Natural Product Synthesis and Development of Novel Reaction Methodology

Abstract

This thesis deals with the development of new reaction methodology for stereoselective synthesis, as well as total synthesis of natural products and investigations of the stereochemical outcome in the Mukaiyama aldol reaction.



Chapter 2 describes efforts made towards the total synthesis of the oxindole natural products perophoramidine and the communesin. The first part of this chapter aims to develop a domino carbopalladation-carbonylation reaction using tetrasubstituted olefins for the installation of the vicinal quaternary stereocenters of the target compounds. This approach was ultimately unsuccessful using tetrasubstituted olefins. The second part of this chapter instead relies on a Diels-Alder reaction for the installation of the quaternary stereocenters, and also describes the attempts made to reach the target compound from the Diels-Alder adduct.



Chapter 3 concerns the investigation of 1,2- and merged 1,2- and 1,3-asymmetric induction in Mukaiyama aldol additions to α-heteroatom and α,β-heteroatom substituted aldehydes, respectively. In particular, the unexpected 1,2-syn selectivity obtained in the addition of sterically hindered nucleophiles to α-chloro aldehydes is studied, and an explanation for the observed stereochemical trends is proposed.



Chapter 4 describes the development of a novel entry to anti-α-amino-β-hydroxy esters by 1,3-dipolar cycloadditions of aldehydes and azomethine ylides, generated by thermolysis of aziridines.

Abstract (Swedish)

Popular Abstract in English

Organic synthesis has been defined as the “intentional construction of molecules by chemical means”1 and is often regarded to have commenced with Wöhler’s preparation of urea in 1828.2 Today, the influence of organic synthesis reaches far beyond the domain of chemistry, touching upon fields such as biology, nanotechnology, material science, and medicine. It has thus supplied mankind with pharmaceutical drugs for the treatment of numerous health related conditions3 as well as novel materials, dyes, plastics, clothing, perfumes etc.4

Organic synthesis can broadly be divided into two main fields: total synthesis and methodology development. Total synthesis can be regarded as the laboratory construction of organic molecules, often naturally occurring, by means of a series of rationally designed chemical reactions, starting from less complex, often commercially available, starting materials. The creative aspect of this field means it is widely recognized as form of art, manifested in both the delicate selection of chemical operations and the target structure itself. To enable such total synthesis endeavors requires an extensive repertoire of chemical reactions, and an understanding of how these can be combined to successfully reach the target structure. The other cornerstone of organic synthesis therefore deals with the development of novel and increasingly efficient reaction methodology.

There are several valid incentives to prepare new or naturally occurring chemical entities. Since isolation from natural sources can often provide only minute quantities, accessing the compound through total synthesis is sometimes the only means by which to obtain large enough quantities for biological evaluations. Such studies may provide valuable intermediates for a host of different investigations, ranging from toxicological and pharmacological evaluations to elucidation of biochemical and metabolic pathways.5 An additional impetus for total synthesis is the possibility to access analogues or isomer of naturally occurring compounds, which can be used to establish structure activity relationships or probe biological mechanisms.6 Sometimes, the complexity and intellectual challenge associated with a certain problem is a contributing reason to pursue a synthetic endeavor, at least within the realm of academia. Such reasons are by no means invalid, since curiosity and intellectual challenge has always been at the heart of scientific discovery. Although total synthesis and methodology development are two distinctly different fields, they are also closely connected. The strength of a particular transformation is often highlighted by its application in total synthesis, which in turn sometimes leads to fortuitous discovery of novel reactivity that can be further developed into new reactions.

• author: Danielsson, Jakob
• supervisor: Peter Somfai
• opponent: Professor Tanner, David, Technical University of Denmark
• organization: Centre for Analysis and Synthesis
• publishing date: 2014
• type: Thesis
• publication status: published
• subject: Chemical Sciences
• keywords: perophoramidine, communesin, quaternary stereocenter, Diels-Alder, 1, 2-asymmetric induction, polar Felkin-Anh, Cornforth-Evans, Mukaiyama aldol, 3-dipolar cycloaddition, azomethine ylide, 2-amino alcohol, anti-α-amino-β-hydroxy ester
• pages: 154 pages
• defense location: Kemicentrum sal B
• defense date: 2014-02-07 15:00:00
• ISBN: 978-91-7422-344-6
• language: English
• LU publication?: yes
• id: 878bacde-bf2a-4a0e-b4aa-49e55cf72847 (old id 4247871)
• date added to LUP: 2016-04-04 12:09:52
• date last changed: 2018-11-21 21:09:22