Trimodular Solution‐Phase Protocol for Rapid Large‐Scale Synthesis of Hydrogen Bond Surrogate‐Constrained α‐Helicomimics

Scalability, optimal reagent usage, high yields, easy isolation, and cost‐effectiveness, are key for the applicability of synthetic methodologies in the production of potential therapeutics. Hydrogen bond surrogate (HBS) constrained α‐helical peptides (α‐helicomimics) have shown promise as therapeutics based on their efficiency to interfere with protein‐biomolecular interactions. The propyl HBS‐constrained α‐helicomimics have shown the highest helicities in both single turn and extended, α‐helices (STαH, EαH). Here we present a solution‐phase synthetic (SPS) method, for the rapid, large‐scale, low‐cost synthesis of libraries of STαH and EαH in high yields. The key to efficiency is our trimodular (M1, M2, M3) synthetic protocol where M1 is a library of HBS‐linked peptidomimetic synthons of both STαH and EαH; M2 and M3 are desired oligopeptide libraries. Advantages of the trimodular method over conventional unimodular methods are demonstrated through the synthesis of large‐scale libraries of M1, STαH, and EαH. A cost‐effective, high‐yielding, rapid trimodular solution‐phase method has been demonstrated to synthesize the hydrogen bond surrogate (HBS) constrained single α‐helical turn and C‐terminal extended helices. The HBS‐constrained α‐helicomimic is divided into three modules and each of them was synthesized in 100 mmol scale followed by connecting them to adopt the α‐helicomimic.