The selective manipulation of Hyp customizable units in DKP substrates allows the generation of a rigid scaffold with four tailor‐made chains which are spatially‐orientated. The key step is a domino radical scission‐oxidation process which allows the generation of N‐substituted DKPs. The versatility of this methodology to produce scaffolds in high optical purity for material and drug discovery is described herein.magnified image

The potential of “customizable units” to generate structural diversity for biological screenings is highlighted in this proof‐of‐concept synthesis of new peptides related to the potent antitumoral Sansalvamide A. Using L‐4‐hydroxyproline (Hyp) as a customizable unit in a linear parent peptide, an improved procedure for selective peptide modification was developed. A divergent Hyp scission‐reductive amination process was carried out, affording five linear peptides with cationic residues, and notably, an N‐alkyl moiety that affected the conformation of the peptide. After two steps (saponification and macrocyclization), sixteen differently N1‐substituted linear and cyclic peptides were obtained. For the first time, the activity of the linear and cyclic compounds was compared. Not only some linear analogs but also cyclic compounds with scarcely studied cationic residues were active against MCF7 breast cancer line. Thus, the structural diversity generated from customizable units can be valuable in drug discovery.

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