Solid‐Phase Thiol–Ene Lipidation of Peptides for the Synthesis of a Potent CGRP Receptor Antagonist

We report a new method herein coined SP‐CLipPA (solid‐phase cysteine lipidation of a peptide or amino acid) for the synthesis of mono‐S‐lipidated peptides. This technique utilizes thiol–ene chemistry for conjugation of a vinyl ester to a free thiol of a semiprotected, resin‐bound peptide. Advantages of SP‐CLipPA include: ease of handling, conversions of up to 91 %, by‐product removal by simple filtration, and a single purification step. Additionally, the desired lipidated products show high chromatographic separation from impurities, thus facilitating RP‐HPLC purification. To showcase the utility of SP‐CLipPA, we synthesized a potent calcitonin gene‐related peptide (CGRP) receptor antagonist peptide in excellent yield and purity. This peptide, selected from a series of lipidated analogues of CGRP8–37 and CGRP7–37, has potential for the treatment of migraine. Making a solid case for CLipPA: Lipidated peptides were synthesized in excellent yields through direct thiol–ene conjugation of a vinyl ester to the free thiol of a resin‐bound peptide by a solid‐phase (SP) version of CLipPA (cysteine lipidation of a peptide or amino acid; see scheme). Through this, a lipidated CGRP8–37 analogue with promising biological activity was prepared as a candidate CGRP receptor antagonist for the treatment of migraines.