Automated Synthesis, Quantum Chemistry and NMR in the Identification of Structurally Related Macrolide Natural Products

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Synthetic organic chemistry has a huge industrial importance and for many years, chemists have been, and are still, constantly in search for more efficient and robust methods for the construction of organic molecules to meet the high demand. Automation is one strand of a digital chemistry future, which, in combination with machine learning and computer assisted retrosynthesis has the potential to dramatically change how we create molecules. Over the last 10 years, the Aggarwal group have created new reactions and strategies based on boron homologations that is now ripe for transferring to an automation platform. We have shown that combining this homologation chemistry with state-of-the-art quantum chemical calculations and NMR spectroscopy provides a synergy that allows us to design, synthesise and elucidate the structure of 3-dimensionally complex natural products, such as baulamycin A. Our goal now is to address the structure of an even more complex molecule, the antifungal marine natural product caylobolide A, and to use the power of automation to aid in its synthesis. Only 5 of the 12 stereocentres of caylobolide A have been assigned in the literature using Mosher's ester analysis, with the remainder not being resolvable by this method. Key structural features of the molecule are 1,3- and 1,5-related hydroxyl groups. We have developed methodology to create any isomer of such motifs, solving a long-standing problem in asymmetric synthesis.We have also established NMR+computation procedures that allow us to probe the stereochemistry of flexible compounds, such as caylobolide A, based on quantum chemical (or machine learning) prediction of NMR parameters such as proton and carbon chemical shifts, 3JHH, 3JCH and nuclear Overhauser enhancements. These work very well for -OH substituted stereocentres that are close to each other, but are less effective when the stereocentres are a long distance apart (as in caylobolide A) and we may need to explore the application of NMR techniques that are sensitive to longer-range interactions, such as residual anisotropic NMR parameters.