An efficient and scalable synthesis of potent TLR2 agonistic PAM2CSK4

Abstract

Diacylated PAM₂CSK₄, a highly expensive lipopeptide with desirable aqueous solubility and a broad spectrum of cytokine/chemokine induction is a most potent dual (human and murine) Toll-Like Receptor-2 (TLR2) agonist. Besides such thrilling characteristics, its synthetic process is not reported in the literature. The present report describes an efficient and scalable 20 step synthesis of PAM₂CSK₄ in good yield (all steps > 60%) along with a clear description of the hindrances and easy solutions adopted in each step. Overall, a convergent synthetic approach was adopted involving synthesis of appropriately protected starting materials, synthesis of a key backbone skeleton PAM₂CS, synthesis of a tetralysine fragment and the final coupling to yield PAM₂CSK₄. Tedious column chromatography was avoided on a large scale in many steps.