Lewis acid catalysis | EPFL Graph Search

In Lewis acid catalysis of organic reactions, a metal-based Lewis acid acts as an electron pair acceptor to increase the reactivity of a substrate. Common Lewis acid catalysts are based on main group metals such as aluminum, boron, silicon, and tin, as well as many early (titanium, zirconium) and late (iron, copper, zinc) d-block metals. The metal atom forms an adduct with a lone-pair bearing electronegative atom in the substrate, such as oxygen (both sp2 or sp3), nitrogen, sulfur, and halogens. The complexation has partial charge-transfer character and makes the lone-pair donor effectively more electronegative, activating the substrate toward nucleophilic attack, heterolytic bond cleavage, or cycloaddition with 1,3-dienes and 1,3-dipoles. Many classical reactions involving carbon–carbon or carbon–heteroatom bond formation can be catalyzed by Lewis acids. Examples include the Friedel-Crafts reaction, the aldol reaction, and various pericyclic processes that proceed slowly at room te

Investigations of Diels-Alder reactions in ionic liquids

Ana Vidis

Room temperature ionic liquids comprise an unique class of solvent composed of organic and inorganic-based ions that are molten under ambient conditions. They are characterised by high solvent polarity and low vapour pressure, and can be tailored to have specific physical and chemical properties. Consequently, there has been great interest in exploiting these attributes to accelerate and control organic reactions. One such reaction, the Diels-Alder reaction, is an important [4+2] cycloaddition reaction used extensively in the preparation of cyclic and heterocyclic compounds. Understanding the factors involved in the enhancing this reaction in ionic liquids remains a subject of intense interest and the centrepiece of the dissertation. The objective of the research is to explore the Diels-Alder cycloaddition reaction in ionic liquids, with a view of developing high effective reactions systems, that operate under mild reaction conditions. The role that ionic liquid media plays in facilitating the Diels-Alder reaction is discussed. A range of physical and chemical modes of activating the reaction are discussed including pressure, the application of Lewis acid catalysts, microwave irradiation and ultrasound sonication and a comparison on the various modes of activation is provided. Importantly, the results of this study can lead to a better understanding of the ionic liquids as well as their utilization for other organic reactions.

EPFL2007

Synthesis of new 1-Vinyl and 1-Alkynyl Triazenes

Carl Thomas Bormann

The recent discovery of an N2O-based synthesis of triazenes in our group has enabled the synthesis and investigation of 1-alkynyl triazenes. Early studies showed their potential for a functional group tolerant synthesis of 1-vinyl triazenes, which is further elaborated in this thesis. Furthermore, limitations in the synthesis of 1-alkynyl triazenes are addressed.In the first part of the work, a Rh-catalyzed annulation reaction of 1-alkynyl triazenes with bifunctional boronic acids is presented. Indenyl triazenes were obtained and the acid-induced cleavage of the triazene group was studied.Furthermore, cyclobutenyl triazenes were synthesized by Ficini-type cycloadditions of 1-alkynyl triazenes to electron deficient alkenes under Lewis-acid catalysis. Depending on the starting material, rearrangement of the addition products to bicyclooctenyl triazenes and subsequent derivatization was achieved.New 1-alkynyl triazenes were synthesized among others hydroxy substituted 1-alkynyl triazenes. The latter allow the synthesis of a terminal 1-alkynyl triazene, which can be derivatized to include a range of functional groups incompatible with the classical N2O-based synthesis of 1-alkynyl triazenes.Finally, the cytotoxicity of some of the newly synthesized 1-alkynyl and 1-vinyl triazenes was assessed.

EPFL2022

Reprogramming the B1 Domain of Streptococcal Protein G (GB1)

Esra Bozkurt

Nature has the ability to cope with extreme pH, temperature and pressure, in addition to bestowing a wide array of functionalities to (bio)macromolecules. These specialized skills have attracted the interest of vast scientific communities especially in view of possible industrial or biomedical applications. In general, the design of functional and thermostable biological constructs is one of the overarching themes in biochemisty. Despite extensive research and some recent breakthroughs, the level of understanding of the factors that determine protein reactivity and stability is still modest. The use of computational methods for an atomic level understanding of the functionality and stability of biomacromolecules is therefore an attractive alternative. This dissertation presents a number of research projects that combine different computational methods in a close blend with experiments in order to identify the crucial determinants that can be used for a rational design of thermostable and catalytically active, (re-)engineered protein domains. The main findings are the following: Chapter 3 of the thesis presents the results of computational studies towards the design of biomimetic compounds capable of performing tetrazole formation based on Lewis acid catalysis. Our quantum chemical calculations suggest the incorporation of unnatural modifications of glutamate residues as a promising starting point for the development of an efficacious bioinspired catalytic system based on a zinc active site. Chapter 4 and 5 focuses on the computational design and re-engineering of the B1 domain of Streptococcal protein G (GB1) to introduce hydrolytic activity. In addition to exhibiting encouraging reaction rates, our computationally designed artificial enzymes are reasonably thermostable. Chapter 6 is about the design of a highly thermostable metallo variant of GB1. It describes the successful attempt to establish a stable tetrahedral zinc binding site in GB1 with the help of a computational protocol based on genetic algorithm optimization. A high resolution crystal structure of this metallo variant reveals a novel head-to-tail organization. Chapter 7 reports the design of two re-engineered thermostable GB1 sequences using a new computational method for thermostability prediction as well as on their expression and structural characterization. Interestingly, one of the mutants show an intertwined dimer organization in the crystal structure. The combined theoretical and experimental approaches reported herein provide valuable insights into the successful design of different GB1 variants with tailored properties and may help to open new avenues for the rational design of new thermostable and functional biomacromolecules.

EPFL2018

Reprogramming the B1 Domain of Streptococcal Protein G (GB1)

Esra Bozkurt

EPFL2018