Tandem and mild synthesis of a symmetric secondary alcohol toward an ionizable lipid analogue of DLin-MC3-DMA

Abstract

DLin-MC3-DMA, the first FDA-approved ionizable lipid and a key component of lipid nanoparticles (LNPs), has enabled the clinical translation of RNA therapeutics. However, large-scale synthesis of DLin-MC3-DMA is limited by the challenging preparation of a symmetric secondary alcohol bearing two C18:2 alkyl chains, which typically requires multi-step procedures, stringent inert conditions and hazardous reagents, and affords only moderate yields. Here we report a tandem, mild synthesis strategy that converts methyl linoleate into a symmetric secondary alcohol bearing two C17:2 chains in 89% yield within 12 h. Subsequent esterification affords CLin-17, a structural analogue of DLin-MC3-DMA. LNPs formulated with CLin-17 exhibit high RNA encapsulation efficiency, a favorable pK_a, and transfection efficiencies comparable to those of DLin-MC3-DMA-based LNPs across multiple cell lines, while maintaining low cytotoxicity and excellent storage stability. This work provides a facile approach to produce symmetric secondary alcohols for ionizable lipid synthesis, facilitating broader and more sustainable access to high-performance RNA delivery materials.