Claisen Self-Condensation of Lactones in the Synthesis of Ionizable Lipids.

The Claisen self-condensation of lactones can be carried out safely and efficiently under Mukaiyama conditions, in the presence of TiCl 4 and triethylamine. The primary Claisen products can be elaborated to various derivatives or converted directly into dihydroxyketones. Such compounds are valuable educts for the synthesis of ionizable lipids for the delivery of nucleic acid therapeutics and can now be accessed through a concise, economical, scalable route that avoids more technically challenging reaction sequences.