Fairchild, Jasper Henry; (2024) Chemoselective Syntheses of Pantetheine with Prebiotic Nitrile Chemistry and an Investigation of the Photochemical Reactivity of Thioacids in Water. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Co-factors are vital nodes in metabolism and perform a wide range of functions at the heart of cellular machinery. Despite the prevalence and conservation of co-factors in extant biology it is unclear why and how these specific molecules came into being. For example, coenzyme A (CoA) is found in all domains in life and is essential in autotrophic carbon fixation pathways, fatty acid, polyketide, and non-ribosomal peptide syntheses. CoA has a complex structure which can be broken down into an adenosine nucleotide and pantetheine residue. It is the thiol bearing pantetheine fragment that is catalytically active, underpinning its metabolic value. This work focuses on prebiotic syntheses of pantetheine which is comprised of pantoate, β-alanine and cysteamine sub-fragments. Previous attempts to synthesise pantetheine from pantolactone, β-alanine and cysteamine gave near negligible yields. However, by utilising the innate reactivity of nitriles this work demonstrates several high yielding routes towards pantetheine in water. The reactivity of nitriles provided a chemical rationale for each element of the canonical structure of pantetheine over non-biological analogues and is concurrent with peptide synthesis. As the functional unit within CoA, pantetheine is involved in many enzymatic reactions (~ 4%) and is implicated in various origins of life scenarios. -Peptides are an essential component of life, enabling catalysis, replication, and structure in cells. Previous work in the Powner group exploited α-aminonitriles in a high-yielding (biomimetic) peptide ligation that’s precedes via thioacid intermediates. The final part of this thesis investigated the UV irradiation of thioacids. The N-acetylation of amines with thioacetate under UV irradiation was demonstrated. However, attempts to ligate α-amidothioacids with α-aminonitriles upon UV irradiation were unsuccessful due to radical dethiocarboxylation. Interestingly, β-amidothioacids did not undergo dethiocarboxylation and were activated towards peptide coupling under UV irradiation. During these studies it was observed that acidic conditions (in the dark) resulted in ligation of α-amidothioacids with glycine nitrile. Proteins are the catalytic workhorse of biology and often require co factors to function efficiently. This work sheds light on the key chemical reactions required to build life and these synergistic qualities present a possible route to a protometabolic network present in the beginning.

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