Potential therapeutic antioxidants that combine the radical scavenging ability of myricetin and the lipophilic chain of vitamin E to effectively inhibit microsomal lipid peroxidation

Article abstract of DOI:10.1016/j.bmc.2004.02.031

The flavonol myricetin, reacts with oxygen-centred galvinoxyl radicals 28 times faster than d-α-tocopherol (vitamin E), the main lipid-soluble antioxidant in biological membranes. Moreover, each myricetin molecule reduces twice as many such radicals as vitamin E. However, myricetin fails to protect vitamin E-deficient microsomes from lipid peroxidation as assessed by the formation of thiobarbituric acid reactive substances (TBARS). Novel and potentially therapeutic antioxidants have been prepared that combine the radical-scavenging ability of a myricetin-like head group with a lipophilic chain similar to that of vitamin E. C₆-C₁₂ alkyl chains are attached to the A-ring of either a 3,3^′,4 ^′,5^′-tetrahydroxyflavone or a 3,2 ^′,4^′,5^′-tetrahydroxyflavone head group to give lipophilic flavonoids (ClogP=4 to 10) that markedly inhibit iron-ADP catalysed oxidation of microsomal preparations. Orientation of the head group as well as total lipophilicity are important determinants of antioxidant efficacy. MM2 models indicate that our best straight chain 7-alkylflavonoids embed to the same depth in the membrane as vitamin E. The flavonoid head groups are prepared by aldol condensation followed by Algar-Flynn-Oyamada (AFO) oxidation or by Baker-Venkataraman rearrangement. The alkyl tails are introduced by Suzuki or Negishi palladium-catalysed cross-coupling or by cross-metathesis catalysed by first generation Grubbs catalyst, which tolerate phenolic hydroxyl and ketone groups.

Full text of DOI:10.1016/j.bmc.2004.02.031

Bioorganic & Medicinal Chemistry 12 (2004) 2079–2098
Potential therapeutic antioxidants that combine the radical
scavenging ability of myricetin and the lipophilic chain of vitamin E
to effectively inhibit microsomal lipid peroxidation
Christopher J. Bennett,a Stuart T. Caldwell,a Donald B. McPhail,b Philip C. Morrice,b
Garry G. Duthieb and Richard C. Hartleya,*
aOxyProTec Research Team, Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, Scotland, UK
bOxyProTec Research Team, Rowett Research Institute, Greenburn Rd, Bucksburn, Aberdeen AB21 9SB, Scotland, UK
Received 22 December 2003; accepted 24 February 2004
Abstract—The flavonol myricetin, reacts with oxygen-centred galvinoxyl radicals 28 times faster than d-a-tocopherol (vitamin E),
the main lipid-soluble antioxidant in biological membranes. Moreover, each myricetin molecule reduces twice as many such radicals
as vitamin E. However, myricetin fails to protect vitamin E-deficient microsomes from lipid peroxidation as assessed by the for-
mation of thiobarbituric acid reactive substances (TBARS). Novel and potentially therapeutic antioxidants have been prepared that
combine the radical-scavenging ability of a myricetin-like head group with a lipophilic chain similar to that of vitamin E. C6–C12
alkyl chains are attached to the A-ring of either a 3,30,40,50-tetrahydroxyflavone or a 3,20,40,50-tetrahydroxyflavone head group to
give lipophilic flavonoids (C log P ¼ 4 to 10) that markedly inhibit iron-ADP catalysed oxidation of microsomal preparations.
Orientation of the head group as well as total lipophilicity are important determinants of antioxidant efficacy. MM2 models indicate
that our best straight chain 7-alkylflavonoids embed to the same depth in the membrane as vitamin E. The flavonoid head groups
are prepared by aldol condensation followed by Algar–Flynn–Oyamada (AFO) oxidation or by Baker–Venkataraman rearrange-
ment. The alkyl tails are introduced by Suzuki or Negishi palladium-catalysed cross-coupling or by cross-metathesis catalysed by
first generation Grubbs catalyst, which tolerate phenolic hydroxyl and ketone groups.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
OH
The damage caused by reactive oxygen species (ROS)
such as hydroxyl radicals, peroxyl radicals and super-
oxide radical anions to the lipid components of cell
O
1 d-α-Tocopherol (Vitamin E)
membranes is implicated in the development of many
clinical conditions including ischaemia-reperfusion
injury, cancers, heart disease, arthritis, neurological
disorders and autoimmune diseases.1 The human body
protects itself from excessive lipid peroxidation in part
by sequestering the vitamin E homologue, d-a-tocoph-
erol (Fig. 1) from the diet and incorporating it into cell
and organelle membranes.2 Vitamin E 1 has two key
structural features: a phenolic component that reacts
with ROS, by donating the hydrogen atom from the
phenolic hydroxyl to generate a more stable tocopher-
oxyl radical; and a hydrophobic chain that anchors the
molecule to the membrane.3
OH
OH
HO
O
O
OH
OH
OH
2 Myricetin
Figure 1. Natural antioxidants.
Many flavonoids, plant secondary metabolites ubiqui-
tous in the diet, also possess phenolic structures capable
of hydrogen donation to reactive radicals.4 For example,
the flavonol myricetin 2 is a particularly powerful
* Corresponding author. Tel.: +44-0141-3304398; fax: +44-0141-330-
4888; e-mail: richh@chem.gla.ac.uk
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.02.031

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C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
+
Et
N
OH
Et
N
S
HO3S
O
S
SO3H
4 ABTS+Þ
1 Vitamin E
tBu
O
OH
OH
OH
But
HO
tBu
B
CO2H
O
O
O
A
C
OH
tBu
3 Trolox
5 Galvinoxyl radical
O
6i Vitamin E - myricetin hybrid
OH
Figure 2. Components of antioxidant assays.
OH
OH
B
HO
O
A
C
antioxidant in vitro. It is more readily reduced than vitamin
E (one-electron reduction potential at pH 7 of 0.36 and
0.48 V, respectively),5 and is almost fourfold more
effective than Trolox 3, a water soluble vitamin E ana-
logue, in scavenging the radical cation 2,20-azinobis(3-
ethylbenzothiazoline-6-sulfonic acid) (ABTSꢁþ) 4 at
physiological pH (Fig. 2).6 Furthermore, myricetin re-
acts 28 times as fast as vitamin E with galvinoxyl radi-
cals 5 (second-order rate constants are 14463 ꢀ 1767 and
524 ꢀ 48 molꢁ1 L sꢁ1, respectively) and has a better
reaction stoichiometry reducing four galvinoxyl radi-
OH
2 Myricetin
OH
O
Figure 3. Novel design of therapeutic antioxidant.
OH
OH
B
1
7
6
R
O
OH
cals while vitamin
E
reduces only two.7 This
A
C
2
R
OH
1
reflects the ability of myricetin to be oxidised to two
different B-ring orthoquinones and an extended par-
aquinone.
O
2
2
n
6 R = H
7 R = H, R =
C
H
21
10
2
1
n
1
8 R = Et, R = C H
a R = OH
17
8
1
b R = Et
However, the potent in vitro antioxidant ability of
flavonoids such as myricetin is less apparent in vivo due
in part to a relatively poor bioavailability8 and low
solubility in cell membranes compared with vitamin E.9
The hydrophobic chain of vitamin E is vital for its
uptake from the gut, systemic transportation and ori-
entation in cell membranes for optimum antioxidant
function. Increasing lipophilicity of water soluble
antioxidants such as myricetin may therefore have
therapeutic potential to treat a range of clinical condi-
tions such as stroke, diabetic complications and neuro-
degenerative conditions where membrane lipid
peroxidation has pathogenetic consequences. In addi-
tion such compounds may improve the prevention of
rancidity and markedly prolong the shelf life of food
products. For example, results from recent studies
with lipophilic analogues of gibbilimbols,10 phaffiaol,11
1
n
c R = Bu
1
d R = Me CH(CH )
2
2 3
1
n
e R = C H
6
13
17
1
n
f R = C H
8
1
g R = Me CH(CH ) CH(Me)(CH )
2
2 3
2 2
1
n
h R
= C H
10 21
1
i R = Me[CH(Me)(CH ) ] CH(Me)(CH )
2 2
2 3 2
1
n
j R
= C H
12 25
1
n
k R = C
H
18 37
HO
OH
OH
2
R
B
8
1
R
O
C
7
A
OH
O
2
1
9 R = R = H
10 R
11 R = H, R
1
n
2
=
C
H
, R = H
n
10 21
chromanols,12
polyprenylated
hydroquinones,13
1
2
= C H
9 19
dihydrobenzofurans14 and esters of gallic15 and ferulic
acids16 emphasise the importance of increased lipophi-
licity in the prevention of lipid oxidation. As myricetin 2
is a much more powerful antioxidant than all these
classes of compounds, we have attempted to generate
potent antioxidants 6 capable of inhibiting lipid perox-
idation within biological membranes by combining the
B and C ring substituents of myricetin 2 with lipophilic
chains similar to that of vitamin E 1 (Fig. 3). Com-
pounds 6–11 were synthesised to determine the effect of
chain length, position and branching, and one variation
in the head group on lipid peroxidation in a microsomal
system (Fig. 4).
Figure 4.
2. Synthetic chemistry
Flavonols 6a and 6b were synthesised from the corre-
sponding acetophenones 12 and 13 (Scheme 1). Aldol
condensation with trimethoxybenzaldehyde 14 gave
chalcones 15 and 16, then Algar–Flynn–Oyamada
(AFO) oxidation17 gave flavonols 17 and 18 and finally,
deprotection gave the desired flavonols 6a and 6b. Fla-
vonol 9 was synthesised in much the same way.

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
2081
I
OH
O
OMe
(i) AcCl, Et3N, DMAP
CH2Cl2 (97%)
I
OH
OMe
OMe
OMe
OMe
OMe
(ii) AlCl3, PhCl (69%)
20
OHC
R1
R1
19
OH
OH
O
14
OMe
KOH, EtOH
OR
O
KOH, EtOH
12 R1 = OBn
13 R1 = Et
15 R1 = OBn 23%
16 R1 = Et 92%
OHC
OMe
14 R = Me
21 R = Bn
H2O2, NaOH
MeOH, THF
OMe
OMe
OH
OMe
OR
OR
OMe
(i) H2O2
NaOH
OH
OH
OMe
OMe
BBr3
CH2Cl2 R1
I
O
O
I
OH
R1
MeOH
O
O
O
O
OMe
(ii) BnCl
K2CO3, KI
acetone
OBn
OH
OH
22 R = Me 54%
23 R = Bn 74%
O
24 R = Me 67%
25 R = Bn 95%
6a R1 = OH 99%
b R1 = Et 70%
17 R1 = OBn 54%
18 R1 = Et 47%
nBuB(OH)2 26 or
9-BBN
THF
R1B
=
B
Scheme 1. Synthesis of modified flavonoids.
R3
R3
28
27
4-7 mol% Cl2Pd(dppf), NaOH(aq), THF
Straight chain 7-alkylflavonols 6c, 6e, 6f, 6h, 6j and 6k
and short branched chain 7-alkylflavonol 6d were syn-
thesised from 3-iodophenol (Scheme 2). Acetophenone
20 was prepared following the literature procedure by
acetylation of 3-iodophenol 19 and Fries rearrange-
ment.18 Aldol condensation with benzaldehydes 14
and 21 gave chalcones 22 and 23. These underwent
Algar–Flynn–Oyamada (AFO) oxidation17 and benzyl
protection to give flavonoids 24 and 25. Suzuki cross-
coupling19 with alkylboronic acid 26 or alkylboranes 27,
prepared by hydroboration of 1-alkenes 28,20 gave
7-alkyl-flavonoids 29 and 30 in modest to excellent yield.
The mild conditions required for coupling tolerate the
C-ring ketone. Surprisingly, although alkyl–aryl Suzuki
couplings can be catalysed by a variety of palladium and
nickel complexes,21–24 they have rarely been employed
in target-based synthesis previously.25–28 Generally,
deprotection with boron tribromide proceeded in high
yield, but acetylation and recrystallisation of the tetra-
acetates 31 followed by deprotection proved to be the
best way to purify flavonoids 6c, 6e and 6f.
OMe
OR
OAc
OAc
OAc
(i) BBr3
R1
O
R1
O
CH2Cl2
OMe
(i) Ac2O
DMAP
pyridine
OBn
OAc
O
O 31c 35% d 8%
e 41% f 36%
29 R = Me
c 23% d 98%
e 24% f 59%
30 R = Bn
h 59% j 35%
k 68%
HCl, MeOH
BBr3
CH2Cl2
OH
OH
OH
R1
O
O
Substituents:
c R1 = nBu
OH
d R1 = Me2CH(CH2)3
e R1 = nC6H13
6 (from 31) c 94% d 93% e 85% f 94%
(from 30) h 95% j 34% k 99%
f R1 = nC8H17
h R1 = C10H21
n
j R1 = nC12H25
k R1 = nC18H37
Scheme 2. Synthesis of 7-alkyl myricetin analogues.
In a related approach, the branched tetrahydrogeranyl
and hexahydrofarnesyl chains of flavonoids 6g and 6i
were introduced by Negishi cross-coupling29 (Scheme 3).
Geraniol 32 and farnesol 33 were hydrogenated to give
saturated alcohols 34 and 35, respectively, as 1:1 mix-
tures of diastereomers. These were converted into iod-
ides 36 and 37. Iodo-flavonoid 25 reacted with excess
organozinc derived from iodide 36 in the presence of a
catalyst that is designed to avoid b-elimination during
alkyl–aryl couplings,30 but gave a poor yield of 7-alkyl-
flavonoid 38. 7-Hexahydrofarnesyl-flavonoid 39 was
made in similarly poor yield from iodo-flavonoid 24 and
an organozinc derived from iodide 37. Deprotection
then gave the desired flavonoids 6g and 6i.
While bromination of acetophenone 13 gave aryl bro-
mide 42. Aldol condensation with aldehyde 21 and AFO
reaction of the resulting chalcones 43 and 44 gave
6-haloflavonols 45 and 46, respectively. Suzuki cross-
coupling proceeded without the need to protect the
3-hydroxyls to give 6-alkyl-flavonoids 47 and 48. Depro-
tection and purification via the tetra-acetates 49 and 50
then gave the target flavonoids 7 and 8.
An alternative approach was employed in the synthesis
of 7-alkyl-flavonol 10, which has a head group with a
different hydroxy substitution pattern from myricetin
(Scheme 5). Here the alkyl chain was introduced by
Suzuki cross-coupling prior to construction of the fla-
vonol by Baker–Venkataraman rearrangement.17 Thus,
resorcinol 51 was converted into acetophenone 52 by the
Houben–Hoesch reaction and selective trifluoro-
methanesulfonation of the unchelated hydroxyl. Suzuki
6-Alkyl-flavonoid 7 and 6,7-dialkyl flavonoids 8 were
prepared by a similar approach (Scheme 4). Friedel–
Crafts acylation of acetamide 40, followed by depro-
tection, diazotisation and iodination gave aryl iodide 41.

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C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
Et
OH
H2, Pd/C
EtOH
OH
OH
n
n
32 n = 1
33 n = 2
34 n = 1 55%
35 n = 2 93%
13
O
(i) Mg, ZnCl2
THF
(ii) 0.24 eq.
24 or 25
5-10 mol%
[(o-Tol)3P]2PdCl2
(76%)
Br , CHCl
2
3
PPh3, I2
imidazole
CH2Cl2
OMe
2
(i) AcCl, AlCl
OR
OMe
OMe
3
OH
R
CH Cl (87%)
2
2
R1
O
O
(ii) HCl ) (84%)
(aq
AcHN
X
I
(iii) NaNO , H SO
4
n
2
2
40
O
(iii) KF
2
OBn
KI, Cu, H O (39%)
2
41 R = H, X = I
36 n = 1 71%
37 n = 2 61%
2
42 R = Et, X = Br
38 R1 = Me2CH(CH2)3CH(Me)(CH2)2
R = Bn, 15% from 25
39 R1 = Me[CH(Me)(CH2)3]2CH(Me)(CH2)2
R = Me, 15% from 24
OMe
OBn
OMe
KOH
EtOH
OHC
21
BBr3, CH2Cl2
OH
OMe
OMe
OH
OH
OBn
OMe
OBn
H O
NaOH
MeOH
2
2
O
O
2
2
O
OH
R
R
OMe
n
OH
X
OH
X
6g n =1, 37%
6i n =2, 87%
O
O
2
2
45 R = H, X = I 49%
43 R = H, X = I 49%
44 R = Et, X = Br 19%
2
2
46 R = Et, X = Br 40%
Scheme 3. Route to branched-chain compounds.
1-decene or 1-octene
9-BBN, 3 mol% Cl Pd(dppf)
2
NaOH , THF
(aq)
cross-coupling proceeded without the need to protect
the free phenolic hydroxyl to give phenol 53. Esterifi-
cation with 2,4,5-trimethoxybenzoic acid gave ester 54,
which underwent base-induced Baker–Venkataraman
rearrangement to give diketone 55. Cyclisation31 gave
the flavone 56, which was then deprotected to give the
7-alkylflavonol 10 in good yield.
OMe
OBn
OAc
OAc
OAc
(i) BBr
3
2
2
R
O
R
O
O
CH Cl
2
2
OMe
(i) Ac O
2
DMAP
pyridine
1
1
OH
2
OR
2
R
R
O
1
n
1
n
47 R = C
48 R
H
10 21
, R = H 72%
2
49 R = C
H
10 21
, R = H 11%
2
Finally, the side chain of 8-nonyl-flavonoid 11 was
introduced by C-allylation using microwave-assisted32
Claisen rearrangement followed by chain extension
using alkene metathesis (Scheme 6).33 O-allylation of
acetophenone 57 followed by Claisen rearrangement
gave C-allylated acetophenone 58 with complete regio-
control.34 Aldol condensation with aldehyde 59 and
AFO oxidation of the resulting chalcone 60 produced
flavonol 61 in good yield. Chain extension by cross-
metathesis35 using first generation Grubbs catalyst36
yielded non-2-enyl derivative 62. Until recently, cross-
metathesis of alkenes had rarely been applied to target-
based synthesis because of the problem of homo-cou-
pling.37 However, it is becoming increasingly popular
since it tolerates a wide range of polar functionality, in
this case both a ketone and a phenolic hydroxyl group
are unaffected. Hydrogenation of alkene 62 gave
8-nonyl-flavonoid 63 and deprotection gave the desired
flavonol, following purification by recrystallisation of
the tetra-acetate derivative 64.
1
n
1
n
=
C H , R = Et 98%
50 R = C H , R = Et 18%
17
8
8
17
HCl, MeOH
OH
OH
OH
2
R
O
1
R
OR
O
1
n
2
7 R = C
H
10 21
, R = H 84%
2
1
n
8 R = C H , R = Et 63%
8
17
Scheme 4. Route to 6-alkyl myricetin analogues.
acid 66 and quantifying the thiobarbituric acid reactive
substances (TBARS e.g., 67) formed from oxidative-
degradation products such as malondialdehyde 65
(Scheme 7).1 Therefore, following the protocol of
Mitchell et al.9 (see experimental for details), each can-
didate compound 6–11 was incubated with hepatic
microsomes38 (membrane-bound vesicles that result
from the fragmentation of the endoplasmic reticulim of
liver cells) prior to 20 min of oxidative stress induced by
Fe(II)-ADP chelate and ascorbate. The oxidative dam-
age was then measured by TBARS formation: the less
TBARS formed, the better the membrane protectant.
Microsomes derived from vitamin E deficient rats were
employed as this increases discrimination of protective
effects and allows the ability of the candidate com-
pounds to suppress peroxidation to be compared to that
3. Inhibition of microsomal peroxidation
Free radical-mediated peroxidation of the polyunsatu-
rated fatty acids within the membrane lipid bilayer can
be initiated by addition of Fe(II)-ADP chelate and
ascorbate. The extent of peroxidation after a given
period of time can be measured by adding thiobarbituric

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
2083
HS
2 eq.
N
OH
(i) MeOCH CN, ZnCl
2
2
HO
OH
TfO
OH
O
HCl , Et O (48%)
(g)
2
N
S
N
OH HO
N
SH
(ii) Tf O, 2,6-lutidine
2
OMe
66
O
O
OH
CH Cl , 0 °C (87%)
N
51
52
2
2
N
H
H
H PO , H O
3
4
2
reflux 45 min
OH
OH
65
67
1-decene, 9-BBN,
1.8 mol% (Ph P) Pd
3
4
K PO , THF, 65 °C
Scheme 7.
3
4
n
n
ArCO H
C H
10 21
O CAr
2
C H
10 21
OH
O
2
EDCI, DMAP
CH Cl
2
2
OMe
OMe
of vitamin E 1 (d-a-tocopherol), which is the major lipid
O
53 76%
soluble antioxidant in biological membranes.39
54 Ar = 2,4,5-(MeO) C H 68%
3
6 2
LiHMDS,
THF, –20 °C
First, we investigated the effect of varying chain length
and chain methylation, while maintaining the same head
group and chain attachment site. The resulting TBARS
data from compounds 6 with vitamin E 1 and myricetin
2 as controls is presented in Figure 5. In the absence of
vitamin E and with no added candidate compound (-E),
lipid-peroxidation was greatest. Confirming previous
studies,9 increased peroxidation of microsomes from
vitamin E-deficient rats (-E) was strongly suppressed by
preincubation with d-a-tocopherol 1 but not with
myricetin 2. Compound 6a that lacks a 5-OH showed
similarly poor protection. However, when the 7-OH is
replaced by an alkyl chain, significant suppression of
lipid peroxidation is observed and this is strongly
dependent on chain-length. Compounds 6e–j with chain
lengths in the range C6–C12 protect the membrane well.
Indeed, 7-(3,7-dimethyloctyl)flavonoid 6g and 7-decyl-
flavonoid 6h are almost as effective as vitamin E 1 itself.
Methylation appears to improve membrane protection
at both ends of the range: thus, 7-(3,7-dimethyloc-
tyl)flavonoid 6g is a better protectant than 7-octyl-
flavonoid 6f, while 7-(3,7,11-trimethyldodecyl)flavonoid
6i is better than 7-dodecylflavonoid 6j. This argues
against a simple correlation of activity with lipophilicity,
although it is clear from Figure 6 that a C log P in the
range 4–10 is good for 7-alkylflavonoids 6 (note that
vitamin E 1 has a C log P of 12). Although slightly less
effective, straight-chain flavonoid 6h is a better drug
candidate than 6g as it is achiral.
n
n
C H
10 21
O
O
Ar
C
10 21
H
Me SiOTf
3
OMe
CH Cl
2
2
Ar
OMe
OH
O
O
56 Ar = 2,4,5-(MeO) C H 69%
55 Ar = 2,4,5-(MeO) C H 88%
3
6 2
3
6 2
BBr , CH Cl
2
3
2
0 °C
HO
OH
n
C
H
O
10 21
OH
OH
O
10 98%
Scheme 5. Synthesis of analogues with different head groups.
(i) CH =CHCH Br, K CO
OH
O
2
2
2
3
OH
O
acetone (97%)
(ii) µw (99%)
57
58
OMe
OHC
MeO
KOH
EtOH
OMe
59
OMe
OMe
OMe
OMe
OMe
Next we briefly investigated the effect of changing the
position of the alkyl chain and of changing the head
group (Figs. 7 and 8). 7-Decylflavonoid 6h, 6-decyl-
flavonoid 7 and 6-ethyl-7-octylflavonoid 8 have the same
head group and almost identical lipophilicities (C log P
values) but suppress lipid peroxidation to different
degrees. Thus, there appears to be an orientation effect
that means that there is an optimum chain length for a
particular site of attachment of the chain to a particular
head group. Compounds 9–11 have the 3,20,40,50-tetra-
hydroxy-flavone head group, which should act as a good
scavenger of ROS as it can form an orthoquinone, a
paraquinone, an extended orthoquinone and an
extended paraquinone when it donates two phenolic
hydrogen atoms. As expected flavonoid 9 is a poor
membrane protectant, but 7-decylflavonoid 10 is similar
to vitamin E in its potency. Again 8-alkylflavonoid 11
that has a similar lipophilicity to 7-alkylflavonoid 10 is
less effective at suppressing lipid peroxidation indicating
that orientation in the membrane is important.
H O
2
2
NaOH
MeOH
O
O
OH
OMe
OH
61 55%
60 98% O
C H
6
13
C H
6
13
3 mol% (Cy P) Cl Ru=CHPh
3
2
2
CH Cl
2
2
C H
6
13
OMe
OR
OR
OMe
OR
n
H
C
9
19
H , Pd/C
2
EtOAc
O
O
O
OMe
OH
OH
O
62 26%
63 R = Me
(i) BBr , CH Cl (98%)
(ii) Ac O, DMAP, py (38%)
2
3
2
2
64 R = Ac
HCl, MeOH
11 R = H 28%
Scheme 6. Synthesis of 8-alkyl flavonoid 11.

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C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
TBARS production: chain variation with myricetin-type head group
250
200
150
100
50
OH
2
4
5*
18
6
12
8
12*
8*
10
0
Compounds (flavonoids 6 ordered by chain length)
Figure 5. Note: The number above each bar indicates the chain length of the 7-alkyl chain (an asterisk implies that there are methyl groups attached
to the chain).
Scatter plot of TBARS and ClogP for compounds 6,
d-α-tocopherol and myricetin
180
2
160
6a
140
120
6b
6d
6e
6c
6k
100
80
60
40
20
0
6j
6f
6i
1
6h
6g
0
2
4
6
8
10
12
14
ClogP
Figure 6.
4. Conclusions
a-d-tocopherol would be required (Fig. 3). However,
our best straight chain flavonols 6h and 10 have a
shorter chain length. Interestingly, aligning the 40-OH
(which is believed to be the best hydrogen atom donor)
of flavonoids 6h and 10 with the OH of vitamin E gives
an excellent molecular match (Fig. 9). These are both
7-alkylflavonols and putting the chain at any other
position does not allow such a straight forward match.
We believe that this is clear evidence for the importance
of orientation within the membrane, both for our
compounds and vitamin E itself.
We have prepared novel flavonoids that combine the
radical-scavenging ability of myricetin with vitamin E’s
ability to embed itself in membranes. Unlike myricetin,
these potential therapeutic antioxidants effectively pro-
tect vitamin E-deficient microsomes from lipid peroxi-
dation. Membrane protection depends not only on
lipophilicity but also on orientation determined by chain
position and length. When we set out on this work, we
believed that an alkyl chain of similar length to that of

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
2085
TBARS for different headgroup and chain
substitution sites
250
200
150
100
50
0
Compounds
Figure 7.
Scatter plot of TBARS and ClogP for different
headgroup and chain substitution patterns
250
200
150
100
50
9
2
11
7
8
1
10
6h
0
0
2
4
6
8
10
12
14
ClogP
Figure 8.
5. Experimental
5.1. Microsomal peroxidation and TBARS
the reaction was stopped by addition of TCA (20%).
Following addition of thiobarbituric acid (0.67%),
samples were boiled for 30 min and TBARS measured
by HPLC.
Microsomes were prepared38 from the perfused livers of
male rats of the Rowett Hooded Lister strain main-
tained on a vitamin E-deficient semi-synthetic diet for 12
weeks by which time vitamin E concentrations were
below the limits of detection by HPLC. Incubations
were carried out as described in Mitchell et al.9 In brief,
protein concentration of the microsomal suspension was
adjusted to 10 mg/mL with 0.05 M potassium phosphate
buffer (pH 7.4) prior to incubation at 25 ꢁC for 30 min
with constant gentle mixing with ethanolic solutions of
the compounds to give a final concentration of 0.05 mM.
Peroxidation was then initiated by addition of Fe-ADP/
ascorbate (final concentrations: Ascorbate, 0.5 mM;
Fe(II), 0.006 mM; ADP, 2 mM) and after 20 min,
5.2. Synthetic chemistry
All reactions were carried out under an inert atmosphere
unless otherwise stated, using oven-dried or flame-dried
glassware. Solutions were added via syringe unless
otherwise stated. Reagents and solvents were obtained
from commercial suppliers and used without further
purification unless otherwise stated. Where dry solvents
were used: THF, was freshly distilled from sodium–
benzophenone; dichloromethane, toluene and pyridine
were distilled from CaH2 prior to use. Purification by
column chromatography was carried out using Fisher

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C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
5.4. 7-Ethyl-3-hydroxy-2-(3,4,5-trihydroxy-phenyl)-chro-
men-4-one 6b
In the same way, 18 (0.504 g, 1.4 mmol) added boron
tribromide (10 mmol) in dichloromethane (60 mL) gave
flavonol 6b (0.313 g, 70%) as a black solid. dH (400 MHz,
acetone-d6) 1.32 (t, 3H, 7.5 Hz), 2.81–2.89 (m, 2H), 7.33
(d, 1H, 8.0 Hz), 7.48 (s, 2H), 7.53 (s, 1H), 8.04 (d, 1H,
8.0 Hz). dC (100 MHz, DMSO-d6) 15.23, 28.53, 107.56,
116.64, 119.58, 121.58, 124.97, 125.15, 135.99, 138.19,
146.07, 146.13, 150.59, 154.89, 172.61. LRMS (FAB):
315 ([MþH]þ, 100%), 314 (Mþ, 73%). HRMS: calcd for
C17H15O6 315.0869 found, 315.0869.
5.5. 7-Butyl-3-hydroxy-2-(3,4,5-trihydroxy-phenyl)-chro-
men-4-one 6c
To a stirring suspension of 31c (19 mg, 0.04 mmol) in
methanol (1 mL) was added concentrated hydrochloric
acid (1 drop). The mixture was heated to reflux for 1 h
then cooled and water (10 mL) added. The precipitated
solid was collected, washed with water and dried under
vacuum to give 6c (12 mg, 94%) as a yellow powder. dH
(400 MHz, DMSO-d6) 0.92 (t, 3H, 7.3 Hz) 1.34 (m, 2H)
1.65 (m, 2H) 2.76 (t, 2H, 7.3 Hz) 7.29–7.31 (m, 3H) 7.48
(s, 1H) 8.00 (d, 1H, 8.1 Hz). LRMS (FAB): 343
([MþH]þ, 10%), 86 (100). HRMS: calcd for C19H19O6
343.1182 found, 343.1184.
Figure 9. Chem3D molecular mechanics (MM2) force field model of
d-a-tocopherol (top) and flavonoids 6h (middle) and 10 (bottom). The
model suggests that if the terminal carbon atoms of the alkyl chains
embed at the same depth in a membrane, then the dominant hydrogen
atom donor group of the flavonoids (40-OH) will occupy a similar
spatial distribution at the membrane surface as the tocopherol coun-
terpart.
5.6. 7-(4-Methyl-pentyl)-3-hydroxy-2-(3,4,5-trihydroxy-
phenyl)-chromen-4-one 6d
Matrex TM silica gel, mesh size 35–70 lm, as the sta-
tionary phase. Melting points are uncorrected. IR
spectra were recorded using a Nicolet Impact 410 FTIR
or JASCO FT/IR spectrometer. NMR spectra were
recorded using a Bruker DPX-400. All NMR J values
are given in Hz. Mass spectra were recorded on a JEOL
JMS700 spectrometer.
In the same way, 31d (11 mg, 0.02 mmol) and concen-
trated hydrochloric acid (1 drop) in methanol (0.75 mL)
gave 6d (7 mg, 93%) as a yellow powder. dH (400 MHz,
DMSO-d6) 0.86 (d, 6H, 6.6 Hz) 1.18–1.24 (m, 2H) 1.51–
1.67 (m, 3H) 2.74 (t, 2H, 7.5 Hz) 7.30–7.33 (m, 3H) 7.48
(s, 1H) 7.99 (d, 1H, 8.0 Hz) 8.80 (s, 1H) 9.22 (s, 3H). dC
(100 MHz, DMSO-d6) 22.82, 27.64, 28.26, 35.66, 38.29,
107.56, 117.24, 119.59, 121.56, 124.92, 125.54, 135.98,
138.20, 146.07, 146.07, 149.29, 154.81, 172.61. LRMS
(EI): 370 (Mþꢂ, 100%). HRMS: calcd for C21H22O6
370.1416 found, 370.1411.
5.3. 3,7-Dihydroxy-2-(3,4,5-trihydroxy-phenyl)-chromen-
4-one 6a
To a stirring solution of 17 (79 mg, 0.2 mmol) in di-
chloromethane (10 mL) under Ar at 0 ꢁC was added
boron tribromide in dichloromethane (1.0 M, 2 mL,
2 mmol). The mixture was warmed to room temperature
and then stirred for 22 h. The reaction mixture was then
cooled to 0 ꢁC and methanol (10 mL) added. The reac-
tion mixture was heated to reflux for 2 h, then concen-
trated in vacuo to give a yellow solid. Water (10 mL) was
added and sonicated then left to stand overnight then 6a
(55 mg, 99%) was collected as a yellow solid.40 dH
(400 MHz, d-6 pyridine) 6.82–6.87 (m, 2H) 7.96 (s, 2H)
8.07 (d, 1H, 10 Hz) dC (100 MHz, D5 pyridine) 97.18,
102.95, 109.65, 109.84, 121.59, 132.12, 133.67, 140.75,
142.27, 151.89, 158.06, 167.79. LRMS (FAB): 303 (Mþꢂ,
40%), 86 (100). HRMS: calcd for C15H11O7 303.0505
found, 303.0505.
5.7. 7-Hexyl-3-hydroxy-2-(3,4,5-trihydroxy-phenyl)-
chromen-4-one 6e
In the same way, 31e (24 mg, 0.04 mmol) and concen-
trated hydrochloric acid (1 drop) in methanol (1 mL)
gave 6e (14 mg, 85%) as a yellow powder. dH (400 MHz,
DMSO-d6) 0.86 (t, 3H, 6.0 Hz) 1.27–1.33 (m, 6H) 1.61–
1.68 (m, 2H) 2.75 (t, 2H, 7.5 Hz) 7.28–7.33 (m, 3H) 7.48
(s, 1H) 7.99 (d, 1H, 8.1 Hz) 8.79 (s, 1H) 9.21 (m, 3H). dC
(100 MHz, DMSO-d6) 14.29, 22.35, 28.60, 30.64, 31.39,
35.42, 107.56, 117.24, 119.57, 121.56, 124.91, 125.56,
135.98, 138.18, 146.06, 146.06, 149.298, 154.81, 172.62.
LRMS (EI): 370 (Mþꢂ, 100%). HRMS: calcd for
C21H22O6 370.1416 found, 370.1414.

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
2087
5.8. 7-Octyl-3-hydroxy-2-(3,4,5-trihydroxy-phenyl)-chro-
men-4-one 6f
(100 MHz, acetone-d6) 14.94, 20.29, 20.36, 23.33, 23.41,
25.43, 25.89, 29.05, 29.73, 29.92, 30.12, 30.31, 30.50,
30.69, 30.89, 31.06, 33.56, 33.86, 34.58, 38.40, 38.45,
38.47, 40.47, 60.98, 108.74, 118.40, 120.13, 123.54,
126.02, 126.64, 128.93, 129.47, 146.67, 151.26, 156.58,
172.04. LRMS (EI): 496 (Mþꢂ, 100%). HRMS: calcd for
C30H40O6 496.2825, obs. 496.2823.
In the same way, 31f (92 mg, 0.2 mmol) and concen-
trated hydrochloric acid (2 drops) in methanol (8 mL)
gave 6f (61 mg, 94%) as a yellow powder. dH (400 MHz,
DMSO-d6) 0.85 (t, 3H, 6.5 Hz) 1.24–1.30 (m, 10H) 1.63–
1.87 (m, 2H) 2.75 (t, 2H, 7.6 Hz) 7.28–7.34 (m, 3H) 7.48
(s, 1H) 7.99 (d, 1H, 8.2 Hz) 8.79 (s, 1H) 9.20 (s, 3H). dC
(100 MHz, DMSO-d6) 14.29, 22.41, 28.95, 29.13, 29.13,
30.66, 31.60, 35.42, 107.56, 117.24, 119.58, 121.57,
124.91, 125.53, 135.98, 138.19, 146.06, 146.06, 149.27,
154.80, 172.61. LRMS (EI): 398 (Mþꢂ, 7%) 134 (100).
HRMS: calcd for C23H26O6 398.1729 found, 398.1733.
5.12. 3-Hydroxy-2-(3,4,5-trihydroxy-phenyl)-7-dodecyl-
chromen-4-one 6j
In the same way as for flavonol 6a, a solution of 30j
(58 mg, 0.09 mmol) and boron tribromide (2.25 mmol) in
dichloromethane (4.75 mL) gave 6j as a waxy solid
(30 mg, 69%) following chromatography (silica gel,
dichloromethane–methanol, 9:1). dH (400 MHz, DMSO-
d6) 0.84 (t, 3H, 6.4 Hz) 1.18–1.34 (m, 18H) 1.62–1.71 (m,
2H) 2.75 (t, 2H, 7.4 Hz) 7.27–7.30 (m, 3H) 7.47 (s, 1H)
7.99 (d, 1H, 8.1 Hz). dC (100 MHz, DMSO-d6) 14.28,
22.42, 28.87, 29.02, 29.11, 29.24, 29.33, 30.63, 31.61,
35.41, 107.56, 117.24, 119.58, 121.57, 124.90, 125.53,
135.99, 138.20, 146.06, 149.27, 154.81, 172.62. LRMS
(EI): 454 (Mþꢂ, 28%), 44 (100). HRMS: calcd for
C27H34O6 454.2355 found, 454.2353. LRMS (FAB): 455
([MþH]þ, 55%), 56 (100). HRMS: calcd for C27H35O6
455.2434 found, 455.2438.
5.9. 7-(3,7-Dimethyl-octyl)-3-hydroxy-2-(3,4,5-trihy-
droxy-phenyl)-chromen-4-one 6g
In the same way as for flavonol 6a, a solution of 38
(28 mg, 0.05 mmol) and boron tribromide (0.7 mmol) in
dichloromethane (1.7 mL) gave 6g (8 mg, 37%) as a
yellow solid following chromatography (silica gel, di-
chloromethane–methanol, 19:1). dH (400 MHz, acetone-
d6) 0.73 (d, 6.6 Hz, 6H) 0.86 (d, 7.6 Hz, 3H) 1.00–1.11
(m, 4H) 1.15–1.30 (m, 4H) 1.36–1.47 (m, 2H) 2.61–2.82
(m, 2H) 7.19 (dd, 1H, 1.1 and 7.0 Hz) 7.35 (s, 2H) 7.39
(s, 1H) 7.90 (d, 1H, 8.0 Hz). dC (100 MHz, acetone-d6)
20.26, 23.28, 23.36, 25.78, 29.03, 33.58, 34.54, 38.17,
39.52, 40.40, 108.63, 118.41, 120.19, 123.60, 125.98,
126.55, 136.38, 138.99, 146.13, 146.66, 151.20, 156.60,
173.66. LRMS (EI): 426 (Mþꢂ, 100%). HRMS: calcd for
C25H30O6 426.2042 found, 426.2043.
5.13. 3-Hydroxy-7-octadecyl-2-(3,4,5-trihydroxy-phen-
yl)-chromen-4-one 6k
In the same way as for flavonol 6a, a solution of 30k
(0.455 g, 0.6 mmol) and boron tribromide (6 mmol) in
dichloromethane (31 mL) gave 6k (0.325 g, 99%) as a
yellow solid. dH (400 MHz, DMSO-d6) 0.84 (t, 3H,
6.2 Hz) 1.18–1.33 (m, 30H) 1.62–1.70 (m, 2H) 2.73 (d,
2H, 6.9 Hz) 7.23–7.30 (m, 3H) 7.46 (s, 1H) 7.99 (d, 1H,
8.1 Hz) 9.18 (s, 3H). dC (100 MHz, DMSO-d6) 14.28,
22.43, 28.92, 29.04, 29.14, 29.26, 29.33, 30.67, 31.63,
35.43, 107.56, 117.22, 119.59, 121.58, 124.90, 125.48,
135.97, 138.20, 146.06, 146.10, 149.22, 154.81, 172.59.
LRMS (FAB): 539 ([MþH]þ, 100%). HRMS: calcd for
C33H47O6 539.3373 found, 539.3367.
5.10. 7-Decyl-3-hydroxy-2-(3,4,5-trihydroxy-phenyl)-
chromen-4-one 6h
In the same way as for flavonol 6a, a solution of 30h
(0.335 g, 0.5 mmol) and boron tribromide (5 mmol) in
dichloromethane (30 mL) gave 6h (0.213 g, 95%) as a
yellow solid. dH (400 MHz, acetone-d6) 0.88 (m, 3H)
1.26–1.47 (m, 14H) 1.75 (m, 2H) 2.78 (m, 2H) 7.34 (d,
1H, 8.0 Hz) 7.49 (s, 2H) 7.54 (s, 1H) 7.87 (br s, 1H) 7.93
(br s, 1H) 8.05 (d, 1H, 8.0 Hz) 8.19 (s, 2H). dC (100 MHz,
DMSO-d6) 14.28, 22.43, 28.90, 29.02, 29.14, 29.28,
29.30, 30.64, 31.62, 35.42, 107.56, 117.23, 119.59,
121.58, 124.90, 125.52, 135.98, 138.20, 146.06, 146.11,
149.25, 154.81, 172.60. LRMS (FAB): 427 ([MþH]þ,
100%). HRMS: calcd for C25H31O6 427.2121 found,
427.2122.
5.14. 6-Decyl-3-hydroxy-2-(3,4,5-trihydroxy-phenyl)-
chromen-4-one 7
In the same way as for 31d, a solution of 47 (0.369 g,
0.7 mmol) and boron tribromide (3.4 mmol) in dichloro-
methane (23.4 mL) gave 7 (0.318 g) as a brown oil. A
solution of crude of 7 (0.318 g, 0.7 mmol), N,N-di-
methyl-4-aminopyridine (4 mg) and acetic anhydride
(0.42 mL, 4 mmol) in pyridine (3.6 mL) was then stirred
for 3 h to give 49 (58 mg, 13%) as a grey solid after
recrystallisation in methanol. In the same way as for 6c,
a solution of acetate 49 (58 mg, 0.1 mmol) and concen-
trated hydrochloric acid (5 drops) in methanol (5 mL)
gave 7 (35 mg, 84%) as a yellow solid. dH (400 MHz,
DMSO-d6) 1.25 (t, 3H, 6.4 Hz) 1.62–1.72 (m, 14H) 1.99–
2.04 (m, 2H) 3.13 (t, 2H, 7.5 Hz) 7.72 (s, 2H) 7.98–8.04
(m, 2H) 8.28 (s, 1H) 9.21 (s, 1H) 9.61 (s, 3H). dC
5.11. 3-Hydroxy-2-(3,4,5-trihydroxy-phenyl)-7-(3,7,11-
trimethyl-dodecyl)-chromen-4-one 6i
In the same way as for flavonol 6a, a solution of 39
(48 mg, 0.08 mmol) and boron tribromide (2.5 mmol) in
dichloromethane (5 mL) gave 6i (33 mg, 87%) as a waxy
solid following chromatography (silica gel, chloroform–
methanol, 9:1). dH (400 MHz, acetone-d6) 0.67–1.61 (m,
29H), 2.52–2.75 (m, 2H), 6.91–6.98 (m, 1H), 7.18 (d,
8.1 Hz, 1H), 7.35–7.38 (m, 2H), 7.91 (d, 1H, 8.2 Hz). dC

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C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
(100 MHz, DMSO-d6) 14.28 (CH3) 22.43 (CH2) 28.86
(CH2) 29.01 (CH2) 29.15 (CH2) 29.15 (CH2) 29.30 (CH2)
31.20 (CH2) 31.62 (CH2) 34.75 (CH2) 107.59 (CH)
118.27 (CH) 121.31 (C) 121.54 (C) 123.50 (CH) 134.30
(CH) 136.04 (C) 138.30 (C) 138.97 (C) 146.06 (C) 146.34 (C)
153.14 (C) 172.69 (C). LRMS (FAB) 427 ([MþH]þ, 100%).
HRMS: calcd for C25H31O6 427.2122 found, 427.2123.
146.10, 146.88, 153.54, 173.09. LRMS (FAB): 413
([MþH]þ, 1%), 86 (100%).
5.18. 40-Benzyloxy-20-hydroxy-acetophenone 12
To a stirring suspension of 20,40-dihydroxy-acetophe-
none (10.02 g, 66 mmol) and potassium carbonate
(9.93 g, 72 mmol) in acetone (250 mL) was added benzyl
bromide (7.9 mL, 66 mmol). The reaction was heated to
reflux for 18 h and then filtered and concentrated in
vacuo to give a pink solid. This was recrystallised from
ethanol to give 12 (27 g, 87%) as a pink solid.41 dH
(400 MHz, CDCl3) 2.55 (s, 3H) 5.09 (s, 2H) 6.49–6.53
(m, 2H) 7.31–7.43 (m, 5H) 7.63 (dd, 1H, 2 and 8 Hz)
12.72 (s, 1H). dC (100 MHz, CDCl3) 26.62, 70.61,
102.27, 108.53, 114.49, 127.92, 128.71, 129.10, 132.73,
136.27, 165.58, 202.98. LRMS (EI): 242 (Mþꢂ, 73%) 91
(Bnþ, 100). HRMS: calcd for C15H14O3 242.0943 found,
242.0943.
5.15. 7-Ethyl-3-hydroxy-6-octyl-2-(3,4,5-trihydroxy-phe-
nyl)-chromen-4-one 8
In the same way as for flavonol 6c, 50 (11 mg,
0.02 mmol) and concentrated hydrochloric acid (1 drop)
in methanol (0.5 mL) gave 8 (5 mg, 63%) as a yellow
powder. dH (400 MHz, DMSO-d6) 0.91 (m, 3H) 1.29–
1.40 (m, 13H) 1.61–1.65 (m, 2H) 2.75–2.88 (m, 4H) 7.35
(s, 2H) 7.49 (s, 1H) 7.86 (s, 1H) 8.81 (s, 1H) 9.16–9.30
(m, 3H). dC (100 MHz, DMSO-d6) 14.30, 14.70, 22.43,
25.33, 29.00, 29.18, 29.34, 30.71, 31.62, 31.69, 108.53,
116.80, 119.40, 121.66, 123.96, 135.91, 137.42, 138.14,
146.06, 146.06, 148.83, 153.38, 172.52. LRMS (FAB):
427 ([MþH]þ, 100%). HRMS: calcd for C25H31O6
427.2121 found, 427.2125.
5.19. 40-Ethyl-20-hydroxy-acetophenone 13
To
a stirring solution of 3-ethyl-phenol (9.95 g,
81 mmol) and triethylamine (14 mL, 100 mmol) in
dichloromethane (100 mL) under nitrogen at 0 ꢁC was
added acetyl chloride (7 mL, 98 mmol) dropwise. The
reaction was allowed to stir at room temperature for 3 h
and then washed with saturated aqueous sodium bicar-
bonate solution (100 mL). The organic layer was then
dried (MgSO4) and concentrated in vacuo to give
3-ethyl-phenyl acetate (13.3 g, 97%) as a pale yellow
solid.42 dH (400 MHz, CDCl3) 1.21 (t, 3H, 7.6 Hz) 2.28
(s, 3H) 2.65 (q, 2H, 7.6 Hz) 6.88–6.92 (m, 2H) 7.06 (d,
1H, 7 Hz) 7.25–7.30 (m, 1H). dC (100 MHz, CDCl3)
15.64, 21.58, 29.01, 119.04, 121.31, 125.84, 129.60,
146.35, 151.09, 170.06. To aluminium chloride (23 g,
172 mmol) was added 3-ethyl-phenyl acetate (14.82 g,
90 mmol) dropwise. The mixture was heated to 130 ꢁC
for 150 min then cooled. HCl (2 M, 50 mL) was added
slowly and the mixture stirred for 45 min, then poured
into 2 M HCl (85 mL) and extracted into diethyl ether
(2x). The combined organic layers were washed with
water, 1% sodium carbonate, water then dried (MgSO4)
and concentrated in vacuo to give 13 (10.8 g, 97%) as a
brown oil.43 dH (400 MHz, CDCl3) 1.81 (t, 3H, 7.6 Hz)
2.60–2.63 (m, 5H) 6.74 (dd, 1H, 1.5 and 8 Hz) 6.79 (br s,
1H) 7.63 (d, 1H, 8 Hz) 12.28 (s, 1H). dC (100 MHz,
CDCl3) 15.12, 26.87, 29.53, 117.55, 118.12, 119.46,
131.09, 154.62, 163.01, 204.28. LRMS (EI): 164 (Mþꢂ,
30%) 149 ([MꢁMe]þ, 100). HRMS: calcd for C10H12O2
164.0837 found, 164.0836.
5.16. 7-Decyl-3,20,40,50-tetrahydroxy-flavone 10
In the same way as for flavonol 6a, a solution of fla-
vone 56 (392 mg, 0.81 mmol) and boron tribromide
(4.06 mmol) in dry dichloromethane (7 mL) gave flavo-
nol 10 as a red/brown amorphous solid (338 mg, 98%).
mp decomp >90 ꢁC. dH (400 MHz: DMSO-d6): 0.84 (3H,
t, J 6.7 Hz, CH2CH3), 1.22–1.28 (14H, m, 7 · CH2),
1.60–1.64 (2H, m, ArCH2CH2), 2.72 (2H, t, J 7.5 Hz,
ArCH2CH2), 6.43 (1H, s, H-30), 6.87 (1H, s, H-60), 7.28
(1H, d, J 8.2 Hz, H-6), 7.39 (1H, s, H-8), 8.00 (1H, d, J
8.2 Hz, H-5). dC (100 MHz: DMSOd6): 14.28 (CH3),
22.42 (CH2), 28.91 (CH2), 29.01 (CH2), 29.13 (CH2),
29.30 (CH2), 29.31 (CH2), 30.70 (CH2), 31.62 (CH2),
35.37 (CH2), 104.55 (CH), 108.65 (C), 116.77 (CH),
117.45 (CH), 120.26 (C), 124.94 (CH), 125.38 (CH),
138.07 (C), 138.28 (C), 148.14 (C), 148.90 (C), 149.05
(C), 149.10 (C), 155.43 (C), 172.59 (C). m=z (FAB): 427.4
[(MþH)þ, 100%]. Found: 427.2120 C25H31O6 requires
[(MþH)þ] 427.2121. tmax (golden gate)/cmꢁ1: 3226
(OH), 2919 (CH2), 1558 (C@O).
5.17. 8-Nonyl-3-hydroxy-2-(2,4,5-trihydroxy-phenyl)-
chromen-4-one 11
In the same way as for flavonol 6c, 64 (96 mg,
0.17 mmol) and concentrated hydrochloric acid (3
drops) in methanol (5 mL) gave 11 (19 mg, 28%) as a
yellow powder following crystallisation in chloroform.
dH (400 MHz, DMSO-d6) 0.83 (t, 3H, 6.7 Hz) 1.17–1.29
(m, 12H) 1.61–1.65 (m, 2H) 2.84 (t, 2H, 7.4 Hz) 7.01 (s,
1H) 7.37 (t, 1H, 1.6 Hz) 7.60 (d, 1H, 7.1 Hz) 7.96 (dd,
1H, 1.4 and 8.0 Hz) 9.45 (s, 1H) 9.65 (s, 1H). dC
(100 MHz, DMSO-d6) 14.31, 22.42, 28.94, 28.98, 29.02,
29.07, 29.26, 29.43, 31.61, 101.53, 109.72, 114.69,
122.27, 122.78, 124.31, 132.25, 133.39, 138.01, 138.79,
5.20. 1-(4-Benzyloxy-2-hydroxy-phenyl)-3-(3,4,5-trimeth-
oxy-phenyl)-propenone 15
To a stirring suspension of 12 (0.617 g, 2.5 mmol) and
3,4,5-trimethoxybenzaldehyde (0.501 g, 2.6 mmol) in
ethanol (25 mL) was added potassium hydroxide
(0.384 g, 6.9 mmol). The reaction mixture was stirred for
144 h then acidified (2 N HCl) and extracted with ethyl
acetate (2x). The combined organic layers were then

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
2089
washed with brine, 10% sodium bisulfite solution (3x)
and then saturated aqueous sodium bicarbonate again.
The organic layer was then dried (MgSO4) and con-
centrated in vacuo to give a yellow solid (31 g). This
solid was heated in ethanol, and the undissolved solid,
15 (0.244 g, 23%), collected. This was used without fur-
ther purification.
water (200 mL) and saturated aqueous sodium bicar-
bonate solution (200 mL). The organic layer was then
dried (MgSO4) and concentrated in vacuo to give
3-iodo-phenyl acetate44 (30.20 g, 97%) as a pale yellow
solid. mp 32.4–34.6 ꢁC. IR (film) 3062, 1765, 1578, 1468,
1369, 1201, 1011, 924 cmꢁ1. dH (400 MHz, CDCl3) 2.29
(s, 3H) 7.06–7.12 (m, 2H) 7.46 (m, 1H) 7.55–7.58 (m,
1H). dC (100 MHz, CDCl3) 20.99, 93.50, 121.14, 130.66,
130.77, 134.94, 150.89, 168.99. LRMS (EI) 262 (Mþꢂ,
34%) 220 (Mþꢂ–CH2CO, 100). HRMS: calcd for
C8H7O2I, 261.9491; found, 261.9489. To a stirring
solution of 3-iodo phenyl acetate (32.20 g, 123 mmol) in
chlorobenzene (250 mL) under nitrogen was added alu-
minium chloride (31.00 g, 232 mmol). The reaction
mixture was heated to 140 ꢁC for 90 h then allowed to
cool. The reaction mixture was poured onto ice/water
and then filtered, and the residue washed with dichlo-
romethane. The filtrate was then extracted with dichlo-
romethane and the combined organic layers extracted
with 10% potassium hydroxide solution (3 · 100 mL).
The combined aqueous layers were then acidified with
6 N hydrochloric acid and extracted with dichlorome-
thane (3 · 75 mL). This organic layer was then dried
(MgSO4) and concentrated in vacuo to give 20 (22.3 g,
69%) as a brown solid.18 mp 51.5–52 ꢁC. IR (GG) 1699,
1558, 1205 cmꢁ1. dH (400 MHz, CDCl3). 2.60 (s, 3H)
7.26–7.28 (m, 2H) 7.42 (s, 1H) 12.26 (s, 1H). dC
(100 MHz, CDCl3) 26.60, 103.77, 118.99, 127.83, 128.33,
131.25, 162.19, 204.21. LRMS (CI): 263 (MþHþ, 98%)
262 (Mþ, 100). HRMS: calcd for C8H8O2I (MþH),
262.9569 found, 262.9568.
5.21. 1-(4-Ethyl-2-hydroxy-phenyl)-3-(3,4,5-trimethoxy-
phenyl)-propenone 16
In the same way, a solution of ketone 13 (5.00 g,
30 mmol), 3,4,5-trimethoxy benzaldehyde (7.20 g,
37 mmol) and potassium hydroxide (4.21 g, 7.5 mmol) in
ethanol (145 mL) were stirred for 200 h and gave chal-
cone 16 (9.62 g, 92%) as a brown tar following work-up
and solvent evaporation. LRMS (EI): 342 (Mþꢂ, 100%).
HRMS: calcd for C20H22O5 342.1467 Found, 342.1467.
5.22. 7-Benzyloxy-3-hydroxy-2-(3,4,5-trimethoxy-phen-
yl)-chromen-4-one 17
To a stirring solution of 15 (0.15 g, 0.4 mmol) in meth-
anol (5 mL), THF (3 mL) and 16% aqueous sodium
hydroxide solution (0.5 mL, 2 mmol) at 0 ꢁC was added
15% aqueous hydrogen peroxide (0.5 mL, 0.5 mmol)
dropwise. The solution was stirred at 0 ꢁC for the 1 h
then sealed and place in a refrigerator for 46 h. The
reaction was acidified (2 N HCl) and extracted into di-
chloromethane (2x). The combined organic layers was
then dried (MgSO4) and concentrated to give a yellow
solid, which was recrystallised from ethanol to give 17
(84 mg, 54%) as a yellow solid. dH (400 MHz, CDCl3)
3.94 (s, 3H) 3.97 (s, 6H) 5.20 (s, 2H) 7.05–7.09 (m, 2H)
7.26 (s, 2H) 7.38–7.50 (m, 5H) 8.15 (d, 1H, 9 Hz). dC
(100 MHz, CDCl3) 56.73, 61.39, 71.04, 101.46, 105.62,
115.56, 127.29, 127.98, 128.89, 129.18, 135.99, 138.14,
144.73, 153.61, 157.87, 164.11, 173.27. LRMS (EI): 434
(Mþꢂ, 63%) 343.1 ([MꢁBn]þ, 100). HRMS: calcd for
C25H22O7 434.1366 found, 434.1365.
5.25. 4-Benzyloxy-3,5-dimethoxy-benzaldehyde 21
To a stirring suspension of syringaldehyde (25.19 g,
138 mmol) and potassium carbonate (38.14 g, 276 mmol)
in N,N-dimethyl formamide (500 mL) was added benzyl
bromide (20 mL, 168 mmol). The reaction was stirred for
25 h, then poured into dichloromethane. The organic
solvent was washed with water (5x) then dried (MgSO4)
and concentrated in vacuo to give a pink oil. This was
recrystallised from hexane to give 21 (32.9 g, 87%). Mp
56–57 ꢁC (lit.45 59–60 ꢁC) dH (400 MHz, CDCl3) 3.92 (s,
6H) 5.15 (s, 2H) 7.13 (s, 2H) 7.28–7.38 (m, 3H) 7.48 (dd,
2H, 7.4 and 1.5 Hz) 9.91 (s, 1H). dC (100 MHz, CDCl3)
56.64, 75.43, 105.09, 128.48, 128.62, 128.80, 132.29,
137.59, 142.79, 154.38, 191.49. LRMS (EI): 272 (Mþꢂ,
17%), 91.1 (Bnþ, 100). HRMS: calcd for C16H16O4
272.1049, obs. 272.1053.
5.23. 7-Ethyl-3-hydroxy-2-(3,4,5-trimethoxy-phenyl)-
chromen-4-one 18
In the same way, a solution of 16 (1.60 g, 4.7 mmol),
sodium hydroxide (6.5 mL of a 16% solution in water,
26 mmol) and hydrogen peroxide (6.5 mL of a 15%
solution in water, 29 mmol) in methanol (45 mL) gave 18
(0.777 g, 47%) as a yellow solid after 26 h at 0 ꢁC. This
was used without further purification.
5.26. 20-Hydroxy-40-iodo-3,4,5-trimethoxy-chalcone 22
In the same way as for the synthesis of chalcone 15, a
solution of ketone 20 (0.55 g, 2.1 mmol) and 3,4,5-tri-
methoxybenzaldehyde (0.66 g, 3.4 mmol) and potassium
hydroxide (0.25 g, 4.5 mmol) in ethanol (10 mL) was
stirred for 119 h to give a yellow solid (1.17 g) following
work-up and solvent removal. This solid was heated in
methanol, and the undissolved solid collected. The fil-
trate was concentrated and then heated in methanol
5.24. 2-Hydroxy-4-iodo-acetophenone 20
To a stirring solution of 3-iodophenol 19 (26.06 g,
118 mmol), triethylamine (18 mL, 129 mmol) and N,N-
dimethyl-4-amino-pyridine (0.62 g, 5 mmol) in dichlo-
romethane (250 mL) under nitrogen was added acetyl
chloride (9 mL, 127 mmol) dropwise over 5 min. The
reaction was allowed to stir for 2 h and then washed with

2090
C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
again. More undissolved solid was collected. Undis-
solved solid is 22 (0.50 g, 54%). mp 140.5–140.9 ꢁC. IR
(GG) 1716, 1684 cmꢁ1. dH (400 MHz, CDCl3) 3.92 (s,
3H) 3.94 (s, 6H) 6.88 (s, 2H) 7.30 (dd, 1.6 and 8 Hz, 1H)
7.42–7.47 (m, 2H) 7.59 (d, 8 Hz, 1H) 7.86 (d, 15 Hz, 1H)
12.89 (s, 1H). dC (100 MHz, CDCl3) 56.27, 61.02, 103.70,
103.70, 106.05, 118.68, 119.32, 128.01, 128.13 129.80,
130.13, 146.27, 153.52, 163.38, 193.15. LRMS (EI): 440
(Mþꢂ, 100%). HRMS: calcd for C18H17O5I, 440.0121,
found, 440.0118.
LRMS (EI): 544 (Mþꢂ, 30%), 453 (MþꢂꢁBnÆ, 47%), 425
(100). HRMS: calcd for C25H21O6I, 544.0383 found,
544.0385.
5.29. 3-Benzyloxy-7-iodo-2-(4-benzyloxy-3,5-dimethoxy-
phenyl)-chromen-4-one 25
In the same way as for flavonol 15, a solution of 23
(0.85 g, 1.6 mmol), sodium hydroxide (2.2 mL of a 16%
solution in water, 8.8 mmol), and hydrogen peroxide
(2.2 mL of a 15% solution in water, 9.7 mmol) in meth-
anol (17 mL) gave 3-hydroxy-7-iodo-(4-benzyloxy-3,5-
dimethoxyphenyl)-chromen-4-one (0.84 g, 96%) as a
yellow solid after 24 h at 0 ꢁC, work-up and trituration
with ethanol. Mp 169–171 ꢁC. dH (400 MHz, CDCl3)
3.93 (s, 6H) 5.12 (s, 2H) 7.04 (br s, 1H) 7.28–7.38 (m,
3H) 7.49–7.52 (m, 4H) 7.72 (dd, 1H, 1.4 and 8.4 Hz) 7.92
(d, 1H, 8.4 Hz) 8.03 (d, 1H 1.4 Hz). LRMS (EI): 530.0
(Mþꢂ, 22%), 439 (MþꢂꢁBnÆ, 100). HRMS: calcd for
C24H19IO6 530.0226, obs. 530.0234. A stirring suspen-
sion of 3-hydroxy-7-iodo-(4-benzyloxy-3,5-dimethoxy-
phenyl)-chromen-4-one (5 g, 9 mmol), potassium
carbonate (6.2 g, 45 mmol), potassium iodide (0.64 g,
4 mmol) and benzyl chloride (1.7 mL, 15 mmol) in ace-
tone (150 mL) under nitrogen was heated to reflux for
19 h. The reaction was filtered and the filtrate concen-
trated in vacuo to give an cream solid. This solid was
recrystallised from isopropanol to give 25 (5.77 g, 99%)
as a white solid. Mp 131–133 ꢁC. dH (400 MHz, CDCl3)
3.73 (s, 6H) 5.11 (s, 2H) 7.21 (s, 2H) 7.26–7.37 (m, 8H)
7.49 (d, 2H, 7 Hz) 7.73 (d, 1H, 8 Hz) 7.97 (m, 2H). dC
(100 MHz, CDCl3) 56.51, 74.87, 75.44, 100.10, 106.78,
123.93, 126.10, 127.40, 127.51, 128.60, 128.68, 128.69,
128.88, 129.27, 134.42, 136.93, 137.83, 139.59, 140.46,
153.60, 155.21, 156.22, 174.97. LRMS (EI): 620 (Mþꢂ,
20%), 91 (Bnþ, 100). HRMS: calcd for C31H25IO6
620.0696, obs. 620.0695.
5.27. 20-Hydroxy-40-iodo-4-benzyloxy-3,5-dimethoxy-
chalcone 23
In the same way, a solution of ketone 20 (0.73 g,
2.8 mmol), aldehyde 21 (0.911 g, 3.3 mmol) and potas-
sium hydroxide (0.42 g, 7.5 mmol) in ethanol (10 mL) was
stirred for 46 h to give a brown oil following work-up and
solvent removal. Chalcone 23 (1.06 g, 74%) was crystal-
lised from methanol as yellow crystals. mp 123.6–
124.6 ꢁC (MeOH). dH (400 MHz, CDCl3) 3.89 (s, 6H) 5.09
(s, 2H) 6.85 (s, 2H) 7.25–7.49 (m, 7H) 7.57 (d, 1H, 8.5 Hz)
7.83 (d, 1H, 15 Hz) 12.91 (s, 1H). dC (100 MHz, CDCl3)
56.67, 75.53, 104.10, 106.54, 119.06, 119.76, 128.42,
128.55, 128.61, 128.84, 130.36, 130.55, 137.79, 140.34,
146.75, 154.26, 163.81, 193.58. LRMS (EI): 516 (Mþꢂ,
42%), 425.0 ([MꢁBn]þ, 100) 91.0 (Bnþ). HRMS: calcd
for C24H21IO5 516.0434, obs. 516.0433.
5.28. 3-Benzyloxy-7-iodo-2-(3,4,5-trimethoxyphenyl)-
chromen-4-one 24
In the same way as for flavonol 15, a solution of 22
(0.165 g, 0.4 mmol), sodium hydroxide (0.6 mL of a 16%
solution in water, 2.4 mmol), and hydrogen peroxide
(0.6 mL of a 15% solution in water, 2.6 mmol) in meth-
anol (4.4 mL) gave 3-hydroxy-7-iodo-2-(3,4,5-trimeth-
oxyphenyl)-chromen-4-one (0.130 g, 76%) as a yellow
solid after 24 h at 0 ꢁC. Mp 151–153 ꢁC. IR (GG) 3749,
1734, 1265, 740 cmꢁ1. dH (400 MHz, CDCl3) 3.95 (s, 3H)
3.97 (s, 6H) 7.03 (br s, 1H) 7.51 (s, 2H) 7.72 (dd, 1.4 and
8 Hz, 1H) 7.93 (d, 8 Hz, 1H) 8.05 (d, 1.4 Hz, 1H). dC
(100 MHz, CDCl3) 56.30, 61.01, 100.11, 105.37, 119.95,
125.79, 126.52, 127.35, 133.87, 138.33, 140.16, 144.70,
153.23, 154.78, 172.83. LRMS (EI): 454 (Mþꢂ, 100%).
HRMS: calcd for C18H15O6I, 453.9913, found, 453.9916.
A stirring suspension of 3-hydroxy-7-iodo-2-(3,4,5-tri-
methoxyphenyl)-chromen-4-one (0.257 g, 0.6 mmol),
potassium carbonate (1.48 g, 11 mmol), potassium
iodide (60 mg, 0.3 mmol) and benzyl chloride (0.16 mL,
1.3 mmol) in acetone (12 mL) under nitrogen was heated
to reflux for 1 h. The reaction was filtered and the filtrate
concentrated in vacuo to give an orange solid. This solid
was recrystallised from isopropanol to give 24 (0.270 g,
88%) as a white solid. Mp 142 ꢁC. IR (GG) 1734, 1558,
1265, 744 cmꢁ1. dH (400 MHz, CDCl3) 3.79 (s, 6H) 3.95
(s, 3H) 5.15 (s, 2H) 7.28–7.30 (m, 5H) 7.35–7.37 (m, 2H)
7.76 (d, 8 Hz, 1H) 7.99–8.01 (m, 2H). dC (100 MHz,
CDCl3) 56.11, 60.97, 74.49, 99.72, 106.33, 123.52,
125.57, 126.99, 127.10, 128.28, 128.83, 134.03, 136.54,
140.98, 141.23, 152.86, 154.80, 155.73, 174.56.
5.30. 3-Benzyloxy-7-butyl-2-(3,4,5-trimethoxy-phenyl)-
chromen-4-one 29c
To a stirring solution of n-butane boronic acid 26
(0.133 g, 1.3 mmol) and dichloropalladium (dppf)
(50 mg) in tetrahydrofuran (7 mL) and 3 M NaOH
solution (1.1 mL) was added 24 (0.500 g, 0.9 mmol)
added and the reaction heated to reflux for 21 h. The
reaction was then quenched with water and diethyl
ether. The organic layer was collected and the aqueous
layer extracted with diethyl ether (2x). The combined
organic layers were washed with 1 M HCl and brine then
dried (MgSO4) and concentrated in vacuo to give a
yellow oil. A silica plug (dichloromethane) yielded 29c
(99 mg, 23%) as an orange oil. LRMS (EI): 474 (Mþꢂ,
15%), 299 (100). HRMS: calcd for C29H30O6 474.2042
found, 474.2041.
5.31. 3-Benzyloxy-7-(4-methyl-pentyl)-2-(3,4,5-trimeth-
oxy-phenyl)-chromen-4-one 29d
To a stirring solution of 4-methyl-pent-1-ene (0.110 g,
1.3 mmol) in tetrahydrofuran (2 mL) under argon at 0 ꢁC
was added 9-BBN in tetrahydrofuran (0.5 M, 2.7 mL,

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
2091
1.4 mmol). The reaction was allowed to warm to room
5.34. 3-Benzyloxy-2-(4-benzyloxy-3,5-dimethoxy-phen-
yl)-7-decyl-chromen-4-one 30h
temperature then stirred for 6 h then 24 (0.499 g,
0.9 mmol) in tetrahydrofuran (5 mL), 3 M NaOH solu-
tion (1.1 mL) and dichloropalladium (dppf) (28 mg,
0.03 mmol) were added and the reaction heated to reflux
for 14 h. The reaction was then quenched with water and
diethyl ether. The organic layer was collected and the
aqueous layer extracted with diethyl ether (2x). The
combined organic layers were washed with 1 M HCl and
brine then dried (MgSO4) and concentrated in vacuo to
give a yellow oil. A silica plug (dichloromethane) yielded
29d (0.197 g, 49%) as a yellow oil. LRMS (EI): 502 (Mþꢂ,
6%), 299 (100). HRMS: calcd for C31H34O6 502.2355
found, 502.2358.
In the same way, a solution of 1-decene (0.176 g,
1.3 mmol) and 9-BBN (1.35 mmol) in tetrahydrofuran
(4.7 mL) was stirred for 6 h, then 25 (0.560 g, 0.9 mmol)
in tetrahydrofuran (5 mL), 3 M aqueous NaOH solution
(1.1 mL) and dichloropalladium (dppf) (27 mg) were
added and the mixture was heated to reflux for 15 h.
Work-up and column chromatography (silica gel,
dichloromethane) gave 30h (0.339 g, 59%) as a pale
yellow oil. dH (400 MHz, CDCl3) 0.88 (t, 3H, 7 Hz) 1.26–
1.42 (m, 14H) 1.65–1.74 (m, 2H) 2.75 (t, 2H, 7 Hz) 3.74
(s, 6H) 5.10 (s, 2H) 5.11 (s, 2H) 7.20–7.38 (m, 12H) 7.49–
7.51 (m, 2H) 8.18 (d, 1H, 8 Hz). dC (100 MHz, CDCl3)
14.11, 22.68, 29.27, 29.31, 29.46, 29.55, 29.60, 31.01,
31.89, 36.13, 56.14, 74.46, 75.06, 106.41, 117.00, 122.09,
125.60, 125.72, 126.31, 128.00, 128.17, 128.21, 128.26,
128.51, 128.90, 136.82, 137.52, 138.24, 139.99, 149.82,
153.16, 155.37, 155.60, 175.01. LRMS (FAB): 635
([MþH]þ, 25%) 91.5 (Bnþ, 100%). HRMS: calcd for
C41H47O6 635.3373 found, 635.3370.
5.32. 3-Benzyloxy-7-hexyl-2-(3,4,5-trimethoxy-phenyl)-
chromen-4-one 29e
In the same way, a solution of 1-hexene (0.109 g,
1.3 mmol) and 9-BBN (1.35 mmol) in tetrahydrofuran
(4.7 mL) was stirred for 8 h then 24 (0.505 g, 0.9 mmol)
in tetrahydrofuran (5 mL), 3 M aqueous NaOH solution
(1.1 mL) and dichloropalladium (dppf) (32 mg) were
added and the mixture was heated to reflux for 15 h.
Work-up and column chromatography (silica gel, di-
chloromethane) then yielded 29e (0.112 g, 24%) as a
colourless oil. dH (400 MHz, CDCl3) 0.89 (t, 3H, 6.5 Hz)
1.30–1.42 (m, 6H) 1.66–1.73 (m, 2H) 2.76 (t, 2H, 7.5 Hz)
3.78 (s, 6H) 3.93 (s, 3H) 5.13 (s, 2H) 7.23–7.37 (m, 9H)
8.19 (d, 1H, 8.1 Hz). dC (100 MHz, CDCl3) 14.45, 22.94,
29.30, 31.35, 32.03, 32.44, 36.50, 56.52, 61.35, 74.87,
106.76, 117.38, 122.48, 125.98, 126.11, 126.58, 128.55,
128.64, 129.25, 137.23, 140.30, 140.48, 150.22, 153.23,
155.75, 155.92, 175.38. LRMS (EI): 503 (Mþꢂ, 35%), 412
([MꢁBn]þ, 42), 383 (100). HRMS: calcd for C31H34O6
502.2355 found, 502.2354.
5.35. 3-Benzyloxy-7-dodecyl-2-(4-benzyloxy-3,5-dime-
thoxy-phenyl)-chromen-4-one 30j
In the same way, a solution of 1-dodecene (0.214 g,
1.27 mmol) and 9-BBN (1.35 mmol) in tetrahydrofuran
(4.7 mL) was stirred for 6 h, then 25 (0.565 g, 0.9 mmol)
in tetrahydrofuran (5 mL), 3 M aqueous NaOH solution
(1.1 mL) and dichloropalladium (dppf) (24 mg) were
added and the mixture was heated to reflux for 15 h.
Work-up and column chromatography (silica gel,
dichloromethane to dichloromethane–MeOH 99:1)
yielded 30j (0.210 g, 35%) as a pale yellow oil. dH
(400 MHz, CDCl3) 0.85–0.89 (m, 3H) 1.20–1.37 (m,
16H) 1.51–1.56 (m, 2H) 1.62–1.71 (m, 2H) 2.75 (t, 2H,
7.4 Hz) 3.74 (s, 6H) 5.11 (s, 2H) 5.11 (s, 2H) 7.23–7.38
(m, 13H) 7.50 (dd, 1H, 1.5 and 6.7 Hz) 8.19 (d, 1H,
8.2 Hz). dC (100 MHz, CDCl3) 14.12, 22.69, 25.75, 27.43,
29.28, 29.35, 29.47, 29.56, 29.64, 31.02, 31.92, 36.14,
56.15, 74.46, 75.06, 106.42, 118.00, 122.10, 125.60,
125.73, 126.32, 128.01, 128.16, 128.21, 128.27, 128.51,
128.90, 136.83, 137.53, 138.94, 139.88, 149.82, 153.17,
155.37, 155.61, 175.00. LRMS (EI): 662 (Mþꢂ, 8%) 571
([MꢁBn]þ, 12) 91 (Bnþ, 100). HRMS: calcd for
C43H50O6 662.3607 found, 662.3600. HRMS: calcd for
C4213CH50O6 663.3641 found, 663.3636.
5.33. 3-Benzyloxy-7-octyl-2-(3,4,5-trimethoxy-phenyl)-
chromen-4-one 29f
In the same way, a solution of 1-octene (0.148 g,
1.3 mmol) and 9-BBN (1.35 mmol) in tetrahydrofuran
(4.7 mL) was stirred for 9 h then 24 (0.504 g, 0.9 mmol)
in tetrahydrofuran (5 mL), 3 M aqueous NaOH solution
(1.1 mL) and dichloropalladium (dppf) (31 mg) were
added and the mixture was heated to reflux for 15 h.
Work-up and column chromatography (silica gel,
dichloromethane) then yielded 29f (0.290 g, 59%) as a
colourless oil. dH (400 MHz, CDCl3) 0.88 (t, 3H, 7.0 Hz)
1.25–1.41 (m, 10H) 1.62–1.74 (m, 2H) 2.76 (t, 2H,
7.5 Hz) 3.78 (s, 6H) 3.89 (s, 3H) 5.13 (s, 2H) 7.21–7.37
(m, 9H) 8.19 (d, 1H, 8.2 Hz). dC (100 MHz, CDCl3)
14.48, 23.03, 29.59, 29.65, 29.80, 31.40, 32.30, 36.51,
56.52, 61.35, 74.87, 106.76, 117.38, 122.48, 125.98,
126.11, 126.58, 128.55, 128.64, 129.25, 137.23, 140.30,
140.49, 150.22, 153.23, 155.75, 155.91, 175.37. LRMS
(CI): 531 ([MþH]þ, 22%), 419 (100). HRMS: calcd for
C33H39O6 531.2747 found, 531.2744.
5.36. 3-Benzyloxy-2-(4-benzyloxy-3,5-dimethoxy-phen-
yl)-7-octadecyl-chromen-4-one 30k
In the same way, a solution of 1-octadecene (0.322 g,
1.3 mmol) and 9-BBN (1.35 mmol) in tetrahydrofuran
(4.7 mL) was stirred for 6 h, then 25 (0.558g, 0.9 mmol) in
tetrahydrofuran (5mL), 3M aqueous NaOH solution
(1.1 mL) and dichloropalladium (dppf) (25mg) were
added and the mixture was heated to reflux for 18h.
Work-up and column chromatography (silica gel,
dichloromethane) yielded 30k (0.455g, 68%) as a white
solid. dH (400MHz, CDCl3) 0.88 (t, 3H, 7 Hz) 1.25–1.39

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C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
(m, 30H) 1.69–1.70 (m, 2H) 2.75 (t, 2H, 7.3 Hz) 3.74 (s,
6H) 5.10 (s, 2H) 5.11 (s, 2H) 7.21–7.38 (m, 12H) 7.50 (d,
2H, 6.7 Hz) 8.18 (d, 1H, 8 Hz). dC (100 MHz, CDCl3)
14.12, 22.70, 29.30, 29.37, 29.48, 29.57, 29.67, 29.70, 31.03,
31.93, 36.14, 56.14, 74.46, 75.06, 106.40, 117.00, 122.20,
125.60, 125.81, 126.33, 128.01, 128.17, 128.21, 128.26,
128.51, 128.90, 140.00, 149.96, 153.16, 155.74, 174.93.
LRMS (FAB): 747 ([MþH]þ, 22%) 91.5 (Bnþ, 100).
HRMS: calcd for C49H63O6 747.4625 Found, 747.4622.
(11 mL) gave crude 6e (66 mg, 93%) as a yellow solid. A
solution of crude 6e (47 mg, 0.1 mmol), N,N-dimethyl-4-
aminopyridine (2 mg) and acetic anhydride (0.11 mL,
1 mmol) in pyridine (0.50 mL) was then stirred for 18 h
to give 31e (30 mg, 44%) as a white solid after crystal-
lisation in methanol. dH (400 MHz, CDCl3) 0.89 (t, 3H,
6.8 Hz) 1.32–1.41 (m, 6H) 1.63–1.69 (m, 2H) 2.33 (s, 6H)
2.34 (s, 3H) 2.39 (s, 3H) 2.75 (t, 2H, 7.6 Hz) 7.24–7.27
(m, 1H) 7.34 (s, 1H) 7.68 (s, 2H) 8.14 (d, 1H, 8.2 Hz). dC
(100 MHz, CDCl3) 14.45, 20.60, 20.88, 21.10, 22.93,
29.21, 31.22, 32.00, 36.49, 117.54, 121.26, 121.88,
126.32, 126.73, 128.37, 134.44, 136.96, 143.94, 151.10,
153.77, 156.08, 166.98, 167.90, 168.57, 172.32. LRMS
(FAB): 539 [(MþH)þ, 100%). MþHþ requires
C29H31O10 calcd 539.1917 found, 539.1917.
5.37. 3-Acetoxy-7-butyl-2-(3,4,5-triacetoxy-phenyl)-chro-
men-4-one 31c
In the same way as for acetate 31d, a solution of 29c
(0.389 g, 1 mmol) and boron tribromide (5 mmol) in
dichloromethane (20 mL) gave crude 6c (0.302 g, 77%) as
a brown solid (no precipitation occurred in water so
extraction with ethyl acetate was employed). A solution
of crude 6c (0.302 g, 0.9 mmol), N,N-dimethyl-4-amino-
pyridine (5 mg) and acetic anhydride (0.50 mL, 5.3 mmol)
in pyridine (3 mL) was then stirred for 1 h to give 31c
(0.302 g, 67%) as a white solid after crystallisation in
methanol. dH (400 MHz, CDCl3) 0.95 (t, 3H, 7.3 Hz)
1.32–1.42 (m, 2H) 1.60–1.70 (m, 2H) 2.33 (s, 9H), 2.39
(s, 3H), 2.75 (t, 2H, 7.8 Hz) 7.21–7.28 (m, 1H) 7.34 (s,
1H) 7.68 (s, 2H) 8.14 (d, 1H, 7.9 Hz).
5.40. 3-Acetoxy-7-octyl-2-(3,4,5-triacetoxy-phenyl)-chro-
men-4-one 31f
In the same way, a solution of 29f (0.290 g, 0.5 mmol)
and boron tribromide (2.7 mmol) in dichloromethane
(12.7 mL) gave crude 6f (0.155 g, 71 %) as a yellow solid.
A solution of crude 6f (0.133 g, 0.3 mmol), N,N-di-
methyl-4-aminopyridine (2 mg) and acetic anhydride
(0.20 mL, 2 mmol) in pyridine (1 mL) was then stirred
for 5 h to give 31f (97 mg, 51%) as a white solid after
crystallisation in methanol. dH (400 MHz, CDCl3) 0.88
(t, 3H, 6.6 Hz) 1.22–1.48 (m, 10H) 1.65–1.70 (m, 2H)
2.33 (s, 6H) 2.34 (s, 3H) 2.39 (s, 3H) 2.74 (t, 2H, 7.5 Hz)
7.24–7.26 (m, 1H) 7.34 (s, 1H) 7.68 (s, 2H) 8.14 (d, 1H,
8.2 Hz). dC (100 MHz, CDCl3) 14.48, 20.60, 20.88, 21.10,
23.03, 29.55, 29.57, 29.78, 31.26, 32.22, 36.50, 117.54,
121.27, 121.88, 126.32, 126.74, 128.37, 134.44, 136.96,
143.94, 151.10, 153.76, 156.08, 166.98, 167.90, 168.57,
172.32. LRMS (FAB): 567 [(MþH)þ, 100%]. MþHþ
requires C31H35O10 calcd 567.2230 found, 567.2228.
5.38. 3-Acetoxy-7-(4-methyl-pentyl)-2-(3,4,5-triacetoxy-
phenyl)-chromen-4-one 31d
To a stirring solution of 29d (0.184 g, 0.4 mmol) in di-
chloromethane (20 mL) under argon at 0 ꢁC was added
boron tribromide in dichloromethane (1.0 M, 1.8 mL,
1.8 mmol). The mixture was warmed to room tempera-
ture and then stirred for 15 h. Methanol (10 mL) was
then added. The reaction was heated to reflux for 2 h,
then concentrated in vacuo to give a brown solid. Water
(20 mL) was added and the mixture sonicated then left
to stand overnight. Crude 6d (0.124 g, 91 %) was then
collected as a yellow solid. To a stirring solution of
crude 6d (88 mg, 0.2 mmol) and N,N-dimethyl-4-am-
inopyridine (2 mg, 0.02 mmol) in pyridine (0.8 mL)
under argon was added acetic anhydride (0.20 mL,
2 mmol). The reaction was stirred for 23 h then poured
into ethyl acetate and washed with 2 M HCl, sodium
hydrogen carbonate solution and brine, then dried
(MgSO4) and concentrated in vacuo to give an off-white
solid. Recrystallisation (methanol) yielded 31d (11 mg,
9%) as a white solid. dH (400 MHz, CDCl3) 0.89 (d, 6H,
6.6 Hz) 1.20–1.26 (m, 1H) 1.54–1.72 (m, 4H), 2.33 (s,
6H), 2.34 (s, 3H), 2.39 (s, 3H), 2.73 (t, 2H, 7.6 Hz) 7.25–
7.27 (m, 1H) 7.34 (s, 1H) 7.68 (s, 2H) 8.14 (d, 1H,
8.2 Hz). LRMS (FAB): 539 (Mþꢂ, 7%), 136 (100).
C29H31O10 calcd 539.1917 found, 539.1919.
5.41. 3,7-Dimethyl-octan-1-ol 34
A flask containing a stirring suspension of geraniol
(10 mL, 58 mmol) and palladium on carbon (10% Pd,
0.494 g) in ethanol (70 mL) was evacuated, and then
filled with hydrogen. The reaction mixture was then
stirred under an atmosphere of hydrogen for 21 h. After
this time the mixture was filtered and the filtrate con-
centrated in vacuo to give 34 (5 g, 55%) as a colourless
oil.46 dH (400 MHz, CDCl3) 0.86–0.90 (m, 10H) 1.11–
1.42 (m, 6H) 1.49–1.68 (m, 3H) 3.63–3.73 (m, 2H). dC
(100 MHz, CDCl3) 20.01, 22.96, 23.06, 25.05, 28.34,
29.89, 37.75, 39.63, 40.36, 61.60.
5.42. 3,7,11-Trimethyl-dodecan-1-ol 35
In the same way, farnesol (5.7 mL, 22.5 mmol) gave a
mixture of diastereomers 35 (4.81 g, 93%) as a colourless
oil.47 IR (film) 2925, 1715, 1459 cmꢁ1. dH (400 MHz,
CDCl3) mixture of diastereoisomers. 0.84–0.90 (m, 12H)
1.05–1.38 (m, 13H) 1.49–1.62 (m, 4H) 3.63–3.73 (m,
2H). dC (100 MHz, CDCl3) 11.78, 11.80, 19.59, 19.64,
20.07, 20.13, 23.00, 23.09, 24.75, 24.88, 25.18, 58.36,
5.39. 3-Acetoxy-7-hexyl-2-(3,4,5-triacetoxy-phenyl)-
chromen-4-one 31e
In the same way, a solution of 29e (96 mg, 0.2 mmol) and
boron tribromide (1.0 mmol) in dichloromethane

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
2093
29.85, 29.95, 33.16, 33.18, 34.80, 37.33, 37.37, 37.68,
37.76, 37.79, 37.84, 39.75, 40.36, 61.65. LRMS (CI): 246
(MþNH4þ, 100%). LRMS (EI): 210 (MþꢂꢁH2O, 11%),
18 (100). HRMS: calcd for C15H32O, (MꢁH2O),
210.2348 found, 210.2346.
5.46. 3-Benzyloxy-2-(3,4,5-trimethoxy-phenyl)-7-(3,7,11-
trimethyl-dodecyl)-chromen-4-one 39
In the same way, the organozinc derived from iodide 37
(1.268 g, 3.8 mmol) was coupled with iodoflavonoid 24
(0.481 g, 0.8 mmol) using dichlorobis-[tri-(o-tolyl)-phos-
phinyl]palladium (63 mg, 0.08 mmol) to give flavonoid
39 (82 mg, 15%) as a pale yellow oil after column
chromatography (silica gel, petrol–EtOAc 9:1 to 2:1). IR
(film) 2928, 1457, 908, 734 cmꢁ1. dH (400 MHz, CDCl3)
0.84–0.92 (m, 7H), 0.96 [d, 6 Hz, 2H (3H of one dia-
stereomer)], 1.05–1.42 (m, 8H), 1.48–1.70 (m, 12H)
2.68–2.83 (m, 2H) 3.78 (s, 6H) 3.93 (s, 3H) 5.13 (s, 2H)
7.21–7.37 (m, 9H) 8.19 (d, 8 Hz, 1H). dC (100 MHz,
CDCl3) 19.56, 19.63, 19.68, 19.75, 22.63, 22.72, 24.38,
24.80, 27.98, 32.60, 32.78, 33.74, 37.22, 37.28, 37.37,
38.45, 38.55, 39.36, 56.15, 60.99, 74.51, 106.39, 116.94,
122.08, 125.65, 126.20, 128.18, 128.27, 128.88, 136.84,
139.92, 150.18, 152.86, 155.41, 175.02. LRMS (EI): 628
(Mþꢂ, 20%) 509 (100). HRMS: calcd for C40H52O6,
628.3764 found, 628.3768.
5.43. 1-Iodo-3,7-dimethyl-octane 36
To a stirring solution of 34 (5 g, 32 mmol), imidazole
(2.59 g, 38 mmol) and triphenylphosphine (9.11 g,
35 mmol) in toluene (100 mL) under nitrogen was added
iodine (10.44 g, 41 mmol). The reaction mixture was
stirred for 18 h then filtered. The filtrate was washed
with 5% sodium thiosulfate solution (3 · 100 mL) then
dried (Na2SO4) and concentrated in vacuo to give a
white solid. This solid was taken up in hexane (20 mL),
cooled and filtered. The filtrate was then concentrated in
vacuo to give 36 (6 g, 71%) as a colourless oil.48 dH
(400 MHz, CDCl3) 0.86–0.90 (m, 9H) 1.10–1.32 (m, 6H)
1.49–1.69 (m, 3H) 1.84–1.90 (m, 1H) 3.14–3.28 (m, 2H).
dC (100 MHz, CDCl3) 5.77, 19.12, 22.97, 24.91, 28.33,
34.27, 36.86, 39.56, 41.37.
5.47. N-(4-Methoxy-phenyl)-acetamide 40
To
a stirring suspension of p-anisidine (6.036 g,
5.44. 3,7,11-Trimethyl-1-dodecyl iodide 37
49 mmol) in dichloromethane (20 mL) was added acetic
anhydride (5 mL, 53 mmol) over 1 h. The reaction was
stirred for 1 h then poured into hexane (60 mL) and
stirred for 1 h. The solid was collected and washed with
hexane to give 40 (7.717 g, 95%) as a pale grey solid.49 dH
(400 MHz, CDCl3) 2.13 (s, 3H) 3.78 (s, 3H) 6.83 (d, 2H,
9 Hz) 7.38 (d, 2H, 9 Hz). dC (100 MHz, CDCl3) 24.66,
55.85, 114.49, 122.37, 131.41, 156.82, 168.79. LRMS
(EI): 165 (Mþꢂ, 71%), 108 ([NH2C6H4O]þ, 100). HRMS:
calcd for C9H11NO2 165.0790 Found, 165.0789.
In the same way, a solution of alcohol 35 (1.5 g,
6.6 mmol), imidazole (1.13 g, 16.6 mmol) and triphenyl-
phosphine (4.40 g, 16.8 mmol) and iodine (3.26 g,
12.8 mmol) in toluene (250 mL) gave a mixture of dia-
stereomers 37 (1.1 g, 61%) as a colourless oil. IR (film)
2955 cmꢁ1. dH (400 MHz, CDCl3) 0.84–0.88 (m, 12H),
0.95–1.38 (m, 11H), 1.49–1.57 (m, 4H), 1.61–1.67 (m,
1H) 1.86–1.89 (m, 1H) 3.13–3.28 (m, 2H). dC (100 MHz,
CDCl3) 5.73, 11.80, 11.82, 19.17, 19.60, 20.09, 20.15,
23.02, 23.11, 24.60, 24.89, 25.20, 28.38. 29.86, 33.17,
33.20, 34.81, 37.34, 37.38, 37.63, 37.65, 37.69, 37.78,
37.80, 37.85, 39.77. LRMS (EI): 338 (Mþꢂ, 2%) 211
(MþꢂꢁIÆ, 24) 57 (100). HRMS: calcd for C15H31I,
338.1471 found, 338.1472.
5.48. 50-Iodo-20-hydroxy-acetophenone 41
To a stirring suspension of 40 (5.253 g, 32 mmol) and
acetyl chloride (6.6 mL, 93 mmol) in dichloromethane
(55 mL) was added aluminium trichloride (14.55 g,
109 mmol) in portions over 90 min. The reaction was
then heated to reflux for 4.5 h and cooled overnight. The
mixture was poured onto ice then extracted into
dichloromethane (5x), dried (MgSO4) and concentrated
in vacuo to give N-(3-acetyl-4-hydroxy-phenyl)-acetam-
ide50 (5.336 g, 87%) as a pale green solid. dH (400 MHz,
CDCl3) 2.19 (s, 3H) 2.63 (s, 3H) 6.94 (d, 1H, 9 Hz) 7.12
(br s, 1H, NH) 7.33 (dd, 1H, 2.6 and 9 Hz) 8.17 (d, 1H,
2.6 Hz) 12.12 (s, 1H). dC (100 MHz, CDCl3) 24.71, 27.16,
119.08, 119.60, 122.94, 129.58, 159.62, 168.86, 204.84.
LRMS (EI): 193 (Mþꢂ, 100%). HRMS: calcd for
C10H11NO3 193.0739 Found, 193.0740. A suspension
of N-(3-acetyl-4-hydroxy-phenyl)-acetamide (1.029 g,
5.3 mmol) in 15% HCl (1.5 mL, 6.2 mmol) was heated to
reflux for 40 min, then cooled and neutralised with 10%
aqueous ammonia. The precipitated solid was collected
by filtration as 50-amino-20-hydroxy-acetophenone50
(0.677 g, 84%) a green solid. dH (400 MHz, CDCl3) 2.58
(s, 3H) 3.47 (br s, 2H) 6.83 (d, 1H, 8.8 Hz) 6.91 (dd, 1H,
2.8 and 8.8 Hz) 7.02 (d, 1H, 2.8 Hz). dC (100 MHz,
5.45. 3-Benzyloxy-2-(4-benzyloxy-3,5-dimethoxy-phen-
yl)-7-(3,7-dimethyl-octyl)-chromen-4-one 38
To a stirring suspension of zinc chloride (0.302 g,
2.2 mmol) and magnesium (86 mg, 3.5 mmol) in tetra-
hydrofuran (2 mL) under argon was added 36 (0.879 g,
3.3 mmol) in tetrahydrofuran (2 mL). The reaction was
heated to 50 ꢁC for 20 h then cooled. 25 (0.465 g,
0.8 mmol) in tetrahydrofuran (6 mL) and dichlorobis-
[tri-(o-tolyl)-phosphinyl]palladium (33 mg, 0.04 mmol)
were added and the reaction stirred for 25 h. The reac-
tion was then quenched with 3 N HCl (10 mL), diluted
with water and extracted into dichloromethane, washed
with brine (2x), dried (MgSO4) and concentrated in
vacuo to give a brown oil. Column chromatography
(silica gel, dichloromethane–MeOH 1:0 to 19:1) yielded
38 (0.143 g, 30%) as a yellow oil. LRMS (FAB): 635
([MþH]þ, 18%) 545 ([MꢁBn]þ, 75) 91.5 (Bnþ, 100).
HRMS: calcd for C41H47O6 635.3373 found, 635.3374.

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C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
CDCl3) 27.12, 115.71, 119.40, 119.87, 125.737, 138.40,
156.03, 204.48. LRMS (EI): 151 (Mþꢂ, 100%). HRMS:
calcd for C8H9NO2 151.0633 found, 151.0632. To a
stirring solution 50-amino-20-hydroxy-acetophenone
(6.856 g, 46 mmol) in 98% sulfuric acid (24 mL) and water
(19 mL) was added sodium nitrite (3.30 g, 48 mmol) in
water (5.5 mL). The reaction was stirred for 35 min, then
sulfuric acid (4 mL), copper powder (0.17 g, 0.3 mmol)
and potassium iodide (8.80 g, 53 mmol) in water (5.5 mL)
added. The mixture was then heated slowly to 65 ꢁC and
maintained at 65 ꢁC for 2 h. The reaction was then
cooled, water (25 mL) and sodium hydrogen carbonate
added. More water was added, then extracted into a
mixture of ethyl acetate and dichloromethane, then ethyl
acetate (2x). The combined organic layers were washed
with brine then concentrated in vacuo. This mixture was
then taken up in ethyl acetate and 2 M HCl, filtered and
the organic layer dried (MgSO4) and concentrated in
vacuo to give 41 (1.339 g, 39%) as a purple oil.50 This was
then used in the next reaction.
(0.918 g, 4.7 mmol) and added potassium hydroxide
(0.545 g, 9.7 mmol) in ethanol (30 mL) was stirred for
26 h to give a brown oil following work-up and solvent
evaporation. Crystallisation (ethanol) yielded chalcone
44 (0.368 g, 19%). dH (400 MHz, CDCl3) 1.26 (t, 3H,
7.5 Hz) 2.76 (q, 2H, 7.5 Hz) 3.92 (s, 6H) 5.10 (s, 2H) 6.88
(s, 2H) 6.94 (s, 1H) 7.28–7.42 (m, 4H) 7.48–7.50 (m, 2H)
7.85 (d, 1H, 15 Hz) 8.03 (s, 1H) 12.78 (s, 1H). dC
(100 MHz, CDCl3) 13.89, 30.25, 56.74, 75.53, 106.61,
113.24, 119.01, 119.54, 119.89, 128.41, 128.61, 128.86,
130.38, 133.16, 137.81, 140.31, 146.77, 152.75, 154.25,
163.24, 192.47. LRMS (EI): 496(þ498) (Mþꢂ, 18%)
405(þ407) ([MꢁBn]þ, 35) 91.1 (Bnþ, 100). HRMS:
calcd for C26H25BrO5 496.0855þ498.0869 found,
496.0884þ498.0863.
5.52. 3-Hydroxy-6-iodo-2-(4-benzyloxy-3,5-dimethoxy-
phenyl)-chromen-4-one 45
In the same way as for flavonol 17, chalcone 43 (4.155 g,
8 mmol) gave flavonol 45 (2.106 g, 49%) as a grey solid
following crystallisation in ethanol. dH (400 MHz,
CDCl3) 3.93 (s, 6H) 5.12 (s, 2H) 7.00 (br s, 1H) 7.25–
7.38 (m, 5H) 7.49–7.51 (m, 3H) 7.95 (dd, 1H, 2.2 and
8.9 Hz) 8.58 (s, 1H). dC (100 MHz, CDCl3) 56.73, 75.71,
105.92, 120.94, 123.00, 128.39, 128.65, 128.86, 134.89,
138.10, 142.43, 154.10, 155.02, 169.89. LRMS (EI): 530
(Mþꢂ, 31%) 439 ([MꢁBn]þ, 35) 91 (Bnþ, 100). HRMS:
calcd for C24H19IO6 530.0226 found, 530.0226.
5.49. 1-(5-Bromo-4-ethyl-2-hydroxy-phenyl)-ethanone 42
To a stirring solution of 13 (1.002 g, 6.1 mmol) in chlo-
roform (10 mL) under argon at ꢁ12 ꢁC was added bro-
mine (0.32 mL, 6.2 mmol) in chloroform (5 mL) over
20 min. The reaction was stirred at ꢁ12 ꢁC for 50 min,
then poured into water (20 mL). The organic layer was
washed with water (10 mL), 10% sodium thiosulfate
(2 · 10 mL) and water (10 mL), dried (MgSO4) then
concentrated in vacuo to give 42 (1.132 g, 76%) as a
brown solid. LRMS (EI): 242(þ244) (Mþꢂ, 16%)
227(þ229) ([MꢁMe]þ, 40), 191 (100). HRMS: calcd for
C10H11BrO2 241.9942þ243.9923, found, 241.9941þ
243.9916.
5.53. 6-Bromo-7-ethyl-3-hydroxy-2-(4-benzyloxy-3,5-
dimethoxy-phenyl)-chromen-4-one 46
In the same way as for flavonol 17, chalcone 44 (0.238 g,
0.5 mmol) gave flavonol 46 (97 mg, 40%) as a yellow
solid following crystallisation in ethanol. dH (400 MHz,
CDCl3) 1.34 (t, 3H, 7.5 Hz) 2.90 (q, 2H, 7.5 Hz) 3.94 (s,
6H) 5.12 (s, 2H) 6.99 (s, 1H) 6.99 (s, 1H) 7.25–7.38 (m,
4H) 7.46–7.52 (m, 4H) 8.40 (s, 1H). dC (100 MHz,
CDCl3) 14.03, 30.23, 56.70, 75.47, 105.82, 118.60,
120.19, 120.92, 126.50, 128.36, 128.60, 129.08,
137.95, 138.52, 139.35, 145.20, 150.03, 153.88, 154.66,
172.32.
5.50. 1-(2-Hydroxy-5-iodo-phenyl)-3-(4-benzyloxy-3,5-
dimethoxy-phenyl)-propenone 43
In the same way as for the synthesis of chalcone 15, a
solution of ketone 41 (4.243 g, 16 mmol), aldehyde 21
(4.51 g, 17 mmol) and potassium hydroxide (1.839 g,
33 mmol) in ethanol (100 mL) was stirred for 191 h to
give a black oil following work-up and solvent evapo-
ration. This was taken up in ethanol (50 mL), potassium
hydroxide (1.97 g) added and stirred for 169 h. The
reaction was then acidified with 6 M HCl and diluted
with water then extracted into ethyl acetate (3x) washed
with brine, dried (MgSO4) and concentrated in vacuo to
give a black foam. Crystallisation (ethanol) yielded
chalcone 43 (4.122 g, 49%). LRMS (EI): 516 (Mþꢂ) 425
([MꢁBn]þ, 32%) 91 (Bnþ, 100). HRMS: calcd for
C24H21IO5 516.0434 found, 516.0435.
5.54. 3-Hydroxy-6-decyl-2-(4-benzyloxy-3,5-dimethoxy-
phenyl)-chromen-4-one 47
In the same way as for flavonoid 29d, a solution of
1-decene (0.189 g, 1.3 mmol) and 9-BBN (1.4 mmol) in
tetrahydrofuran (4.8 mL) was stirred for 8 h then 45
(0.501 g, 0.9 mmol) in tetrahydrofuran (5 mL), 3 M
aqueous NaOH solution (1.26 mL) and dichloropalla-
dium(dppf) (21 mg) were added and the mixture was
heated to reflux for 15 h. After work-up the mixture was
passed through a short plug of silica, eluting with ethyl
acetate to give 47 (0.369 g, 72%) as a red oil. This was
used in the next step.
5.51. 1-(5-Bromo-4-ethyl-2-hydroxy-phenyl)-3-(4-benzyl-
oxy-3,5-dimethoxy-phenyl)-propenone 44
In the same way as for the synthesis of chalcone 15, a
solution of ketone 42 (1.132 g, 4.7 mmol), aldehyde 21

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
2095
5.55. 7-Ethyl-3-hydroxy-6-octyl-2-(4-benzyloxy-3,5-
dimethoxy-phenyl)-chromen-4-one 48
methanesulfonic anhydride (25.5 mL, 155.21 mmol) was
added slowly over 1 h to a solution of 20-40-dihydroxy-2-
methoxy-acetophenone (25.68 g, 141.10 mmol) and 2,6-
lutidine (18.0 mL, 155.21 mmol) in dry dichloromethane
(450 mL) cooled to 0 ꢁC and under an atmosphere of
argon. After 1 h. the solution was diluted with dichloro-
methane (200 mL) and washed with 1 M hydrochloric
acid (600 mL). The organic layer was re-extracted with
dichloromethane (200 mL) and the combined organics
washed with 1 M hydrochloric acid (600 mL). The
organics were then dried over magnesium sulfate and
concentrated under vacuum to give the triflate 52 as a
purple oil suitably pure for the next step (38.84 g, 87%).
The product was contaminated with ꢃ5% ditriflate. dH
(400 MHz: CDCl3): 3.53 (3H, s, OCH3), 4.68 (2H, s,
CH2), 6.84 (1H, dd, J 2.5 and 8.9 Hz, H-50), 6.94 (1H, d,
J 2.5 Hz, H-30), 7.85 (1H, d, J 8.9 Hz, H-60), 12.14 (1H, s,
OH).
In the same way as for flavonoid 29d, a solution of
1-octene (32 mg, 0.3 mmol) and 9-BBN (0.3 mmol) in
tetrahydrofuran (1.6 mL) was stirred for 7 h then 46
(0.102 g, 0.2 mmol) in tetrahydrofuran (4 mL), 3 M
aqueous NaOH solution (0.2 mL) and dichloropalla-
dium(dppf) (5 mg) were added and the mixture was
heated to reflux for 15 h. After work-up, flavonoid 47
(0.369 g, 72%) was obtained as a red oil. This was used
in the next step.
5.56. 3-Acetoxy-7-ethyl-6-octyl-2-(3,4,5-triacetoxy-phen-
yl)-chromen-4-one 50
In the same way as for 31d, a solution of 48 (0.125 g,
0.2 mmol) and boron tribromide (1.2 mmol) in dichlo-
romethane (11.2 mL) gave crude 8 (88 mg, 90%) as a
green solid. A solution of crude 8 (88 mg, 0.2 mmol),
N,N-dimethyl-4-aminopyridine (2 mg) and acetic anhy-
dride (0.20 mL, 2 mmol) in pyridine (0.75 mL) was then
stirred for 2 h to give 50 (25 mg, 20%) as a white solid
after recrystallisation in methanol. dH (400 MHz,
CDCl3) 0.79–0.88 (m, 3H) 1.20–1.36 (m, 12H) 1.50–1.63
(m, 3H) 2.26 (s, 9H) 2.32 (s, 3H) 2.60–2.74 (m, 4H) 7.19
(s, 2H) 7.27 (s, 1H) 7.35 (s) 7.60 (s, 2H) 7.91 (s, 1H) 8.31
(s). dC (100 MHz, CDCl3) 13.09, 13.44, 19.19, 19.50,
19.70, 21.65, 24.81, 28.22, 28.46, 28.63, 28.80, 29.74,
30.85, 31.11, 115.67, 119.86, 120.29, 124.21, 127.13,
132.95, 135.48, 137.90, 142.50, 149.08, 152.22, 153.18,
165.59, 166.51, 167.22, 170.98.
5.58. 20-hydroxy-40-decyl-2-methoxy-acetophenone 53
9-BBN (0.5 M solution in THF, 272.0 mL, 136 mmol)
was added to decene (25.75 mL, 136 mmol) at rt under
argon. The solution was then stirred at rt overnight.
After this time, K3PO4 (39.48 g, 21.8 mmol), Pd(Ph3P)4
(2.54 g, 2.20 mmol, 1.8 mol %), KBr (16.19 g, 136 mmol)
and degassed H2O (2.5 mL, 136 mmol) were added fol-
lowed by a solution of triflate 52 (38.84 g, 124 mmol) in
dry degassed THF (100 mL). The reaction mixture was
then heated to 65 ꢁC under argon for 2 h. Caution!––The
reaction mixture becomes exothermic once at 65 ꢁC. A
2 L round-bottom flask was used to contain the large
expansion of reaction contents, which also occurs. After
cooling the solution was acidified to pH 1 and extracted
into EtOAc (400 mL). The aqueous layer was re-ex-
tracted with EtOAc (200 mL) and the combined organ-
ics washed with H2O (2 · 500 mL) and brine (500 mL).
The organic layer was concentrated under vacuum. The
resulting residue was dissolved in Et2O (200 mL) and
4 M NaOH (100 mL). After stirring for 15 min. the solid
was filtered off and washed with Et2O (2 · 500 mL). The
solid was then acidified with dilute hydrochloric acid
and extracted into DCM (400 mL). The organic layer
was dried over MgSO4 and concentrated under vacuum
to give the acetophenone 53 as a black oil (28.71 g, 76%)
suitably pure for the next step. Further purification of a
small sample by column chromatography on silica
eluting dichloromethane gave the acetophenone as a
pale yellow solid. Mp <25 ꢁC. dH (400 MHz: CDCl3):
0.88 (3H, t, J 6.7 Hz, CH2CH3), 1.22–1.31 (14H, m,
7 · CH2), 1.57–1.65 (2H, m, ArCH2CH2), 2.61 (2H, t, J
7.5 Hz, ArCH2CH2), 3.53 (3H, s, OCH3), 4.71 (2H, s,
OCH2), 6.73 (1H, dd, J 1.6 Hz and 8.2 Hz, H-50), 6.83
(1H, d, J 1.4 Hz, H-30), 7.58 (1H, d, J 8.0 Hz, H-60),
11.98 (1H, s, OH). dC (100 MHz: CDCl3): 14.05 (CH3),
22.61 (CH2), 29.16 (CH2), 29.25 (CH2), 29.37 (CH2),
29.47 (CH2), 29.53 (CH2), 30.53 (CH2), 31.83 (CH2),
36.20 (CH2), 59.48 (CH3), 74.19 (CH2), 115.48 (C),
117.93 (CH), 119.69 (CH), 128.53 (CH), 153.33 (C),
162.52 (C), 200.78 (C). m=z (EI): 306.1 (Mþꢂ, 10%), 261.1
(100), 147.0 (25), 45.0 (30). Found: 306.2194 C19H30O3
requires (Mþ) 306.2195. Found: C, 74.74; H, 10.03.
5.57. 20-hydroxy-2-methoxy-40-trifluoromethanesulfonyl-
oxy-acetophenone 52
Resorcinol 51 (154.9 g, 1.40 mol), methoxyacetonitrile
(50.0 g, 703.4 mmol) and dry diethyl ether (400 mL)
where placed in a three necked flask containing freshly
fused zinc chloride (19.16 g, 140.7 mmol) under argon.
The solution was cooled to 0 ꢁC and the argon inlet
replaced with a calcium chloride drying tube. Dry
hydrochloric acid was bubbled through the solution for
2 h. The resulting precipitate was filtered off and washed
with ether (2 · 100 mL). The hydrochloride salt was
dissolved in water (300 mL) and heated under reflux for
60 min. After cooling the resulting solid was filtered off
and washed with water (2 · 100 mL) and dried by
toluene azeotrope to give 20-40dihydroxy-2-methoxy-
acetophenone as a white solid (62.04 g, 48%). Mp 108–
110 ꢁC. dH (400 MHz: DMSO-d6): 3.35 (3H, s, OCH3),
4.66 (2H, s, OCH2), 6.29 (1H, d, J 2.3 Hz, H-30), 6.36
(1H, dd, J 2.3 Hz and 8.8 Hz, H-50), 7.68 (1H, d, J
8.8 Hz, H-60), 10.59 (1H, s, OH), 11.92 (1H, s, OH). dC
(100 MHz: DMSO-d6): 58.89 (CH3), 74.68 (CH2), 102.80
(CH), 108.55 (CH), 111.99 (C), 132.26 (CH), 163.77 (C),
164.95 (C), 199.52 (C). m=z (EI): 182.1 (Mþ, 10%), 137.0
(100). Found: 182.0581 C9H10O4 requires (Mþ)
182.0579. Found: C, 59.43%; H, 5.50%. C9H10O4
requires C, 59.34%, H 5.53%. tmax (golden gate)/cmꢁ1
3361 (OH), 1633 (C@O). Rf silica EtOAc 0.56. Trifluoro-
:

2096
C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
C19H30O3 requires C, 74.47, H 9.87. tmax (thin film)/
cmꢁ1: 3039 (OH), 2925 (CH2), 1648 (C@O). Rf (silica
DCM) 0.26.
H-60), 11.65 (1H, s, OH). dC (100 MHz: CDCl3): 14.09
(CH3), 22.65 (CH2), 29.23 (CH2), 29.29 (CH2), 29.42
(CH2), 29.52 (CH2), 29.57 (CH2), 30.55 (CH2), 31.87
(CH2), 36.26 (CH2), 55.29 (CH3), 56.14 (CH3), 56.24
(CH3), 58.89 (CH3), 86.83 (CH), 95.70 (CH), 112.08 (C),
116.31 (C), 116.47 (C), 117.83 (CH), 119.94 (CH),
130.45 (CH), 138.10 (C), 143.68 (C), 153.29 (C), 154.92
(C), 163.15 (C), 191.92 (C), 198.68 (C). m=z (EI): 500.3
(Mþꢂ, 1%), 261.1 (10), 195.1 (100). Found: 500.2775
C29H40O7 requires (Mþ) 500.2774. tmax (golden gate)/
cmꢁ1: 2915 (CH2), 1664 (C@O), 1631 (C@O). Rf (silica,
EtOAc–hexane 1:1) 0.41.
5.59. 40-decyl-2-methoxy-20-(200, 400,500-trimethoxy-ben-
zoyloxy)-acetophenone 54
EDCI (860 mg, 4.49 mmol) was added to a solution of
phenol 53 (916 mg, 2.99 mmol), trimethoxybenzoic acid
(634 mg, 2.99 mmol) and DMAP (36 mg, 0.30 mmol) in
dry dichloromethane (10 mL) under argon at rt. The
resulting solution was stirred overnight. The reaction
mixture was then diluted with DCM (20 mL) and
washed with brine (50 mL). The aqueous layer was
re-extracted with DCM (20 mL) and the combined
organics washed with brine (50 mL). The organic layer
was then dried over magnesium sulfate and concentrated
under vacuum. The resulting residue was purified by
column chromatography (silica, EtOAc–hexane 2:1) to
give the ester 54 as a pale yellow solid (1.01 g, 68%). Mp
80–81 ꢁC. dH (400 MHz: CDCl3): 0.88 (3H, t, J 6.8 Hz,
CH2CH3), 1.26–1.31 (14H, m, 7 · CH2), 1.60–1.67 (2H,
m, ArCH2CH2), 2.66 (2H, t, J 7.6 Hz, ArCH2CH2), 3.38
(3H, s, OCH3), 3.92 (3H, s, OCH3), 3.94 (3H, s, OCH3),
3.97 (3H, s, OCH3), 4.56 (2H, s, OCH2), 6.58 (1H, s, H-
300), 7.08 (1H, d, J 1.2 Hz, H-30), 7.15 (1H, dd, J 1.2 Hz
and 8.0 Hz, H-50), 7.65 (1H, s, H-600), 7.80 (1H, d, J
8.0 Hz, H-60). dC (100 MHz: CDCl3): 14.05 (CH3), 22.61
(CH2), 29.21 (CH2), 29.24 (CH2), 29.36 (CH2), 29.47
(CH2), 29.53 (CH2), 30.75 (CH2), 31.82 (CH2), 35.74
(CH2), 56.09 (CH3), 56.41 (CH3), 56.81 (CH3), 59.19
(CH3), 77.18 (CH2), 97.35 (CH), 108.85 (C), 114.77
(CH), 123.79 (CH), 125.97 (CH), 126.53 (C), 129.69
(CH), 142.71 (C), 149.79 (2 · C), 154.69 (C), 156.79 (C),
163.39 (C), 196.20 (C). m=z (EI): 500.3 (Mþꢂ, 5%), 261.1
(10), 195.1 (100). Found: 500.2776 C29H40O7 requires
(Mþ) 500.2774. tmax (golden gate)/cmꢁ1: 2913 (CH2),
1747 (CO2), 1685 (C@O). Rf (silica, EtOAc–hexane 2:1)
0.31.
5.61. Synthesis of 3,20,40,50-tetramethoxy-7-decyl-flavone
56
TMSOTf (0.245 mL, 1.35 mmol) was added slowly to a
solution of diketone 55 (614 mg, 1.23 mmol) in dry
DCM (4 mL) at rt under argon. The yellow solution was
then stirred for 1 h and then quenched with saturated
NaHCO3 solution (30 mL) and extracted into DCM
(20 mL). The aqueous layer was re-extracted with DCM
(20 mL) and the combined organics washed with brine
(50 mL). The organic layer was then dried over magne-
sium sulfate and concentrated under vacuum. The resi-
due was purified by column chromatography on silica
eluting EtOAc–hexane 1:1 to give the flavone 56 as a
viscous yellow oil (409 mg, 69%). dH (400 MHz: CDCl3):
0.88 (3H, t, J 6.8 Hz, CH2CH3), 1.24–1.32 (14H, m,
7 · CH2), 1.63–1.70 (2H, m, ArCH2CH2), 2.72 (2H, t, J
7.5 Hz, ArCH2CH2), 3.82 (3H, s, OCH3), 3.85 (3H, s,
OCH3), 3.87 (3H, s, OCH3), 3.97 (3H, s, OCH3), 6.64
(1H, s, H-30), 7.00 (1H, s, H-60), 7.21 (1H, dd, J 1.3 Hz
and 8.2 Hz, H-6), 7.26 (1H, d, J 1.3 Hz, H-8), 8.18 (1H,
d, J 8.2 Hz, H-5). dC (100 MHz: CDCl3): 14.06 (CH3),
22.63 (CH2), 29.15 (CH2), 29.26 (CH2), 29.39 (CH2),
29.49 (CH2), 29.54 (CH2), 30.87 (CH2), 31.84 (CH2),
35.98 (CH2), 56.07 (CH3), 56.56 (CH3), 56.69 (CH3),
60.28 (CH3), 97.58 (CH), 111.42 (C), 113.62 (CH),
117.08 (CH), 122.29 (C), 125.39 (CH), 125.54 (CH),
141.73 (C), 142.93 (C), 149.39 (C), 151.68 (C), 152.38
(C), 155.41 (C), 155.86 (C), 174.75 (C). m=z (EI): 482.2
(Mþꢂ, 60%), 467.2 (75), 451.2 (100). Found: 482.2672
5.60. 1-(40-decyl-20-hydroxyphenyl)-2-methoxy-3-
(200,400,500-trimethoxyphenyl)-propan-1,3-dione 55
C29H38O6 requires (Mþ) 482.2668. tmax (thin film)/cmꢁ1
:
Lithium hexamethyldisilylazide (1.0 M solution in THF)
(4.88 mL, 4.88 mmol) was added dropwise to a solution
of ester 54 (814 mg, 1.63 mmol) in dry THF (6 mL)
cooled to ꢁ20 ꢁC and under argon. After 1 h. the reac-
tion was quench with saturated NaHCO3 solution
(30 mL) and extracted in EtOAc (50 mL). The aqueous
phase was re-extracted with EtOAc (20 mL) and the
combined organics washed with brine (2 · 100 mL). The
organic phase was then dried over magnesium sulfate
and concentrated under vacuum to give the diketone 55
as an off white solid suitably pure for the next step
(717 mg, 88%). Mp 99–101 ꢁC. dH (400 MHz: CDCl3):
0.88 (3H, t, J 6.8 Hz, CH2CH3), 1.26–1.31 (14H, m,
7 · CH2), 1.58–1.63 (2H, m, ArCH2CH2), 2.62 (2H, t, J
7.5 Hz, ArCH2CH2), 3.48 (3H, s, OCH3), 3.62 (3H, s,
OCH3), 3.91 (3H, s, OCH3), 3.92 (3H, s, OCH3), 5.90
(1H, s, H-2), 6.37 (1H, s, H-300), 6.80–6.82 (2H, m, H-30
and H-50), 7.62 (1H, s, H-600), 7.78 (1H, d, J 8.1 Hz,
2927 (CH2), 1644 (C@O). Rf (silica, EtOAc–hexane 1:1) 0.31.
5.62. 30-Allyl-20-hydroxy-acetophenone 58
To a stirring suspension of 20-hydroxyacetophenone 57
(5 mL, 42 mmol) and potassium carbonate (6.516 g,
47 mmol) in acetone (30 mL) was added allyl bromide
(4 mL, 46 mmol). The reaction was heated to reflux for
20 h. The reaction was then concentrated in vacuo,
taken up in water and extracted into ethyl acetate (2x).
The organic layer was then dried (MgSO4) and con-
centrated in vacuo to give an yellow oil. This was taken
up in diethyl ether, washed with 1 M potassium
hydroxide then dried (MgSO4) and concentrated in va-
cuo to give 20-allyloxy-acetophenone34 (3.70 g, 51%) as a
pale yellow oil. dH (400 MHz, CDCl3) 2.64 (s, 3H) 4.65
(td, 2H, 1.5 and 5.3 Hz) 5.32 (dt, 1H, 10.5 and 1.3 Hz)

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
2097
5.44 (dt, 1H, 17 and 1.5 Hz) 6.04–6.14 (m, 1H) 6.93–7.02
(m, 2H) 7.44 (td, 1H, 7.3 and 1.9 Hz) 7.73 (dd, 1H, 7.7
and 1.8 Hz). dC (100 MHz, CDCl3) 32.38, 69.78, 113.15,
118.58, 121.17, 130.81, 133.02, 133.90, 158.29, 200.32.
LRMS (EI): 176 (Mþꢂ, 21%) 161 ([MꢁMe]þ, 40%) 121
([Mꢁ(Me and CH2CCH2)]þ). HRMS: calcd for
in good agreement with literature.34 20-allyloxy-aceto-
phenone (2.518 g, 14 mmol) was heated to 200 ꢁC for
44 h to give 58 (2.518 g, 100%).51 Alternatively, 20-allyl-
oxy-acetophenone (5.959 g, 34 mmol) was irradiated in a
microwave set to 230 W and 210 ꢁC for 1 h with simul-
taneous air cooling to give 58 (5.959 g, 100%). dH
(400 MHz, CDCl3) 2.63 (s, 3H) 3.43 (d, 2H, 6.6 Hz)
5.06–5.11 (m, 1H) 5.95–6.06 (m, 1H) 6.85 (t, 1H, 7.7 Hz)
7.36 (d, 1H, 7.2 Hz) 7.62 (dd, 1H, 1.4 and 8 Hz). dC
(100 MHz, CDCl3) 27.17, 33.80, 116.39, 118.81, 119.63,
129.20, 129.79, 136.49, 136.87, 160.81, 205.15. LRMS
(EI): 176 (Mþꢂ, 90%) 161.1 ([MꢁMe]þ, 100). HRMS:
calcd for C11H12O2 176.0837 found, 176.0837.
extracted into dichloromethane (3x). The organic layer
was then dried (MgSO4) and concentrated to give an
orange solid. Recrystallisation (ethanol) yielded 61
(4.815 g, 42%) as a yellow solid. dH (400 MHz, CDCl3)
3.66 (d, 2H, 6.5 Hz) 3.89 (s, 6H) 3.98 (s, 3H) 5.07–5.12
(m, 2H) 6.00–6.11 (m, 1H) 6.53 (br s, 1H) 6.67 (s, 1H)
7.19 (s, 1H) 7.34 (t, 1H, 7.7 Hz) 7.53 (dd, 1H, 1.4 and
7.1 Hz) 8.15 (dd, 1H, 1.6 and 8.0 Hz). dC (100 MHz,
CDCl3) 34.15, 56.51, 56.94, 57.14, 98.19, 111.37, 114.00,
116.98, 121.74, 124.05, 124.50, 130.13, 133.72, 135.97,
138.75, 143.49, 145.88, 152.32, 152.94, 154.26, 173.76.
LRMS (EI): 368 (Mþꢂ, 100%). HRMS: calcd for
C21H20O6 368.1260 found, 368.1259.
1
C11H12O2 176.0837 found, 176.0838. H and 13C NMR
5.65. 3-Hydroxy-8-non-2-enyl-2-(2,4,5-trimethoxy-phen-
yl)-chromen-4-one 62
A mixture of 1-octene (7.15 g, 64 mmol) and Grubbs’
catalyst (30 mg, 0.04 mmol, 0.06 mol%) was stirred
under a static vacuum for 15 h, then passed through a
plug of silica eluting with hexane. Concentration gave
tetradec-7-ene (4.982 g, 80%) as a colourless liquid.52 dH
(400 MHz, CDCl3) 0.86–0.90 (m, 6H) 1.21–1.41 (m,
16H) 1.94–2.04 (m, 4H) 5.31–5.43 (m, 2H). dC
(100 MHz, CDCl3) 14.48, 23.04, 27.60, 29.23, 29.38,
30.02, 30.13, 32.15, 32.17, 33.00, 130.28, 130.75. LRMS
(EI): 196 (Mþꢂ, 9%), 84 (100). HRMS: calcd for C14H28
196.2191 Found, 196.2191. To a stirring solution of
tetradec-7-ene (0.539 g, 2.75 mmol) and Grubbs’ catalyst
(29 mg, 0.04 mmol, 3 mol %) in dichloromethane
(13.5 mL) under argon was added 61 (0.479 g, 1.3 mmol).
The reaction was heated to reflux for 5.5 h then con-
centrated in vacuo to give a brown solid. Recrystallisa-
tion (ethanol) yielded 62 (0.258 g, 26%) as a lilac solid,
which was used for the next step.
5.63. 1-(2-Hydroxy-3-allyl-phenyl)-3-(2,4,5-trimethoxy-
phenyl)-propenone 60
To a stirring suspension of 58 (1.779 g, 27 mmol) and
2,4,5-trimethoxy-benzaldehyde 59 (5.89 g, 30 mmol) in
ethanol (50 mL) was added potassium hydroxide (3.23 g,
58 mmol). The reaction mixture was stirred for 191 h
then acidified (2 M HCl) and extracted with ethyl acetate
(3x). The combined organic layers were then washed
with water and brine then dried (MgSO4) and concen-
trated in vacuo to give 60 (11.165 g, 116%) as an orange
solid. dH (400 MHz, CDCl3) 3.47 (d, 2H, 6.6 Hz) 3.92 (s,
3H) 3.94 (s, 3H) 3.96 (s, 3H) 5.08–5.14 (m, 2H) 5.99–
6.10 (m, 1H) 6.53 (s, 1H) 6.88 (t, 1H, 7.7 Hz) 7.13 (s, 1H)
7.36 (d, 1H, 6.5 Hz) 7.63 (d, 1H, 15.5 Hz) 7.82 (dd, 1H,
1.4 and 8.1 Hz) 8.21 (d, 1H, 15.5 Hz) 13.43 (s, 1H). dC
(100 MHz, CDCl3) 33.94, 56.49, 56.73, 57.08, 97.12, 112.20,
115.69, 116.31, 118.49, 118.57, 120.19, 128.04, 129.80, 136.29,
136.68, 138.51, 141.12, 143.71, 153.33, 155.46, 161.97, 194.66.
LRMS (EI): 354 (Mþꢂ, 69%) 323 ([MꢁOMe]þ, 100). HRMS:
calcd for C21H22O5 354.1467 found, 354.1468.
5.66. 3-Hydroxy-8-nonyl-2-(2,4,5-trimethoxy-phenyl)-
chromen-4-one 63
A stirring suspension of 62 (0.258 g, 0.6 mmol) and 10%
palladium on carbon (24 mg) in ethyl acetate (30 mL)
was placed under an atmosphere of hydrogen for 43 h.
The reaction was filtered through celite, the residue
washed with ethyl acetate and the combined filtrates
concentrated in vacuo to give a grey solid. Recrystalli-
sation (petrol–ethyl acetate 2:1) yielded 63 (0.212g, 82%)
as an off-white solid. dH (400 MHz, CDCl3) 0.87 (t, 3H,
6.7 Hz) 1.18–1.39 (m, 12H) 1.68–1.72 (m, 2H) 2.88 (t,
2H, 7.6 Hz) 3.88 (s, 3H) 3.89 (s, 3H) 3.98 (s, 3H) 6.53 (br
s, 1H) 6.67 (s, 1H) 7.18 (s, 1H) 7.32 (t, 1H, 7.7 Hz) 7.50
(d, 1H, 6.2 Hz) 8.12 (d, 1H, 6.6 Hz).
5.64. 8-Allyl-3-hydroxy-2-(2,4,5-trimethoxy-phenyl)-
chromen-4-one 61
To a stirring solution of 60 (11.15 g, 31 mmol) in
methanol (300 mL) and 16% aqueous sodium hydroxide
solution (37 mL, 148 mmol) at 0 ꢁC was added 15%
aqueous hydrogen peroxide (37 mL, 163 mmol) drop-
wise. The solution was stirred at 0 ꢁC for ten min then
sealed and placed in a refrigerator for 23 h. The reaction
was then acidified (2 M HCl) and extracted into chlo-
roform (3x). The organic layer was then washed with
brine, dried (MgSO4) and concentrated to give an or-
ange solid. This was taken up in methanol (300 mL) and
16% aqueous sodium hydroxide solution (37 mL,
148 mmol) at 0 ꢁC, then 15% aqueous hydrogen peroxide
(37 mL, 163 mmol) was added and the solution stirred at
0 ꢁC for the 5 min then sealed and place in a refrigerator
for 18 h. The reaction was then acidified (2 M HCl) and
5.67. 3-Acetoxy-8-nonyl-2-(2,4,5-triacetoxy-phenyl)-
chromen-4-one 64
In the same way as for 31d, a solution of 63 one (0.209 g,
0.5 mmol) and boron tribromide (2.3 mmol) in dichloro-
methane (17.3 mL) gave crude 11 (0.203 g, 107 %) as a
brown solid. A solution of crude 11 (0.203 g, 0.5 mmol),
N,N-dimethyl-4-aminopyridine (3 mg) and acetic anhy-
dride (0.30 mL, 3 mmol) in pyridine (2.5 mL) was then

2098
C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098
24. Guiles, J. W.; Johnson, S. G.; Murray, W. V. J. Org.
Chem. 1996, 61, 5169–5171.
stirred for 22 h to give 64 (0.109 g, 38%) as a brown oil.
This was used without further purification.
25. Ahmad, S.; Doweyko, L. M.; Dugar, S.; Grazier, N.; Ngu,
K.; Wu, S. C.; Yost, K. J.; Chen, B. C.; Gougoutas, J. Z.;
DiMarco, J. D.; Lan, S. J.; Gavin, B. J.; Chen, A. Y.;
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