Synthesis and reactions of α-diazophosphonates in batch and continuous flow; Application to the synthesis of compounds with potential antiviral activity

Lynch, Orla M.

Synthesis and reactions of α-diazophosphonates in batch and continuous flow; Application to the synthesis of compounds with potential antiviral activity

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Date

2026-08-19

Authors

Lynch, Orla M.

Publisher

University College Cork

Abstract

The research described in this thesis investigated the application of continuous-flow chemistry to the safe and efficient synthesis of phosphorus-containing diazo compounds and their use in the preparation of key intermediates for α-carboxynucleoside phosphonates (α-CNPs). The work focused on developing flow-based strategies for diazo transfer and rhodium catalysed O-H and C-H insertion transformations, with the aim of improving reaction safety and efficiency relative to conventional batch methods. Chapter One provides a review of recent relevant literature including the application of continuousflow processing for the safe and efficient generation and use of diazo compounds focusing in particular on how flow technology enables the in-situ formation and immediate consumption of highly reactive species, reducing the risks associated with their isolation, handling, and scale-up. In addition, a summary of organophosphorus chemistry in flow and nucleoside synthesis in continuous flow is included to provide context for the research described in Chapters Two and Three. Chapter Two describes the synthesis of α-CNPs incorporating both natural and unnatural nucleobases, including fluorinated derivatives of potential biological relevance. Key advances include the optimisation of diazo transfer and rhodium-catalysed O–H insertion reactions in batch with a view to translating to continuous-flow conditions described in Chapter Three. Application of these methods to the synthesis of both saturated and unsaturated α-CNP analogues was successfully achieved. The feasibility of extending these approaches to acyclic systems was also explored. Selected compounds were submitted to collaborators for biological evaluation in order to assess their activity against extracellular cancer targets and viral enzymes. Chapter Three describes for the first time the successful translation of diazo transfer to phosphonoacetates and β-ketophosphonates to continuous-flow, and downstream reactivity of these derivatives in O-H and C-H insertion reactions. The key outcomes include the development of efficient and safe flow protocols for diazo transfer to phosphonate substrates, despite their relatively low acidity, and assessment of their compatibility with telescoped rhodium catalysed transformations. Strategies to enable telescoping, are discussed in detail including the use of immobilised azide sources and in-line analytical techniques, to address challenges associated with reagent compatibility, solubility, and by-product formation. Chapters Two and Three contain, in addition to the results and discussion, the full experimental details and spectroscopic characterisation of compounds synthesised in this work. Chapter Four summarises the key outcomes from the research. Overall, diazo transfer to phosphonates has been successfully achieved in flow and the potential to telescope this with their subsequent transformations has been demonstrated. By integrating hazardous reagent generation with downstream reactivity, this work provides a foundation for the development of safer, scalable, and more efficient synthetic routes to complex organophosphorus-containing molecules with potential biological relevance

Description

Controlled Access

Keywords

α-Carboxynucleoside phosphonates , Nucleosides , Phosphonoacetates , Continuous flow , β-Ketophosphonates , O-H insertion , C-H insertion , α-Diazophosphonates

Citation

Lynch, O. M. 2026. Synthesis and reactions of α-diazophosphonates in batch and continuous flow; Application to the synthesis of compounds with potential antiviral activity. PhD Thesis, University College Cork.