An Investigation of Multicomponent Azole Chemistry within a Generational System for the Expression the Canonical Genetic Structures

The underlying biochemical unity of life suggests a chemical origin of life, indeed organic chemistry arose from the desire to synthesise, characterise and understand the chemical constituents of life, and natural products and biocatalysts are benchmarks for what can be achieved in organic chemistry. Despite the scientific advances of the intervening two centuries, discovering the chemical transformations that initiated life represents one of the most important, fundamental and challenging chemical questions being addressed by modern science.

There are three classes of macromolecules that are absolutely necessary for all extant life-DNA, RNA and proteins. We seek to experimentally establish a link between the generational requirements of both classes of nucleic acid and proteins. A systems chemistry research programme will be implemented to elucidate corroborative chemical pathways to understand the generational relationship and commonality of the key constituent molecules of DNA, RNA and proteins.

The work proposed in this fellowship is designed to advance the undeveloped potential of both organosulfur chemistry and multicomponent reactivity in abiogenesis. Within the overall context of organic chemistry and, more specifically, origins of life research, the potential of multicomponent reactions has certainly been recognized as a key element for rapid and succinct build-up of molecular complexity. In contrast to the vast majority of multicomponent reactions, which feature an isonitrile as the key component, the work outlined in this proposal features azoles as an essential element for multicomponent reactivity. New three- and four-component reactivity will be developed. Furthermore, the reactivity of sulfur will be exploited to access new reactivity motifs, allowing unexplored chemistry and chemical pathways to be discovered.

Throughout the course of this fellowship new green chemical reactivity and multicomponent reactions will be discovered. We will continue to develop systems chemistry to broaden and deepen the understanding of how systems chemistry can be used to access commercially important products and, significantly, the generational relationship of the constituent macromolecules of biology as the products of one chemical system.

The origin of life is one of the most challenging and intellectually important questions being addressed by modern science. The question goes to the heart of the human understanding of the natural world; what life is, where life came from, and the possibility for the replication of an origins event, thus how to implement the search for extraterrestrial life. Understanding the predisposed reactivity that could lead from a chemical system to biological organisation is a question almost without parallel for scientific understanding of the natural world. Dr Powner is seeking to investigate the transition from chemistry to biology, to understand the events that led from inanimate materials to life; in essence "biology's big bang".

The original aim of organic chemistry was to empirically realise the link between living and non-living material. Although a great many fields of productive, awe-inspiring science and commercially successful enterprises have developed into multi-million-dollar industries-including the agrochemical, dye/paint, petrochemical, pharmaceutical, plastic and cosmetic/fragrance industries, the ultimate question of how chemistry could yield organic living matter remains absolutely unsolved. Beyond the fundamental intellectual importance, there is immense potential to realise commercial benefits from application of the knowledge accrued from investigating the chemical reactions and interactions that can lead to biological organisation. The proposed research venture is into largely uncharted territory-toward more complex chemical choreography and ultimately a diversity-orientated systems chemistry approach to the expression of biomimetic and biochemical form and function. Dr Powner's specific goals relate to understanding not only the origins of biological organisation, but also the fundamental properties of nucleic acids, peptides, metabolites, and amphiphiles. These molecules are key to biological form and function and, due to their biochemical nature, are of immeasurable importance and commercial value with regards to medicine and the pharmaceutical industry.

To address the fundamental science that describes a transition from chemistry to biology would be of significant cultural value. The potential for knowledge transfer goes far beyond the chemical and biological sciences. Understanding the transition from chemistry to biology has far-reaching implications for the understanding of astronomy and astrobiology, cell biology, chemistry, evolutionary biology, phylogenetics, geology, climatology, materials science and planetary science, and even influences the debates of philosophers and theologians. Over the past 50 years, numerous examples of scientifically important advances in this field have directly impacted on the public awareness of science. Research in the area has been, and continues to be, quoted in theological and philosophical debate. Advances made in the area rightly receive coverage beyond scientific media and are reported in worldwide media resources. Nucleotide evolution and catalysis have also been widely heralded as a major clue to the origins of modern biology. An understanding of the nature and origins of biological structure, particularly the canonical nucleotides, is without doubt a socially and scientifically important pursuit.