Many small molecules targeted for synthesis in the laboratory are inherently modular in their construction. Harnessing this modularity towards a unified strategy for the synthesis of these compounds, this dissertation describes an approach to small molecule making based on the iterative cross-coupling (ICC) of bifunctional haloboronic acid building blocks. Realizing a general ICC approach in the context of small molecule synthesis required the discovery of a ligand with the capacity to attenuate the reactivity of boronic acids under Suzuki-Miyaura cross-coupling (SMC) conditions and then liberate this masked reactivity under mild conditions. Towards this end, N-methyliminodiacetic acid (MIDA) was discovered to be such a ligand, enabling an approach by which the reactivity of boronic acids is modulated via rehybridization of the boron center. Further, MIDA boronates, which result from the condensation of MIDA with boronic acids, were found to possess a number of enabling properties. Specifically, MIDA boronates are uniformly stable to SiO2 chromatography and to storage under ambient air at room temperature. MIDA boronates were also found to be compatible with a broad range of common reagents and reaction conditions, enabling an approach by which relatively simple MIDA boronates can be elaborated through multiple-step organic synthesis en route to structurally complex boronate building blocks. Through a process of rate-controlled in situ release of boronic acids from the corresponding MIDA boronates, MIDA boronates were found to serve as generally effective surrogates for otherwise unstable boronic acids in high-yielding Suzuki-Miyaura cross-coupling reactions with deactivated aryl chlorides. Enabled by these collective discoveries, and towards the goal of a simple and accessible approach to small molecule synthesis, a machine with the capacity to perform fully automated ICC syntheses was developed and was employed in the syntheses of several natural products.
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