Aza‐propargylglycine installation by aza‐amino acylation: Synthesis and Ala‐scan of an azacyclopeptide CD36 modulator

Abstract

Aza‐propargylglycine (azaPra) peptides are branching points for the synthesis of azapeptide libraries. Efficient alkylation of N‐(Fmoc)hydrazine in solution was found to provide N′‐propargyl fluorenylmethyl carbazate 13, which on activation gave N‐(Fmoc)‐azaPra acid chloride for installation into peptides. Reducing the number of steps on resin for azaPra peptide synthesis, which previously necessitated alkylation of a semicarbazone protected aza‐glycine residue, the new method offers potential for higher yield, as demonstrated by the synthesis of azacyclopeptide 1a, as well as by an alanine scan of this potent cluster of differentiation‐36 receptor (CD36) modulator.

Diversity-Oriented A3-Macrocyclization for Studying Influences of Ring-Size and Shape of Cyclic Peptides: CD36 Receptor Modulators

“…Elongation of Dap, Dab, Orn, and Lys resins 18a , d – h using standard Fmoc-based solid-phase peptide synthesis gave tetra- and pentapeptide resins 21 and 22 (Scheme ). The azaPra residue was introduced by employing N -Fmoc-azaPra-Cl ( 23 ), which was prepared from the corresponding carbazate with bis­(trichloromethyl)­carbonate (BTC) . After Fmoc group removal, semicarbazides 26a and 27a,f–h were coupled to the symmetric anhydride from Boc-Ala-OH to furnish azapeptide 28a and 29a,f–h .…”

“…Previously, cyclic (aza)­peptides having 16-, 19-, 22-, and 25-atom ring sizes were, respectively, synthesized using A 3 -macrocyclization and formaldehyde to cross-link different N ε -substituted lysine side chains with ( R )- and ( S )-propargylglycine (Pra) and their azaPra counterpart (Figure ). ,− The semicarbazide served as an amino amide surrogate in the azapeptides . Examining the scope of the A 3 -macrocyclization more deeply, the diversity of the di-amino carboxylate component has now been expanded.…”

Synthesis and Biomedical Potential of Azapeptide Modulators of the Cluster of Differentiation 36 Receptor (CD36)

“…Moreover, [aza-( N , N -diallylaminobut-2-ynyl)Gly 4 ]-GHRP-6 ( 49f ) exhibited therapeutic potential in a model of atherosclerosis ( vide infra ). In addition, intramolecular variations of the A 3 -coupling reaction were developed to access cyclic azapeptide derivatives of GHRP-6 with promising results [ 37 , 38 , 39 ].…”

“…Diverse azacyclopeptides (e.g., 58a – f ) were synthesized by A 3 -macrocyclizations on linear substrates with the N ε -(alkyl)Lys residue in other locations, as well as with different alkyl groups on the N ε -amine. A systematic replacement of key residues in azacyclopeptide 57c by alanine was accomplished by an approach featuring installation of the azaPra residue using the corresponding Fmoc-aza-propargylglycine acid chloride [ 38 ]. Moreover, replacement of the azaPra residue in azacyclopeptides 56 and 57c with R- and S -propargylglycine residues was achieved using the A 3 -macrocyclization to provide configurationally stable cyclic peptides ( R )- and ( S )- 59 and 60 [ 39 ].…”

Recent Advances in Macrocyclic Drugs and Microwave-Assisted and/or Solid-Supported Synthesis of Macrocycles

“…Specifically, cyclic azapeptides 182 were synthesized from linear precursors 181 using A 3 -macrocyclization strategy in aqueous formaldehyde and CuI in DMSO, followed by the resin cleavage and side-chain deprotection using a TFA/TES/H 2 O cocktail ( Scheme 55 ) [ 153 ]. Previously, the same research group studied the dynamic chirality of this cyclic azapeptide class of allosteric CD36 modulators of macrophage-driven inflammation using the same macrocyclization approach [ 154 ], aza-propargylglycine installation via aza-amino acylation strategy [ 155 ], and diverse cyclic azapeptides as CD36-modulating peptidomimetics via A3-macrocyclization approach [ 156 ].…”