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Synthesis of Indole Alkaloids and Development of New Methodology

Hoang, Anita LU (2019)
Abstract
This thesis describes our efforts towards the total synthesis of natural products and the development of a new
methodology to afford a synthetically important scaffold.

Chapter 2 outlines our efforts towards the total synthesis of a marine natural product, perophoramidine as well
as our completed synthesis of dehaloperophoramidine. The focus of the studies was to develop an efficient and
concise strategy to afford the natural products. We aimed at utilising the inherent structure and symmetry of the
natural product to encourage domino processes and gain access to the key features. The vicinal quaternary
stereocenters were installed by employing Overman’s diastereoselective dialkylation protocol. Two new... (More)
This thesis describes our efforts towards the total synthesis of natural products and the development of a new
methodology to afford a synthetically important scaffold.

Chapter 2 outlines our efforts towards the total synthesis of a marine natural product, perophoramidine as well
as our completed synthesis of dehaloperophoramidine. The focus of the studies was to develop an efficient and
concise strategy to afford the natural products. We aimed at utilising the inherent structure and symmetry of the
natural product to encourage domino processes and gain access to the key features. The vicinal quaternary
stereocenters were installed by employing Overman’s diastereoselective dialkylation protocol. Two new domino
processes were discovered. The first domino process led to the formation of the ortho-amide and careful
investigation of its reactivity led to the discovery of the second domino process which ultimately delivered
dehaloperophoramidine. The synthesis was completed in eight steps starting from isoindigo.

Chapter 3 describes our efforts towards the total synthesis of strictamine. The key features of strictamine that
need to be addressed when pursuing the synthesis are: (i) the quaternary stereocenter, (ii) the central
cyclohexane moiety (D ring) with four stereocenters, and (iii) the cage-like methanoquinolizidine core. We aimed
at accessing these key features through intramolecular Heck reaction to access the central D ring with parts of
the substitution pattern already present and the quaternary stereocenter. For the methanoquinolizidine core, we
planned to adopt our previously described domino carbopalladation/carbonylation protocol. The synthesis is in
an advanced state with two additional functionalisation left in order to access the target compound. Described in
this chapter is our effort to access the core structure of strictamine with all the rings installed.

The third part of this thesis deals with the development of a new methodology to access indoline scaffolds that
feature an all-carbon quaternary stereocenter. We were able to synthesise allyl anilines through the regio- and
stereoselective ring-opening of vinyl aziridines with 2-iodoaniline. The final indoline scaffold was furnished by
intramolecular Heck reaction with concomitant formation of the quaternary stereocenter. (Less)
Abstract (Swedish)
Natural products are compounds that exist naturally in living organisms, e.g.,
plants, animal and fungi. These compounds are likely biologically active and can
be used as pharmaceuticals for various diseases. Evolution has made it possible for
living organisms to produce these natural products as a defence mechanism against
various threats. In most cases, the organism only produces a small amount of the
natural product in question which makes it very difficult to get hold of a reasonable
amount to study, and even more so if we would like to use it as a medicine.
Furthermore, most natural products have a very complex three-dimensional
structure. The complexity of these molecules makes it very difficult to... (More)
Natural products are compounds that exist naturally in living organisms, e.g.,
plants, animal and fungi. These compounds are likely biologically active and can
be used as pharmaceuticals for various diseases. Evolution has made it possible for
living organisms to produce these natural products as a defence mechanism against
various threats. In most cases, the organism only produces a small amount of the
natural product in question which makes it very difficult to get hold of a reasonable
amount to study, and even more so if we would like to use it as a medicine.
Furthermore, most natural products have a very complex three-dimensional
structure. The complexity of these molecules makes it very difficult to synthesise
them efficiently and have therefore enticed the synthetic organic community.
Besides the optimal goal of accessing the natural products, method development
can also lead to drug candidates with higher selectivity which ultimately means
that we can use less of a drug and experience much fewer side effects. Our research
interest is to develop strategies and methodologies and implement them on the
syntheses of natural products. In this thesis, we have explored several strategies
towards total syntheses of natural products as well as working with method
development.

The first part describes our efforts towards the total synthesis of perophoramidine
and its synthetic analogue, dehaloperophoramidine. Perophoramidine can be found
in a marine ascidian that is native to the south Pacific ocean. We wanted to utilise
the inherent structure and symmetry of the natural product in our planning to
maximize the likelihood of reactions leading to so-called "domino processes". We
then applied this strategy to the synthesis of perophoramidine and
dehaloperophoramidine, the latter with great success. We successfully made
dehaloperophoramidine in eight steps starting from isoindigo, a compound that can
be easily accessed.

The second part outlines our efforts towards the total synthesis of strictamine,
which is an alkaloid that can be isolated from the leaves of the Rhazya stricta plant.
The complexity of this natural product is ascribed to the highly congested
polycyclic structure. We intended to adopt a methodology that was previously
disclosed in our group to construct the complex ring system found in strictamine.
The synthesis is currently at an advanced state. The core structure of strictamine
was established and to complete the synthesis, two additional steps are required.
The third part of this thesis deals with the development of a new methodology to
access important scaffolds, indolines, that can be used in the synthesis of natural
products. The indoline scaffolds are reoccurring in natural products, and many of
of which have pharmaceutical properties. We were interested in synthesising
indoline scaffolds that have an all-carbon quaternary stereocenter. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Ass. Professor Poulsen, Thomas, Aarhus University, Denmark
organization
alternative title
Syntes av Indol Alkaloider och Utveckling av Ny Metod
publishing date
type
Thesis
publication status
published
subject
keywords
total synthesis, indole alkaloids, Domino reactions, vicinal quaternary stereocenters, quaternary stereocenter, indoline synthesis, communesin alkaloid, perophoramidine, dehaloperophoramidine, akuammiline alkaloids, strictamine, intramolecular Heck reaction, domino carbopalladation carbonylation, indoline alkaloids
pages
161 pages
publisher
Lund University, Faculty of Science, Center for Chemistry and Chemical Engineering
defense location
Sal B, Kemicentrum, Naturvetarvägen 14, Lund
defense date
2019-04-12 09:00:00
ISBN
978-91-7422-645-4
978-91-7422-646-1
language
English
LU publication?
yes
id
a5028c19-1f57-454c-92e3-fecd8a5b8bf3
date added to LUP
2019-03-16 11:49:11
date last changed
2019-03-19 11:36:00
@phdthesis{a5028c19-1f57-454c-92e3-fecd8a5b8bf3,
  abstract     = {This thesis describes our efforts towards the total synthesis of natural products and the development of a new<br/>methodology to afford a synthetically important scaffold.<br/><br/>Chapter 2 outlines our efforts towards the total synthesis of a marine natural product, perophoramidine as well<br/>as our completed synthesis of dehaloperophoramidine. The focus of the studies was to develop an efficient and<br/>concise strategy to afford the natural products. We aimed at utilising the inherent structure and symmetry of the<br/>natural product to encourage domino processes and gain access to the key features. The vicinal quaternary<br/>stereocenters were installed by employing Overman’s diastereoselective dialkylation protocol. Two new domino<br/>processes were discovered. The first domino process led to the formation of the ortho-amide and careful<br/>investigation of its reactivity led to the discovery of the second domino process which ultimately delivered<br/>dehaloperophoramidine. The synthesis was completed in eight steps starting from isoindigo.<br/><br/>Chapter 3 describes our efforts towards the total synthesis of strictamine. The key features of strictamine that<br/>need to be addressed when pursuing the synthesis are: (i) the quaternary stereocenter, (ii) the central<br/>cyclohexane moiety (D ring) with four stereocenters, and (iii) the cage-like methanoquinolizidine core. We aimed<br/>at accessing these key features through intramolecular Heck reaction to access the central D ring with parts of<br/>the substitution pattern already present and the quaternary stereocenter. For the methanoquinolizidine core, we<br/>planned to adopt our previously described domino carbopalladation/carbonylation protocol. The synthesis is in<br/>an advanced state with two additional functionalisation left in order to access the target compound. Described in<br/>this chapter is our effort to access the core structure of strictamine with all the rings installed.<br/><br/>The third part of this thesis deals with the development of a new methodology to access indoline scaffolds that<br/>feature an all-carbon quaternary stereocenter. We were able to synthesise allyl anilines through the regio- and<br/>stereoselective ring-opening of vinyl aziridines with 2-iodoaniline. The final indoline scaffold was furnished by<br/>intramolecular Heck reaction with concomitant formation of the quaternary stereocenter.},
  author       = {Hoang, Anita},
  isbn         = {978-91-7422-645-4},
  language     = {eng},
  publisher    = {Lund University, Faculty of Science, Center for Chemistry and Chemical Engineering},
  school       = {Lund University},
  title        = {Synthesis of Indole Alkaloids and Development of New Methodology},
  url          = {https://lup.lub.lu.se/search/ws/files/61838631/Doctoral_thesis_final_2_.pdf},
  year         = {2019},
}