =R =R =R =H
1
2
3
4
2
R =R =R =R =Me
1
2
3
4
3
4
5
R =H,R =R =R =Me
1
2
3
4
R =H,R =R =R =Me
3
1
2
4
R =R =H,R =R =Me
1
3
2
4
RESULTS AND DISCUSSION
Disconnectionofthetargetmolecule1 re sulted in two
commerciallyavailablestartingmaterials(SchemeI). Two
approacheswillbepursuedtodeterminewhichstrategyisvi-
a ble. The first ap proach in volves the cross-aldol con den sa-
tion re ac tion of ketone 6 and al de hyde 7 un der ba sic con di-
tions, fol lowed by C-3 hydroxylation of flavone to af ford the
desired 1. The sec ond ap proach em ploys the Friedel-Crafts
reactionofcinnamicacid9 and phloroglucinol 8catalyzedby
Lewis acid to pro vide the pre cur sor flavone, fol lowed by C-3
hydroxylation of flavone to achieve 1. The ini tial pro posal
was to use ke tones6 andaldehydes7 via cross aldol re ac tion
for kaempferol syn the sis. The cross-aldol re ac tion showed
only the start ing ketone 6 and the side prod ucts could be de-
tected/isolatedfromthisreactionmixtureunderseveralbasic
con di tions (KOH, NaOH, NaHCO3, Na2CO3, pyridine, and
pyrrolidine). To over come these tech ni cal dif fi cul ties, we
switchedtousingtheFriedel-Craftsreaction.
Starting with the com mer cially avail able 4-hydroxy-

202 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Lee and Wu
Scheme I Retrosynthetic anal y sis of kaempferol (1)
PhSSPh conditions.30 However, we could achieve the
flavanone in very low yield (12%) by treat ment of K2CO3.
The ad van tage of I2 oxidativecyclizationisthatthereaction
canbeaccomplishedinarelativelyhighyieldandaffordonly
thedesiredproduct16 inanone-potreaction.
OH
O
OH
O
OH
a
OHC
+
HO
O
HO
OH
OH
Aldol
At this point, the fi nal step of the syn the sis was fo cused
on the ox i da tive re ac tion of the C-3 flavone. How ever, this
proved impossible to effect lithiolation with LDA or
LHMDS31 (Scheme II). An al ter na tive method for C-3 hy-
droxylationwasalsoexamined.Oxidative-hydroxylationof
dimethyldioxirane (DDO) has been re ported on sev eral fla-
vones.29 In the case of 16 we failed to pro vide C-3 hydroxy-
flavone since the free hydroxyl group of flavone also af fected
the ox i da tive-hydroxylation with DDO. The methylation of
16 with Me2SO4 to give the meth yl ated flavone 17,followed
by C-3 hydroxylation with DDO gen er ated the ex pected
flavonol 3 in 95% yield (Scheme III). The C-3 hydroxy-
flavone3 un der went demethylation smoothly with BBr3 to
accomplishthedesiredproduct1 in ex cel lent yield (91%).
On the other hand, it could be eas ily ma nip u lated from the
com mer cially avail able flavanone 18. The ox i da tion of18
with I2/pyridine was em ployed to ob tain flavone 19 in ex cel-
lent yield (93%). The methylation of 19 with Me2SO4 to pro-
vide the meth yl ated flavone 17 in very good yield (84%),
which could be con verted to af ford1aswell.Themethylated
kaempferolderivatives2-5 werealsoaccomplishedunevenly
(Scheme IV). The flavonol 3 was treated with Me2SO4 to give
2 in ex cel lent yield (98%), and fol lowed by demethylation of
2 with 1 eq. BBr3 to reach 4 in 97% yield. Finally, com pound
4 was readily trans formed to 5 via demethylation with 1 eq.
BBr3 in ex cel lent yield (95%). Melting points and1H and 13C
NMR spec tra of the syn thetic prod ucts 1-5 are in agree ment
OH
1
7
6
b
Friedel-Crafts
OH
O
+
OH
HO
OH HO
9
8
cinnamic acid (9) and thionyl chlo ride, the ex pected acyl
chlo ride was ob tained. The fol low ing acylation of phloro-
glucinol catalyzed by Lewis acid didn’t provide tetra -
hydroxy-chalcone. With the aim of de vel op ing a suc cess ful
route to 1, the hydroxyl groups were first protected as a
methoxy group to pro vide the more lipophilic sub stances. We
then sought to employ the Friedel-Crafts reaction of tri-
methoxybenzene10 and 4-methoxycinnamic acid chlo ride
11 with AlBr3 as a cat a lyst to yield o-hydroxy-chalcone 12 in
35%yield(SchemeII). Tooptimizethisreaction, weapplied
cross-aldol re ac tion of 13 and 14 to pro vide pen ta methyl-
chalcone 15, followed by ortho-demethylation of aceto -
phenone cat a lyzed with AlCl3 to af ford o-hydroxylchalcone
12in high yield (two steps 87%). Com pound 13 wasobtained
via ZnCl2-cat a lyzed acylation of10 with acetyl chlo ride in
ex cel lent yield (98%). Cyclization with I2/pyridine af forded
the flavone 16 in good yield (74%). It is worth not ing that we
failed to ob tain the cyclization prod uct by use of H2O2 or
Scheme II
OMe
O
OMe O
+
Cl
AlBr3
MeO
OMe
MeO
PhNO2
MeO
OH
12
OMe
10
11
35%
O
ZnCl2
Cl
98%
OMe O
OMe O
CHO
KOH
96%
+
MeO
MeO
OMe
OMe
MeO
OMe
13
14
15
OH
O
O
I2
AlCl3
91%
12
pyridine
74%
MeO
OMe
16

To tal Syn the sis of Kaempferol
J. Chin. Chem. Soc., Vol. 48, No. 2, 2001 203
mmol) in nitrobenzene (25 mL) was added AlBr3 (1 M 7.1
mL, 7.1 mmol) so lu tion dropwise at room tem per a ture. The
suspensionwasstirredunderanitrogenatmospherefor24h.
Theresultingsolutionwasquenchedbyadding1NH2SO4 (3
mL), and fol lowed by ex trac tion with ether. The sol vent was
re moved in vacuo to give a solid mix ture which was sub-
jectedtocolumnchromatography(SiO2, Ether:CH2Cl2 1:1)
Scheme III
OMe O
DDO
95%
Me2SO4
16
3
94%
MeO
O
17
OMe
BBr3
91%
o
to ob tain 12 (1.8 g, 35%) as solid: mp 111-113 C (lit.33 mp
1
113-114 oC); 1H NMR (200 MHz, (CD3)2CO) 4.04 and 4.13
(s, 9H), 6.23 (s, 2H), 7.14 and 7.82 (d, J = 8.7 Hz, 4H), 7.90
and 8.05 (d, J = 15.6 Hz, 2H); 13C NMR (50 MHz,
(CD3)2CO): 56.1, 56.4, 56.8, 92.1, 95.0, 107.1, 115.6,
126.1, 129.3, 131.4, 143.6, 162.9, 164.0, 167.6, 169.5, 193.6.
Method (B): A so lu tion of 15 (2.5 g, 7.6 mmol) and an-
hydrousAlCl3 (1.1 g, 8.4 mmol) was stirred at room tem per a-
ture un der a ni tro gen at mo sphere for 10 h. To this so lu tion
was added 1 N H2SO4 (2 mL), and the re sult ing mix ture was
subsequentlyextractedwithether.Evaporationoftheorganic
layer in vacuo gave a light brown solid which was sub jected
tocolumnchromatography(SiO2,Ether:petroleumether1:1)
to give 12 (2.2 g, 91%).
Scheme IV
OH
O
O
OH
O
O
I2/pyridine
Me2SO4
17
reflux
93%
HO
HO
84%
OH
OH
18
19
1 eq. BBr3
97%
Me2SO4
acetone
98%
1 eq. BBr3
95%
3
2
5
4
withthosereportedfornaturallyderivedmaterials.22,32
2,4,6,4’-Tetramethoxychalcone (15)
Inconclusion,wehavedevelopedaneffectivestrategy
tosynthesizekaempferol(1)anditsderivatives2-5. The tac-
ticsinvolvingtheFriedel-Crafts,cross-aldolcondensation,I2
oxidativepromoting-cyclization,andDDOoxidativereac-
tion pro vide an easy ac cess to syn the size other flavonoids as
well. Fur ther bi o log i cal as says to eval u ate the ef fi cacy of
these com pounds 1-5 as agents against tu mors are cur rently
underway.
A mix ture of 2,4,6-trimethoxyacetophenone (2.0 g, 9.5
mmol) and 4-methoxybenzaldehyde (1.3 g, 9.5 mmol) in eth-
a nol (50 mL) was stirred at room tem per a ture for 0.5 h. A so-
lu tion of 50% KOH (38 mL, 330 mmol) was added dropwise,
andthenstirredatroomtemperaturefor6h. Asolutionof4N
HCl was added and the resulting mixture extracted with
CH2Cl2. The or ganic layer was con cen trated and the res i due
wassubjectedtocolumnchromatography(SiO2, EA:CH2Cl2
1:3) to give 15 (3.0 g, 96%) as a yel low solid: mp 116-118 oC
1
(lit.33 mp 119-119.5 oC); H NMR (200 MHz, (CD3)2CO)
EXPERIMENTALSECTION
3.90, 3.99 and 4.02 (s, 12H), 6.46 (s, 2H), 6.97 and 7.41 (d, J
= 16 Hz, 2H), 7.12 and 7.73 (d,J = 8.9 Hz, 4H);13C NMR (50
MHz, (CD3)2CO) 56.1, 56.2, 56.5, 92.0, 113.2, 115.6,
128.4, 128.8, 131.2, 144.5, 159.8, 162.8, 163.5, 194.0.
Melting points were de ter mined on a Mel Temp II melt-
ing point ap pa ra tus and are un cor rected.1H NMR and 13
C
NMR spec tra were ob tained us ing a Bruker AC-200 spec-
trometer.Chemicalshiftsarereportedinpartspermillion( ,
ppm) us ing CHCl3 ( H 7.26)asaninternalstandard. Solvents
werefreshlydistilledpriortousefromphosphoruspentoxide
or CaH2. THF was dis tilled from so dium di phen yl ketyl. All
reactionswerecarriedoutundernitrogenatmosphereunless
oth er wise stated. Sil ica gel (sil ica gel 60, 230-400 mesh,
Merck)wasusedforchromatography.Organicextractswere
driedoveranhydrousMgSO4.
5-Hydroxy-7-methoxy-2-(4-methoxyphenyl)chromen-4-
one (16)
A mix ture of 12 (2.00 g, 6.4 mmol) and I2 (1 eq. 6.5
mmol) in pyridine (10 mL) were refluxed for 8 h. Af ter cool-
ing, the solid was fil tered and the fil trate was sub jected to col-
umnchromatography(SiO2, Ether:CH2Cl2 1:1) to pro vide the
desiredproduct16 (1.5 g, 74%) as a white solid: mp 172-173
oC (lit.34 mp 165 oC);. 1H NMR (200 MHz, (CD3)2CO) 4.06
and 4.07 (s, 6H), 6.47 and 6.83 (d, J = 2.2 Hz, 2H), 6.85 (s,
1H), 7.27 and 8.18 (d, J = 9.0 Hz, 4H); 13C NMR (50 MHz,
CDCl3) 55.5, 55.7, 92.5, 98.0, 104.2, 105.5, 114.4, 123.5,
2-Hydroxy-4,6,4’-trimethoxychalcone (12)
Method (A): To a mix ture of phloroglucinol 10 (1.0 g,
5.9 mmol) and freshly pre pared acid chlo ride 11 (1.3 g, 6.5

204 J. Chin. Chem. Soc., Vol. 48, No. 2, 2001
Lee and Wu
128.0, 157.6, 162.1, 162.5, 164.0, 165.4, 182.4.
M 6.1 mL) in CH2Cl2 (10 mL) was refluxed for 24 h, and then
cooled to room tem per a ture. The re sult ing mix ture was dis-
solved in MeOH and sub jected to col umn chro ma tog ra phy
(SiO2, EA:Hex ane 1:2) to ob tain1 (0.32 g, 91%) as a yel low
5,7-Dimethoxy-2-(4-methoxyphenyl)chromen-4-one (17)
To a sus pen sion of 16 (0.54 g, 1.8 mmol) and K2CO3 (2
eq. 0.50 g) in ac e tone (25 mL) was added Me2SO4 (0.19 mL,
1.99 mmol) dropwise at room tem per a ture, and then refluxed
for 8 h. To the re sult ing so lu tion was added 25 mL H2O, and
the mix ture was ex tracted with CH2Cl2. The or ganic layer
wasconcentrated in vacuo, and the res i due sub jected to col-
umnchromatography(SiO2, Ether:CH2Cl2 1:2) to pro vide 17
o
solid: mp 274-275 oC (lit.4 mp 274-276 C); 1H NMR (200
MHz, (CD3)2CO) 6.41 and 6.68 (d,J = 2.0 Hz, 2H), 7.16 and
8.30 (d, J = 8.9 Hz, 4H) 13C NMR (50 MHz, (CD3)2CO)
94.8, 99.5, 104.5, 116.7, 123.6, 130.8, 137.0, 147.4, 158.1,
160.6, 162.6, 165.4, 177.0.
(0.53 g, 94%) as a yel low solid: mp 157.5-159 C (lit.35 mp
3,5,7-Trimethoxy-2-(4-methoxyphenyl)chromen-4-one (2)
To a mix ture of3 (0.20 g, 0.6 mmol) and K2CO3 (2 eq.
1.66 g) in ac e tone (25 mL) was added Me2SO4 (63 L, 0.70
mmol) dropwise at room tem per a ture, and then refluxed for 8
h. The re sult ing so lu tion was cooled and was added H2O (5
mL), and ex tracted with CH2Cl2. The or ganic layer was con-
cen tratedin vacuo, and the res i due was sub jected to col umn
chromatography(SiO2, MeOH:CH2Cl2 1:20) to pro vide 2
(0.20 g, 98%) as a yel low solid: mp 151-153 oC (lit.38 mp 165
oC); 1H NMR (200 MHz, CDCl3) 3.85, 3.87, 3.88, and 3.93
(s, 12H), 6.30 and 6.47 (d,J = 2.3 Hz, 2H), 6.98 and 8.04 (d, J
= 9.1 Hz, 4H) 13C NMR (50 MHz, CDCl3) 55.3, 55.7, 56.3,
59.8, 92.3, 95.6, 109.4, 113.8, 123.1, 129.7, 141.0, 152.6,
158.7, 160.9, 161.1, 163.8, 174.0.
o
o
1
158.5-159.5 C); H NMR (200 MHz, (CD3)2CO) 4.02,
4.04, and 4.08 (s, 9H), 6.60 and 6.89 (d, J = 2.4 Hz, 2H), 6.63
(s, 1H), 7.23 and 8.09 (d,J = 9.0 Hz, 4H) 13C NMR (50 MHz,
(CD3)2CO) 56.2, 56.6, 56.8, 94.3, 97.2, 108.3. 110.2, 115.6,
125.0, 128.8, 160.9, 161.2, 162.2, 163.4, 165.2, 176.7.
5,7-Dihydroxy-2-(4-hydroxyphenyl)chromen-4-one (19)
A mix ture of 18 (2.00 g, 7.3 mmol) and I2 (1 eq. 7.3
mmol) in pyridine (10 mL) were refluxed for 4 h. Af ter cool-
ing, the solid was fil tered and the fil trate was sub jected to col-
umnchromatography(SiO2, Ether:CH2Cl2 1:3) to pro vide the
de sired prod uct19 (1.85 g, 93%) as a white solid: mp 348-
349oC (lit.36 mp 345-346 oC); 1H NMR (200 MHz, DMSO)
6.21 and 6.50 (d, J = 2.0 Hz, 2H), 6.79, 10.41, and 10.89 (bs, 3
OH), 6.94 and 7.93 (d, J = 8.8 Hz, 4H); 13C NMR (50 MHz,
CDCl3 + DMSO) 92.2, 97.2, 101.1, 102.2, 114.2, 119.6,
126.4, 155.7, 159.4, 159.9, 162.1, 162.4, 180.3.
5-Hydroxy-3,7-dimethoxy-2-(4-methoxyphenyl)chromen-
4-one (4)
To a so lu tion of 2 (0.20 g, 0.58 mmol) in CH2Cl2 (20
mL) was cooled to 0oCfor30min, andintroducedBBr3 (1 eq.
1M0.58mL)intothesolutiondropwise.Theorangemixture
3-Hydroxy-5,7-dimethoxy-2-(4-methoxyphenyl)chromen-
4-one (3)
o
was stirred at 0 C for 30 min, and then MeOH was added.
The re quired amount (26~126 mL) of the DDO (pre-
paredaccordingtoAdam’sprocedure29) in ac e tone (0.01-
0.05 M), was added rap idly un der N2 to a cooled so lu tion of
flavone 17 (0.4 g, 1.3 mmol) in dried CH2Cl2 (100 mL).
Stirringwascontinuedfor5-8h.Thereactionwasmonitored
by TLC anal y sis. The sol vent was re moved and the res i due
was sub jected to col umn chro ma tog ra phy to get the cor re-
spond ing 3-hydroxyflavone 3 (0.4 g, 95%) as a solid: mp
The sol vent was re movedin vacuo, and the res i due was sub-
jectedtocolumnchromatography(SiO2, Ether:Hex ane 1:1)
o
to af ford 4 (0.19 g, 97%) as a yel low solid: mp 141-142 C
(lit.39 mp 138-140 oC); 1H NMR (200 MHz, CDCl3) 3.85,
3.86, and 3.89 (s, 9H), 6.33 and 6.43 (d,J = 2.4 Hz, 2H), 7.01
and 8.08 (d, J = 9.0 Hz, 4H) 13C NMR (50 MHz, CDCl3)
55.4, 55.7, 60.1, 92.1, 97.8, 106.0, 114.0, 122.7, 130.1, 138.8,
155.9, 156.7, 161.6, 162.0, 165.4, 178.7.
132-134 C (lit.37 mp 135-136 C); H NMR (200 MHz,
CDCl3) 3.85, 3.90 and 3.97 (s, 9H), 6.33 and 6.54 (d,J = 1.9
Hz, 2H), 7.26 (s, 1H), 7.02 and 8.16 (d, J = 8.6 Hz, 4H); 13C
NMR (50 MHz, CDCl3) 55.3, 55.7, 56.3, 92.3, 95.6, 106.1,
113.9, 123.5, 128.8, 137.4, 142.2, 158.8, 160.4, 160.6, 164.2,
171.8.
o
o
1
3,5-Dihydroxy-7-methoxy-2-(4-methoxyphenyl)chromen-
4-one (5)
To a so lu tion of 4 (15 mg, 0.046 mmol) in CH2Cl2 (2
mL) was added BBr3 (1.2 eq. 1 M 55 L) at room tem per a-
ture, and the re ac tion mix ture was refluxed for 4 h. The crude
prod uct was dis solved in MeOH and sub jected to col umn
chromatography(SiO2, EA:CH2Cl2 1:5) to achieve 5 (14 mg,
95%) as a yel low solid: mp 178-179oC (lit.40 mp 178-179 oC);
1H NMR (200 MHz, CDCl3) 3.87 (s, 6H), 6.36 and 6.47 (d,J
3,5,7-Trihydroxy-2-(4-hydroxyphenyl)chromen-4-one
(kaempferol 1)
A sealed tube of 3 (0.40 g, 1.2 mmol) and BBr3 (5 eq. 1

To tal Syn the sis of Kaempferol
J. Chin. Chem. Soc., Vol. 48, No. 2, 2001 205
= 2.1 Hz, 2H), 6.56 (bs, OH), 7.02 and 8.15 (d, J = 9.1 Hz,
4H)
Tomas-Lorente, F. J. Sci. Food Agric. 1991, 56, 49.
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ACKNOWLEDGEMENTS
TheauthorswishtothankProfessorTien-YauLuh(De-
partmentofChemistry,NationalTaiwanUniversity)forhelp-
ful dis cus sion on DDO re ac tions. We thank the Na tional Sci-
ence Coun cil of the Re pub lic of China for fi nan cial sup port
(Re search Grant NSC 88-2113-M-018-004, NSC 89-2113-
M-018-003).
18. Brink worth, R. I.; Stoermer, M. J.; Fairlie, D. P. Biochem.
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Received October 31, 2000.
Key Words
Kaempferol; Friedel-Crafts; DDO; Aldol.
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