Studies in solid‐phase peptide synthesis: A personal perspective

Abstract

By the early 1970s it had became apparent that the solid‐phase synthesis of ribonuclease A could not be generalized. Consequently, virtually every aspect of solid‐phase peptide synthesis (SPPS) was reexamined and improved during the decade of the 1970s. The sensitive detection and elimination of possible side reactions (amino acid insertion, Nα‐trifluoroacetylation, Nαϵ‐alkylation) were examined. The quantitation of coupling efficiency in SPPS as a function of chain length was studied. A new and improved support for SPPS, the “PAM‐resin,” was prepared and evaluated. These and many other studies from the Merrifield laboratory and elsewhere increased the general acceptance of SPPS leading to the 1984 Nobel Prize in Chemistry for Bruce Merrifield. © 2007 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 90:215–233, 2008.This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprintversion. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

Diastereoselective liquid assisted grinding: ‘cracking’ functional resins to advance chromatography-free synthesis

“…Merrifield resins are well known for their ability to facilitate solid phase peptide synthesis (SPPS). [11][12][13] Through a series of protection and deprotection steps, peptides with desired sequences can be formed using chromatography-free, facile purification techniques, e.g., filtration. Following this model, solid phase organic synthesis (SPOS), has been gaining popularity and expanding with the development of functional resins that possess similar reactivity to their non-supported counterparts.…”

Cell-free Biosynthesis of Peptidomimetics

“…ncAAs, in general, are not efficiently incorporated into a peptide by the translational machinery, because the ribosome and other enzymes have been evolved to utilize the 20 natural amino acids. However, the polymerization efficiency of amino acid monomers through solid-phase chemical synthesis is almost identical [135], therefore, both canonical and non-canonical libraries can be produced with virtually unlimited structural diversities through chemical synthesis approaches [136]. Building upon these advantages, the production of libraries using chemical synthesis is also poised to significantly impact the rate of drug discovery and grow the realm of therapeutics from small molecules to biological polymers.…”

Synthetic Studies towards the Calcium‐Dependent Lipopeptide Antibiotic Cadaside B

“…It was perhaps non-surprising to find the Glu-12 site prone to epimerization due to its incorporation as a dipeptide building block (S9), rather than a carbamate protected single residue. [53,54] Despite this base-free coupling method proving successful for the model sequence 28, it is plausible it failed to prevent epimerization when coupling the significantly more hindered building block 7 b during preparation of the synthetic cadaside B (2 a), which possessed a bulky TBS protected γ-OH group. Furthermore, analogous to preparation of peptide 2 a, an impurity (ca.…”