UNIVERSITI PUTRA MALAYSIA

SYNTHESIS OF 2-ARYLDIHYDROBENZOFURAN NEOLIGNANS AND 2-ARYLBENZOFURAN NEOLIGNANS AND THEIR LARVICIDAL

ACTIVITIES

SITI FADILAH JUHAN

FS 2018 33

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SYNTHESIS OF 2-ARYLDIHYDROBENZOFURAN NEOLIGNANS

AND 2-ARYLBENZOFURAN NEOLIGNANS AND THEIR

LARVICIDAL ACTIVITIES

By

SITI FADILAH JUHAN

Thesis Submitted to the School of Graduate Studies, Universiti Putra

Malaysia, in Fulfilment of the Requirements for the Degree of Doctor of

Philosophy

January 2018

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Abstract of thesis presented to the Senate of Universiti Putra Malaysia in fulfilment of

the requirement for the degree of Doctor of Philosophy

SYNTHESIS OF 2-ARYLDIHYDROBENZOFURAN NEOLIGNANS AND 2-

ARYLBENZOFURAN NEOLIGNANS AND THEIR LARVICIDAL ACTIVITIES

By

SITI FADILAH JUHAN

January 2018

Chair: Siti Mariam Mohd Nor, PhD

Faculty: Science

2-Aryldihydrobenzofuran neolignans (tomentosanan A, ficusal, tomentosanan B) and 2-

arylbenzofuran neolignans (zanthocapensole, zanthocapensate) have been isolated from

the plants were synthesized and evaluated for their larvicidal activities against

Crocidolimia binotalis. Two Heck coupling methods have been developed are using an

activated C-I bond of iodovanillin or non-activated C-H bond of vanillin and alkene of

cinnamic acid derivatives or methyl cinnamate derivatives. Heck coupling reaction

between iodovanillin or vanillin with a series of cinnamic acid derivatives lead to the

formation of eleven new compounds and four known compounds are 2-

aryldihydrobenzofuran neolignan, 3-arylbenzofuran neolignans, 2-arylbenzofuran

neolignans and stilbenes. The reaction involves a series of methyl cinnamate derivatives

has resulted in the formation of five new compounds and three known compounds are

lignans, neolignans, 2,3-diarylbenzofuran neolignan and coumarins. Both methods have

been developed then have applied to the synthesis of five natural products of 2-

arydihydrobenzofuran neolignans and 2-arylbenzofuran neolignans. All the targeted

dihydrobenzofuran neolignans have synthesized as a single enantiomer form namely (+)-

tomentosanan A, (+)-ficusal and (+)-tomentosanan B. Two routes have utilized to

synthesize zanthocapensole and zanthocapensate and only their derivatives have been

obtained from both routes. The selected compounds have been obtained from the Heck

methods development and syntheses part have tested for larvicidal activity by using

Crocidolomia binotalis larvae and azadirachtin as the commercial standard (LD50 = 2.818).

The results indicate some of the compounds have significant activity such as

dihydrobenzofuran neolignan, benzofuran neolignans, lignans, neolignans, stilbene and

coumarin. Among all active compounds, (2E,3E)-dimethyl 2,3-bis(4-hydroxy-3,5-

dimethoxybenzylidene)succinate (lignan) and methyl-3-(4-hydroxy-3-methoxyphenyl)-2-

{2-methoxy-4[(E)-3-methoxy-3-oxo-prop-1-enyl]phenoxy}-prop-2-enoate (neolignan)

have showed the strongest activity with LD50=1.678 mg/L and LD50=2.218 mg/L,

respectively.

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Abstrak tesis yang dikemukakan kepada Senat Universiti Putra Malaysia sebagai

memenuhi keperluan untuk ijazah Doktor Falsafah

SINTESIS BAGI 2-ARILDIHIDROBENZOFURAN NEOLIGNAN DAN 2-

ARILBENZOFURAN NEOLIGNAN DAN AKTIVITI LARVASIDA MEREKA

Oleh

SITI FADILAH JUHAN

Januari 2018

Pengerusi: Siti Mariam Mohd Nor, PhD

Fakulti: Sains

2-Arildihidrobenzofuran neolignan (tomentosanan A, fikusal, tomentosanan B) dan 2-

arilbenzofuran neolignan (zantokapensol, zantokapensat) yang telah diasingkan daripada

tumbuh-tumbuhan telah disintesis dan dianalisis untuk aktiviti larvasida mereka terhadap

Crocidolomia binotalis. Dua kaedah penggandingan Heck telah dibangunkan

menggunakan ikatan aktif C-I yang diaktifkan daripada iodivanillin atau ikatan tidak

aktif C-H daripada vanillin dan alkena dari terbitan asid sinamik atau terbitan metil

sinamat. Tindak balas penggandingan Heck antara iodovanillin atau vanillin dengan siri

terbitan asid sinamik membawa kepada pembentukan sebelas sebatian baharu dan empat

sebatian diketahui iaitu 2-arildihidrobenzofuran neolignan, neolignan 3-arilbenzofuran,

2-arilbenzofuran neolignan dan stilben. Tindak balas yang melibatkan siri terbitan metil

sinamat telah menghasilkan pembentukan lima sebation baharu dan tiga sebatian

diketahui iaitu lignan, neolignan, 2,3-diarilbenzofuran neolignan dan kumarin. Kedua-

dua kaedah yang telah dibangunkan kemudiannya telah digunakan dalam sintesis lima

hasil semula jadi 2-arildihidrobenzofuran neolignan dan 2-arilbenzofuran neolignan.

Semua sebatian sasaran dihidrobenzofuran neolignan telah disintesis sebagai enantiomer

tunggal iaitu (+)-tomentosanan A, (+)-fikusal dan (+)-tomentosanan B. Dua laluan yang

telah digunakan untuk mensintesis zantokapensol dan zantokapensat dan hanya terbitan

mereka diperolehi daripada kedua-dua laluan. Sebatian terpilih yang telah diperolehi

daripada pembangunan kaedah Heck dan bahagian sintesis telah diuji untuk aktiviti

larvasida dengan menggunakan larva Crocidolomia binotalis dan azadiraktin sebagai

piawai komersial (LD50 = 2.818). Hasilnya menunjukkan bahawa beberapa sebatian

mempunyai aktiviti yang penting seperti neolignan dihidrobenzofuran, neolignan

benzofuran, lignan, neolignan, stilben dan kumarin. Di antara semua sebatian aktif,

(2E,3E)-dimethyl 2,3-bis(4-hydroxy-3,5-dimethoxybenzylidene)succinate (lignan) dan

methyl-3-(4-hydroxy-3-methoxyphenyl)-2-{2-methoxy-4[(E)-3-methoxy-3-oxo-prop-

1-enyl]phenoxy}-prop-2-enoate(neolignan) telah menunjukkan aktiviti terkuat dengan

masing-masing LD50 = 1.678 mg/L dan LD50 = 2.218 mg/L.

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ACKNOWLEDGEMENTS

Firstly, all praises to the Mighty Allah, the Gracious and the Beneficent for the strength

and blessing in this study. Appreciation goes to everybody who directly or in directly

assisted me in finishing this project and thesis.

A big honor and thanks to my supervisor Dr. Siti Mariam Mohd Nor for her guidance

and advice all along the way until the completion of this project. Thank you for your

willingness to give me your time for discussion and helping me to understand the concept

and several good techniques used in this project. My gratitude also goes to my committee

members, Dr. Nur Kartinee Mohd Kassim (UPM), Dr. Siti Munirah Mohd Faudzi (UPM)

and Dr. Mohd Shukri Mat Ali (MARDI) for their valuable time and comments.

An appreciation also goes to Pn. Siti Noor Aishikin Abdul Hamid (MARDI) and Pn.

Fatimah Harun (MARDI) who directly gave me a valuable lesson in carrying out

larvicidal bioassay, Pn. Rusnani Amiruddin (UPM) for IR analyses and En. Zainal

Abidin Kassim (UPM) for MS analyses. My gratitude also goes to the Centre for

Research and Instrumentation (CRIM) UKM for the polarimeter analysis, Malaysia

Genome Institute for Circular Dichrosim analysis and Research Management &

Innovation Complex (UM) for LCMS analysis. Without their help and commitment, this

work would not be finished on time.

Finally, my deepest appreciation is to my family especially to my mom, Kamariah

Binti Hj Talib and my dad, Juhan bin Had for their love, support and courage.

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This thesis was submitted to the Senate of Universiti Putra Malaysia and has been

accepted as fulfilment of the requirement for the degree of Doctor of Philosophy. The

members of the Supervisory Committee were as follows:

Siti Mariam Mohd Nor, PhD

Senior Lecturer

Faculty of Science

Universiti Putra Malaysia

(Chairperson)

Nur Kartinee Binti Kassim, PhD

Senior Lecturer

Faculty of Science

Universiti Putra Malaysia

(Member)

Siti Munirah Binti Mohd Faudzi, PhD

Senior Lecturer

Faculty of Science

Universiti Putra Malaysia

(Member)

Mohd Shukri Bin Mat Ali, PhD

Deputy Director and Principal Research Officer

Malaysian Agricultural Research and Development Institute

Malaysia

(Member)

___________________________

ROBIAH BINTI YUNUS, PhD

Professor and Dean

School of Graduate Studies

Universiti Putra Malaysia

Date:

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Declaration by graduate student

I hereby confirm that:

this thesis is my original work;

quotations, illustrations and citations have been duly referenced;

this thesis has not been submitted previously or concurrently for any other degree

at any other institutions;

intellectual property from the thesis and copyright of thesis are fully-owned by

Universiti Putra Malaysia, as according to the Universiti Putra Malaysia (Research)

Rules 2012;

written permission must be obtained from supervisor and the office of Deputy Vice-

Chancellor (Research and Innovation) before thesis is published (in the form of

written, printed or in electronic form) including books, journals, modules,

proceedings, popular writings, seminar papers, manuscripts, posters, reports,

lecture notes, learning modules or any other materials as stated in the Universiti

Putra Malaysia (Research) Rules 2012;

there is no plagiarism or data falsification/fabrication in the thesis, and scholarly

integrity is upheld as according to the Universiti Putra Malaysia (Graduate Studies)

Rules 2003 (Revision 2012-2013) and the Universiti Putra Malaysia (Research)

Rules 2012. The thesis has undergone plagiarism detection software.

Signature: ________________________ Date: __________________

Name and Matric No.: _________________________________________

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Declaration by Members of Supervisory Committee

This is to confirm that:

the research conducted and the writing of this thesis was under our supervision;

supervision responsibilities as stated in the Universiti Putra Malaysia (Graduate

Studies) Rules 2003 (Revision 2012-2013) are adhered to.

Signature:

Name of Chairman of

Supervisory

Committee:

Signature:

Name of Member of

Supervisory

Committee:

Signature:

Name of Member of

Supervisory

Committee:

Signature:

Name of Member of

Supervisory

Committee:

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TABLE OF CONTENTS

Page

ABSTRACT i

ABSTRAK ii

ACKNOWLEDGEMENTS iii

APPROVAL iv

DECLARATION vi

LIST OF TABLES xi

LIST OF FIGURES xiii

LIST OF SCHEME xvii

LIST OF ABBREVIATIONS xx

CHAPTER

1 INTRODUCTION 1

1.1 Dihydrobenzofuran neolignans and

Benzofuran neolignans

1

1.2 Retrosynthetic analysis of targeted

compounds

2

1.3 The pesticidal/insecticidal activity of lignans

and neolignans

4

1.4 Problem statement and hypothesis 6

1.5 Objectives 7

2 LITERATURE REVIEW 8

2.1 Furan and lignan family 8

2.2 Biosynthesis of lignans 10

2.3 Synthesis of dihydrobenzofuran neolignans 15

2.3.1 Heck Coupling 15

2.3.2 Enantioselective cycloetherification 16

2.3.3 Radical-based dimerizations (SET

reagent)

16

2.3.4 Oxidative dimerization (HRP

enzyme)

17

2.4 Synthesis of benzofuran neolignans 19

2.4.1 Sonogashira coupling 19

2.4.2 Palladium-catalyzed annulation 20

2.4.3 Intramolecular oxidative Heck

cyclization

21

2.4.4 Other method on synthesizing

benzofuran

22

2.5 The bioactivity of dihydrobenzofuran

neolignans

23

2.6 The bioactivity of benzofuran neolignans 28

2.7 The pesticide and insecticide active

compounds

32

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2.8 Life cycle of Crocidolomia binotalis 37

3 MATERIALS AND METHODS 39

3.1 General 39

3.2 Experimental procedure for synthesis 39

3.2.1 Halogenation 40

3.2.2 Heck Coupling 41

3.2.3 Esterification 42

3.2.4 Reduction 42

3.2.5 Demethylation 43

3.3 Experimental data for synthesis 42

3.3.1 Heck coupling method development 42

3.3.2 Synthesis of tomentosanan A 55

3.3.3 Synthesis of ficusal 58

3.3.4 Synthesis of tomentosanan B 60

3.3.5 Synthesis of zanthocapensole and

zanthocapensate

63

3.4 Procedure for larvicidal activity 65

3.4.1 Rearing technique of Crocidolomia

binotalis using plant (cabbage)

66

3.4.2 Rearing technique of Crocidolomia

binotalis using artificial diet

66

3.4.3 Larvicidal bioassay of selected

synthesized compounds against

Crocidolomia binotalis larvae

68

3.4.4 LD50 determination of active

compounds

68

4 RESULTS AND DISCUSSION 72

4.1 General 72

4.2 Heck coupling method development 72

4.2.1 Synthesis of iodovanillin 75

4.2.2 Heck coupling between iodovanillin

and vanillin with cinnamic acid

derivatives

76

4.2.3 Synthesis of methyl cinnamate

derivatives

102

4.2.4 Heck coupling between vanillin and

iodovanillin with methyl cinnamate

derivatives

104

4.3 Synthesis of tomentosanan A 122

4.3.1 Synthesis of sinapyl alcohol 123

4.3.2 Heck coupling between vanillin and

iodovanillin with sinapyl alcohol

(Route 3)

126

4.3.3 Enzymatic coupling between

vanillin with sinapic acid and methyl

sinapate using horseradish

peroxidase

137

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4.4 Synthesis of ficusal and tomentosanan B 143

4.4.1 Synthesis of coniferyl alcohol 145

4.4.2 Coupling between vanillin and

iodovanillin with coniferyl alcohol

(Route 3)

147

4.4.3 Reduction of (+)-ficusal 157

4.4.4 Synthesis of vanillyl alcohol and

iodovanillyl alcohol

163

4.4.5 Coupling between vanillyl alcohol

and iodovanillyl alcohol with

coniferyl alcohol (Route 4)

163

4.4.6 Enzymatic coupling between

vanillin with ferulic acid and methyl

ferulate (Horseradish peroxidase)

164

4.5 Synthesis of zanthocapensole and

zanthocapensate

173

4.5.1 Synthesis of zanthocapensole and

zanthocapensate (Route 1)

175

4.5.2 Synthesis of zanthocapensole and

zanthocapensate (Route 2)

183

4.6 The larvicidal activity 186

4.6.1 Larvicidal bioassay of

dihydrobenzofuran neolignans

against Crocidolomia binotalis

186

4.6.2 Larvicidal bioassay of benzofuran

neolignans against Crocidolomia

binotalis

188

4.6.3 Larvicidal bioassay of lignans

against Crocidolomia binotalis

190

4.6.4 Larvicidal bioassay of neolignans

against Crocidolomia binotalis

191

4.6.5 Larvicidal bioassay of stilbenes and

coumarins against Crocidolomia

binotalis

193

5 CONCLUSION 196

REFERENCES 197

APPENDICES 210

BIODATA OF STUDENT 330

LIST OF PUBLICATIONS AND CONFERENCES 331

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LIST OF TABLES

Table Page

2.1 Summary of natural potential dihydrobenzofuran

neolignan compounds

25

2.2 Summary of natural potential benzofuran

neolignan compounds

31

3.1 Gradient flow for LCMS-QTOF 39

4.2.1 Reaction between iodovanillin (7) and ferulic acid

(53) using Pd(OAc)2 and Pd2(dba)3

78

4.2.2 Reaction between iodovanillin (7) and sinapic acid

(55) at different reaction time

78

4.2.3 Esterification of cinnamic acid derivatives 103

4.2.4 Esterification of ferulic acid (53) at different

reaction time

103

4.2.5 Esterification of sinapic acid (55) at different

reaction time

103

4.2.6 Coupling between iodovanillin (7) and methyl

ferulate (108) with different phase transfer agent

and reaction time.

107

4.2.7 Coupling between vanillin (56) and methyl

ferulate (108) with different catalyst and reaction

time.

109

4.3.1 Reduction of methyl sinapate (261) at different

reaction time and catalyst equivalence.

124

4.3.2 Reaction between vanillin (56) and sinapyl alcohol

(8) at different temperature.

126

4.3.3 Comparison table between synthesized (+)

tomentosanan A (271) and isolated (-)

tomentosanan A (1)

130

4.3.4 Reaction between vanillin (56) and methyl

sinapate (261) at different ratio using HRP

138

4.4.1 Reduction of methyl ferulate (108) using LiAlH4

at different reaction time and catalyst equivalence

146

4.4.2 Reaction between iodovanillin (7) and coniferyl

alcohol (9) at different reaction time

148

4.4.3 Comparison 1H NMR and 13C NMR between

synthesized and isolated (+)-ficusal (6)

150

4.4.4 CD comparison between the isolated and

synthesized compounds

158

4.4.5 Comparison table between synthesized (+)-

tomentosanan B (280) and isolated (-)-

tomentosanan B (3)

160

4.4.6 Reaction of methyl ferulate (108) using HRP at

different reaction condition and time

166

4.5.1 Demethylation of 3',4'-dimethoxyphenylacetylene

(15) at different reaction condition

176

4.5.2 Reaction between 3',4'-dimethoxyphenylacetylene

(15) and iodovanillin (7) at different reaction time

179

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4.5.3 Reaction between methyl ferulate (108) and 3’,4’-

dimethoxyphenyl acetylene (15) using different

catalyst and reaction time

185

4.6.1 Bioassay results of dihydrobenzfuran neolignans

against Crocidolomia binotalis

187

4.6.2 Bioassay results of benzofuran neolignans against

Crocidolomia binotalis

189

4.6.3 Bioassay results of lignans against Crocidolomia

binotalis

191

4.6.4 Bioassay results of neolignans against

Crocidolomia binotalis

192

4.6.5 Bioassay results of stilbenes and coumarins

against Crocidolomia binotalis

194

4.6.6 Comparison of LD50 data between different types

of compounds against Crocidolomia binotalis

195

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LIST OF FIGURES

Figure Page

1.1 Structure of targeted neolignans 1

1.2 Structure of potential pesticidal/insecticidal lignans

and neolignans

6

2.1 Basic skeleton of furan, benzofuran and

dihydrobenzofuran

8

2.2 Phenylpropanoid unit, lignan and neolignan basic

structures

8

2.3 Subclasses of lignans 9

2.4 Examples of neolignan 10

2.5 Life cycle of Crocidolomia binotalis

(Sastrosiswojo and Setiawati, 1992)

38

3.1 Rearing Crocidolomia binotalis using plant 66

3.2 Ingredient for diet preparation 67

3.3 Rearing Crocidolomia binotalis using diet 67

3.4 Larvicidal bioassay of selected synthesized

compounds against Crocidolomia binotalis larvae

68

3.5 The Polo Plus software 71

4.2.1 1H NMR and 13C NMR spectra of 2-methoxy-4-

vinylphenol (246) and 2,6-dimethoxy-4-vinyl

phenol (249) (500 MHz, CDCl3)

81

4.2.2 1H NMR and 13C NMR spectra of 4-hydroxy-3-

methoxy-5-(1-(3-

methoxyphenyl)vinyl)benzaldehyde (240) (500

MHz, CDCl3)

83

4.2.3 HMBC correlation of compound 240 83

4.2.4 1H NMR spectra of 7-methoxy-3-

phenylbenzofuran-5-carbaldehyde (239), 7-

methoxy-3-(3-methoxy phenyl)benzofuran-5-

carbaldehyde (241), 7-methoxy -3-

(4methoxyphenyl)benzofuran-5-carbaldehyde

(242) and 3-(4-Hydroxy-3,5-dimethoxyphenyl)-7-

methoxybenzofuran-5-carbaldehyde (250) (500

MHz, CDCl3)

85

4.2.5 13C NMR spectra of 7-methoxy-3-

phenylbenzofuran-5-carbaldehyde (239), 7-

methoxy-3-(3-methoxy phenyl)benzofuran-5-

carbaldehyde (241), 7-methoxy -3-

(4methoxyphenyl)benzofuran-5-carbaldehyde

(242) and 3-(4-Hydroxy-3,5-dimethoxyphenyl)-7-

methoxybenzofuran-5-carbaldehyde (250) (125

MHz, CDCl3)

86

4.2.6 HMBC correlation of compounds 239, 241, 242

and 250

87

4.2.7 1H NMR spectra of 3-(4-hydroxy-3,5-dimethoxy

phenyl)-7-methoxybenzofuran-5- carbaldehyde

(250) and 2-(4-hydroxy-3,5-dimethoxystyryl)-3-(4-

89

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hydroxy -3,5-dimethoxyphenyl)-7-

methoxybenzofuran-5-carbaldehyde (253) and 13C

NMR spectrum of 253 (500 MHz, CDCl3).

4.2.8 HMBC correlation of compound 253 90

4.2.9 1H NMR and 13C NMR spectra of 3-(3,4-

dihydroxy styryl)-4-hydroxy-5-

methoxybenzaldehyde (243) and 2-(5'-formyl-

2',5,6-trihydroxy-3'-methoxy[1,1'-biphenyl]-3-yl)-

7-methoxy-1-benzofuran-5-carbaldehyde (244)

(500 MHz, CD3OD)

94

4.2.10 1H NMR spectra of 3-(4-hydroxy-3-methoxy

styryl)-4-hydroxy-5-methoxybenzaldehyde (246),

4- formyl-2-methoxyphenyl-3-(4-hydroxy-3-

methoxystyryl)-4-hydroxy-5-methoxybenzoate

(247) and 2-(5'- formyl-2',6-dihydroxy-3',5-

dimethoxy[1,1'-biphenyl]-3-yl)-7-methoxy-1-

benzofuran-5-carbaldehyde (248) (500 MHz,

CDCl3)

95

4.2.11 13C NMR spectra of 3-(4-hydroxy-3-methoxy

styryl)-4-hydroxy-5-methoxybenzaldehyde (246),

4- formyl-2-methoxyphenyl-3-(4-hydroxy-3-

methoxystyryl)-4-hydroxy-5-methoxybenzoate

(247) and 2-(5'- formyl-2',6-dihydroxy-3',5-

dimethoxy[1,1'-biphenyl]-3-yl)-7-methoxy-1-

benzofuran-5-carbaldehyde (248) (125 MHz,

CDCl3)

96

4.2.12 1H NMR and 13C NMR spectra of 2-(4-hydroxy -

3,5-dimethoxyphenyl)-7-methoxybenzofuran-5-

carbaldehyde (2511) and 2,3-dihydro-2-(4-

hydroxy-3,5- dimethoxyphenyl)-7-

methoxybenzofuran-5-carbaldehyde (252) (500

MHz, CDCl3)

98

4.2.13 HMBC correlation of compounds 243, 244, 246,

247, 248 and 252

99

4.2.14 1H NMR and 13C NMR spectra of 3-(5-formyl-2-

hydroxy-3-methoxyphenyl)-7-methoxy-2-(3-

methoxy phenyl)benzofuran-5-carbaldehyde

(262) (500 MHz, CDCl3)

110

4.2.15 HMBC correlation of compound 262 110

4.2.16 1H NMR and 13C NMR spectra of 8-methoxy-4-(4-

methoxyphenyl)-2-oxo-2H-chromene-6-

carbaldehyde (263) and 4-(4-hydroxy-3-

methoxyphenyl)-8- methoxy-2-oxo-2H-chromene-

6-carbaldehyde (264) (500 MHz, CDCl3)

112

4.2.17 HMBC correlation of compound 263 and 264 113

4.2.18 1H NMR and 13C NMR spectra of 267 (500 MHz,

125 MHz, (CD3)2CO)

115

4.2.19 HMBC correlation of compound 267 116

4.2.20 1H NMR and 13C NMR spectra of (2E,3E)-

dimethyl 2,3-bis(4-hydroxy-3-

methoxybenzylidene)succinate (265) and (2E,3E)-

117

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dimethyl 2,3-bis(4-hydroxy-3,5-

dimethoxybenzylidene)succinate (266) (500 MHz,

CDCl3)

4.2.21 1H NMR and 13C NMR spectra of (2E,2’E)-3,3’-

[6,6’-dihydroxy-5,5’-dimethoxy-(1,1’-biphenyl)-

3,3’-diyl]diacrylate (268) (500 MHz, CDCl3)

118

4.2.22 1H NMR and 13C NMR spectra of methyl (Z)-3-(4-

hydroxy-3-methoxyphenyl)-2-{2-methoxy-4[(E)-

3- methoxy-3-oxoprop-1-enyl]phenoxy}-prop-2-

enoate (176) and (Z)-methyl 2-(4-formyl-2-

methoxy phenoxy)-3-(4-hydroxy-3,5-

dimethoxyphenyl) acrylate (269) (500 MHz,

CDCl3)

120

4.2.23 HMBC correlation of compound 268, 177, and

269.

121

4.3.1 1H NMR and 13NMR spectra of sinapyl alcohol (8)

and 3-(4-hydroxy-3,5-dimethoxyphenyl)propanal

(270) (500 MHz, CDCl3)

125

4.3.2 CD spectrum of (+)-tomentosanan A (271). 128

4.3.3 1H NMR and 13C spectra of (+)-tomentosanan A

(271) (500 MHz, CDCl3)

129

4.3.4 HMQC spectrum of (+)-tomentosanan A (271) 131

4.3.5 HMBC spectrum of (+)-tomentosanan A (271) 131

4.3.6 1H NMR and 13C NMR spectra of sinapaldehyde

(67) and 3,4-bis(4-hydroxy-3,5-

dimethoxyphenyl)hexa-2,4 -dienedial (272) (500

MHz, CDCl3)

134

4.3.7 1H NMR and 13C NMR spectra of 4-(3-hydroxy

propyl)-2,6-dimethoxyphenol (273), 2,5-bis(4-

hydroxy-3,5-dimethoxyphenyl)cyclohexane-1,4-

diol (274) (500 MHz, CDCl3)

136

4.3.8 HMBC correlation of compound 274 137

4.3.9 1H NMR and 13C NMR spectra of dimethyl-1,2-

dihydro-7-hydroxy-1-(4-hydroxy-3,5-

dimethoxyphenyl)-6,8-dimethoxynaphthalene-2,3-

dicarboxylate (275) (500 MHz, CDCl3)

139

4.3.10 HMBC correlation of compound 275 140

4.4.1 CD spectrum of (+)-ficusal (6) 148

4.4.2 1H NMR and 13C NMR spectra of (+) ficusal (6)

(500 MHz, (CD3)2CO)

149

4.4.3 COSY spectrum of (+)-ficusal (6) 151

4.4.4 NOESY spectrum of (+)-ficusal (6) 151

4.4.5 HMQC spectrum of (+)-ficusal (6) 152

4.4.6 HMBC spectrum of (+)-ficusal (6) 153

4.4.7 1H NMR and 13C NMR spectra of 4-(3-hydroxy

propyl)-2-methoxyphenol (276) and 3,4-dihydro-4-

hydroxy-2-(4-hydroxy-3-methoxyphenyl)-8-

methoxy-2H-chromene-6-carbaldehyde (277) (500

MHz, (CDCl3).

156

4.4.8 HMBC correlation of compound 277 157

4.4.9 CD spectrum of (+)-tomentosanan B (280) 158

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4.4.10 1H NMR and 13C NMR spectra of (+)-

tomentosanan B (280) (500 MHz, (CD3OD).

159

4.4.11 HMQC spectrum of (+)-tomentosanan B (280) 161

4.4.12 HMBC spectrum of (+)-tomentosanan B (280) 162

4.4.13 1H NMR and 13C NMR spectra of methyl 5-((E)-2-

(methoxycarbonyl)vinyl)-2,3-dihydro-2-(4-

hydroxy-3-methoxyphenyl)-7-methoxybenzofuran-

3-carboxylate (112) and dimethyl-1,2-dihydro-7-

hydroxy -1-(4-hydroxy-3-methoxyphenyl)-6-

methoxynaphthalene-2,3-dicarboxylate (281) (500

MHz, (CDCl3).

167

4.4.14 HMBC correlation of compounds 112 and lignan

281

168

4.4.15 1H NMR and 13C NMR spectra of 2,3-dihydro -2-

(4-hydroxy-3-methoxyphenyl)-3-(hydroxymethyl)-

7-methoxybenzofuran-5-yl)acrylate (282) and 2,3-

dihydro-3-(hydroxymethyl)-5-((E)-3-hydroxyprop-

1-enyl)-7-methoxybenzofuran-2-yl)-2-

methoxyphenol (283) (500 MHz, (CDCl3).

171

4.4.16 HMBC correlation of compounds 282 and 283 172

4.5.1 1H NMR spectra of 3',4'-

dimethoxyphenylacetylene (15), 1-(3,4-

dimethoxyphenyl)ethanone (284), 1-(4- hydroxy-

3-methoxyphenyl)ethanone (285) and 1-(3,4-

dihydroxyphenyl)ethanone (286) (500 MHz,

CDCl3).

177

4.5.2 13C NMR spectra of 3',4'-

dimethoxyphenylacetylene (15), 1-(3,4-

dimethoxyphenyl)ethanone (284), 1-(4- hydroxy-

3-methoxyphenyl)ethanone (285) and 1-(3,4-

dihydroxyphenyl)ethanone (286) (125 MHz,

CDCl3).

178

4.5.3 1H NMR and 13C NMR spectra of 7-methoxy-2-

(3,4 -dimethoxyphenyl)benzofuran-5-carbaldehyde

(287) and 7-methoxy-2-(3,4-dimethoxyphenyl)-3-

(2-(3,4-di methoxyphenyl)ethynyl)benzofuran-5-

carbaldehyde (288) (500 MHz, CDCl3)

181

4.5.4 HMBC correlation of compounds 287 and 288 182

4.6.1 Coumarins insecticidal active compounds 193

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LIST OF SCHEME

Scheme Page

1.1 Retrosynthetic analysis of (-)-tomentosanan A,

(-)-ficusal and (-)-tomentosanan B

3

1.2 Retrosynthetic analysis of zanthocapensole and

zanthocapensate

4

2.1 Metabolic pathways of formation cinnamic acid

derivative in plants

11

2.2 General phenylpropanoid and monolignol

pathway

12

2.3 The possible biosynthetic pathway for various

types of lignans

14

2.4 Synthesis of dihydrobenzofuran by Heck coupling

reaction

15

2.5 Synthesis of dihydrobenzofuran by the

enantioselective cycloetherefication reaction

16

2.6 Synthesis of dihydrobenzofuran neolignan by

using SET reagent

17

2.7 Synthesis of dihydrobenzofuran neolignans by

using enzyme catalyst

18

2.8 Synthesis of benzofuran neolignans by

Sonogashira coupling reaction

20

2.9 Synthesis of benzofuran neolignan by palladium-

catalysed annulation.

21

2.10 Synthesis of benzofurans by Intramolecular

oxidative Heck cyclization

22

2.11 Synthesis of benzofurans by using various method 23

3.1 LD50 determination (Polo Plus) 70

4.2.1 Heck method development using various

cinnamic acid derivatives and methyl cinnamate

derivatives

73

4.2.2 Mechanism for the formation of

dihydrobenzofuran ring using method 1 based on

Emrich and Larock (2004)

74

4.2.3 Mmechanism for the formation of

dihydrobenzofuran ring using method 2 based on

Kuram et al. (2013)

75

4.2.4 Synthesis of iodovanillin 76

4.2.5 Possible position for iodine substitution. 76

4.2.6 Reaction between iodovanillin and cinnamic acid

derivatives by applying method 1 (Pd(OAc)2,

Na2CO3, n-Bu4NBr, DMF, 100℃).

77

4.2.7 Reaction between vanillin and cinnamic acid

derivatives by applying method 2 (A: Pd(OAc)2,

1,10-phenanthroline, NaOAc, Cu(OAc)2.H2O,

1,4-dioxane, 110℃, 3d; B: Pd(OAc)2,

bathophenanthroline, AgOAc, Cu(OAc)2.H2O,

1,4-dioxane, 110℃, 3d).

79

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4.2.8 Decarboxylation of ferulic acid (53) 82

4.2.9 Proposed mechanism for compounds 240

benzofuran neolignan 241 (method 1).

91

4.2.10 Proposed mechanism for benzofuran neolignan

241 (method 2).

92

4.2.11 Proposed mechanism for stilbene 246 100

4.2.12 Proposed mechanism for neolignan 248 from

stilbene 246

101

4.2.13 Proposed mechanism for dihydrobenzofuran

neolignan 252

102

4.2.14 Reaction between iodovanillin (7)and methyl

cinnamate derivatives (257, 258, 259, 260, 108

and 261) by applying method 1 (Pd(OAc)2,

Na2CO3, n-Bu4NBr, DMF, 100℃)

105

4.2.15 Reaction between iodovanillin (7) and methyl

ferulate (108) with base

106

4.2.16 Reaction of methyl sinapate (261) with base 106

4.2.17 Reaction between vanillin (56) and methyl

cinnamate derivatives (257, 258, 259, 260, 108

and 261) by applying method 2 (Pd(OAc)2, 1,10-

phenanthroline, NaOAc, Cu(OAc)2.H2O, 1,4-

dioxane, 110℃)

108

4.2.18 Reaction between methyl ferulate (108) with

vanillin (56) using method 1 and 108 with 7

using method 2

109

4.2.19 Proposed mechanism for compounds 263 (method

1)

114

4.2.20 Proposed mechanism for compounds 263 (method

2)

114

4.2.21 Predominant Diferulates from oxidative coupling

(Azarpira et al., 2011)

122

4.3.1 Synthesis plan of tomentosanan A 123

4.3.2 Reduction of sinapic acid (55) 123

4.3.3 Reduction of methyl sinapate (261) 124

4.3.4 Reaction between vanillin (56) and sinapyl

alcohol (8)

126

4.3.5 Reaction between iodovanillin (7) and sinapyl

alcohol (8)

127

4.3.6 Proposed mechanism of (+)-tomentosanan A

(271)

133

4.3.7 Reaction between vanillin (56) and sinapic acid

(55) using HRP

137

4.3.8 Reaction between vanillin (56) and methyl

sinapate (261) using HRP

138

4.3.9 Proposed mechanism of lignan 266 and neolignan

269 by oxidative coupling using HRP (initiation

and propagation step)

141

4.3.10 Proposed mechanism of lignan 266 and neolignan

269 by oxidative coupling using HRP

(termination step)

142

4.4.1 Synthesis plan for ficusal and tomentosanan B 144

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4.4.2 Reduction of ferulic acid (53) 145

4.4.3 Reduction of methyl ferulate (108) 146

4.4.4 Reaction between vanillin (56) and coniferyl

alcohol (9)

147

4.4.5 Reaction between iodovanillin (7) and coniferyl

alcohol (9)

147

4.4.6 Proposed mechanism for (+)-ficusal (6) 154

4.4.7 Reduction of (+)-ficusal (6) 157

4.4.8 Reduction of vanillin (56) and iodovanillin (7) 163

4.4.9 Reaction between vanillyl alcohol (278) with

coniferyl alcohol (9)

164

4.4.10 Reaction between iodovanillyl alcohol (279) with

coniferyl alcohol (9)

164

4.4.11 Reaction between vanillin (56) and ferulic acid

(53) using HRP

165

4.4.12 Reaction between vanillin (56) and methyl

ferulate (108) using HRP

165

4.4.13 Reaction of methyl ferulate (108) using HRP

(control)

166

4.4.14 Proposed mechanism of dihydrobenzofuran

neolignan 112 by oxidative coupling using HRP

169

4.4.15 Reduction of dihydrobenzofuran neolignan 112 170

4.5.1 Synthesis plan for zanthocapensole (4) and

zanthocapensate (5) (Route 1)

174

4.5.2 Synthesis plan for zanthocapensole (4) and

zanthocapensate (5) (Route 2)

175

4.5.3 Demethylation of 3',4'-dimethoxyphenylacetylene

(15)

176

4.5.4 Reaction between 3',4'-dimethoxyphenylacetylene

(15) and iodovanillin (7)

179

4.5.5 Proposed mechanism of 2-arylbenzofuran

neolignan 287

183

4.5.6 Reaction between ferulic acid (53) and 3’,4’-

dimethoxyphenylacetylene (15)

184

4.5.7 Halogenation of ferulic acid (53) 184

4.5.8 Reaction between methyl ferulate (108) and 3’,4’-

dimethoxyphenyl acetylene (15)

185

4.5.9 Halogenation of methyl ferulate (108) 186

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LIST OF ABBREVIATIONS

% Percentage

𝛼 Alpha

𝛽 Beta

λ Wavelength

br Broad

𝛿 Chemical shift in ppm

c Concentration 13C Carbon-13

COSY Correlation Spectroscopy

CD Circular dichrosim

d Doublet

dd Double of dublet

dt Double of triplet

DI-MS Direct Injection-Mass Spectrometry

EIMS Electron Ionization Mass Spectrometry

EC50 Half maximal effective concentration

FT-IR Fourier Transform-Infrared Spectroscopy

GC-MS Gas Chromatography-Mass Spectrometry

h hour

HMBC Heteronuclear Multiple Bond Correlation

HMQC Heteronuclear Multiple Quantum Coherence 1H Proton-1

IR Infrared

IC50 Half maximal inhibitory concentration

LD50 Lethal dose

LCMS Liquid chromatography mass spectrometry

m Multiplet

m/z Mass per charge

M+ Molecular ion

mp Melting point

MS Mass spectroscopy

NMR Nuclear Magnetic Resonance

NEOSY Nuclear Overhauser Effect Spectroscopy

q Quartet

RT Room temperature

Rf Retention factor

s Singlet

t Triplet

TLC Thin Layer Chromatography

QTOF Quadrupole Time Of Flight

UV Ultraviolet

UATR Universal Attenuated Total Reflection

Hela Cervical cancer

HepG2 Liver hepatocelular carcinoma

A375-S2 Human melanoma cells (skin cancer)

HT1080 Fibrosarcoma cell (tumor cancer)

HL60 Human promyelocytic leukemia cells

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CHAPTER 1

INTRODUCTION

1.1 Dihydrobenzofuran Neolignans and Benzofuran Neolignans

Dihydrobenzofuran and benzofuran neolignans are common compounds that are found

in plants and appeared as a promising compound to study due to its potential bioactivity.

Some of their activities are antimicrobial (Kirilmis et al., 2007), anti-inflammatory

(Hwang et al., 2010; Tan et al., 2010; Lee et al., 2012), HIV integrase inhibitor (Abd-

Elazem et al., 2002), antioxidant and anticancer (Rakotondramanana et al., 2007). Other

reported biological activity of these compounds are insecticidal (González-Coloma et

al., 2002), anti-complement (Luo et al., 2013), pesticidal (Cutillo et al., 2003) and

antileishmanial (Miert et al., 2005). Five natural product compounds were studied in this

research where three of them are dihydrobenzofuran neolignans, (-)-tomentosanan A (2S,

3R) (1), (-)-ficusal (2S, 3R) (2) and (-)-tomentosanan B (2S, 3R) (3) while the other two

are benzofuran neolignans, zanthocapensole (4) and zanthocapensate (5) (Figure 1.1).

O

H

OCH3

O

OH OCH3

OH

OCH3

HO

OCH3

O

OH

OH

OCH3

H

OCH3

O

OH

OH

OCH3

O

(-)-Tomentosanan A (2S, 3R) (1) (-)-Tomentosanan B (2S, 3R) (3)(-)-Ficusal (2S, 3R) (2)

O

OCH3

HO

O

O

Zanthocapensole (4)

O

OCH3

H3CO

O

O

Zanthocapensate (5)

O

H

OCH3

O

OH

OH

OCH3

O

(+)-Ficusal (2R, 3S) (6)

2

33

2 2

2

3

3

Figure 1.1: Structure of targeted neolignans

2-Aryldihydrobenzofuran neolignans, (-)-tomentosanan A (1), (-)-ficusal (2) and (-)-

tomentosanan B (3) were isolated from the seed of Prunus tomentosa (Liu et al., 2014).

Compound 2 was reported to be isolated from several species such as leaves and stems

of Manglietia insignis (Shang et al., 2013), Acanthopanax senticosus (Li et al., 2015)

and the seed of Crataegus pinnatifida (Huang et al., 2015). Both 1 and 3 are in colorless

oil meanwhile compound 2 was isolated as pale yellow oil. Compounds 1 and 3 were

identified as new neolignans in 2014 by Liu and their co-worker. In contrast, its analog

(+)-ficusal (2R, 3S) (6) was isolated from leaves of Ficus microcarpa L.f. (Moraceace)

(Li and Kuo 2000), fruits of Vitex agnus-castus L (Chen et al., 2011), and Metasequoia

glyptostroboides Hu et Cheng (Taxodiaceae) (Zeng et al., 2013).

Compounds 1-3 shown strong antioxidant activity when tested against DPPH and ABTs

radical. The compound also displayed strong anti-inflammatory activity on nitric oxide

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(NO) production in murine microlia BV-2 with compound 2 gives the stronger activity

(IC50= 4.8 µM) compared to the standard drug used, minocycline (IC50= 19.7 µM) (Liu

et al., 2014). Some other activity that has been reported for compound 2 were antitumor

when tested upon human tumor cell lines of HL-60, SMMC-7721, MCF-7 and SW480

(Shang et al., 2013), tumor necrosis factor α (TNF-α) production by the PLS-induced

murine macrophage cell line RAW264.7 (Huang et al., 2015) and in vitro inhibitory

activities against protein tyrosine phosphatase 1B(PTP1B), human vaccina H1 related

protein (VHR) and protein phosphatase 1 (PP1) (Li et al., 2015). In addition, the

enantiomer of 1 (compound 6) found significantly inhibited MDA-MB-231 cells at 50

μM by 69.3% (Chung et al., 2012).

Zanthocapensole (4) and zanthocapensate (5) are 2-arylbenzofuran neolignans that were

isolated from methanol extract of African Zanthoxylum capense root which have been

ethnopharmacologically used to treat tuberculosis. They are analogs with the same

appearance as white amorphous solid and have a good antibacterial activity against gram-

positive (Staphylococcus aureus and Enterococcus aureus) and gram-negative

(Pseudomonas aeruginosa and Escherichia coli). Compounds 4 and 5 were tested on

human THP-1 macrophages and showed cytotoxicity at 72.3 µg/mol and 52.1 µg/mol,

respectively (Luo et al., 2013). Both neolignans also have been tested on HCT116 cells

and exhibited significant cytotoxicity activity.Compound 5 literally induced the highest

percentage of apoptosis after 24 hours exposure at 20 M (Mansoor et al., 2013).

1.2 Retrosynthetic Analysis of Targeted Compounds

The retrosynthetic analysis showed that (-)-tomentosanan A (1) can be produced by

coupling reaction between iodovanillin (7) and sinapyl alcohol (8) (Scheme 1.1).

Meanwhile, the synthesis of (-)-ficusal (2) can be achieved by coupling between

iodovanillin (7) with coniferyl alcohol (9) and further reduction resulted in production

of (-)-tomentosanan B (3). The (-)-tomentosanan B (3) could as well be directly

synthesized by coupling between iodovanilyl alcohol (10) with coniferyl alcohol (9).

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OHC

OCH3

O

OCH3

OH

OCH3

HO

OCH3

OH

OCH3

HO

OHC I

OH

OCH3

Heck

(-)-Tomentosonan A (1)Sinapyl alcohol (8)

+

Iodovanillin (7)

OHC

OCH3

O

OH

OCH3

HO

OH

OCH3

HOOHC I

OH

OCH3

Heck

Coniferyl alcohol (9)

+

OCH3

O

OH

OCH3

HO

(-)-Tomentosanan B (3)

Reduction

HO

(-)-Ficusal (2)

I

OH

OCH3

Iodovanillyl alcohol (10)

HO

Heck

Iodovanillin (7)

Reduction

OH

OCH3

HO

Coniferyl alcohol (9)

+

Scheme 1.1: Retrosynthetic analysis of (-)-tomentosanan A, (-)-ficusal and (-)-

tomentosanan B

The retrosynthetic analysis of zanthocapensole (4) and zanthocapensate (5) were

proposed in two routes (Scheme 1.2). The first route is proposed by coupling of 3’,4’-

dihydroxyphenylacetelyne (12) with iodovanillin (7) to produce an intermediate of 11

before proceeding with acetalation and Wittig reactions to get zanthocapensate (5) and

further reduce to obtain zanthocapensole (4). The second route was proposed by the

reaction between methyl iodoferulate (14) and 3,4-dimethoxyphenylacetylene (15) to

produce an intermediate of 13, in which further demethylation and acetalation results in

the synthesis of zanthocapensate (5).

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HO

OCH3

O

O

O

H3COOC

OCH3

O

O

O

H3COOC

OCH3

O

OCH3

OCH3

Reduction

Zanthocapensole (4)

Zanthocapensate (5)

OHC

OCH3

O

OH

OH

Wittig

AcetalationAcetalation

Demethylation

OCH3

OCH3

H3COOC I

OH

OCH3

+

Heck (Route 1)

3',4'-dimethoxyphenylacetylene (15)Methyl iodoferulate (14)

Heck (Route 2)

OHC

OH

OCH3

I

+

Iodovanillin (7)

OH

OH

3',4'-Dihydroxyphenylacetylene (12)

11 13

Scheme 1.2: Retrosynthetic analysis of zanthocapensole and zanthocapensate

1.3 The Pesticidal/Insecticidal Activity of Lignans and Neolignans

Pesticides are essential to control pest and disease infestations in crop plantation or food

production. However, resistance development of plant pathogens to conventional

pesticide along with toxic effects initiated researcher's interest towards developing

insecticide from natural origin. Pesticide mode of action is by targeting the systems or

enzymes in the pest. The targeted enzymes or system might be identical or similar to the

systems or enzymes in human beings thus, they pose risks to the human health and

environment. Plant-derived compounds are believed to exert low-toxicity and high

mortality target of insect population which would not cause ecosystem disturbance

(Emberger, 2015). Various phytochemicals have been investigated for insecticidal, insect

repellent and insect antifeedant activity such as diterpene ryanodanes and isoryanodanes

from Persea indica (Lauraceae), lignans from Machilus japonica (Lauraceae) and

diterpenoid alkaloids from Delphinium cardiopetalum (Ranunculaceae) (González-

Coloma et al., 2002).

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Crocidolomia binotalis (croci) is one of the agricultural pests that has been threatening

crops plantation. Croci also known as cabbage head caterpillar have a life cycle

completed depending on temperature and humidity approximately 28 days at a

temperature of 26-33℃ or 30-41 days at lower temperature 16-22℃. They are almost

exclusively found in hot humid highland tropics and constitute a more serious pest

problem during the dry season since heavy rains can drown small larvae. The percentage

of hatching could reach until 92% in each of their life cycles. If suitable control is not

undertaken, especially in the dry season, the yield loss caused by this pest may reach up

to 100% (Sastrosiswojo and Setiawati, 1992).

Croci is a serious pest in the highland area, especially for cabbage in Indonesia. The

study conducted in Indonesia showed that hand-picking leaves with the egg masses and

larvae were preferred to avoid the chemical spray (Shepard and Schellhorn 1994).

However, this method can only be applied in a small plantation area. The adult moth can

be killed by light traps, whereas its larva only can be killed by some type of commercial

pesticides such as dust DDT (10%) or carbaryl (10%) malathion, monocrotophos and

quinalphos. Some of the chemicals were already listed as the Persistent Organic

Pollutants (POPs) pesticides and already banned by the Stockholm convention.

Therefore, alternative methods to control insect pests through friendlier environment

approach need to be done.

Based on the previous study, podophyllotoxin (16) is one of the most popular precursors

that come from the lignan family that has potential as a pesticide. In 1978, Singh et al.

isolated an active constituent, namely, peltatin methyl ether A (deoxpodophyllotoxin)

which was toxic towards housefly (Musca domestica) and codling moth (Laspayressia

pomonella). Further study on podophyllotoxin derivatives found that podophyllotoxin

with pyridin ring (Di et al., 2007) and phenoxyanillin substituents (Liu et al., 2008) gave

greater insecticidal activity against Pieris rapae than podophyllotoxin itself. An ester of

2-chloropodophyllotoxin (Xu and Xiao, 2009) and hydrazone derivatives of

podophyllotoxin (Wang et al., 2014) also showed good insecticidal activities against the

oriental armyworm, Mythimna seperata.

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O

O

O

H3CO

OCH3

OCH3

OH

O

O

H3CO

OCH3

OH

OCH3

O

H3CO

OCH3

OCH3

OCH3

O

O

O OCH3

OCH3

O

O

O OCH3

OCH3

Licarin A (18)

(-)-Machilusin (20) (2R,3S,4R,5R)-2-(3,4-dimethoxyphenyl)-3,4-dimethyl-5-piperonyltetrahydrofuran (21)

(2S,3S)-2,3-dihydro-7-methoxy-3-methyl-2-(3,4-dimethoxyphenyl)-5-trans-(1-propenyl)-benzofuran (19)

Podophyllotoxin (16)

O

OO

O

O

HO

O

O

OH

Phrymarolin B (17)

Lignans Neolignans

Figure 1.2: Structure of potential pesticidal/insecticidal lignans and neolignans

Phymarolin B (17), a furan type lignan which was isolated from Phryma leptostachya

was evaluated for its insecticidal activity against the fourth instar larva of Mythimna

separata. The compound exhibited moderate activity with LC50 of 502 μg/mL (Xiao et

al., 2013). Another four furan type neolignans (18, 19, 20 and 21) from Machilus

japonica were identified to have insecticidal activities against neonate Spodoptera litura

larva with the significant EC50 of 0.20, 0.24, 0.19 and 0.13 μg/mL each by comparison

to the positive control used, azadirachtin (0.25 μg/mL) thus further confirms that this

specific group of compound have great potential as insecticide (González-Coloma et al.,

2002).

To date, there are limited study focusing on dihydrobenzofuran neolignan and fewer

investigations have been reported on benzofuran neolignan as pesticide. Therefore, it is

a great need to study and identify the potential of lignans and neolignans as pesticides as

the paradigm of agriculture needs.

1.4 Problem Statement and Hypothesis

Currently, the used of synthetic chemical pesticides is harmful towards human and

environment which lead to the development of insecticide resistence in insects

(Emberger, 2015), whereas the use of natural occurring pesticide from plant are eco-

friendly and less toxic but comes with limited resources (González-Coloma et al., 2002).

Therefore, it is important to study the synthetic chemical pesticide with the basic of

potential natural dihydrobenzofuran neolignans and benzofuran neolignans to produce a

more efficient, economical, safe and eco-friendly pesticides in Malaysia. Crocidolomia

binotalis was chosen as the target pest in this study since it is one of the most popular

pests other than Plutella xylostella, Spodoptera litura and Hellula undalis in Malaysia

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(Lim et al., 1996). Besides, this pest is one of the most common cabbage pests identified

in Cameron Highlands, Malaysia (Oii and Kelderman, 1979) and other crop plantation

area in Indonesia (Sastrosiswojo and Setiawati, 1992; Shepard and Schellhorn 1994).

All pesticides or insecticides as mentioned in 1.3 (page 7) have similar structure with the

targeted dihydrobenzofuran and benzofuran neolignans introduced in 1.1 (page 1).

Evidently, the structure of active pesticide/insecticide compound consist a 5-membered

heterocyclic; either dihydrofuran or tetrahydrofuran or two benzene rings. Furthermore,

substituent such as hydroxyl, methyl or methoxy and the presence of double bond and

acetal group also plays a significant role. All of these characteristics can be observed in

the structure of tomentosanan A (1) and tomentosanan B (3), ficusal (2 and 6),

zanthocapensole (4) and zanthocapensate (5). According to these facts, it can be deduced

that the targeted compounds might display the same activity, and the presence of furan

ring in their structures may enhance the insecticidal activity.

To the best of our knowledge, there are limited research on dihydrobenzofuran or

benzofuran neolignans as pesticide or insecticide. This is the first research which focuses

on the synthesis of neolignans 1-5. The findings of this investigation provide a paradigm

route to synthesize dihydrobenzofuran and benzofuran neolignans together with its

derivatives as well as their insecticidal activity.

1.5 Objectives

The synthesis of neolignan especially dihydrobenzofuran and benzofuran are crucial in

order to manufacture an efficient, safe and eco-friendly pesticides in Malaysia. This

research project aimed to search insecticidal compounds which can lead to the discovery

of insecticide candidates for Crocidolomia binotalis or for the future of agriculture

research. Therefore, three objectives were proposed for this research:

1. To develop the Heck coupling method in the synthesis of neolignans via

activated C-I bond of iodovanillin and non-activated C-H bond of vanillin.

2. To synthesize 2-aryldihydrobenzofuran and 2-arylbenzofuran neolignans

and their derivatives via the developed Heck coupling reaction.

3. To determine the larvicidal activities of all the intermediate compounds

and neolignans obtained.

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LIST OF PUBLICATIONS AND CONFERENCES

Publications

Juhan, S. F., Nor, S. M. M., Sukari, M. A. M., Azziz, S. S. S. A., Fah, W. F and Alimon,

H. (2016). New Synthesized Aminoanthraquinone Derivatives and Its

Antimicrobial and Anticancer Activities (Route II). International Journal of

Contemporary Applied Sciences 3 (1) 18-33.

Nor, S. M. M., Sukari, M. A. M., Azziz, S. S. S. A., Fah, W. F., Alimon, H. and Juhan,

S. F. (2013). Synthesis of New Cytotoxic Aminoanthraquinone Derivatives via

Nucleophilic Substitution Reactions. Molecules 18: 8046-8062.

In Progress article:

1. 2-Aryldihydrobenzofuran neolignans: synthesis of ficusal and tomentosanan B

(accepted for publication on 9 May 2018 in Der Chemica Sinica).

2. Chemical and Enzymatical Synthesis of Lignans and Neolignans derivatives

and its larvicidal activities.

3. Synthesis of new derivatives of benzofuran neolignans and stilbenes via Heck

coupling.

4. Synthesis of New Derivatives of Phenylcoumarins and Neolignans via Heck

Coupling

5. Synthesis of (+)-Tomentosanan A via Heck Coupling Approach

6. Synthesis of zanthocapensole and zanthocapensate derivative using Heck

coupling method.

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Conferences

1. 29th The Malaysian Analytical Chemistry Symposium (SKAM 29) on 15 to 17

August 2016 at Bayview Beach Resort, Penang organized by Universiti Sains

Malaysia. Participation as a poster presenter.

2. Fundamental Science Congress (FSC) on 12 to 13 November 2015 at Faculty

of Science veterinary organized by Universiti Putra Malaysia. Participation as

an oral presenter.

3. Fundamental Science Congress (FSC) on 20 to 21 August 2013 at Faculty of

Science veterinary organized by Universiti Putra Malaysia. Participation as a

poster presenter.

4. International Conference on Natural Products (ICNP2013) on 4 to 6 March

2013 at Shah Alam Convention Centre (SACC) organized by Universiti

Teknologi MARA Shah Alam, Selangor and Malaysian Natural Product

Society. Participation as an oral presenter

5. 2nd National Symposium in Organic Synthesis 2012 (New Frontiers in Organic

Chemistry) on 16 and 17 July 2012 at Concorde Hotel Shah Alam organized by

Institute of Science (IOS) Universiti Teknologi MARA Shah Alam, Selangor,

Malaysia. Participation as a poster presenter.

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