The iterative assembly of interchangeable parts (or the building block-based approach) is increasingly transforming chemists’ capacity to synthesize chemical matter. Such methods facilitate the synthesis of complex organic molecules as both functionality and stereochemistry can be installed upfront in the reagents, which are then assembled in a controlled manner. There is a growing body of evidence which indicates that a building block-based approach to small molecule synthesis stands to unlock the tremendous synthetic potential that this class of chemical matter possesses. In this regard much important progress has been made in the synthesis of small biopolymers such as polypeptides, oligosaccharides and oligonucleotides. Automated methods now exist for their synthesis in part due to the obvious common linkages and building blocks required for their construction. Applying similar methods to small organic molecules, especially natural products, is significantly more challenging as the common repeating units and assembly methods non-obvious. However, if cross-coupling chemistry were to be regarded as sufficiently general it could be envisioned that the C-C bonds themselves would then become the common linkages for building block-based assembly. Our ongoing research program focuses on developing a strategy for small molecule synthesis by employing organoboron-based coupling reactions to iteratively form C-C bonds. Specifically, we have found that the ligand MIDA can reversibly attenuate the reactivity of a boronic acid within Suzuki-Miyaura cross-coupling reactions and thereby enable iterative cross coupling cycles. On the basis of this advance we have developed an automated synthesis machine which can iteratively assemble Csp2-Csp2 bonds performing all the required steps including purification – preparing 14 distinct classes of small organic molecule. A limitation of this platform is that many of the natural products/natural product fragments which represent exceptionally promising starting points for new drug development are rich in sp3 and not the sp2 carbons assembled by this approach. Moreover, the aqueous conditions permissive of many common Csp3 cross coupling reactions lead to cleavage of our MIDA ligand and prevent practical iterative synthesis. We herein report the development of a next-gen MIDA which tollerates aqueous Suzuki-Miyaura reactions and enables automated iterative synthesis synthesis via Csp3 cross coupling.

Next-Gen MIDA enables automated Csp3 cross-coupling

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.