| DNA-templated synthesis exploits the changes in effective molarity that occur upon DNA hybridization to direct the chemical reactivity of DNA-linked substrates. This effective molarity-based control of reactivity is potentially enabling in the context of small-molecule library synthesis. Split-pool solid-phase synthesis is the most common means of accessing small-molecule libraries. However, technical considerations limit the amount of diversity accessible by split-pool solid-phase methodologies, and DNA-templated synthesis provides a potentially complementary means of accessing highly diverse libraries.; In this thesis, we introduce a library synthetic design principle, "iterated branching reaction pathways," enabled by DNA-templated synthesis. Library syntheses utilizing iterated branching reaction pathways contain multiple diversification branch points, allowing rapid buildup of diversity within a library. We demonstrate that DNA-templated synthesis can direct multiple, otherwise incompatible reaction types in a single solution, a property that makes DNA-templated synthesis well-suited for use in iterated branching reaction pathway-based library syntheses. We also describe the development of new template architectures that expand the capabilities of DNA-templated synthesis to allow any region of template sequence to encode any viable DNA-templated reaction type, as well as reactions. We applied these two concepts to a pilot library synthesis utilizing iterated branching reaction pathways to obtain a collection of DNA-linked small molecules comprised of five distinct structural classes. Notably, it would be impossible to obtain a similarly diverse small-molecule library using standard split-pool solid-phase methods. Finally, we discuss the possible relevance of DNA-templated synthesis as a model system for prebiotic translation. |
