Atroposelective Total Synthesis of Darobactin A

01 June 2022, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


A concise, modular synthesis of the novel antibiotic darobactin A is disclosed. The synthesis successfully forges the hallmark strained macrocyclic ring systems in a sequential fashion. Key transformations include two atroposelective Larock-macrocylizations, one of which proceeds with exquisite regioselectivity despite bearing an unprotected alkyne. The synthesis is designed with medicinal chemistry considerations in mind, appending key portions of the molecule at a late-stage. Requisite unnatural amino acid building blocks are easily prepared in enantiopure form using C–H activation and decarboxylative cross-coupling tactics.


total synthesis
natural products
antibacterial agents


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