SE5:E3: A Process Chemist's Romance with Scaling a Macrocyclic Peptide

<p>Last episode, we watched medicinal chemistry dream up enclitide (MK-0616) — this week we find out what happens when someone actually has to <em>make</em> it. Dani and LC are joined by David Thaisrivongs and Gao Shang to unpack their recent <em>JACS</em> paper on the total synthesis of enlicitide, a macrocyclic peptide complex enough to keep company with taxol, vancomycin, and eribulin. Along the way they get into the pivot from solid-phase to solution-phase peptide synthesis, the perpetual headache of sourcing non-canonical amino acids and how biocatalysis cracked it open, and the crystallization detective work that let the team ditch chromatography entirely. There&#39;s also a great discussion on why a late-stage macrolactamization became a late-stage RCM — the kind of route decision that looks obvious only in hindsight. </p><p>Fair warning: this one was among <em>JACS</em>&#39;s top-accessed papers of 2025, so you&#39;re in good company!</p><p>If you enjoyed this chapter of the enlicitide story, stay tuned—we&#39;ve got plenty more peptide chemistry, process development adventures, and behind-the-scenes drug discovery stories coming your way this season.</p><p><br></p><p><strong>Read some of the papers we discussed today:</strong></p><p><em>Total Synthesis of Enlicitide Decanoate - </em>⁠⁠<a href="https://pubs.acs.org/jacsat/article/147/13/11036/3736593/Total-Synthesis-of-Enlicitide-Decanoate" target="_blank" rel="noopener noreferer"><em>J. Am. Chem. Soc.</em></a>⁠⁠</p><p>Follow the Pharm to Table podcast on X - ⁠⁠⁠⁠@PharmtoTablePod</p><p>⁠⁠⁠⁠Visit our website at <a href="https://podcasters.spotify.com/pod/show/pharm-to-table">⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠https://podcasters.spotify.com/pod/show/pharm-to-table⁠⁠⁠⁠⁠⁠⁠</a> </p><p><br></p><p></p>