Graduate / 0485

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Domino catalysis is an ideal strategy in the synthesis of heterocyclic scaffolds, as multiple bonds can be formed under a single set of reaction conditions. In this work, we present the development of two novel domino processes which afford access to aza-analogues of the dihydrodibenzoxepine motif. Careful optimisation revealed that the Rh catalysed hydroarylation proceeds under mild conditions as compared to the C-O coupling. Furthermore, Pd was not required for the C-O bond formation when using alkenyl pyrazines as substrates. Variation of the substituents on both the heterocycle and on the boronic ester provided insight into the structural features required for successful domino reaction, and a stepwise protocol was developed for incompatible substrates. We have also developed the first multi-metal, multi-ligand domino reaction featuring both a chiral and achiral ligand in the same pot, still leading to an enantioenriched product.

Domino catalysis is an ideal strategy in the synthesis of heterocyclic scaffolds, as multiple bonds can be formed under a single set of reaction conditions. In this work, we present the development of two novel domino processes which afford access to aza-analogues of the dihydrodibenzoxepine motif. Careful optimisation revealed that the Rh catalysed hydroarylation proceeds under mild conditions as compared to the C-O coupling. Furthermore, Pd was not required for the C-O bond formation when using alkenyl pyrazines as substrates. Variation of the substituents on both the heterocycle and on the boronic ester provided insight into the structural features required for successful domino reaction, and a stepwise protocol was developed for incompatible substrates. We have also developed the first multi-metal, multi-ligand domino reaction featuring both a chiral and achiral ligand in the same pot, still leading to an enantioenriched product.

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Automation plays an integral role in our daily lives. From transportation to agriculture, we rely on robots and programs to assist in accomplishing tasks. Chemistry is no except with the deployment of high throughput screening and the recent machine-led reaction discovery, there is increased interest to integrate artificial intelligence and robotics beyond medicinal and synthetic organic chemistry. The addition of automation to mechanistic studies can improve the method in which reactions are understood experimentally and fundamentally. Chapter 1 introduces the basics of reaction chemistry. As we are interested in how the reaction occurs, for this work, there is a natural bias towards understanding kinetic behaviour. Chronograms obtained through mass spectrometry facilitate understanding of kinetics. The introduction of mass spectrometry in this chapter establishes the foundation of this technique for the subsequent experimental chemistry chapters. Chapter 2 investigates the reduction and subsequent oxidation of titanocene, generating a complex mixture of oxidized products. During this investigation, an interesting and rare methyl abstraction event occurred that led to the deuterium label study to understand a radical-based oxo-titanium reaction. This was made possible by Pressurized Sample Infusion Electrospray Ionization Mass Spectrometry (PSI-ESI-MS) coupled with a smartphone colorimetry technique developed herein known as ColorPixel. In Chapter 3 we explore the integration of machine learning with reaction monitoring. The attempt to classify reaction roles based on kinetic traces was done to automate the process of identifying important species in a reaction. Often there is a large amount of data from a PSI-ESI-MS experiment, but it is time-consuming to pick out the most important species. Implementing machine learning for reaction role classification can ease this process from taking three months to accomplish to one day. This chapter also outlines the development of Kendrick, an automated reaction sampler. Combined, these tools have the potential to impact reaction monitoring through robotic assistance and can speed up the process of reaction quantification through automated processing platforms to handle the streams of data. Chapter 4 starts with the implementation of a lightweight mass spectrometry library, Spectra.ly, that is suitable for any developers using python. This platform establishes a firm foundation that can enable developers to build complex programs using simple code. This chapter also describes the collaboration project PythoMS and the development process for this framework. In addition to the framework, the chapter also describes the development of two pieces of processing software: Sinatra – a cloud-ready EDESI processing platform, and AutoMRM – a cloud-based Multiple Reaction Monitoring method development web application. / Graduate

Functionalized cyanophosphates are important starting materials for the synthesis of beta-lactam ring moiety of beta-lactam antibiotics. The cyanophosphates are synthesized starting from easily available acylphosphonate and ethylcyanoformate. Acylphosphonates are synthesized starting from acylchloride and trimethylphosphite. Addition of acylphoshonate to ethylcyanoformate furnishes the cyanophosphate with the quaternary center.

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