Scaling Complexity: A Streamlined Route to the Northern Fragment of Enlicitide

Keywords

enlicitide decanoate - PCSK9 inhibitor - fragment synthesis - process development - one-pot reactions - macrocyclization - chemoselectivity - regioselectivity

Significance

This study presents a robust and scalable synthetic route for the northern fragment of enlicitide decanoate (MK-0616), a macrocyclic peptide inhibitor of PCSK9 currently under development for the treatment of hypercholesterolemia. The process delivers this fragment on a > 150 kg scale with high purity and 50 % overall yield. By addressing issues of chemoselectivity, impurity control, and process efficiency, the authors significantly improved the yield, reduced the process mass intensity (PMI), and replaced restricted reagents (like T3P), establishing a practical route suitable for large-scale pharmaceutical production.

Comment

The synthesis commences from tryptophan derivative A. The core of the route is a one-pot two-step sequence that uses unprotected amino acid A as a linchpin for two consecutive peptide couplings (B and D). This way, the peptide backbone of the northern fragment (E) was assembled without elaborate protecting group manipulations (b). Next, deprotection of both Boc groups and the tert-butyl ester was performed with TMSI. Liberation of both amino groups created a challenge in terms of regioselectivity for the final macrolactamization. However, the authors found that addition of MgCl₂ during the macrocyclization largely supressed the undesired cyclization. Overall, this work demonstrates how precise control of regio and chemoselectivity can enable concise syntheses of complex chemical structures on an industrial scale.

Publication History

Article published online:
23 June 2025