Synthesis of Ionizable Lipid ALC‐0315 Using Hydrogen Borrowing Catalysis

The ionizable lipid ALC‐0315 was one of the crucial compounds that made the Pfizer/BioNtech COVID‐19 mRNA vaccine successful. Herein, we developed an Ir‐catalyzed approach where both the fatty aldehyde synthesis and the double reductive amination proceed simultaneously in a one‐pot approach. Using this hydrogen borrowing catalysis methodology, we have multiplied the yields of ALC‐0315 compared to the original process and improved step economy without the use of highly toxic reagents. As the second alkylation step in the Ir catalysis is much slower, the strategy is also amenable to asymmetric lipids, which can be challenging via other methods.