università degli studi di milano synthesis and biological activity evaluation of natural antifungals

201 Pages·2013·1.65 MB·English

UNIVERSITÀ DEGLI STUDI DI MILANO

SCUOLA DI DOTTORATO

SCIENZE MOLECOLARI E BIOTECNOLOGIE AGRARIE, ALIMENTARI ED
AMBIENTALI

CORSO DI DOTTORATO
CHIMICA, BIOCHIMICA ED ECOLOGIA DEGLI ANTIPARASSITARI
(XXV CICLO)

TESI DI DOTTORATO DI RICERCA

SYNTHESIS AND BIOLOGICAL ACTIVITY
EVALUATION OF NATURAL ANTIFUNGALS AND THEIR
ANALOGUES

CHIM/06
CHIMICA ORGANICA

SACHIN TANAJI AIWALE

TUTORE

PROF.SSA SABRINA DALLAVALLE

COORDINATORE

PROF.DANIELE DAFFONCHIO

ANNO ACCADEMICO 2011/2012
1
Dedicated to
my beloved
parents

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CERTIFICATE

This is to certify that the work incorporated in the thesis entitled “Synthesis and biological activity
evaluation of natural antifungals and their analogues” which is being submitted to the
University of Milan for the award of Doctor of Philosophy in Chemistry, Biochemistry and
Ecology of pesticides by Sachin Tanaji Aiwale was carried out by him under my supervision at
University of Milan, Milan. This work is original and has not been submitted in part or full, for
any degree or diploma to this or any other University.

Prof. Sabrina Dallavalle
(Research Supervisor)

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Candidate’s Declaration

I hereby declare that the thesis entitled “Synthesis and biological activity evaluation of natural
antifungals and their analogues” submitted for the award of degree of Doctor of Philosophy in
Chemistry, Biochemistry and Ecology of pesticides to the University of Milan, Milan. This work
is original and has not been submitted in part or full, for any degree or diploma to this or any other
University. This work was carried out by me at the Organic Chemistry Department, Faculty of
Agriculture, University of Milan, Milan, Italy.

Sachin Tanaji Aiwale January 03, 2013
Organic Chemistry Department
Faculty of Agriculture (DeFENS)
University of Milan
Milan, Italy.

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Acknowledgements

It is a great pleasure to express my thanks and appreciations towards the people who have
in many ways assisted me to reach this stage. First of all, I would like to express my unreserved
thanks to my research supervisor Prof. Sabrina Dallavalle for offering me the opportunity and
ample resources to pursue this research project. Her guidance and constant encouragement has
been very inspiring. I owe my most sincere gratitude to Prof. Lucio Merlini for his guidance and
unabated perseverance, which has played a key role in the success of this thesis. I do sincerely
acknowledge freedom rendered to me by them for independent thinking, planning and executing the
research. Although this eulogy is insufficient, I preserve an everlasting gratitude for him.
It is really a great help and guidance rendered by Prof.Dr. Paola Sardi in evaluation for
biological activity of synthesized molecules, without their help it would be an incomplete research. I
extend my thanks to Eleo and Jyotsna for their help in experimental part of biological activity
evaluation.
My sincere thanks for the help rendered by my labmates Dr. Alberto Bargiotti, Dr. Loana,
Dr. Raffaella Nannei, Dr. Raffaella Cincinelli, Dr. Narayan, Dr.Jyotsna, Dr. Salvatore and Santosh
for their co-operation during my tenure of research work. I extend my thanks to all technical and
official staff of DeFENS for their assistance.
I am thankful to all my Italian friends namely Claudia, Arrieana, Matteo, Alice, and Susel
for teaching me Italina language and Italian food. My special thanks to my room mate Lucio
Melone and Suresh for the time with laughter, mutual encouragement, and love I had during three
years of PhD.
My warm thanks due to Dr. Mrs. S.P.Maybhate, Scientis E, National Chemical Laboratory,
Pune who introduced me to this fascinating field of research. I would like to thanks Dr. Anil
Srivastava, Group Leader, Jubilant Chemsys Ltd, Delhi, Noida, for the systematic guidance and
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great effort he put into training me in the scientific field. Like a charm!.I am thankful to past
colleagues ,form Jubilant Chemsys Ltd., Mahesh, Narrybhai, Pramod, Nishant, Sultan, Datta,
Piyush, MP, and Amit. I would like to express my very sincere gratitude to Dr. Yogesh Shinde,,
Group Leader, Acoris Ltd, Pune., for the support and encouragement whenever I was in need. My
special thanks to my past colleagues from Acoris Ltd, Sandeep, Prashant, Amit, Gangadhar,
Sahebrao, and Sameer for the fun time I had in Acoris Ltd, at Pune.
I would like to acknowledge all my former teachers, who guided me towards the right path
to reach the present stage; especially Dr. Nazeruddin Sir, Prof. Wadia sir, Dr. Aziz Sir, Dr.
Alamgir, Dr. Mahamulkar, and Iqbal Sir, who helped me to learn and understand chemistry. The
cooperation and support extended by my close friends Rahul, Yasin, Vajir, Giridhar, Rafik, Adita,
Archana, Vijay, Kiran, John, and, Sallauddin is exemplary, I will cherish their friendship forever.
It is impossible to express my sence of gratitude for my parents Shri. Tanaji Malhari Aiwale
and Sau. Mangal Tanaji Aiwale, in mere words. Whatever I am and whatever I will be in future is
because of their enormous blessings, commitments to my ambitions, and altruistic sacrifices. My
successes are dedicated to them now and always. Special mention for my sister Dipali, and Vaishali
and my brother Pankaj for their love and co-operation. My sincere thanks to my grandparents for
their love and care. I also would like to thank my nephew, Mitesh, and the niece Tanishka, for the
laughter gifted to me with your cute and tender voice. I take this opportunity to thank all my
relatives and well-wishers for their support.
At last but not the least, I thank whole heartedly, the omnipotent God Lord Ganesha and
Siddhanath, the llimitable superior spirit, who revels himself in the slight details I am able to
perceive with my frail and feeble mind.
Sachin Tanaji Aiwale

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CONTENTS

Chapter 1: Introduction

Natural products in crop protection
1. Background 17
1.1 Table 1.1 Important Diseases of crop plant 20
1.1. why are fungicides needed 21
1.2 A Short History of fungicides 23
1.2.1 1807-The first fungicide 23
1.2.2 1885- The First Foliar Fungicide 23
1.2.3 1915-Broad-Spectrum Control of Seed-Borne Disease 24
1.2.4 1969-The First Systemic Seed Treatment. 27
1.2.5 1970- The First Broad-Spectrum Foliar Systemic Fungicide 28
1.2.6 1976-A Systemic, Curative Foliar Fungicide for Cereals 29
1.2.7 1977-The First Systemic Oomycete Fungicides 31
1.2.8 1996-Broad-Spectrum Fungicides with Novel Spectrum and
New Mode-of-Action 33
1.2.9 1976-1996-Fungicides with In direct Modes-of-Action 35
1.3 Application Methods 37
1.4 What is a natural substance 38
1.5 Natural products in crop protection 39
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1.5.1 Kasugamycin 40
1.5.2 Blasticidin S 41
1.5.3 Mildiomycin 42
1.5.4 Natamycin 43
1.5.6 The polyoxins 44
1.5.7. Validamycin 45
1.5.8 Soraphen A 47
1.5.9 Bilanafos 48
1.6 The Future of Fungicides 49
1.7 References 52

Chapter 2: Scope of the thesis 57

Chapter 3: Improved Synthesis of farinomalein and its analogues and their
evaluation for biological activity.
3.1 Introduction 60
3.2 Biological activity 62
3.3 Reported Synthesis of farinomalein 63
3.3.1.Retrosynthetic Approach 65
3.3.2 Synthesis of Farinomalein 65
3.4 Synthesis of analogues 67
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3.4.1 Natural compounds bearing maleimide rings. 68
3.4.2 Pencolide from Penicillium multicor 68
3.4.3 Turrapubesin B 69
3.4.4 Showdomycin 70
3.4.5 N-methylmaleimide, N-ethylmaleimide and PhenylmaleimidePM 20. 71
3.5 Structure-Activity Relationship 72
3.6 Synthesis of analogues 74
3.7 Evaluation of Fungicidal Activity 75
3.7.1 Bioassay evaluation 75
3.7.2 Result and discussion 76
3.8 Conclusion 78
3.9 Experimental 79
3.10 References 87

Chapter 4: Epicoccamide D
4.1 Introduction 90
4.2 Biological activity 92
4.3 Synthesis of Epicoccamide D (4) 93
4.4 Reported synthetic methodologies for 3-acyltetramic acids. 94
4.5 Convergent synthetic strategy 97
4.5a Retrosynthetic Approach 97
4.6 Synthesis of subunit 6 99
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4.7 Synthesis of subunit 5 100
4.8 Liner synthetic strategy 107
4.9 Future perspectives 118
4.10.Conclusion 118
4.11 Experimental 119

4.12 Reference 143

Chapter 5: Harzianic Acid

5.1 Introduction 147

5.1 Biological activity 148

5.3 Synthesis of Harzianic Acid 149
5.3.1 Retrosynthesis 149
5.3.2 Synthesis of Subunit 3 151
5.3.3 Synthesis of (2S,5S)-2-(tert-Butyl)-5-isopropyl-1,3-
dioxolan-4-one (4) 152

5.4.Future perspectives 156
5.5. Conclusion 160
5.6 Experimental section 160
5.7 References 170

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