Synthesis of a Complex and Highly Potent PCSK9 Inhibitor

The solution-based gram-scale synthesis of complex and highly potent proprotein convertase subtilisin-like/kexin type 9 (PCSK9) inhibitor 1 is presented. Construction of Northern fragment 2, followed by stepwise installation of Eastern 3, Southern 4, and Western 5 fragments, provided macrocyclic precursor 19. This intermediate was cross-linked via an intramolecular azide–alkyne click reaction, which preceded macrolactamization to afford the core framework of compound 1. Finally, coupling with poly­(ethylene glycol) side-chain-based 6 gave the PCSK9 inhibitor 1.