chemical investigations of the alkaloids from the plants of the family elaeocarpaceae

319 Pages·2007·3.63 MB·English

CHEMICAL INVESTIGATIONS OF THE
ALKALOIDS FROM THE PLANTS OF THE
FAMILY ELAEOCARPACEAE

Peter L. Katavic, BSc (Hons)

School of Science/Natural Product Discovery (NPD)
Faculty of Science, Griffith University

Submitted in fulfillment of the requirements of the
degree of Doctor of Philosophy

December, 2005
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Abstract

A phytochemical survey to detect alkaloids was performed on extracts of 339 discrete
plants parts from a total of 77 species from five genera of Elaeocarpaceae, including 30
species from Queensland, 38 from PNG, and nine from China. An alkaloid detecting
reagent, bismuth (III) tetraiodide (Dragendorff’s reagent) was used in a preliminary test
for alkaloids, with positive ESIMS used to confirm the presence of alkaloids. A total of
35 extracts of various plant parts produced positive results with Dragendorff’s reagent.
Positive ESIMS detected alkaloids in only 13 of these extracts. Bismuth (III) tetraiodide
was demonstrated to produce false positive results with the new non-alkaloidal poly-
oxygenated compounds 112 and 113, which were purified from the extract of Sloanea
tieghemii. Two new alkaloid producing species, Elaeocarpus habbeniensis, and E.
fuscoides were detected from the survey. These species were chemically investigated for
the first time. Two other previously investigated species, E. grandis and Peripentadenia
mearsii, were also studied.

A total of 16 alkaloids, 11 of which are new, were purified from the extracts of these four
species. The novel pyrrolidine alkaloids habbenine (114) and peripentonine (123), were
isolated from the leaves of E. habbeniensis and Peripentadenia mearsii, respectively.
Both of these compounds were purified as inseparable mixtures of diastereomers. The
new pyrrolidine alkaloid mearsamine 1 (124), and the novel amino alkaloid mearsamine 2
(125), were also purified from the leaves of P. mearsii. The known pyrrolidine alkaloid
peripentadenine (81), was purified from the bark of P. mearsii. Peripentonine (123) was
reduced to peripentadenine (81) upon reaction with Pd/C.

Four aromatic indolizidine alkaloids were isolated from the extract of the leaves of E.
fuscoides. One new compound, elaeocarpenine (122), was isolated from this New
Guinean plant. Three known Elaeocarpus alkaloids, isoelaeocarpicine (62), elaeocarpine
(60) and isoelaeocarpine (61) were also purified from E. fuscoides. Elaeocarpenine (122)
was demonstrated to produce the epimeric compounds elaeocarpine and isoelaeocarpine
via reaction with ammonia.
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The chemical investigation of the Queensland plant E. grandis by two separate
purification procedures was performed. An SCX/C18 isolation protocol was used to
purify the new indolizidine alkaloids grandisine C (127), D (126), and E (128), in
conjunction with the known tetracyclic indolizidine isoelaeocarpiline (63). The second
purification of E. grandis was achieved with the use of ammonia in an acid/base
partitioning protocol. Grandisine F (129) and G (130), and compounds 131a and b were
purified by this procedure, as were 63, 126 and 127. Grandisine F and G were proposed
to be ammonia adducts of grandisine D (126). Compound 131a and b were isolated as a
mixture of diastereomers. The reduction of grandisine D (126) with Pd/C yielded a
mixture of isoelaeocarpine (61) and elaeocarpine (60), whereas the reduction of
isoelaeocarpiline (63) produced isoelaeocarpine (61).

All of the alkaloids isolated from the Elaeocarpaceae, except grandisine E (128) and 131a
and b, were evaluated for binding affinity against the human δ opioid receptor. Every
compound except mearsamine 2 (125) possessed a binding affinity of less than 100 μM.
The most active compounds were grandisine F (129), D (126), C (127), elaeocarpenine
(122), isoelaeocarpine (61), isoelaeocarpiline (63) and peripentadenine (81). The IC
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values for these compounds were 1.55, 1.65, 14.6, 2.74, 13.6, 9.86 and 11.4 μM,
respectively. The SAR of the active compounds was compared. These observations
indicated that the indolizidine alkaloids were more active than the pyrrolidine alkaloids,
and a phenol or ketone at position C-12 of the indolizidine alkaloids produced better
binding affinity. All of these alkaloids, except 129, were proposed to interact with two of
the three binding domains of the δ opioid receptor. Grandisine F (129) was proposed to
have a different mode of action than the other alkaloids in the series.

Synthetic modifications to isoelaeocarpine (61) and peripentadenine (81) were
investigated in an attempt to incorporate an extra aromatic group into these molecules.
An extra aromatic group was proposed to provide increased binding affinity to the δ
opioid receptor by interaction with the third binding domain of the receptor. Two
different aromatic amines were successfully attached to peripentadenine (81) by a
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reductive amination reaction using NaBH(OAc) and a titanium catalyst. The reductive
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amination of the ketone in isoelaecarpine (61) with various amines and NaBH(OAc) or
3
NaBH proved unsuccessful.
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Declaration

"This work has not previously been submitted for a degree or diploma in any university.
To the best of my knowledge and belief, the thesis contains no material previously
published or written by another person except where due reference is made in the thesis
itself"

_____________ _________
Name Date
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Acknowledgments

First of all, I would like to thank my supervisors, A. R. Carroll and D. A. Venables, for
their patience and guidance during this PhD experience. My skills as a scientist have
definitely matured under the supervision of Tony and Debra, and for that I am most
grateful.

I am also most grateful for receiving financial assistance from the Australian Research
Council for an Australian Postgraduate Award, and from AstraZeneca for an industry
funded scholarship, which allowed me to pursue my research full-time.

I wish to thank the following people for help with the project: Greg Pierens for advice
and help with NMR experiments, Greg Fechner and Matthew Crampton for assistance
with δ opioid screening, Paul Baron and Jennifer Mitchell for acquiring high resolution
mass spectra, Leanne Towerzey and Carolyn Tranter for computer related issues, Justin
Ripper for invaluable discussions on synthetic chemistry, and Marc Campitelli for advice
on molecular modeling.

I would like to extend thanks to my friends and colleagues Fredrik Lindahl, Rohan Davis,
Declan McKeveney, Carla Rosell and Brendan Wilkinson for many scientific and non-
scientific conversations.

I could not have achieved what I have without the love and support of my mum, for being
there and having faith in me.
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Table of Contents

Abstract iii
Declaration vi
Acknowledgements vii
Abbreviations xv
List of Figures xvii
List of Tables xxi
List of Schemes xxii
List of publications arising from this thesis xxiii

CHAPTER 1 - INTRODUCTION 1
1.1 The Significance of Medicines, Toxins and Hallucinogens from Nature 1
1.2 Alkaloids 5
1.3 Natural Products and the Pharmaceutical Industry 13
1.4 The Family Elaeocarpaceae 23
1.4.1 Distribution 23
1.4.2 Previous Chemical Investigations of the Family Elaeocarpaceae 24
1.4.3 Previous Chemical Investigations of Species from the Genus Aristotelia 25
1.4.4 Previous Chemical Investigations of Species from the Genus Elaeocarpus 25
1.4.5 Previous Chemical Investigations of Species from the Genus Peripentadenia 37
1.4.6 The Value of Chemical Investigations of the Family Elaeocarpaceae 39
1.4.7 The Extraction Process used in the Isolation of Elaeocarpus and Peripentadenia
Alkaloids 39
1.5 Pharmacological Activity of Indolizidine and Elaeocarpus Alkaloids 43
1.6 The Aims of the Chemical Investigation 47
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1.7 References 48
CHAPTER 2 – Phytochemical Evaluation of Plants from the Family
Elaeocarpaceae for Alkaloids 55
2.1 Introduction 55
2.2 Procedure of the CSIRO Phytochemical Survey 59
2.3 Procedure and Results of the Phytochemical Survey of Plants from the Family
Elaeocarpaceae 60
2.4 Investigation of Sloanea tieghemii 64
2.4.1 The Isolation of 112 and 113 64

2.4.2 Structure Elucidation of 112 65

2.4.3 Structure Elucidation of 113 72
2.4.4 Determination of the Absolute Stereochemistry of the Biphenyl Group in 112 and
113 76

2.5 The Application of Strong Cation Exchange to Alkaloid Isolation 78

2.6 Structure Elucidation Strategy 79

2.7 References 80
CHAPTER 3 – Isolation and Structure Elucidation of Habbenine, a
Novel Pyrrolidine Alkaloid from Elaeocarpus habbeniensis 83
3.1 Introduction 83
3.2 The Isolation of Habbenine (114) from the Leaves of E. habbeniensis 83
3.3 Structure Elucidation of Habbenine (114) 85
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3.4 The Proposed Biogenesis of Habbenine (114) and Chemotaxonomic Considerations
93
3.5 Habbenine as a Potential Inhibitor of Ion Channels 96
3.6 References 97
CHAPTER 4 – Isolation and Structure Elucidation of Indolizidine
Alkaloids from Elaeocarpus fuscoides. 99
4.1 Introduction 99
4.2 The Isolation of Indolizidine Alkaloids from the Leaves of E. fuscoides 100
4.3 Structure Elucidation of Elaeocarpenine (122) 102
4.4 Structure Elucidation of Isoelaeocarpicine (63) 107
4.5 Structure Elucidation of Isoelaeocarpine (61) 112

4.6 Structure Elucidation of Elaeocarpine (60) 118
4.7 The Conversion of Elaeocarpenine (122) to Isoelaeocarpine (61) and Elaeocarpine
(60) 122
4.8 Proposed Biogenesis of the E. fuscoides Alkaloids 123
4.9 References 125
CHAPTER 5 – Isolation and Structure Elucidation of Novel Alkaloids
from Peripentadenia mearsii. 127
5.1 Introduction 127
5.2 Isolation of Peripentonine (123), Peripentadenine (81), and Mearsamine 1 (124) and 2
(125) 128
5.3 Structure Elucidation of Peripentonine (123) 133