Convergent and step-economical synthesis of Adda: Enabling access to cyanobacterial toxin building blocks

Abstract: The non-proteinogenic amino acid Adda is a structurally complex and biologically essential residue found in cyanobacterial toxins such as microcystins and nodularins, where it plays a critical role in protein phosphatase inhibition and hepatotoxicity. Despite it is importance in environmental monitoring, toxicology, and chemical biology, the synthesis of Adda remains challenging due to its multiple stereocenters, sensitive functionality, and reliance on lengthy or resource-intensive synthetic routes. Herein, we report a highly convergent and operationally efficient nine-step synthesis of Boc-Adda-OH featuring a key intermolecular Heck coupling between two advanced fragments. This strategy replaces traditional Wittig and organometallic cross-coupling approaches that often require toxic reagents, extensive step counts, and limited scalability. Notably, the Heck reaction proceeds with excellent regio- and stereoselectivity in the presence of a labile isoxazolidinone moiety, demonstrating for the first time that palladium-catalyzed Heck chemistry can be successfully employed without compromising sensitive N-O bonds. The route benefits from high step economy, improved functional-group tolerance, and minimized protecting-group manipulations, aligning well with green chemistry principles such as waste reduction and process efficiency. Final N–O bond cleavage affords Boc-Adda-OH in high yield, providing rapid access to this key building block for downstream peptide synthesis. This concise and scalable approach enables more sustainable access to Adda and related cyanobacterial peptide motifs, facilitating future studies in environmental toxicology, harmful algal bloom monitoring, and the synthesis of biologically relevant peptide analogues.