Conversion of “Customizable Units” into N-Alkyl Amino Acids and Generation of N-Alkyl Peptides

Abstract

An efficient conversion of hydroxyproline “customizable” units into new amino acids with a variety of N-alkyl substituents is described. The process is versatile and can afford valuable N-methyl amino acids and N,O-acetals. In addition, it allows the introduction of N-homoallylic substituents and N-chains with terminal ester, ketone, or cyano groups. These chains could be used for peptide extension or conjugation to other molecules (e.g., by olefin metathesis, peptide ligation, etc.). The transformation is carried out in just two (for R = CH2OAc) or three steps (scission of the pyrrolidine ring, manipulation of the α-chain, and the N-substituent) under mild, metal-free conditions, affording products with high optical purity.

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.…”

An Electrochemical Approach to Designer Peptide α-Amides Inspired by α-Amidating Monooxygenase Enzymes

“…Given the above considerations, we therefore aimed to exploit the availability, rich functional diversity, and facile couplings of amino acids bearing side-chain rather than N -alkyl substituents (e.g., R a = H; R b = alkyl, aryl; see Scheme ). To this end, it was envisaged that electrochemical oxidation to deliver α-substituted N , O -acetals could be followed by a tandem reduction pathway, to afford substituted amide products via retention of the side-chain functionality of the C-terminal amino acid (e.g., path b, Scheme C). Notably, the competitive, silane-mediated reduction observed in the preparation of N -benzyl peptide 10 (Scheme ) lent credence to the viability of this pathway.…”

“Cut and Paste” Processes in the Search of Bioactive Products: One-Pot, Metal-free O-Radical Scission-Oxidation-Addition of C, N or P-Nucleophiles

“…After deprotection of the 4-hydroxy group, the resultant pryrrolidine 30 underwent a second O -radical scission, to afford compound 31, which presented two new chains which could be manipulated independently (conversion 31→ 32). Thus, the α-chain was subjected to a reductive amination, while the addition of allylTMS to the N,O -acetal gave an olefinic chain, that could be further diversified using olefin metathesis ( Saavedra et al, 2019 ; Hernández et al, 2021 ).…”