Boronic ester functionalisations for the automated synthesis of natural products

Lipopeptide natural products have garnered significant attention from the synthetic chemist due their potent biological activity against a range of targets. Aggarwal has developed a suite of synthetic methods leveraging boronic-ester homologation chemistry to construct these molecules efficiently. The macrolipopeptide dysoxylactam A, isolated and characterised in 2019 by Yue and co-workers, was synthesised in 11 steps. Key features of the synthesis are the utilisation of iterative lithiation-borylation reactions (assembly-line synthesis) for the construction of the stereochemically dense lipophilic portion of the molecule, the use of a single protecting group and a total of 5 chromatographic purifications. Other steps include a Steglich esterification, macrolactamisation and Fleming oxidation. The automated synthesis of (+)-kalkitoxin required starting with a thiazoline containing boronic ester, performing six automated iterative lithiation-borylation reactions, and then boronic ester amination, acylation and amide methylation. The boronic ester amination proved to be exceptionally challenging due to undesired isomerisation of the thiazoline ring. After extensive investigations into this transformation, a new boronic ester amination procedure was discovered, in which the reaction proceeds rapidly at room temperature. Although this method was unsuitable for the thiazoline containing boronic ester, it represents the mildest and simplest direct conversion of a boronic ester to an amine.