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

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,^aStuart T. Caldwell,^aDonald B. McPhail,^bPhilip C. Morrice,^b

Garry G. Duthie^band Richard C. Hartley^a,*

^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.

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.¹The 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.²Vitamin 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

HO

O

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.⁴For 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

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

Bu^t

HO

^tBu

B

CO₂H

O

A

C

OH

^tBu

3 Trolox

5 Galvinoxyl radical

O

6i Vitamin E - myricetin hybrid

OH

Figure 2. Components of antioxidant assays.

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),⁵and 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) (ABTSꢁ^þ) 4 at

physiological pH (Fig. 2).⁶Furthermore, 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 mol^ꢁ1L s^ꢁ1, respectively) and has a better

reaction stoichiometry reducing four galvinoxyl radi-

OH

2 Myricetin

OH

O

Figure 3. Novel design of therapeutic antioxidant.

OH

B

1

7

6

R

O

OH

cals while vitamin

E

reduces only two.⁷This

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

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 bioavailability⁸and 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,¹⁰phaﬃaol,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

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

dihydrobenzofurans¹⁴and esters of gallic¹⁵and ferulic

acids¹⁶emphasise 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) oxidation¹⁷gave 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

(ii) AlCl₃, PhCl (69%)

20

OHC

R¹

19

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

OH

OMe

OR

OMe

(i) H₂O₂

NaOH

OH

OMe

BBr₃

CH₂Cl₂R¹

I

O

I

OH

R¹

MeOH

O

OMe

(ii) BnCl

K₂CO₃, KI

acetone

OBn

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)₂26 or

9-BBN

THF

R¹B

=

B

Scheme 1. Synthesis of modiﬁed ﬂavonoids.

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.¹⁸Aldol condensation with benzaldehydes 14

and 21 gave chalcones 22 and 23. These underwent

Algar–Flynn–Oyamada (AFO) oxidation¹⁷and benzyl

protection to give ﬂavonoids 24 and 25. Suzuki cross-

coupling¹⁹with alkylboronic acid 26 or alkylboranes 27,

prepared by hydroboration of 1-alkenes 28,²⁰gave

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,^21–24they have rarely been employed

in target-based synthesis previously.^25–28Generally,

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

(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

R¹

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,³⁰but 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.¹⁷Thus,

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

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

3

OH

R

CH Cl (87%)

2

R¹

O

(ii) HCl ) (84%)

(aq

AcHN

X

I

(iii) NaNO , H SO

4

n

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

OH

OBn

OMe

OBn

H O

NaOH

MeOH

2

O

2

O

OH

R

OMe

n

OH

X

OH

X

6g n =1, 37%

6i n =2, 87%

O

2

45 R = H, X = I 49%

43 R = H, X = I 49%

44 R = Et, X = Br 19%

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. Cyclisation³¹gave

the ﬂavone 56, which was then deprotected to give the

7-alkylﬂavonol 10 in good yield.

OMe

OBn

OAc

(i) BBr

3

2

R

O

R

O

CH Cl

2

OMe

(i) Ac O

2

DMAP

pyridine

1

OH

2

OR

2

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).³³O-allylation of

acetophenone 57 followed by Claisen rearrangement

gave C-allylated acetophenone 58 with complete regio-

control.³⁴Aldol condensation with aldehyde 59 and

AFO oxidation of the resulting chalcone 60 produced

ﬂavonol 61 in good yield. Chain extension by cross-

metathesis³⁵using 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.³⁷However, 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

17

HCl, MeOH

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).¹Therefore, 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

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

OH

CH Cl , 0 °C (87%)

N

51

52

2

N

H

H PO , H O

3

4

2

reflux 45 min

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

ArCO H

C H

10 21

O CAr

2

C H

10 21

OH

O

2

EDCI, DMAP

CH Cl

2

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,⁹increased 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

C H

10 21

O

Ar

C

10 21

H

Me SiOTf

3

OMe

CH Cl

2

Ar

OMe

OH

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

O

10 98%

Scheme 5. Synthesis of analogues with diﬀerent head groups.

(i) CH =CHCH Br, K CO

OH

O

2

3

OH

O

acetone (97%)

(ii) µw (99%)

57

58

OMe

OHC

MeO

KOH

EtOH

OMe

59

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

NaOH

MeOH

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

CH Cl

2

C H

6

13

OMe

OR

OMe

OR

n

H

C

9

19

H , Pd/C

2

EtOAc

O

OMe

OH

O

62 26%

63 R = Me

(i) BBr , CH Cl (98%)

(ii) Ac O, DMAP, py (38%)

2

3

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

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 prepared³⁸from 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.⁹In 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 CaH₂prior to use. Puriﬁcation by

column chromatography was carried out using Fisher

2086

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. d_H(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). d_C(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 (M^þ, 73%). HRMS: calcd for

C₁₇H₁₅O₆315.0869 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. d_H

(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. d_H(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). d_C

(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 (M^þꢂ, 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.⁴⁰d_H

(400 MHz, d-6 pyridine) 6.82–6.87 (m, 2H) 7.96 (s, 2H)

8.07 (d, 1H, 10 Hz) d_C(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 (M^þꢂ,

40%), 86 (100). HRMS: calcd for C₁₅H₁₁O₇303.0505

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. d_H(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). d_C

(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 (M^þꢂ, 100%). HRMS: calcd for

C₂₁H₂₂O₆370.1416 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 (M^þꢂ, 100%). HRMS: calcd for

C₃₀H₄₀O₆496.2825, 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. d_H(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). d_C

(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 (M^þꢂ, 7%) 134 (100).

HRMS: calcd for C₂₃H₂₆O₆398.1729 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). d_H(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). d_C(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 (M^þꢂ, 28%), 44 (100). HRMS: calcd for

C₂₇H₃₄O₆454.2355 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). d_H(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). d_C(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 (M^þꢂ, 100%). HRMS: calcd for

C₂₅H₃₀O₆426.2042 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. d_H(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). d_C(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

C₃₃H₄₇O₆539.3373 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. d_H(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). d_C(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 C₂₅H₃₁O₆427.2121 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. d_H(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). d_C

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). d_H(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). d_C

2088

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 C₂₅H₃₁O₆427.2122 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.⁴¹d_H

(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). d_C(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 (M^þꢂ, 73%) 91

(Bn^þ, 100). HRMS: calcd for C₁₅H₁₄O₃242.0943 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. d_H(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). d_C(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.⁴²d_H(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). d_C(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.⁴³d_H(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). d_C(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 (M^þꢂ,

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. d_H(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). d_C(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 C₂₅H₃₁O₆requires

[(MþH)^þ] 427.2121. t_max(golden gate)/cm^ꢁ1: 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.

d_H(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). d_C

(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 cm^ꢁ1. d_H(400 MHz, CDCl₃) 2.29

(s, 3H) 7.06–7.12 (m, 2H) 7.46 (m, 1H) 7.55–7.58 (m,

1H). d_C(100 MHz, CDCl₃) 20.99, 93.50, 121.14, 130.66,

130.77, 134.94, 150.89, 168.99. LRMS (EI) 262 (M^þꢂ,

34%) 220 (M^þꢂ–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.¹⁸mp 51.5–52 ꢁC. IR (GG) 1699,

1558, 1205 cm^ꢁ1. d_H(400 MHz, CDCl₃). 2.60 (s, 3H)

7.26–7.28 (m, 2H) 7.42 (s, 1H) 12.26 (s, 1H). d_C

(100 MHz, CDCl₃) 26.60, 103.77, 118.99, 127.83, 128.33,

131.25, 162.19, 204.21. LRMS (CI): 263 (MþH^þ, 98%)

262 (M^þ, 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 (M^þꢂ, 100%).

HRMS: calcd for C₂₀H₂₂O₅342.1467 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. d_H(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). d_C

(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

(M^þꢂ, 63%) 343.1 ([MꢁBn]^þ, 100). HRMS: calcd for

C₂₅H₂₂O₇434.1366 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.⁴⁵59–60 ꢁC) d_H(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). d_C(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 (M^þꢂ,

17%), 91.1 (Bn^þ, 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 cm^ꢁ1. d_H(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). d_C(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

(M^þꢂ, 100%). HRMS: calcd for C₁₈H₁₇O₅I, 440.0121,

found, 440.0118.

LRMS (EI): 544 (M^þꢂ, 30%), 453 (M^þꢂꢁBnÆ, 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. d_H(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

(M^þꢂ, 22%), 439 (M^þꢂꢁBnÆ, 100). HRMS: calcd for

C₂₄H₁₉IO₆530.0226, 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. d_H(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). d_C

(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 (M^þꢂ,

20%), 91 (Bn^þ, 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). d_H(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). d_C(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 (M^þꢂ,

42%), 425.0 ([MꢁBn]^þ, 100) 91.0 (Bn^þ). HRMS: calcd

for C₂₄H₂₁IO₅516.0434, 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 cm^ꢁ1. d_H(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). d_C

(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 (M^þꢂ, 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 cm^ꢁ1. d_H(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). d_C(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 (M^þꢂ,

15%), 299 (100). HRMS: calcd for C₂₉H₃₀O₆474.2042

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 (M^þꢂ,

6%), 299 (100). HRMS: calcd for C₃₁H₃₄O₆502.2355

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. d_H(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). d_C(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 (Bn^þ, 100%). HRMS: calcd for

C₄₁H₄₇O₆635.3373 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. d_H(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). d_C(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 (M^þꢂ, 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. d_H

(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). d_C(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 (M^þꢂ, 8%) 571

([MꢁBn]^þ, 12) 91 (Bn^þ, 100). HRMS: calcd for

C₄₃H₅₀O₆662.3607 found, 662.3600. HRMS: calcd for

C₄₂¹³CH₅₀O₆663.3641 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. d_H(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). d_C(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

C₃₃H₃₉O₆531.2747 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. d_H(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). d_C(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 (Bn^þ, 100).

HRMS: calcd for C₄₉H₆₃O₆747.4625 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. d_H(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). d_C

(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%). MþH^þrequires

C₂₉H₃₁O₁₀calcd 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. d_H(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. d_H(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). d_C(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%]. MþH^þ

requires C₃₁H₃₅O₁₀calcd 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. d_H(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 (M^þꢂ, 7%), 136 (100).

C₂₉H₃₁O₁₀calcd 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.⁴⁶d_H(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). d_C

(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.⁴⁷IR (ﬁlm) 2925, 1715, 1459 cm^ꢁ1. d_H(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). d_C(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

(MþNH₄^þ, 100%). LRMS (EI): 210 (M^þꢂꢁH₂O, 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 cm^ꢁ1. d_H(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). d_C(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

(M^þꢂ, 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.⁴⁸d_H

(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).

d_C(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.⁴⁹d_H

(400 MHz, CDCl₃) 2.13 (s, 3H) 3.78 (s, 3H) 6.83 (d, 2H,

9 Hz) 7.38 (d, 2H, 9 Hz). d_C(100 MHz, CDCl₃) 24.66,

55.85, 114.49, 122.37, 131.41, 156.82, 168.79. LRMS

(EI): 165 (M^þꢂ, 71%), 108 ([NH₂C₆H₄O]^þ, 100). HRMS:

calcd for C₉H₁₁NO₂165.0790 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 cm^ꢁ1. d_H(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). d_C(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 (M^þꢂ, 2%) 211

(M^þꢂꢁIÆ, 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. d_H(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). d_C(100 MHz, CDCl₃) 24.71, 27.16,

119.08, 119.60, 122.94, 129.58, 159.62, 168.86, 204.84.

LRMS (EI): 193 (M^þꢂ, 100%). HRMS: calcd for

C₁₀H₁₁NO₃193.0739 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. d_H(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). d_C(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 (Bn^þ, 100).

HRMS: calcd for C₄₁H₄₇O₆635.3373 found, 635.3374.

2094

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 (M^þꢂ, 100%). HRMS:

calcd for C₈H₉NO₂151.0633 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.⁵⁰This 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%). d_H(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). d_C

(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) (M^þꢂ, 18%)

405(þ407) ([MꢁBn]^þ, 35) 91.1 (Bn^þ, 100). HRMS:

calcd for C₂₆H₂₅BrO₅496.0855þ498.0869 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. d_H(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). d_C(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

(M^þꢂ, 31%) 439 ([MꢁBn]^þ, 35) 91 (Bn^þ, 100). HRMS:

calcd for C₂₄H₁₉IO₆530.0226 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) (M^þꢂ, 16%)

227(þ229) ([MꢁMe]^þ, 40), 191 (100). HRMS: calcd for

C₁₀H₁₁BrO₂241.9942þ243.9923, 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. d_H(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). d_C(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 (M^þꢂ) 425

([MꢁBn]^þ, 32%) 91 (Bn^þ, 100). HRMS: calcd for

C₂₄H₂₁IO₅516.0434 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. d_H

(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. d_H(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). d_C(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. d_H(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). d_C(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 (M^þꢂ, 10%), 261.1

(100), 147.0 (25), 45.0 (30). Found: 306.2194 C₁₉H₃₀O₃

requires (M^þ) 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. d_H(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). d_C

(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 (M^þ, 10%), 137.0

(100). Found: 182.0581 C₉H₁₀O₄requires (M^þ)

182.0579. Found: C, 59.43%; H, 5.50%. C₉H₁₀O₄

requires C, 59.34%, H 5.53%. t_max(golden gate)/cm^ꢁ1

3361 (OH), 1633 (C@O). R_fsilica EtOAc 0.56. Triﬂuoro-

:

2096

C. J. Bennett et al. / Bioorg. Med. Chem. 12 (2004) 2079–2098

C₁₉H₃₀O₃requires C, 74.47, H 9.87. t_max(thin ﬁlm)/

cm^ꢁ1: 3039 (OH), 2925 (CH₂), 1648 (C@O). R_f(silica

DCM) 0.26.

H-6⁰), 11.65 (1H, s, OH). d_C(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

(M^þꢂ, 1%), 261.1 (10), 195.1 (100). Found: 500.2775

C₂₉H₄₀O₇requires (M^þ) 500.2774. t_max(golden gate)/

cm^ꢁ1: 2915 (CH₂), 1664 (C@O), 1631 (C@O). R_f(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. d_H(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). d_C(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 (M^þꢂ, 5%), 261.1

(10), 195.1 (100). Found: 500.2776 C₂₉H₄₀O₇requires

(M^þ) 500.2774. t_max(golden gate)/cm^ꢁ1: 2913 (CH₂),

1747 (CO₂), 1685 (C@O). R_f(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

NaHCO₃solution (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%). d_H(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). d_C(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

(M^þꢂ, 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

C₂₉H₃₈O₆requires (M^þ) 482.2668. t_max(thin ﬁlm)/cm^ꢁ1

:

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 NaHCO₃solution

(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. d_H(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). R_f(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. d_H(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). d_C(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 (M^þꢂ, 21%) 161 ([MꢁMe]^þ, 40%) 121

([Mꢁ(Me and CH₂CCH₂)]^þ). HRMS: calcd for

in good agreement with literature.³⁴2⁰-allyloxy-aceto-

phenone (2.518 g, 14 mmol) was heated to 200 ꢁC for

44 h to give 58 (2.518 g, 100%).⁵¹Alternatively, 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%). d_H

(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). d_C

(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 (M^þꢂ, 90%) 161.1 ([MꢁMe]^þ, 100). HRMS:

calcd for C₁₁H₁₂O₂176.0837 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. d_H(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). d_C(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 (M^þꢂ, 100%). HRMS: calcd for

C₂₁H₂₀O₆368.1260 found, 368.1259.

1

C₁₁H₁₂O₂176.0837 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.⁵²d_H

(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). d_C

(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 (M^þꢂ, 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. d_H(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). d_C

(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 (M^þꢂ, 69%) 323 ([MꢁOMe]^þ, 100). HRMS:

calcd for C₂₁H₂₂O₅354.1467 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. d_H(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.;

Dorso, C. R.; Seraﬁno, R.; Kirby, M.; Atwal, K. S.

J. Med. Chem. 2001, 44, 3302–3310.

Acknowledgements

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J. Chem. Soc., Perkin Trans. 1 2000, 2591–2599.

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Scottish Enterprise Proof of Concept Fund. Scottish

Executive Environment and Rural Aﬀairs Department

(SEERAD).

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

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