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

Abstract

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.