Structural and synthetic studies of alkaloids of the Proteaceae

290 Pages·2014·12.3 MB·English

STRUCTURAL AND SYNTHETIC STUDIES
OF ALKALOIDS OF THE PROTEACEAE
by
John W. Gillard B.Sc.(Hons.)
Submitted in fulfilment of the requirements
for the degree of
Doctor of Philosophy
University of Tasmania
Hobart
August, 1975
(i)
Except as herein stated, this thesis contains no material or paraphrase
of material presented or accepted for the award of any degree or
diploma in any university. To the best of my knowledge, this thesis
contains no copy or paraphrase of material previously published,
except where due reference is made in the text.
John W. Gillard
Contents
Page
Abstract (iii)
Acknowledgements ( iv)
Chapter 1 - Introduction 1

Chapter 2 - Isolation and Structural Elucidation of 66
Alkaloids from the Proteaceous Species
Bellendena montana R.BR. and Agastachys
odorata R.BR.

Chapter 3 - Isolation and Structural Elucidation of 151
Alkaloids from the Proteaceous species
Darlingia darlingiana (F. MUELL),
L.A.S. JOHNSON and Darlingia ferruginea
J.F. BAILEY
Chapter 4 - Synthesis of Pyronotropanes 211
Appendix - 2.1. 142
Appendix - 3.1. 204
(iii)
ABSTRACT
Following the discovery of the presence of alkaloids in an endemic
Tasmanian Proteaceous species, Bellendena montana R.BR., a detailed
phytochemical examination for alkaloids has been undertaken. In
addition, three other species of the Proteaceae, Darlingia darlingiana
(F. MUELL) L.A.S. JOHNSON, Darlingia ferruginea, J.F. BAILEY, and
Agastachys odorata R.BR., also found to contain alkaloids, have been
subjected to a similar examination.
This study has resulted in the isolation of fifteen alkaloids,
of which twelve have been structurally identified by spectroscopy and
synthesis. The structures of the bases have been shown to be
derivatives of the tropane class; eight alkaloids with novel structures
have been classified in two new tropane categories, those of
y-pyronotropanes and 2-benzoyl tropanes. Use has been made of proton
magnetic resonance and carbon magnetic resonance spectroscopy in
determining relative stereochemistries of the bases, and a discussion
of the 13C N.M.R. of y-pyrones is given. Two stereochemical series
of tropane diol esters have been prepared and the spectroscopic data
relating to these bases are presented.
A general synthetic procedure has been developed to apply to the
y-pyronotropanes; each of the naturally occurring alkaloids has been
synthesized by a condensation between tropan-3-one and an enol
ether derivative of a 8-keto acid chloride.
The probable biogenetic relationships between the alkaloids of the
species under study and those recently described, of Knightia deplanchei
VIEILL. ex BROGN et GRIS (Proteaceae) are described in terms of a
biosynthesis from ornithine and a polyketide chain terminated with a
non-acetate moiety.
(iv)
ACKNOWLEDGEMENTS
I wish to express my sincere thanks to my supervisor
Dr. I.R.C. Bick for the help and guidance given to me during the period
this research was undertaken.
I also wish to acknowledge the advice and help given by
Dr. J.B. Bremner and other staff members of this department throughout
the course of this work.
Thanks are due to Mr. R. Thomas and Mr. M. Power for determining
the N.M.R. and Mass Spectra and to Dr. S.R. Johns, C.S.I.R.O. (Melbourne)
and Dr. C. MacDonald, C.S.I.R.O. (Canberra) for assistance received in
13
determining C N.M.R. and High-resolution Mass Spectra.
To Mrs. H. Hen and Mrs. B. Thomson, who carefully and tirelessly
prepared the diagrams and typed this thesis, my sincere thanks.
Finally, I acknowledge the financial assistance of a
Commonwealth Post Graduate Award throughout the duration of this
work.
1
CHAPTER 1
Page
1.1. Introduction 2
1.2. Structural Determination of the Tropane Bases 10
1.2.1. Tropan-3-ol Esters 10
1.2.2. C-6, C-7 Hydroxylated or Epoxidized Tropan-3-ols 12
1.2.3. Ecgonines 15
1.2.4. Pyronotropanes 17
1.2.5. 2-Benzyl and 2-acyl tropanes 18
1.3. Configurational Assignments and Conformation Studies 23
1.3.1. Chemical Methods 23
1.3.2. Spectroscopic Methods 31
( i) Infrared Spectroscopy 31
( ii) Proton Magnetic Resonance (P.M.R.) 33
(iii) Carbon-13 Magnetic Resonance (C.M.R.) 39
( iv) Shift Reagents 43
1.4. Fragmentation of Tropane Alkaloids under Electron Impact 45
1.4.1. a-Cleavage Mechanism 45
1.5. Synthesis of Tropane Alkaloids 48
1.5.1. Willstaetter's Tropan-3-one Synthesis 48
1.5.2. Robinson-Schopf Method 50
1.5.3. Michael Addition 53
1.5.4. Diels-Alder Methods 54
1.6. Biosynthesis of Tropane Alkaloids 57
1.7. References 60
2
1.1. Introduction
The therapeutic application of extracts of a number of species
of the Solanaceae dates from mankind's early history. The use of
Mandragora officinarum L. (Mandrake) as a soporific and analgesic is
recorded in the Ancient Egyptian Ebers Papyrus of 1500 B.C. 1,2;
Hyoscyamus niger (Henbane), Atropa belladonna L. (Belladonna) and
Datura stramonium L. (Thorn Apple) are each recorded as contributing
to the pharmacopoeia of cultures as early and diverse as those of
3
the Aztec Indians and the Babylonians4.
This long-standing recognition of the powerful physiological
action of these extracts has contributed to the zeal with which
chemists and pharmacologists have studied the alkaloids they contain,
as it is these which are responsible for the physiological activity
associated with the plant.
The basic skeleton of this group of alkaloids, also found in the
Convolvulaceae, Erythroxylaceae, Euphorbiaceae, Rhizbphoraceae, and
Proteaceae is 8-azabicyclo[3.2.1]octane. (1.1).
1.I
Five distinct classes of naturally occurring alkaloids are derived
from substitution of this ring system; the first three have provided
the basis for much of the structural and synthetic knowledge of the
tropaneso and the literature pertaining to these classes has received
5(a)(b)(c) 6
excellent coverage in reviews by Fodor and others . The
majority of bases are N-methylated and are hydroxylated at position
C-3. The simplest class of tropanes, bearing only these substituents,
are termed tropanols, and their esters, tropeines. Variety in this
class results from the range of organic acids, which esterify the
secondary hydroxyl group, the most common being 2-methylbutyric,
(isovaleric) 2-methylbut-2-enoic, (tiglic) and 3-hydroxy-2-phenyl
propanoic acid (tropic). In addition, unusual acids such as
112 6 .
2-hydroxy-5-phenyl propanoic and butane-1,2-dithiolane-3-carboxylate
have been noted. Two series occur within this class depending on the
stereochemistry of the hydroxylation of C-3. There is general
7 •
acceptance of the Fodor proposal that the steroid nomenclature
convention should apply to substituted tropanes. Hence, substituents
lying above the plane of the carbocyclic ring in Figure 1.1 are termed
0 and those below the plane are termed a. The 3a nomenclature (or endo)
corresponds to the tropine series and the 30 nomenclature (or-exo) to the
pseudotropine series of the early literature.
Oxidation of the ethano bridge carbons C-6 and/or C-7 in addition
to C-3, produces a second distinct class of tropane alkaloids.
Esterification of the resultant alcohol generates the tropane diol and
triol ester series, the same convention being used to describe the
stereochemistry. All naturally occurring diol and triol esters have
the 6, 70 configuration. In addition, epoxidation may occur across
C-6 and C-7 to produce the scopine series: 60, 70-oxy tropan-3-ols.
Esterification of the C-3 hydroxyl with tropic acid produces the
medicinally useful scopolamine (1.II).
OCOCHPh
1.11
CH2OH
4
Those alkaloids which are carboxylated at position C-2 and
hydroxylatPd at C-3 are known as the ecgonines. The carboxyl group in
this class is esterified with either methanol or ethanol and a variety
of acids esterify the C-3 hydroxy group; thus, cocaine constitutionally
is the benzoate of 2-carbomethoxy tropan-3-ol. The epimeric centres
C-2 and C-3, however, generate four configurational forms whose
8,9
chemical interrelationships and proton magnetic resonance (P.M.R.)
10
spectroscopic parameters are known. Cocaine (1.IV) is the benzoate
derived from 20-carbomethoxy tropan-30-ol, allococaine (1.V)
from 28-carbomethoxy tropan-3a-ol, pseudococaine (1.VI) from
2a-carbomethoxy tropan-30-ol, and allopseudococaine, (1.VII) from
2a-carbomethoxy tropan-3a-ol.
CH3
eCO2Me CH3
c
L:ti
e.) CO2Me
OCOPh
OCOPh
1.IV 1.V

CH3 CH3 N
[110
11012:''CO2Me
OCOPh OCOPh
1.VI 1.VII
Hydrolysis of the cocaines followed by dehydration and methylation
produces a compound identical with the naturally occurring base methyl
11
anhydroecgonine .
The three classes described above have,until recently, constituted
the entire tropane field. The remaining two classes have been
5
discovered recently in the family Proteaceae; a detailed examination of
these novel alkaloids is the subject of this thesis.
The incorporation of the 2- and 3-positions of the tropane nucleus *
into a y-pyrone ring is the structurally characteristic aspect of the
tropane alkaloids isolated from the Bellendena and Darlingia species.
These constitute a new class of tropane bases which have been
12
called pyronotropanes .
R = H, R1 = CH Bellendine (1.VIII)
3
R = CH R1 =H Isobellendine (1. IX)
3'
R = CH , Ri = CH Darlingine (1.X)
3 3
1
R = CH R H
3' Dihydroisobellendine (1. XI)
5,11 cis dihydro
The Proteaceous species Darlingia ferruginea BAILEY and the
13
related species Knightia deplanchei VIEILL ex BROGN. et GRIS also
elaborate closely related alkaloids of the type 1.XII constituting the
fifth class of tropane alkaloids derived from 2-acyl tropane.
X = 0, Y = H Ferrugine
X = 2H, Y = OCOR Knightia bases

= H2OH Minor ferruginea bases
1.XII
A summary of the known tropane bases is shown in Table 1-1.
No indication of absolute stereochemistry is intended by specifically
noting substituents at C-6, C-7, C-2 or C-3 in this table.
In later chapters, where only relative stereochemistries are known, the
lowest numbering sequence is employed and one projection is arbitrarily
employed, there being no intention of implying a knowledge of absolute
configuration.