Switching the Stereochemical Outcome of 6-<i>Endo</i>-<i>Trig</i> Cyclizations; Synthesis of 2,6-<i>Cis</i>-6-Substituted 4‑Oxopipecolic Acids

A base-mediated 6-<i>endo</i>-<i>trig</i> cyclization of readily accessible enone-derived α-amino acids has been developed for the direct synthesis of novel 2,6-<i>cis</i>-6-substituted-4-oxo-l-pipecolic acids. A range of aliphatic and aryl side chains were tolerated by this mild procedure to give the target compounds in good overall yields. Molecular modeling of the 6-<i>endo</i>-<i>trig</i> cyclization allowed some insight as to how these compounds were formed, with the enolate intermediate generated via an equilibrium process, followed by irreversible tautomerization/neutralization providing the driving force for product formation. Stereoselective reduction and deprotection of the resulting 2,6-<i>cis</i>-6-substituted 4-oxo-l-pipecolic acids to the corresponding 4-hydroxy-l-pipecolic acids was also performed

Design and Application of a DNA-Encoded Macrocyclic Peptide Library

A DNA-encoded macrocyclic peptide library was designed and synthesized with 2.4 × 10¹² members composed of 4–20 natural and non-natural amino acids. Affinity-based selection was performed against two therapeutic targets, VHL and RSV N protein. On the basis of selection data, some peptides were selected for resynthesis without a DNA tag, and their activity was confirmed