Synthesis of lamellarin alkaloid analogues from enaminone precursors

322 Pages·2013·9.74 MB·English

Synthesis of lamellarin alkaloid analogues
from enaminone precursors

Stefania Margherita Scalzullo

A thesis submitted to the Faculty of Science,
University of the Witwatersrand,
Johannesburg
In fulfilment of the requirements for the Degree of Doctor of Philosophy

October 2013
Declaration

I declare that the work presented in this thesis was carried out exclusively by myself under the
supervision of Professor Joseph P. Michael and assisted by Professor Willem A. L. van Otterlo.
It is being submitted for the Degree of Doctor of Philosophy in the University of the
Witwatersrand, Johannesburg. It has not been submitted before for any degree or examination in
any other University.

Stefania Margherita Scalzullo
October 2013

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Abstract

The synthesis of alkaloids from enaminones has been used extensively in the University of the
Witwatersrand’s organic chemistry laboratories. In this thesis enaminone precursors are one of
the main ways of accessing lamellarin analogues. The lamellarin alkaloids are an important
family of marine alkaloids, owing to their vast biological properties. A brief background to
marine alkaloids and their general potential is given, followed by a review of lamellarin
alkaloids, their structural and biological properties and some of the major syntheses carried out
over the past few years.

Two novel features form the basis of the synthetic methods described in the thesis. The first is an
approach to forming the lamellarin alkaloids from enaminone precursors, which are prepared
through the Eschenmoser sulphide contraction. The second method uses a novel pyrrole
formation, which was initially conceptualized by Garreth L. Morgans in his PhD thesis (2008).
The main target of the investigation was lamellarin G trimethyl ether.

In Chapter 3, the syntheses of a range of mono-, di- and tetra-substituted phenacyl halides are
discussed. The phenacyl halides were used in the preparation of various enaminone precursors.
The tetrasubstituted phenacyl halide 2-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone 3.17
is required for the synthesis of our target lamellarin G trimethyl ether. The phenacyl halides are
important in both the model synthesis described in Chapter 4 and the synthesis toward
lamellarins in Chapter 5.

Chapter 4 deals mainly with the synthesis of pyrrolizine systems. Methodology is described for
the preparation of a variety of enaminones, pyrroles and tetracyclic lamellarin analogues. The
closest pyrrolizine system to lamellarin G trimethyl ether, 11-(3,4-dimethoxyphenyl)-2,3-
dimethoxy-9,10-dihydrochromeno[4,3-b]pyrrolizin-6(8H)-one 4.52, was the final and most
complex tetracyclic model structure analogous to lamellarin G trimethyl ether. Indolizine and
pyrroloazepine adaptations were also demonstrated and tetracyclic systems 10,11-dihydro-8H-
chromeno[3,2-a]indolizin-12(9H)-one 4.39 and 9,10,11,12-
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tetrahydrochromeno[3',2':3,4]pyrrolo[1,2-a]azepin-6(8H)-one 4.40 were successfully prepared,
even though the pyrrole formed in an unexpected way.

Finally in Chapter 5, the methodology established in the model study was used in the attempted
synthesis of lamellarin G trimethyl ether. A second method was also investigated. Thus, various
N-alkylated and N-H enaminones were successfully synthesized, from which novel and
unexpected pyrrole-containing products 8-(3,4-dimethoxyphenyl)-2,3-dimethoxy-5H-
chromeno[3',2':3,4]pyrrolo[2,1]isoquinolin-14(6H)-one 5.28 and (3-ethoxy-8,9-dimethoxy-2-
phenyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-1-yl)(phenyl)methanone 5.37 were formed, even
though our desired product lamellarin G trimethyl ether could not be attained from either method.

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This thesis is dedicated to
my parents,
Roberto and Rita

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Acknowledgements

I would like to give a special thank-you to my supervisor Professor Joseph Michael. I am truly
grateful for your guidance, wisdom and valuable input throughout my PhD project. You were
truly instrumental in nurturing me throughout my post-graduate degrees.

Professor Willem van Otterlo, Professor Charles de Koning, Doctor Amanda Rousseau, Doctor
Moira Bode, Doctor Stephen Pelly and Doctor Christopher Perry, I would like to thank you for
your continual support and encouragement throughout the duration of this project. Thank you for
all the inspirational discussion, not just concerning chemistry but also about life, love and what
the future holds. You instilled a confidence in me and when times got tough you made me
believe in myself.

Without the generous funding I received, this PhD would not have been possible and I would like
to express my sincere appreciation to the National Research Foundation and the University of the
Witwatersrand.

Thanks to all the members of the organic team, both past and present, in particular Tlabo Leboho,
my lab mate in Lab C319. We have shared a lab from honours to PhD. Thank you for your
patience and some excellent heartfelt and interesting discussions throughout the years. To my
dearest and most treasured friend Sameshnee, thanks for everything, you are truly a treasure
always stay as wonderful and sweet as you are. Lastly, a special thanks to all the people in the
laboratories who have made the difficulties in chemistry so much more bearable with the laughs
and good times throughout the years. A special thanks to Jeremy, Chevonne, Candice, Darren,
Jenny-Lee, Saleem, Siyanda, Winston, Susan, Lee, Warren, Tanya, Garreth, Caitlin, Gail, Thato,
Priya, Kathy, Jean, Adushan, Hanna and everyone I had the pleasure of interacting with.

I would like to acknowledge Doctor Richard Mampa and Professor Lawrence Carlton from the
NMR spectroscopy department for the training and guidance on the NMR spectrometer and for
your patience and assistance with my countless NMR spectra. To Doctor Andrew Dinsmore, Lee
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Madeley, Marelize Ferreira and Professor Willem van Otterlo (and the mass spectral department
at Stellenbosch University), I would like to express my gratitude for the numerous low and high
resolution mass spectral analyses. For data collection and crystallographic analyses, I would like
to thank Doctor Manuel Fernandes sincerely, you are a genius and I thank you for never giving
up on my crystals. Thanks for all the inspirational discussions and support.

My family, my mother and father, I would especially like to thank you for all you have sacrificed
for me over the years while I have been studying, for this I am forever grateful. Thank you for
giving me the freedom to pursue what I loved and encouraging me to persevere no matter how
tough it got! Thank you to my brothers Pietro and Paolo for all your patience and support, I
know it seemed forever, but I am really finished now!

Finally, I would like to thank Myron Johnson, my best friend and the love of my life. Thank you
for your patience, inspiration and motivation throughout the PhD, I know I was impossible to
bear at times! In you I have found someone to share my dreams with and with you I am
complete. I look forward to many years of friendship and love with you.

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Table of Contents

Declaration ___________________________________________________________________ i
Abstract _____________________________________________________________________ ii
Acknowledgements ____________________________________________________________ v
Table of Contents _____________________________________________________________ vii
Chapter 1: Introduction ________________________________________________________ 1
1.1 Alkaloid chemistry: History and background ____________________________________ 1
1.2 A brief background to some of the main classes of marine alkaloids _________________ 4
1.2.1 Marine alkaloids from bacteria, fungi and algae __________________________________________ 4
1.2.2 Marine alkaloids from sponges, molluscs and tunicates ____________________________________ 8
1.3 Lamellarin alkaloids ________________________________________________________ 15
1.3.1 Background _____________________________________________________________________ 15
1.3.2 Biomedical aspects of the lamellarins _________________________________________________ 19
1.4 A selection of reported syntheses of lamellarin alkaloids __________________________ 23
1.4.1 Synthesis by Steglich et al. _________________________________________________________ 24
1.4.2 Syntheses by Banwell et al. _________________________________________________________ 25
1.4.3 Syntheses by Álvarez, Albericio et al. _________________________________________________ 29
1.4.4 Syntheses by Ishibashi, Iwao et al. ___________________________________________________ 31
1.4.5 Syntheses by Ruchirawat et al. ______________________________________________________ 34
1.4.6 Synthesis by Guitian, Diaz and Castedo _______________________________________________ 36
1.4.7 Synthesis by Handy et al. __________________________________________________________ 37
1.4.8 Synthesis by Yadav et al. __________________________________________________________ 38
1.4.9 Synthesis by Jia et al. _____________________________________________________________ 39
Chapter 2: Background, aims and strategies of the project ___________________________ 41
2.1. Background _______________________________________________________________ 41
2.1.1. Introduction _____________________________________________________________________ 41
2.1.2. Enaminones and the Eschenmoser sulphide contraction ___________________________________ 41
2.1.3. Selected syntheses performed in our laboratories using enaminone intermediates _______________ 43
2.1.4. Initial studies conducted for pyrrole formation on silica gel ________________________________ 48

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2.2. Aims and strategies of the project _____________________________________________ 50
2.2.1. Preparation of phenacyl halides ______________________________________________________ 50
2.2.2. Proposed strategy for the synthesis of pyrrolizines from N-alkylated and N-phenacyl analogues ___ 51
2.2.3. Proposed strategy for the synthesis of indolizinone and pyrroloazepinone compounds ___________ 54
2.2.4. Proposed strategies for the synthesis of lamellarin G trimethyl ether _________________________ 56
2.3. Summary of aims __________________________________________________________ 57
Chapter 3: Preparation of phenacyl halides _______________________________________ 60
3.1. Introduction _______________________________________________________________ 60
3.2. Outline of the synthetic strategy ______________________________________________ 61
3.3. Preparation of 2-iodo-1-phenylethanone _______________________________________ 63
3.4. Synthesis of ortho-hydroxy acetophenones ______________________________________ 64
3.4.1. Preparation of 2-bromo-1-(2-hydroxyphenyl)ethanone ____________________________________ 64
3.4.2. Preparation of 1-(2-hydroxyphenyl)-2-iodo-1-ethanone ___________________________________ 65
3.4.3. Preparation of 2-(2-bromoacetyl)phenyl methanesulphonate _______________________________ 66
3.5. Synthesis of tetrasubstituted acetophenones ____________________________________ 67
3.5.1. Preparation of 2-bromo-1-(2-hydroxy-4,5-dimethoxyphenyl)ethanone _______________________ 67
3.5.2. Preparation of 1-(2-hydroxy-4,5-dimethoxyphenyl)-2-iodoethanone _________________________ 70
3.5.3. Preparation of 2-(2-bromoacetyl)-4,5-dimethoxyphenyl methanesulphonate ___________________ 71
3.5.4. Preparation of 2-bromo-1-(2,4-dihydroxy-5-methoxyphenyl)ethanone _______________________ 72
3.6. Preparation of 2-bromo-1,2-bis(3,4-dimethoxyphenyl)ethanone ____________________ 75
3.7. Conclusions for Chapter 3 ___________________________________________________ 77
Chapter 4: Towards tetracyclic pyrrolizinone, indolizinone and pyrroloazepinone analogues of
lamellarins __________________________________________________________________ 78
4.1. Introduction _______________________________________________________________ 78
4.2. Outline of the synthetic strategy ______________________________________________ 81
4.3. Preparation of thiolactam precursors __________________________________________ 82
4.3.1. Preparation of ethyl 2-(2-thioxo-1-pyrrolidinyl)acetate ___________________________________ 83
4.3.2. Synthesis of thiolactams with N-phenacyl substitution ____________________________________ 84
4.3.3. Preparation of thiolactams from piperidinone and caprolactam _____________________________ 87

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4.4. Preparation of enaminones through the Eschenmoser sulphide contraction __________ 88
4.4.1. Synthesis of enaminones from ethyl 2-(2-thioxo-1-pyrrolidinyl)acetate _______________________ 88
4.4.2. Synthesis of N-phenacyl enaminones _________________________________________________ 95
4.4.3. Synthesis of piperidine and azepane enaminones ________________________________________ 97
4.5. Pyrrole synthesis by acid-induced ring closure of enaminones ____________________ 100
4.5.1. A model study of bicyclic systems __________________________________________________ 101
4.5.2. Synthesis of tetracyclic pyrrolizinones _______________________________________________ 104
4.5.3. Attempted synthesis of pyrrolizines from N-phenacyl enaminones _________________________ 106
4.5.4. Synthesis of tetracyclic indolizinone and pyrroloazepinone analogues _______________________ 109
4.6. Brominations and Suzuki-Miyaura coupling reactions ___________________________ 118
4.6.1. Brominations and Suzuki coupling on simple bicyclic compounds _________________________ 119
4.6.2. Brominations and Suzuki couplings of tetracyclic compounds _____________________________ 124
4.6.3. Suzuki reactions using 3,4-dimethoxyphenylboronic acid ________________________________ 126
4.7. Novel methods for introducting lactones into the bicyclic systems _________________ 129
4.7.1. Preparation of 6-phenyl-2,3-dihydro-1H-pyrrolizine-5-carboxylic acid ______________________ 130
4.7.2. Alternative preparation of 9,10-dihydrochromeno[4,3-b]pyrrolizin-6(8H)-one ________________ 131
4.8. Conclusions for Chapter 4 __________________________________________________ 132
Chapter 5: Towards lamellarin alkaloids ________________________________________ 134
5.1 Introduction ______________________________________________________________ 134
5.2 Outline of the synthetic strategy _____________________________________________ 135
5.3 Preparation of dihydroisoquinoline-1-thiones __________________________________ 137
5.3.1 Preparation of 6,7-dimethoxy-3,4-dihydroisoquinoline-1(2H)-thione ______________________ 137
5.3.2 Methods for the preparation of precursor 6,7-dimethoxy-3,4-dihydroisoquinolin-1(2H)-one ____ 139
5.3.3 Preparation of ethyl 2-(6,7-dimethoxy-1-thioxo-3,4-dihydroisoquinolin-2(1H)-yl)acetate ______ 144
5.3.4 Initial studies for alternative aromatic substituents on the dihydroisoquinoline core ___________ 145
5.4 Attempted synthesis of lamellarins with ethyl 2-(6,7-dimethoxy-1-thioxo-3,4-
dihydroisoquinolin-2(1H)-yl)acetate __________________________________________ 147
5.4.1 Preparation of N-alkylated enaminones _______________________________________________ 147
5.4.2 Pyrrole formation through silica gel-mediated ring-closure _______________________________ 152
5.4.3 Bromination and Suzuki-Miyaura coupling reactions ____________________________________ 165

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