cliapter 1 - inflibnetshodhganga.inflibnet.ac.in/bitstream/10603/18445/8/08_chapter 1.pdf ·...

Cliapter 1

(Benzo[61furanScajfoftls: natura{ protfuct, synthesis ant! 6iofogica{ activity

Chapter I Ben=o[b]furan scaffolds: Natural product, Synthesis and biological activity

1.1 Introduction

Nature is a phenomenal source of biologically active simple and complex scaffolds,

which are originated from eclectic array of natural sources and prepared through various

selective enzymatic reactions. One such scaffold is Benzofuran (coumarones)1 which was

first isolated in coal tar by Kraemer and Spiller in 1890, since then tremendous work has

been done in isolation and characterization of this class of compounds.

Benzofurans are usually important constituents of plant extracts used in traditional

medicine' and some of them play an important role in the natural defence mechanisms of

their sources. Naturally occurring substituted Benzofurans derivatives are in great demand

because they possess diverse biological activities such as modulators of androgen

biosynthesis (furano steroids),2 as inhibitors of 5-lipoxygenase, as antagonists of angiotensin

II receptors/ as blood coagulation factor Xa inhibitors,4 and as ligands for the adenosine A,

receptor.5 Among them, 2-arylbenzofurans are of particular interest which are central

component of a diverse class of biologically active heterocyclic natural products. Many 2-

arylbenzofuran derivatives are known to exhibit a broad range of biological activities,

including anticancer,6 antiproliferative/ antiviral,8 antifungal,9 immunosuppressive,10

antiplatelet, 11 antioxidative, 12 insecticidal, 13 antiinflammatory, 14 antifeedant, 15 and cancer

preventative activity. 16 These compounds are also important calcium blockers 17 and

phytoestrogens. 18 Their application in organic light emitting devices (OLED) 19\

agrochemicals, 19b pharmaceuticals, 19

c·20 cosmetics,21

• polymers and dyes19 prompted

development of various synthetic methods.

1.2 Characterization of benzo[b]furan

Table 1: UV-data ofbenzo[b]furan derivatives.22

S. No. RI Rz A max·· nm (log e) I H H 244(4.03), 274 (3.39), 281 (3.42) II Cl H 246 (4.15), 276 (3.53), 282 (3.53) III Me H 246 (4.09), 276 (3.51), 282 (3.51) IV Ph H 210 ( 4.29), 302 ( 4.52), 316 ( 4.39) v OMe H 219 (3.70). 271 (3.23). 277 (3.20) VI H Me 248 (3.97), 276 (3.40), 282 (3.40)

3ethanol

Chapter 1 Ben::o[b}furan scaffolds: Natural product, Synthesis and biological activity

The structure of benzo[b]furan have been assigned by UV, IR and NMR spectroscopy. The

unsubstituted benzo[b]furan (Ii2 shows three characteristic peaks at 244, 274, and 281 nm in

UV spectrum (Table I). The presence of electron withdrawing and electron donating group

at position 2 or 3 to furan ring caused red or blue shift.

A 1HNMR and 13C NMR studies23 of the unsubstituted benzo[b]furan (I) and 5-

chlorobenzo[b]furan (VII) are summarized in Table 2.

VII

Table 2:

Benzo(b]furan (I) 5-Chlorobenzo(b]furan (VII) Carbon 1H NMR 13C NMR 1H NMR 13C NMR

2 ------~7~.5~5~(~d.~2~.2~H~z~)-------714~4~.8~1~----~7.~63~(~d~,2~.2~H~z) ______ 714~6~.2~9~

3 6.70 (dd, 2.2, 0.8 Hz) 106.48 6.71 (dd, 2.2, 1.0 Hz) 106.26 4 7.57 (dd, 7.8, 1.6 Hz) 121.12 7.56 (d, 2.2 Hz) 120.78 5 7.19 (td, 7.2, 1.6 Hz) 122.65 128.37 6 7.26(td, 7.2, 1.6Hz) 124.15 7.24(dd,8.8,2.2Hz) 124.50 7 7.49 (ddd, 7.8, 1.6, 0.8 Hz) 111.35 7.42 (d, 8.8 Hz) 112.34 8 154.91 153.38 9 127.37 128.80

Th~ mass spectrum of benzo[ b ]furan24e.f (I) is characterized by an intense molecular

ion peak at 118 as the base peak; its high stability is due to extension of the conjugation of

the furan ring to the benzofuran system and to lack of easily cleaved bonds.

CQ-().} -a-} M+,lm/z 1 ~ (100%~ • ? H .o. 0{11 H

J-co .. ~cHy +·

Hl . 0 ® ()><HJ ..:.!::!_. ® or (±) I "":::: H ~ ~ .0 CHO

Ia lb lc mlz 90 (33%) \ mlz 89 (30%) ;

v ~-C2H2

CsH3+

mlz63 (16%)

Figurel: Mass spectrum ofunsubstituted Benzo[b]furan.

The two major fragments at m!z 89 and 90 are due to loss of ·cHO and CO from the

parent ion, respectively. Loss of CO may be envisaged as resulting in the benzocyclo

propene radical ion (Ib) and/or (Ic) (Figure 1). Elimination of acetylene from mlz 89 ion

may also arise directly from the parent ion Studies with deuterated benzo[ b ]furan have

2


shown that partial hydrogen scrambling occurs in the molecular ion before fragmentation in

contrast to the minor degree of scrambling observed with furan itself.

The frequent natural occurrence of benzofuran ring system, coupled with the wide

range of interesting biological activities that they display, has made these scaffolds of

considerable interest to biologists, pharmacologists, and synthetic chemists. Exploration of

these compounds has been aided by the remarkable advances in the field of new techniques

of isolation as well as modern scientific instruments employed for the structure elucidation

along with synthetic renovation of historical methods.

A review by G. D. McCallion25 on benzofuran scaffolds was published in 1999,

which focused on the isolation of various classes of natural products, the chemistry of these

privilege structures and bioactivity associated with them. Soon after this articulated report, a

review by Gilchrist et a/.26 on the synthesis of various benzofuran skeletons was appeared

which contained a brief overview of the synthetic methodologies developed during March

1999 to February 2001.

Since then the number of new molecules has considerably increased, their biological

activities have been better documented, and significant efforts have been devoted to the

synthesis of these molecules. Due to these advances, an updated review covering the new

developments in this area since 1999 is warranted. This review will emphasize the isolation;

biological activities exhibited by these naturally occurring compounds particularly those

having isolated benzofuran scaffolds derived from various sources, and syntheses of

benzofuran derivatives developed during last eight years.

1.3 Naturally occurring benzo[b]furans and dihydrobenzo[b]furans

1.3.1 2-Alkylbenzo[b)furans

Benzofurans functionalized at position 2 with various alkyl and aromatic

functionalities are chief constituent of many natural products. Recently, 2,3-unsubstituted

benzofuran, 5-benzofuran carboxylic acid-6-formyl methyl ester 27 (1) has been isolated

from the plant Morinda citrifolia, Linn., which are being used as deobstruent and

emmenagogue, infantile diarrhea, dysentery, relief of cough, nausea, asthma, spleen and

colic enlargement.

Oat et a/.28 isolated a new benzofuran derivative, named gymnastone 2 from the

methanol extract of the aerial part of Gymnaster koraiensis, together with known viscidone

(3) by repeated column chromatography.

3


Ligularia stenocephala (Maxim.) Matsum. et al. Koidz (Compositae) is widely

distributed in China. The whole plant has been used as a Chinese folk medicine in the

treatment of edema and scrofula.29 Numerous benzofuran derivatives have been previously

isolated from L. stenocephala. Recently four new benzofuran derivatives,30 named as

ligustenin A (4), B (5), C (6) and D (7) were isolated from the roots of L. stenocephala.

Ligustenin A (4) was found to exhibit potent anti-tumor activity against HL-60 (human

leukemia cells), Bel-7402 (human hepatoma cells) and H0-8910 (human ovarian neoplasm

cells) with IC50 values of 18.6, 27.6 and 57.5 J..tM, respectively.

The polyspore-derived mycobionts of Pyrenula sp. afforded two benzofuran

derivatives 8 and 9313• The latter was previously isolated from mycelium of Aspergillus

amstelodami IF0-6667.31b

MeO

MeO 4

HO

8

1.3.2 2-Arylbenzofurans

I ~ OH ~'-':: OH

O h 0 OH

2

OY'IfCHO

0 '~ MeO OMe

MeO

MeO

OMe HO

OMe 0

HOI(Y) ... ,J' 0~0 \_OH

3

OMe

OMe

9

Benzo[b]furans functionalized at 2-position with aryl moiety are ubiquitously

encountered in many natural products. Pacher et al. isolated eleven 2-arylbenzofurans,

stemofuran A-J, (10-19i2 from the methanolic extract of root of Stemona collinsae, and

tested their antifungal activity against five microfungi using the microdilution technique

linked with digital image analysis of germ tubes. Stemofuran 8 (11) showed good antifungal

4

Chapter 1 Ben=o[b]furan scaffolds: Natural product, Synthesis and biological activity

activity against the four parasitic fungi, Alternaria citri (EC5o = 5 IJ.g/mL), Fusarium

avenaceum (EC50 = I 0 f.!g/mL), Pyricularia grisea, (ECso = I .4 fJ.g/mL) and Botrytis cinerea

(EC50 = 8 IJ.g/mL). Stemofuran E (14) showed strong antifungal activity against C. herbarum

with ECso of 0.8 fJ.g/mL.

R1 R2 Entry R, R2 R3 ~ R5 oo-uR, Stemofuran A (10) H OH H OH H

Stemofuran C (12) H OH CH3 OH H R5 R4

Stemofuran D (13) CH3 OH CH3 OCH3 CH3

OH R1 R2 Stemofuran B (11) H OH H OCH3 H

~R, Stemofuran E (14) CH3 OH CH3 OCH3 H

Stemofuran F (15) CH3 OH CH3 OCH3 CH3 R5 R4

Stemofuran J (19) CH3 OCH3 CH3 OCH3 H

OH R1 R2 Stemofuran G (16) CH3 OH CH3 OCH3 H

~c~ Stemofuran H (17) H OH CH3 OH CH3 I .& ~ ~ /; Ra

Rs R4 Stemofuran I (18) CH3 OCH3 CH3 OCH3 H

A new benzofuran derivative 23 has been isolated from the leaves of Styrax

ferrugineus Ness et. a/.33a Mart., along with the known nor-lignan type benzofurans 20-22.

Compounds 20 and 21 exhibited antifungal and antibacterial activities against C.

sphaerospermum, C. albicans and S. aureus, with MIC of 5, IO, IO and IO, I2, 10 fJ.g/mL

respectively whereas compounds 22 and 23 inhibited only S. aureus and C. albicans, with

MIC of 15, I5 and 20, 20 fJ.g/mL respectively.

An ethanolic extract from the stems of Styrax campo rum Pohl (Styracaceae ),

popularly used in gastrointestinal diseases, also afforded benzofuran lignans,33b egonol (20)

and homoegonol (26). Egonol (20) showed cytotoxicity against C6 (rat glioma) with ICso 3.2

fJ.g/mL and against Hep-2 (larynx epidermoid carcinoma) with IC50 3.6 f.!g/mL, and

homoegonol (26) exhibited cytotoxicity against C6 with IC50 4.9 IJ.g/mL and against HeLa

(human cervix carcinoma) with ICso 5.3 IJ.g/mL.

A new benzofuran, 5-[3" -(2-methylbutanoylloxy)propyl]-7-methoxy-2-(3 ',4'

dimethoxyphenylbenzofuran (24) was isolated from the seeds of Styrax officina/is, the plant

was traditionally used by Romans, Egyptian, Phenicians, and lonians to treat a variety of

ailments and as a incense 34

A new 2-aryl benzofuran,35 oryzafuran (25) was isolated from the black colored rice

bran of Oryza sativa cv. Hueugjinjubyeo. The compound 25 showed strong antioxidative

5

Chapter 1 Ben::o[b]furan scaffolds: Natural product, Synthesis and biological activity

activity in a 1, 1-diphenyl-2-picrylhydrazyl free radical scavenging assay with EC50 of 1.58

f..lg/mL.

Yao et a/.36 isolated two new benzofuran derivatives, named gnetucleistol A (27),

and C (28) together a known compounds, gnetifolin A (29), from ethylacetate extract of

Gnetum c/eistostachyum C.Y. Cheng (Gnetaceae).

R R, R2 20 H -CH2-21 H CH3 CH3 22 Glu -CH2-23 Glu CH3 CH3 HO

c::y:rO:Mo OMe HO

26

COOMe OH

HO:cQ--6 I '\: ~ !J OH HO .,.:; 0

24 25

OMe

OH

Morus macroura Miq. belongs to the genus morus of the family Moraceae,

distributed in the south part of China, especially in Xishuangbanna, Yunnan province. The

ethanol extract of the barks of Morus macroura resulted in the isolation of five benzofuran

derivatives,37 macrourin D (30), macrourin B (31), 2-(3,5-dihydroxyphenyl)-5,6-

dihydroxybenzofuran (32), moracin M (33) and mulberroside C (34).

OH

-H H

30 (~-OH HO

HO

"P-LJC(" HO OH

H~ HO . OH

32 33

OH HO

OH

-H :.~----H

31 r~-OH HO

34

HO

OH

6


Artocarpus species are evergreen trees distributed over tropical regions of Asia, and

some members are used as traditional folk medicines in Indonesia, Thailand, Sri Lanka and

China. Artocarpus dadah is known as "Tam pang" in Kalimantan, Indonesia, and its bark has

been used as an ingredient in the betel nut chewing mixture. The ethyl acetate-soluble extract

of the bark of Artocarpus dadah Miq. (Moraceae) afforded a benzofuran derivative38 3-(y,y

dimethylpropenyl)moracin M (35). The compound 35 showed weak inhibitory effects

against both cyclooxygenase-1 (COX-I) and cyclooxygenase-2 (COX-2) and in a mouse

mammary organ culture assay, having IC50 values of 4.9, 31.86 and 66.7 J..lg/mL,

respectively.

OH OH HO

HO HO OH OMe

35 36 37

~

HO

HO

38 39 40

HO HO HO

42 43

HO HO HO

44 45

7

Chapter 1 Benzo[b]furan scaffolds: Natural product, Synthesis and biological activity

Hakim et a/.39 isolated a new prenylated arylbenzofuran, named artoindonesianin 0

(36), from Artocarpus gomezianus Wall. Ex Tree. (Moraceae), which is commonly found in

the western part of Indonesia and are locally known as 'tam pang burung'.

Soekamto et a/.40 isolated two isoprenylated 2-arylbenzofurans, artoindonesianins X

(37) and Y (38), from the roots and tree bark of Artocarpus .fretessi. Compounds 37 and 38

showed moderate activity against the brine shrimp Artemia salina with LCso of 78.7 and

294.1 Jlg/mL respectively.

Puntumchai et a/. 41 isolated two new stilbene derivatives, lakoochins A (39) and B

( 40), from the roots of Artocarpus lakoocha. Lakoochins A (39) and B ( 40) exhibited

antimycobacterial activity with the respective MIC values of 12.5 and 50 Jlg/mL. The

compound 39 was cytotoxic against the BC (breast cancer) cell line (IC5o 6.1 Jlg/mL) but

inactive (at 20 Jlg/mL) towards KB (nasopharyngeal carcinoma) cells, and compound 40

possessed cytotoxicity against the BC and KB cell lines with IC5o values of 3.1 and 6.1

Jlg/mL, respectively.

HO

48R=H 49 R= OH

50

Chen et a/.42 isolated three new 2-arylbenzofurans, artopetelins A-C (41-43), from the

ethanol extract of the root barks of A. petelotii. Further phytochemical investigations on the

ethanol extract of the root barks of Artocarpus petelotii GAGNEP afforded four novel

isoprenylated 2-arylbenzofuran derivatives,43 namely artopetelins 0-G (44-47). Their

structures were elucidated by spectroscopic methods, mainly by 2D-NMR techniques.

Machaerium multiflorum Spruce (Fabaceae) is a native Amazonian Iiane found throughout

the tropical part of Mexico and as far as South America. The ethanolic extract of the stem

bark of M multiflorum produced machaeriol B ( 48), D ( 49), machaeridiol C (50).44

Machaeriol B (48) demonstrated in-vitro antimalarial activity (IC50 120ng/mL) against

Plasmodium falciparum W-2 clone. The Machaeriol D (49) showed activity against S.

aureus A TCC 29213, and methicillin-resistantS. aureus ATCC 43300 (MRSA) with IC50 of

25 and 30 Jlg/mL, respectively. The compound Machaeridiol C (50) showed antifungal

8

Chapter 1 Ben=o[b}furan scaffolds: Natural product, Synthesis and biological activity

activity against Candida albicans and Cryptococcus neoformans having IC50 45 and 25

J..Lg/ml respectively as well as antibacterial activity against Mycobacterium intracellulare and

Aspergil/usfumigutus with ICso value of 3.3 and 2.5 J..Lg/mL respectively.

Two novel tetrabrominated benzofuran derivatives,45 named iantherans A (51) and B

(52) have been isolated from the ethyl acetate soluble fraction of an Australian marine sponge

of the genus Ianthe/la. The unique structures comprised of 2,3-bis(sulfooxy)-1 ,3-butadiene

and two brominated benzofuran moieties were determined by spectroscopic and chemical

methods. lantheran A has a (Z,Z)-1,3-butadiene moiety, whereas iantheran B is the

geometrical isomer possessing a (Z,E)-1 ,3-butadiene moiety. The inhibitory activities of the

iantherans A (51) and B (52) against NaK-ATPase were demonstrated with IC50 of 4 and 7

J..LM respectively.

Br

HO 51

OH

Br

Br OH

R4

53 R1 = R5 = H, R2= R3 = R4 = OH 54 R1 = R3 = R4 = OH, R2 = H, R5 =CHO 55 R1 = R3 = R4 = OH, R2 ~.R5 = CHO

Br

OH

52

Halabalaki et a/.46 isolated three new 2-phenyl-benzofurans, ebenfuran I (53),

ebenfuran II (54) and ebenfuran III (55), from the methanolic extract of Onobrychis

ebenoides. The relative binding affinity (RBA) with estrogen receptor for ebenfuran I (53)

and ebenfuran II (54) was 0.29% (IC50 0.046 J..LM) and 0.28% (IC50 0.043 J..LM) respectively.

Erythrina poeppigiana is widely distributed in Central and South America and is

cultivated in Okinawa prefecture, Japan as an ornamental plant with brilliant orange colored

flowers. A new 2-arylbenzofuran,47 erypoegin F (56) has been isolated from the root of E.

poeppigiana.

9


Bioactivity-guided fractionation of the ethanolic extract of root of Psorothamnus

arborescens produced a new 2-arylbenzofuran, 2-(2'-hydroxy-4',5'-methylenedioxyphenyl)-

6-methoxybenzofuran-3-carbaldehyde 57.48

Belofsky et a/.49 isolated two new 2-arylbenzofuran aldehydes spinosans A (58) and

B (59) from the organic extracts of Dalea spinosa. Spinosan A is a potent new potentiator of

antibiotic activity against multidrug-resistant (MDR) Staphylococcus aureus.

OHC HO

HO OMe OMe

56 57 58

H

HO OH

OMe OMe

59 60

Pueraria /obata (WILL D) OHWI [Leguminosae] is a deciduous woody vine and is

widely distributed in temperate regions of Far Eastern Asia including Korea, Japan, Taiwan,

NE China, and FE Russia. Traditionally this species has been used as an antipyretic,

antimigraine, and antispasmodic agent and studied extensively on the constituents and

bioactive substances. A new 2-arylbenzofuran,50 puerariafuran (60) was isolated from

methanol extract of the roots of Pueraria /obata as active constituents for advanced

glycation end products (AGEs) with IC50 of 1.5 f..!g/mL.

R1

61 R1 R2

62 OMe ~ R1 R2 R3

650H H ~ 63 H CHO 66 OH OMe ~ 64 H OMe 67 -OCH20- ~

68 -OCH20- -CH2COCH3

69 -OCH20- H)--<OH

10

Chapter I Ben::o[b]furan scaffolds: Natural product, Synthesis and biological activity

Maxwell et a/.51 isolated nine benzofuranoid neolignans (61-69) and a dineolignan (70) from

the acetone extract of the aerial part of Piper aequale.

The tree bark of Machilus odoratissima NEES (Vietnamese name Khao nham) is

used in the folk medicine as antiseptic and anti-inflammatory remedies. The leaves are used

to treat snake bite and bum wounds. 52 The methanol extract of the bark of M odoratissima

furnished benzofuran lignan,53 named odoratisol A (71) and a known (-)-licarin A (72) The

structure as well as absolute configurations were established by spectroscopic and CD

technique.

Millettia pendula BENTH timber is produced in Myanmar and Thailand and is called

Thinwin in Myanmar. Takahashi et a/.54 isolated millettilone B (73), from the methanol

extract of M pendula.

Lin et a!. 55 isolated two benzofuran-type neolignan (74 & 75) from chloroform

extract of the leaves of Taiwania crytomerioides Hayata.

The light petroleum and acetone extract of the core of Hibiscus cannabinus afforded

four new benzofuran lignans56 designated as boehmenan H (76), boehmenan K (77),

boehmenan (78), boehmenan 0 (79) and their structures were assigned through NMR

studies.

MeO O:r HOh, .. I"=::~ y 0 ~

MeO OMe 71

MeO ~ 0 HO h,,.. I""=:: ~ ~OMe ~ 0 ~ HO~c{~

72 OMe 73 O H0¥0H MeO -..;:: -~ ..... ~ ~

MeO~ 0 OMe 74

0 HO~ 6-n..... 1

""=:: OH

\d 0 ~ 75 OMe

Lee et a!. 57 isolated a benzofuran lignan, (-)-morrisonicolanin (80) from acetone

extract of the heartwood of Picea morrisonicola Hayata. Stilbenolignan58 gnetucleistol F

(81), and gnetofuran A (82) were isolated from the lianas of Gnetum c/eistostachyum C. Y.

CHENG (Gnetaceae) and their structure and absolute configuration were determined through

NMR and circular dichroism methods. The compound 81 and 82 showed moderate anti

inflammatory activities against TNF-a. with IC50 0.103 f..tg/mL and 0.109 f..tg/mL

respectively, and compound 81 also showed potent anti-oxidant activity with IC50 of 6.36

f..tg/mL.

II


0

Meo~0 HO)l)

76

0

Meo~0 HO)l)

HO

R

HO~O--,,--·

MeO

OMe

OH

78R= H 79 R= OMe

81 R=OMe 82R= H

0

H _...OH .. ~::-

OH OMe

R OMe 80

OMe

OH OH

HO OMe

OH

Herpetospermum caudigerum grows widely in the southwest of China, Nepal and the

northeast of India. In Tibet it is used in traditional medicine for the treatment of liver

diseases, cholic diseases, and dyspepsia. 59 The ethyl acetate fraction ofthe ethanol extract of

the seed of Herpetospermum caudigerum, afforded a new benzofuran type lignan60 (83). The

study showed that compound 83 is effective in reducing the replication and expression of

HBsAg and HBeAg, and has significant inhibitory effect on HBV -DNA.

HO ··''\

aOH

~

OH 0 OH

85 84

OH OH

aOH HO HO

.o~\\

OH 0 OH 0 OH

87 OH HO

12


A new benzofuran dimer, kynapcin-2461 (84), isolated from fruiting bodies of

Polyozel/us multiflex (Therephoraceae) and was shown to noncompetitively inhibit prolyl

endopeptidase (PEP) with an ICso value of 1.14 f.J.M.

Ochna afzelii 0/iv. (Ochnaceae), a small tree of the Ochnaceae family, found in

groups on rocky peaks in forest areas of tropical Africa, is traditionally used in the treatment

of jaundice, toothache, female sterility, menstrual complaints, lumbago and dysentery. The

methanol extract ofthe stem bark ofthe tree afforded two novel biflavonoids,62 isolophirone

C, (86) and dihydrolophirone C, (87) with the known lophirone C, (85).

1.3.3 Benzofuran-glycosides

Hamed et a/. 63 isolated three new benzofuran glycosides (88-90) from the aerial parts of the

Psoralea plicata Del., along with psoralic acid (6+---1 )-0-13-D-glucopyranoside (91) (£-form)

previously isolated from the aerial parts of the same plant.

OAc OAc

A cO

O AcO O AcO

0 0

~OCH,CH, ---'-----:r OAc 0 0

~OH OAc

88 89 90

OAc 91

Tyrolobibenzyl A (92), and B (93) were isolated from the methanolic extract of Scorzonera

humilis (Asteraceae) of Tyrolean origin.64 Traditionally, it has been used as a remedy for

wound healing and gastro-intestinal disorders.

The fruits of Psoralea corylifolia L. (Fabaceae), well known as a traditional Chinese

medicine "Buguzhi", are widely applied for the cure of gynaecological bleeding, vitiligo and

psoriasis. The methanol extract of the fruits of Psoralea corylifolia, afforded two new

benzofuran glycosides, called psoralenoside (94) and isopsoralenoside (95) together with

13


nine known compound,65 they were identified as psoralen, isopsoralen, psoralidin,

corylifolin, corylin, corylifolinin, isobavachalcone, corylifol A, and bakuchiol.66 Their

structures were elucidated by detailed spectral analyses including extensive two dimensional

(20) NMR spectra.

OAc

RO OR

O~OR ~COOH

O OR O 0 0 CH20H

H~OH 92 R=R1=H 93 R= H, R1=0H

OH 96 R1= R2 = H 97 R1= 13-D-glc, R2 = H

98 R1= H, R2 = 13-D-glc

99 R1= R2 = 13-D-glc

94 OH

HO

Ho-{4· L(

OR1 104 R1 = 13-glc, R2 = H

105 R1 = H, R2 =13-glc

106 R1 = R2 = H

R1 R2 R3 100 Glu H H 101 H Glu H 102 H Glu H 103 H H S03H

OH

The HPLC analyses of the n-hexane, dichloromethane and ethylacetate fractions of

the sterile root cultures of Anigozanthos preissii, furnished three glucosides of anigopreissin

A (97-99) and a benzofuran-type resveratrol dimer anigopreissin A (96).67

The n-BuOH-soluble fraction of a methanol extract of the leaves of Glochidion

zeylancium (Gaertn) A. Juss, afforded three lignan glucosides,68 dihydrodehydrodiconiferyl

Alcohol 4-0-J3-o-Giucopyranosides (100), dihydrodehydrodiconiferyl Alcohol 9-0-J3-o

Giucopyranosides (101}, dihydrodehydrodiconiferyl Alcohol 9'-0-J3-o-Glucopyranosides

(102) and a neolignan sulphate, dihydrodehydrodiconiferyl 9'-0-sulfate (103).

14


Two new stilbene dimer glucosides,69 resveratrol (E)-dehydrodimer 11-0-,8-D

glucopyranoside (104) and resveratrol (E)-dehydrodimer 11 '-0-.B-D-glucopyranoside (105),

were isolated together with the known resveratrol (E)-dehydrodimer (106) from Vitis

vinifera cell cultures. Compounds 104 and 106 demonstrated IC50 values of 5.2 and 4.3 !J.M

respectively, against COX-1, and 7.5 and 3.7 !J.M respectively against COX-2.

1.3.4 Naturally-occurring naphthofurans

The plant Caesalpinia crista L., known locally as 'Taepee' in Thai, is a climber

distributed from India and Ceylon through most of Southeast Asia to the Ryu-Kyu Islands,

Queensland, and Caledonia. The leaves, roots, and fruits of this plant are being used as a

tonic and an antiperiodic. The hexane extract of the root and stem of the plant afforded five

new benzofuran based cassane-type diterpenoids (107-111).70

Ahmed et a/.71 isolated three new furanoeremophilanes from the aerial parts of

Senecio asirensis (N. 0. Asteraceae), named as asirensane-A (112), asirensane-B (113),

asirensane-C (114) along with two known furanoeremophilanes 9-methoxyl-4, 11-

dimethylnaphtho[2,3-b ]furan, 14-nordehydrocalohastine (115), earlier reported also from

Senecio linifolius728 and 4, 11-dimethylnaphtho[2,3-b ]furan-6, 9-dione designated as

maturinone (116) previously isolated from Caca/ia decomposita 72b.

107 R1 = C02Me, R2 =Me, R3 = H

108 R1 = C02H, R2 =Me, R3 = H

109 R1 = C02Me, R2 =Me, R3 = OH

110 R1 = C02Me, R2 =Me, R3 = OCOMe

111 R1 = C02Me, R2 = CHO, R3 = H

MoO ~'1, Me

~ 113

~e ~a'

OMe

112 R= CH20H 115 R= H

~e ~a'

0 116

P. decompositum is taken orally in Mexico and the United States, usually in the form

of aqueous decoctions, as a remedy for diabetes. 3-Hydroxycacalolide (117), epi-3-

hydroxycacalolide (118), cacalone (119) and epicacalone (120) were also isolated from the

15


aqueous nonalkaloid fraction of P. decompositum. The 1:1 mixture of 117/118 showed

potent antihyperglycemic activity at 1.09 mmol/kg dose in oblob mice.73

Ito et a/.74 isolated three new naphthoquinones and their analogues, named

Avicequinone A-C (121-123) and avicenol A-C (124-126), respectively, from the stem bark

of the Avicennia alba (Avicenniaceae).

Mo

0 ~OH o OH

121

c(v 117 R1= OH, R2 = CH3, 118 R,= CH3, R2 = OH

o)roH

0 123

1 2

119 R1= OH, R2 = CH3, 120 R1= CH3, R2 = OH

~OH 124

:¢5 OMe

125

0

~ HO~ 127

0 OMe

MeOWo I I .o

OH

135

139

128, R1 = CH3, R2 = OH 129 R, = OH, R2 = CH3

$ 0

136

130

HO$ 0

137 O:;QOAo OMe

141

0

122

~OH OMe

126

R2Wq':'o I~ R3 .o

R.t R, R2 R3 R4

131 H OMe H H 132 H OMe H OH 133 Me OMe H H 134 Me OMe H OH

HOJCQ--<

138

O(Q 0

142

Psacalium radulifolium, a member of the matarique complex of medicinal plants, are

traditionally used for treating diabetes, kidney pain, and rheumatism and applied as a wash

or cataplasm to treat wounds and skin ulcers.The n-hexane fraction of the roots of P

radulifo/ium afforded cacalol (127), cacalone (128), epi cacalone (129) and radulifolin C

(130). Cacalol 127 showed anti microbial activity against S. aureus, E. coli, P. aeruginosa,

16


Proteus micranthus, and C. albicans with MIC (f.!g/mL) of 0.012, 0.025, >0.4, 0.012 and

0.012 respectively.75

A petroleum ether-diethyl ether extract of the whole plants of Colombian S.

madagascariensi afforded new cacalolides (131-135) and which were confirmed by

spectroscopic analysis and/or by single crystal X-ray diffraction.76The series of naturally

occurring furannonapthoquinones (136-138) were isolated from the stem barks of

Newbou/dia laevis, along with the rare atraric acid (139).77

The methanol extract of dried stem bark and leaves of T. cuneata, which showed

inhibition for mitochondrial and microsomal lipid peroxidation and weak antibacterial

activities, afforded two furanoeremophilane-type sesquiterpenes, 13-hydroxy-14-

nordehydrocacalohastine (140) and 13-acetoxy-14-nordehydrocacalohastine (141) along

with a known compound, maturinone (142). The antioxidative activities of these compounds

were evaluated. The NADH-dependent mitochondrial and NADPH-dependent microsomal

lipid peroxidations were inhibited with IC50 values (f.!M) of 16.4 and 41.6 for 2, 59.7 and

54.3 for 3, and 71.7 and 74.4 for 4, respectively.78

1.3.5 Naturally occurring benzofurans in complex rigid conformation

In a chemical investigation on the stem bark of Ouratea flava, tlavumone A (143) and

tlavumone B (144) were isolated. 79 Ito et a/. 80 isolated three new benzofuran based stilbenes

viniferifuran (145), (+)-vitsifuran A (146) and (-)-vitsifiran B (147) from the cork of 'Vitis

vinifera' 'Kyohou'.

HO

HO

HO HO

143 144

HO

OH HO

OH

OH

145 OH

The methanol extract of stem bark of Shorea hemsleyana (Dipterocarpaceae)

afforded four new benzofuran stilbene derivatives, (+)-a-viniferin-l3b-O-f3-

glucopyranosides (149), hemsleyana A (150) and B (151) and along with known stilbenoids

(+)-a-viniferin (148), davidiol A (152), (-)-hopeaphenol (153) and (+)-isohopeaphenol

17


(154).81 Three new C-glucopyranosides of resveratrol oligomers, hemsleyanosides B-D

(155-157)82 have been isolated from the root bark of Shores hemsleyana.

HO

146

'-'::: OH

HO HO

OH 150

HO

HO

HO

155

147 qH:

HO 151

OH HO

OH HO

153 R1 = 13. R2 =a 154 R, =a, R2 = 13

156

OH

HO 148 R = H 149 R = glc

HO

OH OH

152

OH

OH

157

18


HO HO

HO

HO

HO

HO

OH 161

HO

The ethanolic extract of the roots of Vitis amurensis Rupr. resulted in the isolation of

four novel oligistilbene,83 Amurensin C (158), Amurensin D (159), Amurensin E (160) and

Amurensin F (161). Amurensin F (161) exhibited strong inhibition effect on biosynthesis of

leukotriene B4(L TB4) at concentration of 1 o-5moi/L with an inhibitory rate of 76%.

Dipterocarpaceous plants are well known and abundant source of stilbenoids. Many

stilbene derivatives have been isolated from these plants84 and they showed diverse

biological activities such as chemoprevention of cancers85 and hepatoprotective activity.86

Stilbenoids are therefore, regarded as potential lead compounds for drug development.

Three resveratrol oligomers, vaticanols A (162), B (163) and C (164), as well as two

known stilbenoids, resveratrol and (-)-e-viniferin (148) have been isolated from acetone

extract of the stem bark of Vatic a rassak (Dipterocarpaceae ). 87

The dried roots ofCaragana sinica (Buc'hoz) Rehd. (Leguminose) have been used in

China as folk medicine (Chinese name: Jinguegen) for the treatment of asthenia syndrome,

vascular hypertension, leukorrhagia, bruises and contused wounds. Luo et a/. 88 isolated a

oligostilbenes (165) besides (+)-a-viniferin (148), miyabenol C (166) and kobophenol A

(167), from the ethylacetate extract of the roots of C. sinica.

19


HO

HO

OH

Recently, a new resveratrol tetramer,89 shoreaketone (168) was isolated from acetone

extract of the dried and ground bark of Shorea uliginosa (Dipterocarpaceae).

Caragana sinica (BUCHOLZ.) REGD. (Leguminosae) is widely distributed in

China. Its dried root named 'Jinquegen' has been used as a folk medicine90• Wang et a/.91

isolated and characterized two new oligostilbenes, carasiphenol C (169) and carasiphenol D

(170), together with a known compound caraphenol A (171)92 from the ethylacetate extract

of the aerial parts of this plant. Carasiphenol D (170) showed significant activity against the

mycelial growth of Pyricularia oryzae with MIC of0.017J..t.M.

Liu et a/.93 isolated three new resveratrol oligomers, hopeahainanphenol (172),

neohopeaphenol A (173) and neoisohopeaphenol A (174) from the stem bark of Hopea

hainanensis (Dipterocarpaceae ). Their structures were elucidated by in-depth spectroscopic

analyses, including ID- and 20-NMR techniques, and by HR-ESI-MS. All the three

compounds were tested in vitro for acetylcholinesterase (AChE) inhibitory and antitumor

activity and the dimeric compound 173 showed significant activity against AChE, with an

I Cso value of 7 .66±0 .13 f.!M.

20

Chapter I

OH

HOY"o

0''·· 0 H

HO

169

172

OH 167

Ben=o[blfuran scaffolds: Natural product, Synthesis and biological activity

OH

HO

OH

OH

OH

HO

HO

b "'-:...

HO

P" HO HO

173

HO

HO

HO

OH

HO

HO

OH

OH

168 OH

171

y OH

174

OH

21

Chapter I Ben=o[bjjiJran scaffolds: Natural product, Synthesis and biological activity

Cyperaceae, a genus comprising about 50 species distributed in the northern

hemisphere, particularly at high altitudes in the Himalayas, China and Central Asia. K.

nepa/ensis is an important species in the alpine flora of the Nepalese Himalayas and is an

economically important pasture crop.94 Kobresia. nepalensis belongs to the family

Cyperaceae, and is an important species in the alpine flora of the Nepal Himalayas. The

three new resveratrol oligomers, nepalensinol A (175), B (176) and C (177), were isolated

from ethyl acetate extract of stems of K. nepalensis. Nepalensinol A, B and C showed a

potent inhibitory effect on topoisomerase II, with IC50 values of 0.30, 0.02 and 7.0 J..Lg/mL

respectively.95

Recently, four new resveratrol oligomers, nepalensinols D (178), E (179), F (180),

and G (181), were isolated from the ethylacetate extract of the stem of Kobresia nepalensis

(Cyperaceae). The compounds were assessed for their inhibitory activity against human

topoisomerase II, a potential target for anti-tumor agents. These stilbenoids showed potent

inhibitory activity against human topoisomerase II with IC50 value of 5.5 J..LM for

Nepalensinol F (180) and ICso value of 14.8 J..LM and 11.7 J..LM for Nepalensinol D (178) and

E (179) respectively.96

OH

H c OH ·' (l .• OH ~I

.·······'~ OH

HO

OH

175

177

~I HO HO:o

OH~ '•····

~I ~

HO

HOD,,, .......

'·· ..

·.

0~--o 176 -- OH

OH

22


OH OH

HO HO '----.. c Co-HO ··-....... ; ···-o~ ~ ~--

HO~ ~~ OH 178 OH

;:: OH HOA)',,, __

OH

OH HO

179

HO~

0'·· OH

180 181

1.4 Methods for the synthesis of benzo[b]furan derivatives

The synthesis ofbenzo[b]furan can be divided in two broad categories one such category in

which benzene ring is constructed and another class in which the furan ring is constructed. A

review published by Kadieva et a/.97 some ten years back deals with the various synthetic

methodology for the construction of benzofuran skeleton. We tried to concisely present the

synthetic approaches developed after that period.98

()_ '> 0

c -

~ Vcf

Figure 2: Synthetic route for the synthesis of benzo[b]furan.

23


The methods known as well as widely explored for the synthesis ofbenzo[b] furan is

the annulations of furan ring with aromatic skeleton, the furan ring in tum build up through

four possible routes as shown in the figure 2. Of these the first three routes (A-C) have been

used for a long time. The route D, involving the formation of a bond between the oxygen and

the aryl carbon, was only proposed recently. In this section we concisely discussed the latest

developments and exploration work for the synthesis ofbenzo[b]furan skeleton.

1.4.1 Synthesis ofbenzo[b]furan through route -A

The starting compounds for the synthesis of benzofurans through this route are in general

ortho-substituted phenols or their analogue. Substituents at the ortho position must contain

an electron-deficient-J3-carbon atom, which is the structural unit of some unsaturated

fragment or is attached to an atom characterized by a sufficiently strong mesomeric effect.

Among the known methods of the first category, the metal-catalyzed intramolecular

cyclization of arylsubstituted alkynes possessing a nucleophile in proximity to the triple

bond has been proven to be effective for the synthesis of five-membered heterocycles. More

recently, Flynn and colleagues99 disclosed an efficient approach to the synthesis 2-

substituted-3-arylbenzo[ b ]furan by the palladium-catalyzed multicomponent sequential

coupling strategy, starting from iodophenol and terminal phenyl acetylenes. In this reaction,

MeMgBr was used as an essential base to form the corresponding magnesium salts of

phenolate and acetylene.

+XY, ROH,CO

Base

182

Nan et a/. 100 put forward a highly effective co-catalysis system (Pdh-thiourea and CBr4) for

carbonylative cyclization of both electron-rich and electron-deficient o

hydroxylarylacetylenes to the corresponding methyl benzo-[b]furan-3-carboxylates D (182).

24

Chapter I Ben=o{b}furan scaffolds: Natural product, Synthesis and biological activity

The overall process may involve attack of a carboalkoxypalladium(II) intermediate on the

arylacetylene A to generate the complex B, followed by nucleophilic addition of the phenolic

oxide to the XPd11(CO)OR-activated arylacetylene B to give intermediate C. Reductive

elimination of C produces ester 182 and palladium(O). The palladium(O) is then oxidized to

palladium(II), completing the cycle. In this catalytic cycle, the nature of the base (B-),

palladium(II) complex (XPd11(CO)OR), and oxidative agent (XY) [which promotes the

turnover of Pd0 to Pd11] is paramount to the success of the reaction. The base should allow

the desired catalytic cycle to proceed while minimizing the unwanted direct cyclization of A

to 183. The XPd11(CO)OR complex has to be active enough to coordinate with acetylene to

form B, and the oxidative agent (XY) has to efficiently promote the turnover of the

palladium catalyst from Pd0 to Pd11 without disrupting the carbonylative cyclization.

On further exploring the carbonylative cyclization by variety of catalyst such as

Pd(PPh3)4, Pd2-(dba)3, Pd2(dba)J/PtBu3, and Pd2(dba)J/dppf) under different conditions

ended up to afford 2-arylbenzo[b]furan 184 as major product along with 2,3-

diarylbenzo[b]furan 185 in minor quantity. So they modified their strategy for the synthesis

of 2,3-di arylbenzo[ b ]furan, by simple combination of Pd-catalyst with bipyridine (bpy) as a

ligand and obtained the 2,3-diarylbenzo[b]furan 185 as major product. The mechanistic

overview for the synthesis of2,3-diarylbenzo[b]furan 185 is presented in the Figure 3.

Figure3:

~-'\R' R~o~

Base ( ArP: .. XLI

o~.Ln ~ ::?.::

I ""': ) R-' h o-

18410 1 <.:n ~ !-R• R~ .. \ ~I -...:::,

I~ X

Base

185

Hu et a/. 101 disclosed highly efficient synthetic approach for the carbonylative

cyclization of o-alkynylphenols 186 to the corresponding 2-substituted-3-aroyl

benzo[b]furans 187 under mild conditions using a simple combination of 4-iodoanisole,

Pd(Ph3P)4, and K2C03 in acetonitrile at 45 oc under a balloon pressure of CO (ca. 5 psi) and

extent their approach to solid phase.

25


More recently, a simple and one pot synthesis of 2-substituted 3-halobenzo[b]furans

189102 as major product has been reported through palladium-catalyzed annulation of 2-

alkynylphenols 188 with CuCL2, and HEt3NX. The role of HEt3NX may be the formation of

complex with Pd(O) which favour the generation of Pd(O); in other words, HEt3NX might

labilize the palladium-carbon cr-bond, thereby converting palladium into a good leaving

group.

cLR X H

PdCI21CuCI2 oo-R oo-R OH HEt3NX, DCE,rt 0 0

X=CI, Br major minor 188

189 190

Palladium chloride-catalyzed intramolecular activation of electroneutral

cyclopropane derivatives (191) bearing ortho hydroxyl group in aromatic ring has been

reported as the efficient method for the synthesis ofbenzofuran derivatives (192). 103

191

~. ~d 192

2,3-Disubstituted benzo[b]furans104 194 have been readily prepared under very mild

reaction conditions by the palladium/copper-catalyzed cross-coupling of various o

iodoanisoles and terminal alkynes (193), followed by electrophilic cyclization with h.

PhSeCI, or p-02NC6H4SCI. Aryl- and vinylic-substituted alkynes undergo electrophilic

cyclization in excellent yields.

193

E

~R ~6

194

E+= 10, l2, PhSeCI, p-N~Cs~SCI

26


The construction of functionalized benzofuran scaffolds 197 has been achieved by

the reaction of alkylidenetetrahydrofurans 195, which was subsequently brominated,

followed by sequential Suzuki-coupling with arylboranic acid 196 followed by BBr3-

mediated domino "ring cleavage-deprotection-cyclization" reaction and aromatization by

extrusion of water led to the product.105

B(OHh

MeO'O 1) suzuki-coupling + I

:::::,.,. 2) 8Br3, H20

Br Li);OMe 3) -B{OHh, -HBr,

195 196 4) -H20 197

Various non-palladium catalyzed coupling of aryl acetylene with o-halophenols have

been developed as valuable source for the construction ofbenzo[b]furan skeleton. Recently,

Bates and co-worker106 reported a palladium-free synthesis of2-arylbenzo[b]furans 200 via a

copper(l)-catalyzed coupling reaction of o-iodophenols 199 and aryl acetylenes 198 using

[Cu(phen)(PPh3)2]N03 as the catalyst.

~+ Ry~

198

R'

_[/~ HO 'J----!1

I

199

10 mol% [Cu(phen){PPh3h]N03 2.0 eq Cs2C03

Toluene, 110°C co-o R'-0 R

200

The VO(acac)2 based oxidative system has also been employed to epoxidize various

double bonds under mild conditions. Thus a one pot synthesis of 2,3-

dihydrobenzo[b]furanols107 202 was achieved in high regio- and diastereoselectivity manner

in the presence of a catalytic amount ofTFA(20 mol%). This metal catalyzed methodology

was shown to be more practical and superior to the previously employed m-CPBA based

methods.

VO(acach. 1BuOOH

TFA-DCM, 40°C

A metalative 5-endo-dig cyclization reaction of 2-ynylphenols 203 effected by BuLi and

ZnCh produces an intermediate 3-zinciobenzofuran, which has been trans-metalated to the

27


corresponding cuprates 204 and allowed to react with carbon electrophiles to produce a

variety of 2,3-disubstituted benzofurans 205.108

R 1) BuLi 2) ZnCI2

OH . 3) CuCN.2LiCI 203

~·cu~

lAc{ 204

E

C-electrophile ~ R

~d 205

Kumar et a/. 1 09 efficiently used Zn(OTf)2 ( 1 0 mol %) as catalyst for the cyclization of

propargyl alcohols 207, as a two-carbon building unit, with substituted phenols 206 in hot

toluene to furnish functionalized benzofurans 208.

OH Zn(0Tf)2 ===-----<(

R

207 208

Hendrickson et al. 110 reported an efficient route for the syntheis of benzofuran skeleton 210

utilizing substituted phenol and 0-arylsulfoxonium species 209.

R~ -OCOCF3 H H H H RQ1 O~SrH (CF3C0)20

F,cYo:t?XH OH ~ H

-CF3COOH o'S~ H I

Ph 0 Ph + 'Ph 209 I -GF,COOH

RO:J -PhSH ~~ I 0 H

O SPh 210

7-(Alkoxycarbonyl)benzofurans 212 and 7-(alkoxycarbonyl)-2,3-dihydrobenzofurans

213 have recently been prepared through base mediated cyclization of 2-oxocycloalkane-1-

carboxylate-derived I ,3-dicarbonyl dian ions (free dian ions) or 1 ,3-bis-silyl enol ethers 211,

(masked dianions) with various 1,2-dielectrophiles, followed by DDQ mediated

dehydrogenation afforded the corresponding benzofurans. 111

28

Chapter I Ben::o[b].furan scaffolds: Natural product, Synthesis and biological activity

A new and convenient acid catalysed ring formation reaction for the synthesis of 3-

aryl-2,2-dialkyl-2,3-dihydrobenzofurans 217 has been achieved using phenols 214 and 2-

aryl-2,2-dialkylacetaldehydes 215 as substrates. The results indicated that although electron

donating substituents are required on the phenols for good conversion, the substituents on

the aldehydes have little effect on the reaction, and therefore a variety of 2-aryl-2,2-

dialkylacetaldehydes may be used. The reaction initiated by acid catalyzed condensation of

phenol214 and aldehyde 215 to form an intermediate 216, which after protonation followed

by dehydration, leads to cation 216b. The cation 216b undergoes Wagner-Meerwein type

rearrangement and cyclization to form the desired product 217.112

4 9 :71

~ ::::,....

+I - ~ // ~· ~

OH I "' I CHO *OH~~ 214 215 ~

\

216c

Lee et a/. 113 put forward the reaction of diazocyclohexane-1 ,3-dione with vinyl

acetates in presence of rhodium acetate followed by dehydration, acetylation and

aromatization to yield the substituted benzofuran 219 in good yield. Recently same group

proposed the Ag2C03/Celite-mediated cycloaddition of 1 ,3-dicarbonyl compounds 218 to

vinyl sulfides which offers a simple and new strategy for the synthesis of medium- and large

sized ring substituted furans 220. The proposed mechanism states that the dicarbonyl

compound is first oxidized by silver(I) to generate R-oxoalkyl radical, which then attacks

vinyl sulfide to give radical, which undergoes fast oxidation by another silver(!) to form a

cation, the cyclization of cation, and subsequent elimination followed by DDQ-mediated

dehydration led to substituted benzofurans.

29


0

QSPh 0

co Ru-catalyst Q 090 R-~ • ....

0 0 Ag2C031Celite

219 CH3CN, reflux 220 218 n=1,2,3,7,10

2,3-Dimethylhydroquinone 221 is electrochemically oxidized to its respective p

benzoquinone 222 by consumption of electrons, the quinone intermediate is subsequently

attacked by nucleophiles, 1,3-cyclohexanedione, to form benzofuran skeleton 223. 114

OH

¢cCH3

CH3

OH

221

0

0 1Yc1

1ycH3 ~0 YcH3

0

222 223

Recently, a one-pot synthesis of 2-aminobenzofurans115 226 was achieved which involves

treating a solution of 1-aryl-2-nitroethylenes 225 and cyclohexane-1 ,3-diones 224 in THF in

the presence of catalytic EtJN.

0

~0 224

Et3N (10mol%) + t;J02 ~ _rt_._1_2h ___ _

~ Ac20, Et3N, DMAP, rt, 5h

225

X

y

226

The ferric ion-catalyzed cycloaddition116 of the styrene derivatives 227 with the

quinone 228 afforded the 2,3-dihydrobenzo[b]furan 229 in excellent yield.

Me +

0 Me

~ ¢ Fe3+ Oj .. ·Q--oMe OMe

0 227 228 229

30


An interesting method to the synthesis of dihydrobenzofuran 232 was recently

developed by employing a [3+2] dipolar cycloaddition of attysilane 231 and a-benzoquinone

230.117

0:0

R-0

S·ip Zn2+, OCM + ~ 1 r3

-5°C to r.t

230 231

Thus, the most important condition for the production of benzenes by intramolecular

cyctization of ortho-substituted phenols is the presence of a substituent containing an

electron-deficient J3-carbon atom. This restricts the use of this type of synthesis for the

production of 2(3)-substituted benzofurans on account of the possibility of deactivation of

the attacking center.

1.4.2 Synthesis of benzo[b]furan through route-B

Synthesise of functionatized benzofurans from base catalyzed condensation of substituted

benzaldehydes is effective provided that at least one of the substituents R1 or R2 on the

benzyl subunit is an electron-withdrawing group such as a nitro or cyano group. Potassium

tert-butoxide and sodium ethoxide are typicatly used to effect this reaction. Recently, Kraus

et a/.118 overcome this drawback and put forward a methodology in which a hindered

nonionic phosphazene base (P4-t-Bu) efficiently deprotonates ortho-substituted-benzyt

benzatdehydes 233, leading to a direct synthesis of substituted benzofurans 234.

Katritzky et a/. 119 reported base catalyzed condensation of o-hydroxyphenyl ketones

or o-(1-hydroxy-2,2-dimethylpropyl)phenol 235 with 1-benzotriazol-1-ylalkyl chlorides to

yield 2,3-disubstituted benzofurans 236 in two or three steps. The sequence works welt for 3-

aryl- and 3-tert-butylbenzofurans but could not be extended to other 3-alkyl analogues.

31


0

~H VOH

235

1) t-Buli/THF 2) PDC/DMF 3) LDAITHF ot 4) TiCI3/Li/DME

236

The reduction of 2,6-diacetoxy-2'-bromoacetophenone 237 with NaBH4 led to 3,4-

diacetoxydihydrobenzofuran in a process involving acyl migration and cyclization,

subsequent hydrogenolysis gave 4-acetoxydihydrobenzofuran 238 in good yield. 120

Figure-4

~Br llAOAc

237

1)NaBH4 ~ ___!2)_P_d_-C....!:[-'H]~_.. llAc?

238

32


Gabriele and co-worker122 prepared 2-benzofuran-2-ylacetic methyl esters 240

through tandem Pd(O)-catalysed carbonylative deallylation-Pd(II)-catalysed carbonylative

cyclisation of 1-(2-allyloxyphenyl)-2-yn-1-ols 239 in high yields together with but-3-enoic

acid methyl ester as coproduct. A catalytic sequence involving two sequential catalytic

cycles as described in the Figure 4.

Nicolaou et a/. 121 efficiently synthesis 3-arylbenzofuran 242 through novel

cyclofragmentation-release pathway and explored this both in solution and solid phase. The

alkylation of 2-hydroxy benzophenone with chloromethylphenylsulphide, with subsequent

epoxidation with trimethyl sulfoniumiodide, followed by m-CPBA mediated oxidation

resulted in desired sulfones 241 in high yield, which on base treatment furnished 3-

arylbenzofuran in good to excellent yield. The mechanism proposed for this transformation.

I

Tsai and co worker123 uses various 0-vinyl and C-propenylated phenols 243 as

precursor for the ring closing metathesis to synthesize various benzofurans 244

( R1 0

R _)-=\___;;-- Grubbs cat. 2---u-

R3 ~

243 244

Carbonyl compounds and also the corresponding aryl sulfoxides i.e., any compounds

containing substituents with an electron-deficient a-carbon atom at the ortho position to the

alkoxy group, can be used for the synthesis of benzofurans by this method. By using this

type of method it is possible to introduce any substituents into the benzene ring and at

position 2 or 3 of the benzofuran ring.

33

Chapter 1 Ben=ofb}furan scaffolds: Natural product, Synthesis and biological activity

1.4.3 Synthesis of benzo[b]furan through route-C

A variety of allyl aryl ether underwent tandem Claisen rearrangement and subsequent

oxidative cyclization in the presence of Pd(CH3CN)2Cb, I ,4-Benzoquinone and Na2C03 to

form corresponding 2-methyl substituted benzofurans 245. This method was compatible with

functional groups such as methoxy, methylenedioxy, and free hydroxyl. While reactions of

electron-rich arenes were facile, higher catalyst loading and increased temperatures were

required for relatively electron-deficient arenes. 124

Plausible mechanisms for Pd-catalyzed cyclizations are based on the Wacker

oxidation mechanism. 125 For allyl aryl ethers, the Pd-complexed olefin first undergoes

Claisen rearrangement126 to form the corresponding 2-allylphenol intermediate.

Subsequently, intramolecular cyclization proceeds via oxypalladation. Coordination of the

C-C cr-bond by palladium activates the olefin toward intramolecular nucleophilic attack by

the phenolic oxygen, which is readily deprotonated by the stoichiometric quantity of base.

Subsequent 13-hydride elimination produces Pd(H)CI and the 2,3-dihydro-2-methylene

benzofuran, which isomerizes to the thermodynamically stable 2-methylbenzofuran 245.

Pd(H)Cl eliminates HCI and forms Pd0, which is reoxidized by benzoquinone to regenerate

the catalytically active Pd(II) species.

3-Substituted-2,3-dihydrobenzofurans 247 were obtained in very good yields by SRN I

photo-stimulated reactions in liquid ammonia from appropriate halo-aromatic compounds

ortho-substituted with suitable double bond and Me3Sn-, Ph2P-, -cH2N02 and h- anions. The

novelty of work involves the versatile application of 5-exo ring closure processes during the

propagation cycle of the SRN I reaction; the alkyl radical intermediates 246a formed then

reacted with the nucleophiles to afford the ring closure-substituted heterocycles. 127

34


_h_v __ ~O "CH2N02

NH3 ~j 246 246a 247

The synthesis of bis-dihydrobenzofuran 249 through rhodium-catalyzed tandem C-H

activation/C-C bond formation, in which [RhCl(coe)2]2 act as catalyst with the electron-rich

dicyclohexyl ferrocenyl phosphine act as ligand, led to the desired product in excellent

yield. 128

CHO

l 6 j o¥o OMe

248

Rh (I) catalyst

FcPCy2, c::¢0 OMe

249

Kraus et a/. 129 disclosed the synthesis of 3-aryl(alkyl)-benzofurans 251 via halogen

metal exchange/cyclization. The synthesis of desired 3-substituted benzofuran was achieved

by the treatment of iodoaryloxyketones 250 with methyi-L.ithium, followed by acid

treatment.

1) Meli/THF ,-78°C

2)PTSA

Ar

~ ~d

251

Rao et a/130 proposed a solvent free microwave assisted one-pot synthesis of several

fluoro-substituted 3-cyano-2-methyl-benzo[ b ]furans/ethyl 2-methyl-benzo[ b ]furan-3-

carboxylates 253 from the corresponding [(aryloxyacetyl) alkylidene] triphenylphosphoranes

252.

R1 R1 0 R1 R2Xror intramolecular R2x:ro~ Jl R ~Me

1 .wittig reaction I ~ "'-./' [=PPh3 MW . 2 ~ I I R ~ II R ~ Z 6-8 m1n. ~

3 3 R3 Z Claisen l z 252 Z = CN; C02Et f 253 rearrg.

R X!R1 0 R XxR1 OH + R XxR1 o·\ R2m,R1 0 (7'1. 2 ~ §-

2 Y" I -:::? -H

2 Y" I ~ cyclization Y" I

R3 ~ H r R3 ~ r R3 ~ f() R3 ~ Z z z z

The reaction combines intramolecular Wittig reaction of phosphoranes and Claisen

rearrangement of the resulting aryl propargylic ethers followed by ring closure resulting in

35


the exclusive formation of the corresponding benzo[b]furan derivatives and

triphenylphosphine oxide in good yield.

Treatment of benzyl 2-halophenyl ethers 254 with 3 equiv of t-BuLi results in Li

halogen exchange and lithiation at benzylic methylene simultaneously. The dianions thus

formed react with carboxylic esters to afford the corresponding 2-aryl-3-hydroxy-2,3-

dihydrobenzo[b ]-furans as a mixture of diastereoisomers. 131 Subsequent acid-catalyzed

dehydration gives moderate to good overall yield of a variety of 2-aryl-3-substituted

benzo[b]furans 255. The dehydration process could be carried out with similar overall yields

but in milder conditions under Lewis acid-catalyzed conditions by treatment of

dihydrobenzofuranols with InCh

CCX

G-O~r

254 G= H, Me, Cl X=CI,I

1) t-Buli, THF,-78 to -25°C

2) RC02Et, -78 to -25°C

3) H3o•, 20°C or lnCI3,

DCM, 20°C

R

Gco-~ ":::: Ar I~

0 255

R = Alkyl, hetroaryl

Ar = substituted aryl

2,2-Dimethyl-2,3-dihydrobenzofurans132 257 has been prepared by HY zeolite

promoted tandem Claisen rearrangement-cyclization reaction of methallyl aryl ethers 256, in

moderate to good yields. The more acidic HY zeolite is the best choice of catalyst for the

preparation of the dihydrobenzofuran compared with NaY, CaY and LaY zeolites. Since the

number and strength of acid site in zeolite increases with metal cation exchanged in the order

ofNa+ < Ca2+ < La3•, the increase in the yield ofbenzofuran according to this order suggests

that acid sites on zeolite work as active sites for this reaction.

256

Zeoite solvent

Cl

RCLi 257

PdCh-catalyzed intramolecular Heck reaction of ortho-iodo benzyl allyl ether 258 in

ionic liquid, 1-n-butyl-3-methylimidazolium tetraborate ([BMim]BF4), was used for the

synthesis of substituted benzofurans133 259 in modest to satisfactory yields.

CCOI ~--5-%""'P_d..._C_I2_· _<n_-B_u_) .... 3N

NH40 2CH •

[BMim]BF4 , ~ 258 60°C,24h 259

36

Chapter 1 Ben=o[bjfuran scaffolds: Natural product, Synthesis and biological activity

Goel et a/. 134 efficiently synthesized various benzofuran methyl ketones 261 through

Amberlyst-15 catalyzed cyclization of phenoxyacetal 260 in excellent yield. The protocol

offers reusability of catalyst.

OH OH

&COCH_3_A-_15_....,. o):!......../CH3 EtO 0- .J ~ )--I toulene, reflux 0 0 EtO 260 Dean-stark 261

Willis et a/. 135 demonstrated that the combination of Pd2(dba)3 and DPEphos

generates an effective catalyst for the intramolecular 0-arylation of enolates, allowing 1-(2-

haloaryl) ketones 262 to be efficiently converted to benzofurans 263.

Pd2(dba)J. DPEphos base

toluene, 110°C

263

Zhao eta/. 136 developed a cationic palladium complex catalyst [(bpy)Pd+(JJ-OH)hC

0Tt)2 or [(bpy)Pd2+-(H20)2]COTt)2, for the synthesis of phenoxyacetonitrile 264 and

efficiently used these for the one-step synthesis ofbenzofurans 265

;ce CN

)lAA MeO~ 0 R [Pd]+ 2M OMe ,

Pathway ',

ArB(OHh 1 0 --<~ [Pdt ~ I Ar .,.-:::.

0 MeO 0 e R A OXA.:_ Friedel-~ reaction

MeO)lAO R b OMe +

Pathway BPdJ.0 2 I ~ rAr

MeO .,.-:::. o--\ C-H activation R

g'

OMe Ar

~

MeO 0 R

1

265

+[Pd]

MOMe O

Ar

MeO 0 R h

. Arylboronic acids with electron donating groups gave better yields than those with

electron withdrawing groups. Interestingly reaction behaves with high chemoselectivity

between nitrile groups and Br· or TfU anions which are highly reactive to Pd(O) species.137

37


1.4.4 Synthesis of benzo[b]furan through route-D

A distinctive feature of reactions of type D is the fact that the furan ring is formed through

the formation of a bond between the oxygen and an aryl carbon.

Pd2(dbah;Ligand

Base, touene, reflux

267

The combination of Pd2( dbah and the ligand DPEphos effective catalyst the

intramolecular C-0 bond formation between enolates and arylhalides in the direct

conversion of 1-(2-haloaryl)ketones 266 into the corresponding 2,3-disubstituted

benzofurans 267. 138

Moreover Chen and co-worker139 efficiently synthesize the wide variety of 2,3-disubstituted

benzofurans through Cui- Cs2C03 catalysed ring closure of 2-haloaromatic ketones.

Electrochemical oxidation of diol derivatives of benzoic acid 268 in the presence of

acetylacetone 269 as the nucleophile in aqueous solutions, using cyclic voltammetry and

controlled-potential coulometry, led to isolation of corresponding benzofurans140 270. The

results indicate that the quinones derived from dihydroxybenzoic acids participated in

Michael addition reactions with acetylacetone and via various mechanisms converted to the

corresponding benzofurans.

0 0

+AA o=( ~ ... PH ~-=l:J'

OH 268 269 ' 270

1.4.5 Combinatorial approach

Combinatorial syntheses of benzofuran molecules have been achieved in a number of ways.

A number of groups have utilized the benzofuran moiety as a substituent on other scaffolds

for combinatorial synthesis. 141-144 Other groups synthesized combinatorial libraries based

upon the benzofuran scaffold, but started with a pre-synthesized benzofuran moiety. 145-147

Nevertheless, at least four different strategies have been recently reported for the synthesis of

benzofuran scaffolds.

38


+Ou HN "'= R1~ Br3- I~

R N h3 toluene 2 271

0

R1xn:Br I~ R

R 3 2 272

~ 274

The first methodology utilizes a condensation reaction between a ketone and a

nucleophilic group. The nucleophile can take several forms. For example, Fecik et al.

reported the use of a Wittig reaction to close the furan ring of the benzofuran moiety and

generate a combinatorial library, 148 and Boehm and Showalter reported cyclization to the

benzofuran ring via an aldol-type reaction. 149 Habermann et a/. 150 reported a cyclization

dehydration reaction to yield the benzofuran. The synthesis begins with the bromination of

commercially available acetophenones 271 to yield 272. Following this, 272 was reacted

with commercially available phenols using 1 ,5, 7 -triazabicyclo[ 4.4.0]dec-5-ene {TBD-P) as a

base, affording- 273 in fair to excellent yields (>30%) and good purities {>75%). The

benzofuran ring system (274) was then assembled through a clean cyclodehydration reaction

ofthe a-phenoxyacetophenones using Amberlyst 15 as a cyclizing agent (>57% yield, >90%

purity). Interestingly, all reaction steps in this scheme utilized solid-supported reagents. This

technique has shown to be a clean and efficient method for the generation of chemical

libraries. 151"152

The second methodology involves a palladium catalyzed heteroannulation reaction.

Many syntheses suitable for combinatorial synthesis have been proposed using this

reaction. 153-154 One procedure that has been reported by Fancelli et a/. 155 begins with the

reaction between the starting carboxylic acid 275 and TentaGe) resin via the Mitsunobu

reaction, producing 276. Following this, the acetate group was deprotected to allow further

derivatization 277. A palladium-catalyzed heteroannulation of terminal acetylenes then

followed to yield the benzofuran scaffold 278, which could be cleaved from resin to yield

279.

39

Chapter 1

OH

J~o AeON

275

Ben=o[b}furan scaffolds: Natural product, Synthesis and biological activity

o__Q o~ resin, THF

DEAD, PPh3

1~0 6%NH3 1~0

AcOV 16h r.t HON

276 277

OH

R~o ~-Z)

279

NaOHaq i-PrOH

- Rj DMF 50°C, Pd{PPh3)2CI2, 16h Cui,TMG ~

0

R~o ~-Z)

278

DEAD = Diethyl Azodicarboxylate TMG = Tetramethylguanidine

A third strategy was presented by Guthrie and co-workers who utilized a traceless

solid-phase synthesis of 2-substituted benzofurans.156 Compounds synthesized via this route

may theoretically be substituted at any site on the benzofuran ring. First, I ,3-

diisopropylcarbodiimide was used to couple carboxylic acids to Wang-resin 280, producing

281. 283 was then assembled through an alkylidenation reaction, using thioacetal 282 and

the low-valent titanium complex Cp2 Ti[P(OEt)3]2. The workup of this reaction is relatively

simple, merely requiring washing with various solvents. Deprotection of the phenol with

tetrabutylammonium fluoride (TBAF) followed by treatment with 50% aqueous

trifluoroacetic acid in dichloromethane then yielded the benzofuran 284.

RC02H HO~ PrNi=C=NiPr

W DMAP, THF 280

~R ~d

284

The fourth protocol was presented by Nicolaou and co-workers both the solution- and solid

phase synthesis of 3-arylbenzofurans by via a cyclofragmentation-release pathway. 121

Previously synthesized chloromethyl sulfide resin 285 was treated with a series of

functionalized salicylaldehydes 286 to produce 287. These resin supported aldehydes were

then treated with several arylmagnesium bromides 288 to yield 289, which could

subsequently be selectively oxidized with IBX (1-hydroxy-1,2-benziodoxol-3(1/1)-one) to

form benzophenones 290. Sulfur ylide epoxidation afforded 291 followed by mCPBA (meta

chloroperoxybenzoic acid) oxidation yielded the sulfone 292. Treatment with potassium tert

butyl alcohol deprotonated the methylene group adjacent to the sulfone, which the authors

40

Chapter 1 Ben::o{b}furan scaffolds: Natural product, Synthesis and biological activity

suggested attacked the quarternary carbon of the epoxide via a 5-exo-trig cyc!ization, which

then collapsed to 293 expelling both formaldehyde and the resin phenylsulfinate anion.

Cl ~ Ls-.

285

HJ:>o I : ~ ,Q~Br 0 0/'.._s~ I

R2 .o )?. R .o ---::,...;2::..:8::::6:=-'--'R-'--1 - H I ""::

3

288 R. • Cs2C03 ""'

R2 """" 95°C R

1287

As can be seen, this synthetic strategy permits a great deal of diversity to be

incorporated on either aromatic ring, and the cyclization-cleavage step not only allows for a

traceless synthesis, but also increases the purity of the product, as only the desired

benzofuran scaffold can undergo cleavage from resin. Unfortunately, both aryl groups

appear to be required for regioselective epoxide opening.

1.5 Conclusion

As one can see from the work covered in this review nature is abundant source of

benzofuran analogues and large number of isolated compounds showed diverse biological

activities. Certain benzofurans are also of growing interest in different types of biochemical

and physiological studies.

Many of the synthetic procedures used in the preparation of benzofurans derivatives

have been already known for a considerable time and are still in use today due to their

efficiency and simplicity. Advances in this area have mainly led to improved, shorter and

more general routes or, in other cases, to the resolution of specific problems or deficiencies

related to particular synthetic methods. In addition, more complex benzofurans have been

41

Chapter 1 Ben=o[h]furan scaffolds: Natural product, Synthesis and biological activity

isolated from different plant species. The biophysical characteristics of benzofurans are the

main reasons for the high degree of interest they attract for synthesis.

In the coming years, research into this class of compounds will uncover further

interesting aspects in the fields covered in this review as well as in other scientific and

industrial areas. In this respect it is of vital importance to access specific benzofurans

through more direct and selective synthetic procedures.

1.6 References:

1. (1) (a) Dean, F. M. In Advances in Heterocyclic Chemistry; Katritzky, A R., Ed.;

Academic Press: New York, 1982; Vol. 30, p 167. (b) Dean, F. M.; Sargent, M. V. In

Comprehensive Heterocyclic Chemistry; Bird, C. W., Cheeseman, . G. W. H., Eds.;

Pergamon Press: New York, 1984; Vol. 4, Part 3, p 531. (c) Lipshutz, B. H. Chern. Rev.

1986, 86, 795.

2. Kumar, V.; Ackerman, J. H.; Alexander, M.D.; Bell, M. R.; Christiansen, R. G.; Dung,

J. S.; Jaeger, E.P.; Herrmann, J. L. Jr.; Krolski, M.E.; McKioskey, P.; Batzold, F. H.;

Juniewicz, P.E.; Reel, J.; Snyder, B. W.; Winneker, R. C. J Med Chern. 1994, 37, 4227.

3. Ohemeng, K.A.; Appollina, M.A.; Nguyen, V. N.; Schwender, C. F.; Singer, M.; Steber,

M.; Ansell, J.; Argentieri, D.; Hageman, W. J Med.Chem. 1994, 37, 3663.

4. Nagahara, T.; Yokoyama, Y.; lnamura, K.; Katakura, S.; Komoriya, S.; Yamaguchi, H.;

Hara, T.; Iwamoto, M. J Med. Chern. 1994, 37, 1200.

5. (a) Yang, Z.; Liu, H. B.; Lee, C. M.; Chang, H. M.; Wong, H. N.C. J Org. Chern. 1992,

57, 7248. (b). Cagniant, P.; Cagniant, D. Adv. Heterocycl. Chern. 1975, 18, 337.

6. (a) Navarro, E.; Alonso, S. J.; Trujillo, J.; Jorge, E.; Perez, C. J Nat. Prod. 2001, 64,

134. (b) Lambert, J. D.; Meyers, R. 0.; Timmermann, B. N.; Dorr, R. T. Cancer Lett.

2001, 171, 47. (c) Takasaki, M. T.; Komatsu, K.; Tokuda, H.; Nishino, H. Cancer Lett.

2000, 158, 53. (d) Banskota, A.; Tezuka, Y.; Midorikawa, K.; Matsushige, K.; Kadota, S.

J Nat. Prod. 2000, 63, 1277. (e) Lee, S. K.; Cui, B.; Mehta, R. R.; Kinghorn, A. D.;

Pezzuto, J. M. Chem.-Biol. Interact. 1998, 115,215. (f) Thompson, L. U.; Rickard, S. E.;

Orcheson, L. J.; Seidl, M. M. Carcinogenesis 1996, 17, 1373. (g) Thompson, L. U.;

Seidl, M. M.; Rickard, S. E.; Orcheson, L. J.; Fong, H. H. Nutr. Cancer 1996, 26, 159.

7. Ikeda, R.; Nagao, T.; Okabe, H.; Nakano, Y.; Matsunaga, H.; Katano, M.; Mori, M.

Chern. Pharm. Bull. 1998, 46, 871. (4) (a) Craigo, J.; Callahan, M.; Huang, R. C. C.;

42

Chapter I Ben:o{b}furan scaffolds: Natural product, Synthesis and biological activity

DeLucia, A. L. Antiviral Res. 2000, 47, 19. (b) Leung, C.; Charlton, J. L.; Cow, C. Can.

J. Chern. 2000, 78, 553. (c) Charlton, J. L. J. Nat. Prod. 1998, 61, 1447.

8. (a) Carter, G. A.; Chamberlain, K.; Wain, R. L. Ann. Appl. Bio/.1918, 88, 57. (b)

Zacchino, S.; Rodriguez, G.; Pezzenati, G.; Orellana, G.; Enriz, R.; Gonzalez, S. M. J.

Nat. Prod. 1997, 60, 659.

9. (a) Gordaliza, M.; Castro, M.; del Corral, J. M.; Lopez-Vazquez, M.; Feliciano, A. S.;

Faircloth, G. T. Bioorg. Med. Chern. Lett. 1997, 7, 2781. (b) Cho, J. Y.; Kim, A. R.; Yoo,

E. S.; Baik, K. U.; Park, M. H. J. Pharm. Pharmacol. 1999,51, 1267.

10. Chen, C. C.; Hsin, W. C.; Ko, F. N.; Huang, Y. L.; Ou, J. C.; Teng, C. M. J. Nat. Prod.

1996, 59, 1149.

11. (a) Masuda, S.; Hasuda, H.; Tokoroyama, T. Chern. Pharm. Bull. 1994, 42, 2500. (b) Lu,

H.; Liu, G.-T. Planta Med. 1992, 58, 311. (c) Silva, D. H. S.; Pereira, F. C.; Zanoni, M.

V. B.; Yoshida, M. Phytochemistry 2001, 57, 437.

12. (a) Findlay, J. A.; Buthelezi, S.; Li, G.; Seveck, M.; Miller, J.D. J. Nat. Prod. 1997, 60,

1214. (b) Brader, G.; Greger, H.; Bacher, M.; Kalchhauser, H.; Hofer, 0.; Vajrodaya, S.

J. Nat. Prod. 1998, 61, 1482.

13. (a) Day, S. H.; Chiu, N.Y.; Tsao, L. T.; Wang, J.P.; Lin, C. N.J. Nat. Prod. 2000, 63,

1560. (b) Borsato, M. L. C.; Grael, C. F. F.; Souza, G. E. P.; Lopes, N. P. Phytochemistry

2000, 55, 809.

14. Ward, R. S. Nat. Prod. Rep. 1995, 12, 183.

15. Gubin, J.; de Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J.; Mahaux, J.; Rosseels,

G.; Peiren, M.; Polstre, P.; Chatelain, P.: Clinet, M. J. Med. Chem. 1993, 36, 1425.

16. Pietinen, P.; Stumpf, K.; Mannisto, S.; Kataja, V.; Uusitupa, M.; Ad1ercreutz, H. Cancer

Epidemio/. Biomark. Prev. 2001, 10, 339.

17. Chang, H. M.; Cheng, K. P.; Choang, T. F.; Chow, H. F.; Chui, K. Y.; Hon, P.M.; Tan,

F. W. L.; Yang, Y.; Zhong, Z. P.; Lee, C. M.; Sham, H. L.; Chan, C. F.; Cui, Y. X.;

Wong, H. N.C. J. Org. Chern. 1990, 55, 3537

18. Yang, Z.; Hon, P.M.; Chui, K. Y.; Xu, Z. L.; Chang, H. M.; Lee, C. M.; Cui, Y. X.;

Wong, H. N.C.; Poon, C. D.; Fung, B. M. Tetrahedron Lett. 1991, 32, 2061.

19. Keay, B. A.; Dibble, P. W. In Comprehensive Heterocyclic Chemistry 11-A Review of the

Literature 1982-1995; Pergamon: New York, 1996; Vol. 2, pp 413-436.

20. (a) Powers, L. J. J. Med. Chern. 1976, 19, 57-62. (b) Lambert, C. M.P.; Ple, P. PCT Int.

Appl. WO 0230, 924; (c) Chern. Abstr. 2002, 136, 325553.

43

Chapter 1 Ben::o[b}furan scaffolds: Natural product, Synthesis and biological actil'ity

21. (a) Chatterjee, R.; Kapoor, R. US Patent US 5118707; Chern. Abstr. 1992, 117, 97119r.

(b) Leung, A. Y.; Foster, S. Encyclopedia ofCommon Natural Ingredients Used in Food,

Drugs and Cosmetics; Wiley: New York, 1996.

22. (a) Badger, G. M.; Christie, B. J. J. Chern. Soc. 1956, 3438. (b) Anderisano, R.; Duro, F.;

Pappalardo, G. Gazz. Chim. Ita/. 1956, 86, 1257. (c) Anderisano, R.; Pappalardo, G.

Gazz. Chim. Ita/. 1953, 83, 1953. (d) Clark, E. R.; Williams, S. G. J. Chern. Soc. 1967,

859.

23. (a) Givens, E. N.; Alexakos, L. G.; Venuto, P. B.; Tetrahedron 1969, 25, 2407-2412.

24. Willhalm, B. A.; Thomas, F.; Gautschi, F. Tetrahedron 1964, 20, 1185.

25. McCallion, G. D. Current Org. Chern. 1999, 3. 67-76.

26. Gilchrist, T. L. J. Chern. Soc., Perkin. Trans. I, 2001, 2491-2551.

27. (a) Siddiqui, B. S.; Ismail, F. A. S.; Guizar, T.; Begum, S. Nat. Prod Res. 2003, /7, 355-

360. (b) Nadkami, K. M. Indian Materia Medica, 1986,Vol. 1, pp. 809-810. Ramdas

Bhatkal for Popular Prakashan, Bombay. (c) Perry, L. M.; Metzger, J. Medicinal Plants

of East and South East Asia, 1895, pp. 352-353. The Mit Press, Cambridge,

Massachusetts, London, England.

28. Oat, N. T.; Kiem, P. V.; Cai, X. F.; Shen, Q.; Bae, K.; Kim, Y. H. Arch. Pharm. Res.

2004, 27, 1106-1108.

29. (a) Editorial Committee of Zhongguozhiwuzhi, Chinese Academy of Sciences.

Zhongguozhiwuzhi; Science Press: Beijing China, 1989, 77, 77. (b) Jiang, Z.-R. J.

Shenyang College of Pharmacy 1985, 2, 170.

30. Yan, F.-I.; Wang, A.-x.; Jia, Z.-j. J Chin. Chern. Soc. 2004, 51, 863-868.

31. (a)Takenaka, Y.; Tanahashi, T.; Nagakura, N.; Itoh, A.; Hamada, N. Phytochemistry

2004, 65, 3119-3123.(b) Inoue, S.; Hashizume, K.; Takamatsu, N.; Nagano, H.; Kishi,

Y. Yakugaku Zasshi 1977, 97, 569-575.

32. Pacher,T.; Seger, C.; Engelmeier, D.; Vajrodaya, S.; Hofer, 0.; Greger, H. J. Nat. Prod

2002, 65, 820-827.

33. (a)Pauletti, P.M.; Araujo, A. R.; Young, M. C. M.; Giesbrecht, A.M.; Bolzani V. d. S.

Phytochemistry 2000, 55, 597-601.(b) Teles, H. L.; Hemerly, J. P.; Pauletti, P. M.;

Pandolfi, J. R. C.; Araujo, Valentini, S. R.; Young, M. C. M.; Bolzani, V. D. S.; Silva, D.

H. S. Nat. Prod Res. 2005, 19, 319-323.

34. Akgul, Y. Y .; Ani I, H. Fitoterapia 2003, 7 4, 743-745. (b) Davis, PH. Flora of Turkey

and the East Aegean islands. Edinburgh, University Press, 1972. (c)Vardar, V.; Oflas, S.

Qual. Plant Mater. Veg. 1973,22, 145.

44


35. Han, J. H.; Ryu, S. N.; Kang, S. S. Chern. Pharm. Bull. 2004, 52, 1365-1366.

36. Yao, C. -S.; Lin, M.; Liu, X.; Wang, Y. -H. J. Asian Nat. Prod Res. 2005, 7, 131-137.

37. Dai, J. S.; Ma, B. Z.; Li, S.; Chen, Y. R.; Yu, Q. D. Chin. Chern. Lett. 2004, 15, 951-953.

38. Su, B. -N.; Cuendet, M.; Hawthorne, M. E.; Kardono, L. B.S.; Riswan, S.; Fong, H. H.

S.; Mehta, R. G.; Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod 2002, 65, 163-169

39. Hakim, E. H.; Ulinnuha, U. Z.; Syaha, Y. M.; Ghisalberti, E. L. Fitoterapia 2002, 73,

597-603.

40. Soekamto, N. H.; Achmad, S. A.; Ghisalberti, E. L.; Hakim, E. H.; Syah, Y. M.

Phytochemistry 2003, 64, 831-834.

41. Puntumchai, A.; Kittakoop, P.; Rajviroongit, S.; Vimuttipong, S.; Likhitwitayawuid, K.;

Thebtaranonth, Y. J. Nat. Prod 2004, 67, 485-486.

42. Chen, L.; Hou, A. -J. Helv. Chim. Act. 2005,88,2910-2917.

43. Chen, L.; Jiang, W.; Hou, A. -J. Helv. Chim. Act. 2006, 89, 1000-1007.

44. (a) Muhammad, 1.; Li, X.-C.; Jacob, M. R.; Tekwani, B. L.; Dunbar, D. C.; Ferreira, D.

J. Nap. Prod. 2003, 66, 804-809. (b) Muhammad, I.; Li, X.-C.; Dunbar, D. C.; ElSohly,

M.A.; Khan, I. A. J. Nat. Prod 2001, 64, 1322-1325.

45. Okamoto,Y.; Ojika, M.; Suzuki, S.; Murakami, M.; Sakagamia, Y. Bioorg. Med Chern.

2001, 9, 179-183.

46. Halabalaki, M.; Aligiannis, N.; Papoutsi, Z.; Mitakou, S.; Moutsatsou, P.; Sekeris, C.;

Skaltsounis, A. -L. J. Nat. Prod 2000, 63, 1672-1674.

47. Tanakaa, H.; Oh-Uchia, T.; Etoh, H.; Sako, M.; Sato, M.; Fukai, T.; Tateishi, Y.


48. Salem, M. M.; Werbovetz, K. A. J. Nat. Prod. 2006,69,43-49

49. Belofsky, G.; Carreno, R.; Lewis, K.; Ball, A.; Casadei, G.; Tegos, G. P. J. Nat. Prod

2006, 69, 261-264.

50. Jang, D. S.; Kim, J. M.; Lee, Y. M.; Kim, Y. S.; KIM, J. -H.; Kim, J. S. Chern. Pharm.

Bull. 2006,54, 1315-1317.

51. Maxwell, A.; Dabideen, D.; Reynolds, W. F.; McLean, S. Phytochemistry 1999, 50, 499-

504.

52. (a) Nguyen D. M., "Anti-infective Drugs from Plants of Vietnam," Medicine, Ho Chi

Minh city, 1995, pp. 105-109. (b) Aiba C. J., Campos Correa R. G., Gottlieb 0. R.,

Phytochemistry, 12, 1163-1164 (1973).

53. Giang, P. M.; Son, P. T.; Katsuyoshi, M.; Otsuka, H. Chern. Pharm. Bull. 2006, 54, 380-383.

45


54. Takahashi, M.; Fuchino, H.; Sekita, S.; Satake, M.; Kiuchi, F. Chern. Pharm. Bull. 2006,

54,915-917.

55. Lin,W.-H.; Fang, J.-M.; Cheng, Y.-S. Phytochemistry 1999, 50, 653-658.

56. Seca, A.M. L.; Silva, A.M. S.; Silvestre, A. J.D.; Cavaleiro, J. A. S.; Domingues, F. M.

J.; Pascoal-Neto, C. Phytochermistry 2001, 56, 759-767.

57. Lee, T. -H.; Yeh, M. -H.; Chang, C. -1.; Lee, C. -K.; Shao, Y. -Y.; Kuo, Y. -H. Chern.

Pharm. Bull. 2006, 54, 693-695.

58. Yao, C. -S.; Lin, M.; Wang, L. Chern. Pharm. Bull. 2006,54, 1053-1057.

59. (a) Brend E. K., J. Antiviral Res., 29, 49-53 (1995). (b) Cheng Y. M., "Flora

Xizangica," Science Press, Beijing, 1985, pp.537-539.

60. Yuan, H. -L.; Yang, M.; Li, X. -Y.; You, R. -H.; Liu, Y.; Zhu, J.; Xie, H.; Xiao, X. -H.

Chern. Pharm. Bull. 2006, 54, 1552-1554.

61. Song, -S. K.; Raskin, I. J Nat. Prod 2002, 65, 76-78.

62. (a) Pegnyemb, D. E.; Tiha, R. G.; Sondengam, B. L.; Blond, A.; Bodo, B.

Phytochemistry 2001, 57, 579-582. (b) Ghogomu,T. R., Sondengam, B. L., Martin,

M.T., Bodo, B., Phytochemistry 1989.28, 1557-1559.

63. Hamed, A. 1.; Springuel, I. V.; El-Emary, N. A. Phyochemistry 1999, 50, 887-890.

64. Zidom, C.; Ellmerer-Muller, E. P.; Stuppner, H. Helv. Chim. Act. 2000, 83, 2920-2925.

65. Qiao, C. -F.; Han, Q.-B.; Mo, S. -F.; Song, J. -Z.; Xu, L. -J.; Chen, S. -L.; Yang, D. -J.;

Kong, L. -D.; Hsiang-Fu, K.; Xu, H. -X. Chern. Pharm. Bull. 2006, 54, 714-716.

66. (a) Zhao, L. H.; Wu, M. H.; Xiang B. R. Chern. Pharm. Bull., 2005, 53, 1054-1057. (b)

Yin, S.; Fan, C. Q.; Wang, Y.; Dong, L.; Yue, J. M.; Bioorg. Med Chern. 2005, 12,

4387-4392.

67. Schneider, B. Phytochemistry 2003, 64, 459-462.

68. Otsuka, H.; Hirata, E.; Shinzato, T.; Takeda, Y. Chern. Pharm. Bull. 2000, 48, 1084-

1086.

69. Teguo, P. W.; Lee, D.; Cuendet, M.; Merillon, J.-M.; Pezzuto, J. M.; Kinghorn, A. D. J

Nat. Prod. 2001, 64, 136-138.

70. Cheenpracha, S.; Srisuwan, R.; Karalai, C.; Ponglimanont, C.; Chantrapromma, S.;

Chantrapromma, K.; Fun, H. -K.; Anjum, S.; Rahman, A. -u. Tetrahedron 2005, 61,

8656-8662.

7,,1. Ahmed, B.; Howiriny, AI-, T. A.; Mossa, J. S.; Said AI-, M. J Asian. Nat. Prod Res.

2004, 6, 167-175.

46


72. (a) Torres, P. Phytochemistry, 1989, 28, 3093-3095. {b) Correa, J.; Romo, J.

Tetrahedron 1966,22, 685-691.

73. Inman,W. D; Luo, J.; Jolad, S.D.; King, S. R.; Cooper, R. J Nat. Prod 1999, 62, 1088-

1092.

74. Ito, C.; Katsuno, S.; Kondo, Y.; Tan, H. T. -W.; Furukawa, H. Chern. Pharm. Bull. 2000,

48, 339-343.

75. Gardufto-Ramirez, M.; Trejo, A.; Navarro, V.; Bye, R:;Linare~,E.; Delgado, G. J Nat.

Prod. 2001, 64, 432-435.

76. Burguefto-Tapia, E.; Bucio, M.A.; Rivera, A.; Joseph-Nathan, P. J Nat. Prod 2001, 64,

518-521.

77. Germann, R.; Kaloga, M.; Li, X-C.; Ferreira, D.; Bergenthal, D.; Kolodziej, H.


78. Doe, M.; Shibue, T.; Haraguchi, H.; Morimoto, Y. Org. Lett. 2005, 7, 1765-68.

79. Mbing, J. N.; Pegnyemb, D. E.; Tih, R. G.; Sondengam, B. L.; Blond, A.; Bodo, B.


80. Ito, J.; Takaya, Y.; Oshima, Y.; Niwa, M. Tetrahedron 1999, 55, 2529-2544

81. Ito, T.; Tanaka, T.; Ido, Y.; Nakaya, K. -1.; Iinuma, M.; Riswan, S. Chern. Pharm. Bull.

2000, 48, 1001-1005.

82. Ito, T.; Tanaka, T.; Ido, Y.; Nakaya, K. -i.; Iinuma, M.; Riswan, S. Chern. Pharm. Bull.

2000, 48, 1959-1963.

83. Huang, K. -S.; Lin, M.; Yu, L. -N.; Kong, Man. Tetrahedron 2000,56, 1321-1329.

84. Sotheeswaran, S.; Pasupathy, V. Phytochemistry 1993, 32, 1083.

85. Jang, M.; Cai, L.; Udeani, G. 0.; Slowing, K.V.; Thomas, C.F.; Beecher, C. W. W.;

Fong, H. H. S.; Farnsworth, N. R.; Kinghorn, A. D.; Mehta, R. G.; Moon, R.C.; Pezzuto,

J. M. Science 1977, 275, 218.

86. Oshima, Y., Namao, K., Kamijou, A., Matsuoka, S., Nakano, M., Terao, K., Ohizumi, Y.

Experientia 1995,51,63.

87. Tanakaa, T.; Itoa, T.; Nakayaa, K.; Iinumaa, M.; Riswan, S. Phytochemistry 2000, 54,

63-69.

88. Luo, H. -F.; Zhang, L. -P.; Hu, C. -Q. Tetrahedron 2001, 57, 4849-4854.

89. Jiangsu New Medical College, -The Dictionary of Traditional Medicine, Shanghai

Scientific & Technical Press, Shanghai, 1975, p. 1402.

90. H. F. Luo, L. P. Zhang, C. Q. Hu, Tetrahedron 2001, 57, 4849.

91. Wang, S.; Ma, D.; Hu, C. Helv. Chern. Vet. 2005,88,2315-2321.

47


92. Ito, T.; Furusawa, M.; Iliya, I.; Tanaka, T.; Nakaya, K. -i.; Sawa, R.; Kubota,Y.;

Takahashi, Y .; Riswand, S.; linuma, M. Tetrahedron Lett. 2005, 46, 3111-3114.

93. Liu, J. Y.; Ye, Y. H.; Wang, L.; Shi, D. H.; Tan, R. X. Helv. Chim. Act. 2005,88,2910-

2917.

94. Yamada, M.; Hayashi, K. -i.; Hayashi, H.; Ikeda,S.; Hoshino, T.; Tsutsui, K.; Tsutsui,

K.; Iinuma, M.; Nozaki, H. Phytochemistry 2006, 67, 307-313.

95. "The Himarayan Plants" Vol. 2, ed. by Rajbhandari K. R., Ohba H., University of Tokyo

Press, Tokyo, 1991, pp. 117-167.

96. Yamada, M.; Hayashi, K. -1.; Hayashi, H.; Tsuji, R.; Kakumoto, K.; Ikeda, S.; Hoshino,

T.; Tsutsui, K.; Tsutsui, K.; Ito, T.; Iinuma, M.; Nozaki, H. Chern. Pharm. Bull. 2006,

54, 354-358.

97. (a) Nozaki, H.; Hayashi, H.; Hayashi, K.; Ohira, S.; Ikeda, S.; Iinuma, M.; Tanaka, T.;

Ohyama, M.; Tsutsui, Ke.; Tsutsui, Ki.; Takaoka, D.; Yamada, M. 39'h Tennen Yuki

Kagobutsu Toronkai Koen Yoshishu, 1997, pp. 571-576. (b) Yamada, M.; Hayashi, K.;

Hayashi, H.; Ikeda, S.; Hoshino, T.; Tsutsui, Ke.; Tsutsui, Ki.; Iinuma, M.; Nozaki, H.;

Phytochemistry, 2006, 67, 307-313.

98. For reviews dealing with benzofuran synthesis, see: (a) Hou, X.-L.; Yang, Z.; Wong, H.

N.C. Prog. Heterocycl. Chern. 2002, 14, 139. (b) Gilchrist, T. L. J. Chern. Soc., Perkin

Trans. 1 2001, 2491. (c) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chern. ReV. 2003,

103, 893. (d) Donnelly, D. M. X.; Meegan, M. J. In ComprehensNe Heterocyclic

Chemistry; Katritzky, A. R., Rees, C. W., Eds,; Pergamon Press: New York, 1984; Vol.

4, p 657. Reviews: (e) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;

Pergamon: Amsterdam, 2000. (f) Nakamura, 1.; Yamamoto, Y. Chern. Rev. 2004, 104,

2127.

99. (a) Chaplin, J. H.; Flynn, B. L. Chern. Commun. 2001, 1594. (b) Flynn, B. L.; Hamel,

E.; Jung, M. K. J. Med Chern. 2002, 45, 2670.

100. Nan, Y.; Miao, H.; Yang, Z. Org. Lett. 2000,2, 297-299.

101. Hu, Y.; Nawoschik, K. J.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z. J. Org. Chern. 2004, 69,

2235-2239. Hu, Y.-H.; Yang, Z. Org. Lett. 2001, 3, 1387-1390

102. Liang,Y.; Tang, S.; Zhang, X. -D.; Mao, L. -Q.; Xie, Y. -X.; Li, J. -H. Org. Lett. 2006,

8, 3017-3020.

103. He, Z.; Yudin, A. K. Org. Lett. 2006, 6, 4755-4757.

104. Yue, D.; Yao,T.; Larock, R. C. J. Org. Chern. 2005, 70, 10292-10296

105. Bellur, E.; Langer, P. J. Org. Chern. 2005, 70, 7686-7693.

48


106. · Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett. 2002, 4, 4727-

4729.

107. Ranu, B. C.; Samanta, S.; Hajra, A. Synlett. 2002, 987.

108. Nakamura, M.; Ilies, L.; Otsubo, S.; Nakamura, E. Org. Lett. 2006, 8, 2803-2805.

109. Kumar, M.P.; Liu. R. -S. J. Org. Chern. 2006, 71,4951-4955.

110. Hendrickson, J. B.; Walker, M.A. Org. Lett. 2000,2, 2729-2731.

Ill. Bellur, E.; Langer, P. J. Org. Chern. 2005, 70, 10013-10029.

112. Yamashita, M.; Ono, Y.; Tawada, H. Tetrahedron 2004, 60, 2843-2849.

113. Lee, Y. R.; Suk, J. Y.; Kim, B.S. Org. Lett. 2000,2, 1387-1389.

114. Davarani, S. S. H.; Nematollahi, D.; Shamsipur, M.; Najafi, N. M.; Masoumi, L.;

Ramyar, S. J. Org. Chern. 2006, 71,2139-2142.

115. Ishikawa, T.; Miyahara, T.; Asakura, M.; Higuchi, S.; Miyauchi, Y.; Saito, S. Org. Lett.

2005, 7, 1211-1214.

116. Compernolle, F.; Mao, H.; Tahri, A.; Kozlecki, T.; Van der Eycken. E.; Madaer, B.;

Hoornaert, G. J. Tetrahedron Lett. 2002, 43, 3041-3044.

117. Nagumo, S.; Ishii, Y.; Kakimoto, -1.; Kawahara, N. Tetrahedron Lett. 2002, 43, 5333-

5338.

118. Kraus, G. A.; Zhang, N.; Verkade, J. G.; Nagarajan, M.; Kisanga, P. B. Org. Lett. 2000,

2, 2409-241 0.

119. Katritzky, A. R.; Ji, Y.; Fang, Y.; Prakash, I. J. Org. Chern. 2001, 66, 5613-5615.

120. Li, W. -S.; Guo, Z.; Thornton, J.; Katipally, K.; Polniaszek, R.; Thottathil, J.; Vu, T.;

Wong, M. Tetrahedron Lett. 2002,43, 1923-1925.

121. Nicolaou, K. C.; Snyder, S. A; Bigot, A.; Pfefferkorn, J. A. Angew. Chern. Int. ed. 2000,

39, I 093-1 096.

122. Gabriele, B.; Mancuso, R.; Salerno, G.; Veltri, L. Chern. Cornrnun. 2005, 271-273.

123. Tsai, T. -W.; Wang, E. -C.; Li, S. -R.; Chen, Y. -H.; Lin, Y. -L.; Wang, Y. -F.; Huang, K.

-S. J. Chin. Chern. Soc. 2004, 51, 1307-1318.

124. Youn, S. W.; Eom, J. I. Org. Lett. 2005, 7, 3355-3357.

125. Backvall, J. E.; Akermark, B.; Ljunggren, S. 0. J. Am. Chern. Soc. 1979, 101, 2411.

126. For a review, see: (a) Castro, A.M. M. Chern. Rev. 2004, 104, 2939.(b) Hiersemann, M.;

Abraham, L. Eur. J. Org. Chern. 2002, 1461. For Claisen rearrangement of allyl aryl

ethers with catalytic amount ofmetal catalysts, see: (c) (IrCh/AgOTt) Grant, V. H.; Liu,

B. Tetrahedron Lett. 2005, 46, 1237 and references therein. (d) (Yb(OTt)3) Sharma, G.

V. M.; Ilangovan, A.; Sreenivas, P.; Mahalingam, A. K. Synlett 2000, 615. (e)

49


(Pd(MeCN)2Ch) Anjaneyulu, A. S. R.; Isaa, B. M. J. Chern. Soc., Perkin Trans. 1 1991.

2089.

127. Vaillard, S. E.; Postigo, AI.; Rossi, R. A. J. Org. Chern. 2002, 67, 8500-8506.

128. Ahrendt, K. A.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2003,5, 1303-1305.

129. Kraus, G. A.; Schroeder, J.D. Synlett 2005, 2504-2506.

130. RamaRao, V. V. V. N. S. G.; Reddy,V.; Maitraie, D.; Ravikanth, S.; Yadla, R.;

Narsaiah, B.; Rao, P. S. Tetrahedron 2004, 60, 12231-12237.

131. Sanz, R.; Miguel, D.; Martinez, A.; Perez, A. J. Org. Chern, 2006, 71,4024-4027.

132. Kim, H. J.; Seo, G.; Kim, J. -N.; Choi, K. H. Bull. Korean Chern. Soc. 2004, 25, 1726-

1728.

133. Xie, X.; Chen, B.; Lu, J.; Han, J.; She, X.; Pan, X. Tetrahedron Lett. 2004, 45, 6235-

6237.

134. Goel, A.; Dixit, M. Synlett. 2004, 1904.

135. Willis, M. C.; Taylor, D.; Gillmore, A. T. Org. Lett. 2006,6, 4755-4757.

136. Zhao, B.; Lu, X. Org. Lett. 2006, 8, ASP.

137. Guy, M.; Alois, V.; Richard, B. Tetrahedron Lett. 1994, 35, 3277.

138. Willis, M. C.; Taylor, D.; Gillmore, A. T. Org. Lett. 2004, 6, 4755-4757.

139. Chen, C. -Y.; Dormer, P. G.; J. Org. Chern 2005, 70, 6964-6967.

140. Nematollahi, D.; Rafiee, M. Green Chern. 2005, 7, 638-644.

141. Halfpenny, P.R.; Horwell, D. C.; Hughes, J.; Hunter, J. C.; Rees, D. C. J. Med. Chern.

1990, 33, 286.

142. Wipf, P.; Reeves, J. T.; Balachandran, R.; Giuliano, K. A.; Hamel, E.; Day, B. W. J. Am.

Chern. Soc. 2000, 122, 9391.

143. van Wijngaarden, 1.; Kruse, C. G.; van der Heyden, J. A. M.; Tulp, M. T. M. J. Med.

Chern. 1988,31, 1934.

144. Juteau, H.; Gareau, Y.; Labelle, M.; Lamontagne, S.; Tremblay, N.; Carriere, M. C.;

Sawyer, N.; Denis, D.; Metters, K. M. Bioorg.Med Chern. Lett. 2001, 11, 747.

145. Middlemiss, D.; Watson, S. P.; Ross, B. C.; Dowie, M.D.; Scopes, D. I. C.; Montana, J.

G.; Shah, P.; Hirst, G. C.; Panchal, T. A.; Paton, J. M. S.; Pass, M.; Hubbard, T.;

Hamblen, J.; Cardwell, K. S.; Jack, T. I.; Stuart, G.; Coote, S.; Bradshaw, J.; Drew, G.

M.; Hilditch, A.; Clark, K. L.; Robertson, M. J.; Bayliss, M. K.; Donnelly, M.; Palmer,

E.; Manchee, G. R. M. Bioorg. Med Chem.Lett. 1993, 3, 589.

50


146. Su, T.; Naughton, M.A. H.; Smyth, M.S.; Rose, J. W.; Arfsten, A. E.; McCowan, J. R.;

Jakubowski, J. A.; Wyss, V. L.; Ruterbories, K. J.; Sail, D. J.; Scarborough, R. M. J.

Med Chern. 1997,40,4308.

147. Gammill, R. B.; Bell, F. P.; Bell, L. T.; Bisaha, S. N.; Wilson, G. J. J. Med Chern. 1990,

33,2685.

148. Fecik, R. A.; Frank, K. E.; Gentry, E. J.; Mitscher, L.A.; Shibata, M. Pure Appl. Chern.

1999, 71' 559.

149. Boehm, T. L.; Showalter, H. D. H. J. Org. Chern. 1996,61,6498.

150. Habermann, J.; Ley, S. V.; Smits, R. J. Chern. Soc., Perkin Trans.11999, 2421.

151. Drewry, D. H.; Coe, D. M.; Poon, S. Med Res. Rev. 1999, 19, 97.

152. Ley, S. V.; Baxendale, I. R.; Bream, R.N.; Jackson, P. S.; Leach, A. G.; Longbottom, D.

A.; Nesi, M.; Scott, J. S.; Storer, R. 1.; Taylor, S. J. J. Chern. Soc., Perkin Trans. 1 2000,

3815.

153. Zhang, H.-C.; Maryanoff, B. E. J. Org. Chern. 1997,62, 1804.

154. Wang, Y.; Huang, T.-N. Tetrahedron Lett. 1998, 39, 9605.

155. Fancelli, D.; Fagnola, M. C.; Severino, D.; Bedeschi, A. Tetrahedron Lett. 1997, 38,

2311.

156. Guthrie, E. J.; Macritchie, J.; Hartley, R. C. Tetrahedron Lett. 2000, 41, 4987.

51

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