Aqueous Synthesis of Membrane Lipids via Amide Formation between Amphiphilic Amines and Thioacids

Protocell membranes were likely formed through primitive metabolic reactions that synthesized more complex membrane lipid species from simpler precursors. Thioacids have been shown to be prebiotically plausible and chemoselective <i>N</i>-acylating reagents. They have been successfully employed for the acylation of peptides and RNA. However, the ability of thioacids to acylate lipid species has not yet been explored. Here, we demonstrate <i>N</i>-acylation of natural amine-containing amphiphiles using fatty thioacids. This reaction occurs spontaneously in aqueous conditions and is chemoselective,and traceless. The synthesis of several natural sphingolipids via direct <i>N</i>-acylation is possible and their subsequent de novo formation into vesicular membranes is shown. Aqueous thioacid coupling provides a route for generating membrane-forming lipids in the context of protocells and for the in situ synthesis of relevant sphingolipid species.