Synthesis of Kaempferol 3-O-[2″,3″- and 2″,4″-Di-O- (E)-p-coumaroyl]-α-Lrhamnopyranosides

Article abstract of DOI:10.1055/s-0030-1259702

Kaempferol 3-O-[2″,3″- and 2″,4″-di-O-(E)-p- coumaroyl]-α-L-rhamnopyranoside, two acylated flavonol 3-O-glycosides with potent inhibitory activity against methicillin-resistant Staphylococcus aureus, were synthesized for the first time, employing glycosyl

Full text of DOI:10.1055/s-0030-1259702

LETTER
915
Synthesis of Kaempferol 3-O-[2¢¢,3¢¢- and 2¢¢,4¢¢-Di-O-(E)-p-coumaroyl]-a-L-
rhamnopyranosides
Synthesis of
K
aem
a
pferol Rha
n
a
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: byu@mail.sioc.ac.cn
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P. R. of China
Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, P. R. of China
b
c
Received 15 September 2010
Dedicated to Professors Xiyan Lu and Lixin Dai
Compounds 1 and 2 are typical naturally occurring acylat-
ed flavonol 3-O-glycosides.14 A key step to synthesize
this type of natural metabolites is the construction of the
phenolic 3-O-glycosidic linkage, which has been mainly
Abstract: Kaempferol 3-O-[2¢¢,3¢¢- and 2¢¢,4¢¢-di-O-(E)-p-couma-
royl]-a-L-rhamnopyranoside, two acylated flavonol 3-O-glycosides
with potent inhibitory activity against methicillin-resistant Staphy-
lococcus aureus, were synthesized for the first time, employing gly-
cosyl o-cyclopropylethynylbenzoates as donors and Ph3PAuNTf2 as resorted to the glycosylation protocol with glycosyl bro-
a catalyst for the construction of the flavonol glycosidic linkages.
mides as donors under phase-transfer-catalysis
conditions15 (PTC) or under the action of silver salts.16
Key words: flavonol glycosides, glycosylation, glycosyl o-alky-
nylbenzoate, antibacterial activity
Recently, we disclosed an efficient alternative to the syn-
thesis of this type of linkage with glycosyl o-alkynylben-
zoates as donors and gold(I) complex as a catalyst.17
Herein, we report the synthesis of compounds 1 and 2 em-
ploying this new protocol for the flavonol 3-O-glycoside
formation (Scheme 1).
Kaempferol
3-O-[2¢¢,3¢¢-di-O-(E)-p-coumaroyl]-a-L-
rhamnopyranoside (1), named platanoside, has been
isolated from Platanus acerifolia (Platanaceae),1 P. orien-
talis,2 P. occidentalis,3 Pentachondra pumila (Epacri-
daceae),4a Faeniculum vulgare (Apiaceae), and F. dulce.4b
Recently, this compound was found to have selective and
potent activity against methicillin-resistant Staphylococ-
cus aureus (MRSA) with an IC50 of 2.0 mg/mL.3 MRSA is
a serious pathogen with significant patient mortality.5
Hospital-acquired infections of MRSA have shown resis-
tance to multiple antibiotics. Daptomycin is currently the
most useful anti-MRSA drug, however, various side ef-
fects have been registered, including an increase in blood
creatine phosphokinase, rhabdomyolysis, skin exfolia-
tion, and skin ulcers. Thus, development of new anti-
MRSA drugs is a matter of great urgency.
OBn
O
BnO
OH
OH
4'
OR
O
7
HO
O
O
3 R = H
4 R = Bn
+
3
O
5
1''
OH
O
R3O
O
OR1
R2O
1 R1 = R2 = (E)-p-coumaroyl, R3 = H
2 R1 = R3 = (E)-p-coumaroyl, R2 = H
O
Kaempferol
3-O-[2¢¢,4¢¢-di-O-(E)-p-coumaroyl]-a-L-
O
R3O
rhamnopyranoside (2), the regioisomer of compound 1,
has been identified from Ocotea vellosiana (Lauraceae),6
Laurus nobilis (Lauraceae),7 Mammea longifolia (Gut-
tiferae),8 Eriobotrya japonica (Rosaceae),9 Cinnamomum
kotoense (Lauraceae),10 Epimedium sagittatum (Berberi-
daceae),11 and Machilus philippinensis (Lauraceae).12 In-
dependently, compound 2 was also found to be a potent
anti-MRSA agent, with the minimum inhibitory concen-
trations (MICs) being 0.5–2.0 mg/mL.13 In addition, com-
pound 2 could suppress proliferation of human peripheral
blood mononuclear cells induced by phytohemagglutinin,
with an IC50 of ca. 6.0 mM.10
R2O
OR1
5 R1 = R2 = (E)-p-Bn-coumaroyl, R3 = Bn
6 R1 = R3 = (E)-p-Bn-coumaroyl, R2 = Bn
HO
O
(E)-p-coumaroyl
Scheme 1 Acylated flavonol 3-O-glycosides 1 and 2 and their retro-
synthetic perspective
We have described recently the synthetic routes toward
7,4¢-di-O-benzyl-kaempferol (3) and 5,7,4¢-tri-O-benzyl-
kaempferol (4).17 Worth mentioning is that direct benzy-
lation of kaempferol (2.5 equiv BnBr, K2CO3, DMF, r.t.)
led to 3,7-di-O-benzyl-kaempferol (instead of the desired
7,4¢-di-O-benzyl-kaempferol) as the major product in ca.
30% yield.18 In the present synthesis of 4, the transforma-
tion from methyl ketone 7 to bromide 8 was greatly im-
SYNLETT 2011, No. 7, pp 0915–0918
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259702; Art ID: W32210ST
© Georg Thieme Verlag Stuttgart · New York

916
Y. Li et al.
LETTER
OBn
OBn
O
O
1) PhMe3NBr3 (2.5 equiv), THF, r.t.
2) (EtO)2POH, Et3N, THF, r.t.; 98%
ref. 17
BnO
O
O
BnO
O
O
4
Br
OBn
OBn
7
8
Scheme 2 Improved synthesis of 5,7,4¢-tri-O-benzyl-kaempferol (4)
proved by dibromination (with 2.5 equiv of PhMe3NBr3) nor 6 was prepared from allyl 3-O-benzyl-a-L-rhamno-
first followed by selective debromination [(EtO)2POH, pyranoside (12)22 in three steps and 51% overall yield.
Et3N, THF, r.t.],19 providing bromide 8 in an excellent
The glycosidic coupling of 7,4¢-di-O-benzyl-kaempferol
98% yield (Scheme 2); previous attempts in direct mono-
(3) with rhamnosyl o-cyclopropylethynylbenzoate (5) un-
der the action of Ph3PAuNTf2 led unexpectedly to a com-
plex mixture (Scheme 4). In contrast, the coupling of
bromination of 7 led to 8 in less than 49% yield (1 equiv
of PhMe3NBr3, THF, r.t.).17
The required rhamnosyl donors 5 and 6 were prepared as 5,7,4¢-tri-O-benzyl-kaempferol (4) with 5 under similar
shown in Scheme 3. Here we used o-cyclopropylethynyl- conditions (0.2 equiv Ph3PAuNTf2, 4 Å MS, CH2Cl2, r.t.)
benzoate as the anomeric leaving group instead of the pre- proceeded smoothly, providing the desired 3-O-a-L-
vious o-hexynylbenzoate.20 Although the preparation rhamnoside (14) in a good 74% yield. Similarly, glycosy-
procedure is similar,20c this small variation brings two div- lation of 4 with o-cyclopropylethynylbenzoate donor 6
idends: the reagent ethynyl cyclopropane is cheaper than gave a-L-rhamnoside (15) in 89% yield. Finally, removal
1-hexyne, in addition, o-cyclopropylethynylbenzoic acid of the six O-benzoyl groups on 14/15 was achieved with
(11) is a crystalline solid (mp 79–82 °C) while o-hexynyl- an excess amount of BBr3 (18 equiv) in CH2Cl2 at low
benzoic acid is a liquid at room temperature.
temperature (–78 °C), furnishing the target flavonol gly-
cosides 1 and 2 in 68% yield, respectively. The spectro-
scopic data of the synthetic compounds are identical to
those reported for the natural products.23
Thus, allyl 4-O-benzyl-a-L-rhamnopyranoside (9)21 was
condensed with (E)-4-benzyloxycinnamic acid under the
action of DCC and DMAP to provide compound 10
(85%). Removal of the anomeric allyl group on 10 was ef- In summary, two acylated flavonol 3-O-glycosides 1 and
fected with PdCl2, the resulting lactol was then directly 2 with potent anti-MRSA activities were synthesized for
subjected to condensation with o-cyclopropylethynylben- the first time. The synthesis features formation of the fla-
zoic acid (11, DIPEA, DMAP, EDCI, CH2Cl2, r.t.)20 to af- vonol 3-O-glycosidic linkages with glycosyl o-alkynyl-
ford the desired rhamnosyl donor 5 in 74% yield (two benzoates as donors under the catalysis of a gold(I)
steps). Employing similar transformations, rhamnosyl do- complex. This is especially advantageous for the present
O
OAll
O
OAll
(E)-4-benzyloxycinnamic acid,
DCC, DMAP, CH2Cl2, r.t., 85%
1) PdCl2, CH2Cl2, MeOH, r.t.
O
O
O
BnO
BnO
MeO
BnO
2) 11, DIPEA, DMAP, EDCI,
CH2Cl2, r.t.; 74%
RO
HO
RO
OR
OH
OR
9
10
5
HO
O
I
O
1) Pd(PPh3)2Cl2, CuI, Ph3P, i-Pr2NH, r.t.
2) aq NaOH (1 N), THF, 50 °C; 98%
+
11
O
O
OAll
OAll
(E)-4-benzyloxycinnamic acid,
DCC, DMAP, CH2Cl2, r.t., 78%
1) PdCl2, CH2Cl2, MeOH, r.t.
O
O
O
HO
RO
RO
2) 11, DIPEA, DMAP, EDCI,
CH2Cl2, r.t.; 66%
BnO
BnO
BnO
13
OH
OR
6
OR
O
12
BnO
R =
Scheme 3 Preparation of rhamnosyl o-cyclopropylethynylbenzoates 5 and 6
Synlett 2011, No. 7, 915–918 © Thieme Stuttgart · New York

LETTER
Synthesis of Kaempferol Rhamnopyranosides
917
5 + 3
complex
OBn
BnO
O
O
O
68%
74%
OBn
O
5 + 4
O
1
OBn
O
O
BnO
O
14
Ph3PAuNTf2 (0.2 equiv),
4 Å MS, CH2Cl2, r.t.
BBr3, CH2Cl2, –78 °C
BnO
BnO
OBn
O
O
89%
68%
OBn
O
O
6 + 4
2
O
OBn
O
OBn
O
O
15
BnO
Scheme 4 Completion of the synthesis of compounds 1 and 2
Ward, M. M.; Franciscus, C. L.; Pfaller, M. A.; Doebbeling,
B. N. Clin. Infect. Dis. 2004, 38, 78. (b) Mahamat, A.;
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synthesis of the flavonol 3-O-a-L-rhamnosides; the previ-
ous methods involve unstable rhamnosyl bromides and
stochiometric amount of silver salts.24 Additionally, gly-
cosyl o-cyclopropylethynylbenzoates have been used for
the first time as glycosyl donors instead of the previous o-
hexynylbenzoates. The advantage of this slight variation
lies in the more convenient and cheaper preparation of the
reagent o-cyclopropylethynylbenzoic acid.
(6) Garcez, W. S.; Yoshida, M.; Gottlieb, O. R. Phytochemistry
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Acknowledgment
Financial support from the National Natural Science Foundation of
China (20932009 and 20621062) and the National Major Project of
China (Grants 2009ZX09311-001 and 2008ZXJ09004-007) are
gratefully acknowledged.
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Synlett 2011, No. 7, 915–918 © Thieme Stuttgart · New York

918
Y. Li et al.
LETTER
Biochemistry; Farkas, L.; Gábor, M.; Kállay, F., Eds.;
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(d, J = 8.6 Hz, 1 H), 7.38 (d, J = 8.5 Hz, 1 H), 6.99 (d, J = 8.7
Hz, 1 H), 6.81 (d, J = 8.6 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H),
6.41 (d, J = 2.0 Hz, 1 H), 6.38 (d, J = 15.8 Hz, 1 H), 6.29 (d,
J = 15.8 Hz, 1 H), 6.21 (d, J = 2.0 Hz, 1 H), 5.82 (dd, J = 1.5,
3.2 Hz, 1 H), 5.60 (s, 1 H), 5.28 (dd, J = 3.2, 9.5 Hz, 1 H),
3.64 (t, J = 9.8 Hz, 1 H), 3.51–3.58 (m, 1 H), 1.05 (d, J = 6.0
Hz, 3 H). 13C NMR (100 MHz, CD3OD): d = 179.4, 168.5,
167.8, 165.9, 163.4, 161.8, 161.5, 161.3, 159.1, 158.6,
147.8, 147.0, 135.5, 131.9, 131.4, 131.2, 127.1 (d), 122.4,
116.9, 116.8 (d), 114.9, 114.4, 105.9, 100.3, 99.9, 94.8, 73.0,
72.2, 71.0, 70.9, 17.8. ESI-HRMS: m/z calcd for C39H31O14
[M – H]–: 723.1719; found: 723.1740.
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W.-D.; Yu, B. J. Org. Chem. 2010, 51, 1504.
(18) 3,7-Di-O-benzyl-kaempferol
1H NMR (300 MHz, CDCl3): d = 12.72 (s, 1 H), 10.29 (s, 1
H), 7.93 (d, J = 8.8 Hz, 2 H), 7.47–7.32 (m, 9 H), 6.92 (d,
J = 8.8 Hz, 2 H), 6.74 (d, J = 2.0 Hz, 1 H), 6.42 (d, J = 2.0
Hz, 1 H), 5.19 (s, 2 H), 5.03 (s, 2 H). 13C NMR (100 MHz,
CDCl3): d = 178.0, 164.0, 161.0, 160.2, 156.5, 156.1, 136.6,
136.4, 136.0, 130.3, 128.4, 128.3, 128.2, 128.0, 127.7,
120.5, 115.4, 105.2, 98.3, 93.0, 73.3, 69.9, 40.1, 39.9, 39.7,
39.5, 39.3, 39.1, 38.9.
Compound 2: [a]D25 –36.6 (c 0.3, MeOH); lit.10 [a] –44.8. 1H
NMR (500 MHz, CD3OD): d = 7.81 (d, J = 8.7 Hz, 2 H),
7.69 (d, J = 15.6 Hz, 1 H), 7.58 (d, J = 15.6 Hz, 1 H), 7.53
(d, J = 8.7 Hz, 2 H), 7.50 (d, J = 8.7 Hz, 2 H), 7.04 (d, J = 8.7
Hz, 2 H), 6.84 (d, J = 8.7 Hz, 2 H), 6.81 (d, J = 8.7 Hz, 2 H),
6.43 (d, J = 16.1 Hz, 1 H), 6.40 (d, J = 1.4 Hz, 1 H), 6.32 (d,
J = 15.6 Hz, 1 H), 6.20 (d, J = 1.8 Hz, 1 H), 5.76 (s, 1 H),
5.43 (t, J = 1.4 Hz, 1 H), 4.98 (t, J = 9.9 Hz, 1 H), 4.55 (s, 1
H), 4.16 (dd, J = 3.2, 9.7 Hz, 1 H), 3.29–3.26 (m, 1 H), 0.86
(d, J = 6.0 Hz, 3 H). 13C NMR (125 MHz, CD3OD): d =
179.3, 168.5, 168.4, 166.0, 163.3, 161.9, 161.4, 159.5,
158.6, 147.5, 147.0, 134.7, 132.0, 131.4, 131.3, 127.2,
122.5, 116.8, 116.7, 115.0, 114.7, 106.0, 100.0, 99.2, 94.9,
74.7, 73.2, 69.8, 68.5, 17.7.
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(23) Spectroscopic Data for Synthetic Compounds
Compound 1: [a]D25 72.1 (c 0.2, MeOH); lit.4 [a] 89.6. 1H
NMR (400 MHz, CD3OD): d = 7.87 (d, J = 8.8 Hz, 2 H),
7.62 (d, J = 15.8 Hz, 1 H), 7.60 (d, J = 15.8 Hz, 1 H), 7.46
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