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Trimodular Solution‐Phase Protocol for Rapid Large‐Scale Synthesis of Hydrogen Bond Surrogate‐Constrained α‐Helicomimics
Author(s) -
Pal Sunit,
Prabhakaran Erode N.
Publication year - 2021
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.202001359
Subject(s) - chemistry , synthon , combinatorial chemistry , hydrogen bond , reagent , peptidomimetic , scalability , peptide bond , stereochemistry , nanotechnology , peptide , molecule , organic chemistry , computer science , biochemistry , materials science , database
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 (M 1 , M 2 , M 3 ) synthetic protocol where M 1 is a library of HBS‐linked peptidomimetic synthons of both STαH and EαH; M 2 and M 3 are desired oligopeptide libraries. Advantages of the trimodular method over conventional unimodular methods are demonstrated through the synthesis of large‐scale libraries of M 1 , STαH, and EαH.