Stereoselective synthesis and iterative coupling of Csp3 boronates for automating small molecule synthesis

Small molecules perform many important functions in nature, medicine, and technology. However, efforts to discover and optimize new small molecule function are often impeded by limitations in synthetic access to this class of compounds. In contrast to peptide and oligonucleotide syntheses, small molecule syntheses typically employ strategies and purification methods that are highly customized for each target. A broadly applicable automated process for the synthesis of different classes of small molecules has thus far remained elusive. To enable the more generalized automation of small molecule synthesis, a common building block-based strategy and a common purification process for the preparation of many different types of small molecules are needed. Towards this goal, we focused on expanding the scope of a building block-based strategy involving the iterative coupling of boronate building blocks to include Csp3-rich linear and polycyclic small molecules. The first approach undertaken was the discovery of a pinene-derived iminodiacetic acid (PIDA) ligand which enabled the stereoselective synthesis of a wide range of new types of Csp3 boronates. The utility of these Csp3 boronates was demonstrated in the synthesis of a pharmaceutically relevant target using a previously undescribed iterative Csp3-Csp2 coupling. In order to access Csp3-rich cyclic and polycyclic molecules via the same building block-based iterative coupling process, a linear-to-cyclized strategy inspired by the biosynthesis of polycyclic natural products was formulated. Iterative coupling of Csp3 boronates generates linear precursors which can then be polycyclized to give the complex topology found in many polycyclic natural products. This strategy was utilized in the synthesis of four natural products and natural product-like cores from boronate building blocks. This building block-based approach to synthesis was successfully automated with the discovery of a new type of catch-and-release purification protocol applicable to the boronate intermediates used in synthesis. 14 distinct classes of small molecules were constructed from boronate building blocks on a small molecule synthesizer using the same iterative coupling process. The synthesis-enabled advances in automating small molecule synthesis described in this dissertation now stands to better enable the scientific community to bring the substantial power of small molecule synthesis to bear upon many important unsolved problems in society