Nitrocatechols as Tractable Surface Release Systems

Anchor aweigh! The synthesis and evaluation of new nitrochatechols for surface modification and tractable release on TiO2 are reported. The properties of catecholate anchoring and nitrobased photocleavable release were merged to create a new tool for surface immobilization and controlled release of small molecules, which was investigated on caged fluorophores as proof-of-principle

Design of bio-inspired materials and total synthesis of "Securinega" alkaloids

This thesis is divided into four chapters presenting distinct research projects that address challenges in the fields of functional systems chemistry, chemical biology, and the total synthesis of natural products. Experimental details, analytical data and appendices are enclosed at the end of this work. Chapter 1 introduces the concept of electron-poor catechols as surface binding agents and highlights some of the natural role models. The development of a synthetic surface modification platform for the controlled release of small molecules is described. Nitrocatechol-based anchoring units allowed for the immobilization of a molecular cargo on titanium dioxide surfaces and cleavage on demand by UV irradiation. Chapter 2 expands the application of small catechol binders. The design and synthesis of new polar derivatives facilitated the use of boronate esters in dynamic functional systems and led to the discovery of the third orthogonal dynamic covalent bond. Chapter 3 reports on the preparation of biochemical probes for the investigation of the cellular target of rapamycin. An efficient assembly of natural product hybrids from rapamycin was achieved without the need for protection of the macrolide. The antiproliferative activity of the parent compound was shown to be largely conserved in the novel substances. Chapter 4 provides a detailed review of the literature on Securinega alkaloids. The first enantioselective total synthesis of secu’amamine E was accomplished in twelve linear synthetic steps and 8.5% overall yield. Three examples of an intriguing rearrangement process were studied allowing for the direct interconversion of natural products with implications for a new biogenetic hypothesis

Design of bio-inspired materials and total synthesis of "Securinega" alkaloids

This thesis is divided into four chapters presenting distinct research projects that address challenges in the fields of functional systems chemistry, chemical biology, and the total synthesis of natural products. Experimental details, analytical data and appendices are enclosed at the end of this work. Chapter 1 introduces the concept of electron-poor catechols as surface binding agents and highlights some of the natural role models. The development of a synthetic surface modification platform for the controlled release of small molecules is described. Nitrocatechol-based anchoring units allowed for the immobilization of a molecular cargo on titanium dioxide surfaces and cleavage on demand by UV irradiation. Chapter 2 expands the application of small catechol binders. The design and synthesis of new polar derivatives facilitated the use of boronate esters in dynamic functional systems and led to the discovery of the third orthogonal dynamic covalent bond. Chapter 3 reports on the preparation of biochemical probes for the investigation of the cellular target of rapamycin. An efficient assembly of natural product hybrids from rapamycin was achieved without the need for protection of the macrolide. The antiproliferative activity of the parent compound was shown to be largely conserved in the novel substances. Chapter 4 provides a detailed review of the literature on Securinega alkaloids. The first enantioselective total synthesis of secu’amamine E was accomplished in twelve linear synthetic steps and 8.5% overall yield. Three examples of an intriguing rearrangement process were studied allowing for the direct interconversion of natural products with implications for a new biogenetic hypothesis

Securinega Alkaloids : Complex Structures, Potent Bioactivities, and Efficient Total Syntheses

The Securinega alkaloids feature a compact tetracyclic structural framework and can be divided into four subclasses characterized by either a bridged [2.2.2]‐ or a [3.2.1]‐bicyclic core with two homologous series in each subclass. In the last two decades, many innovative strategies to chemically access the Securinega alkaloids have been developed. This Focus Review discusses the selected structures and syntheses of representative members of the Securinega alkaloids. Ring‐closing metathesis has enabled the syntheses of securinine and norsecurinine, and different cycloaddition approaches were key to the syntheses of nirurine and virosaines A and B. Virosine A was accessed through a Vilsmeier–Haack/Mannich reaction cascade. A bio‐inspired vinylogous Mannich reaction has enabled the synthesis of allosecurinine and this strategy has been extended by an intramolecular 1,6‐addition to obtain bubbialidine and secu′amamine E. A rearrangement process of the latter two alkaloids has furnished allonorsecurinine and allosecurinine, respectively. Finally, an expanded model for the biogenesis of the Securinega alkaloid subclasses is discussed

The third orthogonal dynamic covalent bond

Orthogonal dynamic covalent bonds are of interest for the construction of functional systems. The orthogonality of disulfide and hydrazone exchange under basic and acidic conditions, respectively, is well established. However, the integration of boronate esters as the third bond has failed so far because they exchanged too easily, especially under hydrazone exchange conditions. In this report, a collection of bioinspired catechols derived from adhesive natural products from cyanobacteria is screened with phenylboronic acids with proximal alcohols (benzoboroxoles), amines and fluorines to identify the least labile boronate esters. Moreover, Kool's 2-aminophenol catalysts are introduced to selectively accelerate hydrazone exchange without disturbing sufficiently inert boronate esters. Based on these results, we identified three different conditions to selectively exchange disulfides, hydrazones and boronate esters, that is to demonstrate the existence of three orthogonal dynamic covalent bonds. Moreover, their compatibility with functional systems is confirmed by successful hydrazone exchange in multicomponent surface architectures in the presence of intact boronate esters and disulfides

Investigating biogenetic hypotheses of the securinega alkaloids: enantioselective total syntheses of secu’amamine E/ent-virosine A and bubbialine

The synthesis of the Securinega alkaloid secu’amamine E (ent–virosine A) has been accomplished for the first time in 12 steps and 8.5% overall yield. In addition, bubbialine has been prepared and characterized. These two alkaloids and bubbialidine, all featuring an azabicyclo[2.2.2]octane core, were rearranged to their azabicyclo[3.2.1]octane congeners, a framework found in many Securinega alkaloids. These experiments suggest that azabicyclo[2.2.2]octane derivatives could serve as intermediates in the biosynthesis of the rearranged azabicyclo [3.2.1]octane products

Investigating Biogenetic Hypotheses of the <i>Securinega</i> Alkaloids: Enantioselective Total Syntheses of Secu’amamine E/<i>ent</i>-Virosine A and Bubbialine

The synthesis of the <i>Securinega</i> alkaloid secu’amamine E (<i>ent</i>-virosine A) has been accomplished for the first time in 12 steps and 8.5% overall yield. In addition, bubbialine has been prepared and characterized. These two alkaloids and bubbialidine, all featuring an azabicyclo­[2.2.2]­octane core, were rearranged to their azabicyclo­[3.2.1]­octane congeners, a framework found in many <i>Securinega</i> alkaloids. These experiments suggest that azabicyclo­[2.2.2]­octane derivatives could serve as intermediates in the biosynthesis of the rearranged azabicyclo­[3.2.1]­octane products