Improving Solid-State Properties of the Side-ChainPeptide Building Blocks for the Synthesis of GLP‑1 Analogsthrough Their Complexation with Metal Cations

Glucagon-like peptide-1 analogs are receiving exponential attention for the treatment of type II diabetes and controlling weight due to their unique structure with non-natural lipidated side chains. However, the industrial-scale manufacturing of such peptides poses noticeable challenges due to the gel-like appearance of the peptide intermediates used to form the branched structure. Here, we found an efficient approach for the complexation of these protected peptide building blocks with magnesium chloride, which allows for obtaining free-flowing stable solids suitable for the more process-friendly synthesis of the peptides. A screening of the solvents and magnesium chloride content allowed us to determine the optimal parameters for the preparation of the complexes. NMR spectral analysis showed the involvement of amide groups in the interaction with the magnesium salt. Lastly, the efficiency of the coupling of the Mg-complexed lipidated side-chain building blocks was confirmed for the synthesis of tirzepatide and semaglutide fragments, showing a comparable performance with respect to the noncomplexed derivatives.