Biomimetic Approach towards Alkaloid Natural Product Synthesis and the Synthesis of ...

396 Pages·2014·14.87 MB·English

by  Wendy Loa

Biomimetic Approach towards
Alkaloid Natural Product Synthesis
and the
Synthesis of Epicocconone Analogues
with Near Infra-Red Fluorescence

Wendy L. Loa-Kum-Cheung
BMedScs (Hons 1st Class), Macquarie University, Australia

This thesis is submitted in partial fulfilment of the requirements for the degree of
Doctor of Philosophy

Department of Chemistry and Biomolecular Sciences
Faculty of Science

Macquarie University
Sydney, Australia
June 2014

Supervisor: Prof Peter H. Karuso

DECLARATION OF ORIGINALITY
I declare that the work described in this thesis was carried out by me and has not been
submitted, in part or in full, to any other university or institution for any other degree.
To the best of my knowledge and belief, the thesis contains no material previously
published or written by another person except where due references are made.

Wendy L. Loa-Kum-Cheung
2nd June 2014

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ABSTRACT
Nature generates huge diversity in molecular frameworks by using the
simplest route, starting from abundantly available precursors. The biogenesis of
natural products provides valuable information for the design of efficient routes for
complex natural products based on structural analysis and biosynthetic pathways.
Chapter 1 investigates the diastereoselective biomimetic synthesis of the natural
products mikimopine and cucumopine, based on their biogenesis from the Pictet-
Spengler reaction between the naturally abundant precursors !-ketoglutaric acid and
L-histidine. Chapter 2 and 3 then focus on the structurally diverse and complex
family of natural products, known as the oroidin alkaloids. In Chapter 2, a
comprehensive review of the oroidin alkaloids isolated thus far, is first provided. The
biogenesis of all the currently known oroidin alkaloids has been analysed and this has
led, for the first time, to a unifying theory for their formation in Nature.
Haloperoxidase enzymes are thought to play an important role in the biosynthesis of
these marine natural products. Taking this into account, our proposed biogenesis
explains the formation of every oroidin alkaloid from the reactive intermediate
epoxide or bromonium ion of the precursor oroidin or dihydrooroidin, and forms the
basis of a biomimetic approach towards the synthesis of these fascinating and
biologically active alkaloids. Our efforts towards this, are described in Chapter 3,
first by exploring the epoxide route and then the bromonium ion route, and have led to
the synthesis of some natural and unnatural oroidin alkaloids. Chapter 4 then moves
away from the topic of biomimetic synthesis and describes the synthesis of
hemicyanine hybrids of the fluorescent natural product epicocconone. The
photophysical properties of these novel near infra-red dyes are reported and their
potential in the detection of biomolecules demonstrated. Finally the experimental and
appendices for the whole thesis are provided in Chapter 5 and 6 respectively.

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GRAPHICAL ABSTRACTS
Chapter 1: Diastereoselective biomimetic synthesis of natural products
mikimopine and cucumopine
!"ketoglutaric acid
O HOOC HOOC
HO OH
COOH COOH
H H
O O HN S N or HN R N
s s
NH NH HO N HO N
2
HO O O
N
cucumopine mikimopine
O L-histidine

Chapter 2: Biogenesis of the oroidin alkaloids AND
Chapter 3: Biomimetic approach towards the synthesis of oroidin alkaloids from
their biogenetic precursor(s)
O
O
Br
N N
Br H H HN
NH HO Cl Br Y
N
Br N NOH
H2N N X N
Cl N H NH2 H
H2N N NH2 X= Y = H or Br
H
OH X = O, Br+, Cl+
NH
2
N
NH X
2 NH
RHN Br
N NH
Br NH2 Br O
N N N NH H2N NN N
Br RHN
O HN
X
HO
H N
2
N
HN O H NH2
NH Cl
Br O H H OH
NH N Br N NH
Br N H2N N HN N N NH
H O HN O H Br NH2NH2
N Br
N
H N N
2 H
HN O Br

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Chapter 4: Synthesis of epicocconone-hemicyanine hybrids for near infra-red
fluorescence
O
O
O
O
OH
OH Epicocconone !em 535 nm
O

O
OMe O O
O O O O
11 steps HO HO N
MeO R
O O OH
O
OH
NIR fluorescent
! 730 nm
2nd Generation Analogue em
green fluorescent
!em 530 nm

A diastereoselective biomimetic synthesis for the natural products mikimopine
and cucumopine, have been developed. Screening of solvents, bases and lewis acids
showed the bases triethylamine and potassium carbonate to be responsible for the
80% diastereoselectivity achieved in the synthesis of mikimopine and cuccumopine
respectively.
We have proposed a unifying theory for the formation of the structurally
diverse and complex family of oroidin alkaloids based on the enzymatic catalysis of
haloperoxidases and have validated this proposal by synthesising 2 natural and 6
unnatural products from the oroidin family using the oxidant bromodiethylsulfide
bromopentachloroantimonate (BDSB) as a source of bromonium ion with oroidin and
dihydrooroidin.
Seven hemicyanine hybrids of the fluorescent natural product epicocconone
have been synthesised. These are novel near infra-red (NIR) dyes with potential as
molecular probes.

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TABLE OF CONTENTS
DECLARATION OF ORIGINALITY i
ABSTRACT iii
GRAPHICAL ABSTRACTS iv
TABLE OF CONTENTS Vii
ABBREVIATIONS xii
ACKNOWLEDGEMENTS xv

Chapter 1: Diastereoselective biomimetic synthesis of natural products
mikimopine and cucumopine 1
1.1. Introduction 2
1.1.1. The Pictet-Spengler Reaction 3
1.1.1.1. The Pictet–Spenglerases 4
1.1.1.2. P-S Reaction of Imidazoles 5
1.1.2. Previous Work 9
1.1.3. Cucumopine and Mikimopine 11
1.2. Results and Discussion 12
1.2.1. Screening of Bases 12
1.2.2. Screening of Solvents 14
1.2.3. Equivalence of the Base TEA 15
1.2.4. The Carbonates as Base 16
1.2.5. Thermodynamic Product versus Kinetic Product 18
1.2.6. Lewis Acids 20
1.2.7. Substrates Scope 21
1.2.8. Potential Siderophores 26
1.2.8.1. Fluorescence-based Assay to Assess the Fe(III) Chelating
Ability of Mikimopine 27
1.3. Summary 29
1.4. References 30

Chapter 2: Biogenesis of the oroidin alkaloids 35
2.1. Introduction 36
2.1.1. The Oroidin Alkaloids 36
2.1.1.1. Oroidin 36
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2.1.2. Linear Monomers 37
2.1.3. Cyclic Monomers 40
2.1.4. Bicyclic Monomers 43
2.1.5. Dimers 47
2.1.5.1. Acyclic Dimers 48
2.1.5.2. Monocyclic Dimers 51
2.1.5.3. Bicyclic Dimers 54
2.1.5.4. Tricyclic Dimers 56
2.1.6. Tetramers 58
2.1.7. Summary of the Oroidin Alkaloids 59
2.2. Biosynthetic Studies 60
2.3. Biogenesis of the Oroidin Alkaloids 62
2.4. Marine Haloperoxidases 69
2.5. Alkene Double Bond Character in the 2-Aminoimidazole Ring 71
2.6. Bromonium to Epoxide 73
2.7. Proposed Biogenesis of the Oroidin Alkaloids 73
2.7.1. Linear monomers 74
2.7.2. Monocyclic monomers 76
2.7.3. Bicyclic monomers 78
2.7.4. Acyclic Dimers 79
2.7.5. The More Complex Oroidin Alkaloids 80
2.8. Conclusions 86
2.9. References 86

Chapter 3: Biomimetic approach towards the synthesis of oroidin alkaloids
from their biogenetic precursor(s) 93
PART A: Investigation of the Epoxide Route
3.1. Introduction 94
3.1.1. Biomimetic Synthesis of the Oroidin Alkaloids 94
3.2. Results and Discussion 100
3.2.1. Epoxidation using DMDO 101
3.2.2. Other Epoxidation Conditions 103
3.2.3. Biomimetic synthesis of Dispacamide A and Unnatural
Dihydrodispacamide A 106
3.3. Summary- Epoxidation Route 107

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