Synthesis of Diketopiperazine Scaffolds with Tailored N‐ and α‐Chains by Selective Modification of Customizable Units

Abstract

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

Structural Diversity using Hyp “Customizable Units”: Proof‐of‐Concept Synthesis of Sansalvamide‐Related Antitumoral Peptides

“…This set of linear compounds 6 a – e is particularly interesting for future structure‐activity studies, not only due to their linear backbone (in contrast to the cyclic Sansalvamide core) but also because the N ,O‐acetals can be readily transformed into a variety of N ‐alkyl groups, even bulky ones [8b,c] . As commented before, the conformations of N ‐alkylated compounds such as 6 a – e can be quite different to the ones of N ‐unsubstituted, linear peptides, and rigid cyclic Sansalvamides.…”

Site-selective modification of peptide backbones

“…The scission-reductive amination was then used to ligate two peptides, and at the same time, to generate a rigid α-amino-γlactam unit to rigidify the backbone (conversion 64→66, Scheme 16). 11,50b Other applications of this methodology have allowed the preparation of diketopiperazine scaffolds with four different substituents, 51 and the production of a library of cyclic antitumoral peptides, as sansalvamide A analogues. 52 Recently the use of Hyp as a doubly customizable unit was reported by the same group (Scheme 17).…”

“…20 An application of this methodology to the preparation of tetrasubstituted diketopiperazine scaffolds was also reported (Scheme 34, conversion 132→136). 51 This conversion is usually carried out by alkylation of unsubstituted N-diketopiperazines with strong bases and very reactive electrohiles, and usually heating or other activation source is required. 109 These harsh conditions were avoided using the methodology shown in Scheme 34.…”

“…In the final step (conversion 134→135, the two N,O-acetals were allylated, to give a diolefinic compound 135 that could be the base of dimers or oligomers 136. 51…”

Diketopiperazine Gels: New Horizons from the Self-Assembly of Cyclic Dipeptides

“…All these features make CDPs an attractive choice as biocompatible, green, functionalizable, and cheap building blocks for smart materials with a wide scope of applications from industry to medicine. The basic design is very simple: two amino acids bound together in a cyclic structure with a defined stereochemistry (i.e., LL, LD/DL, or DD) and the possibility to further derivatize the side chains [ 42 , 43 , 44 , 45 , 46 ] of selected amino acids [ 47 , 48 , 49 , 50 ], as widely applied in nature [ 51 , 52 , 53 , 54 , 55 , 56 ].…”