Synthesis and alkylation of aza‐glycinyl dipeptide building blocks

Abstract

Aza-glycinyl dipeptides are useful building blocks for the synthesis of a diverse array of azapeptides. The construction of the aza-glycine residue is however challenging, because of the potential for side reactions, such as those leading to formation of oxadiazalone, hydantoin and symmetric urea by-products. Employing N,N'-disuccinimidyl carbonate to activate benzophenone hydrazone, we have developed a more efficient approach for the synthesis of aza-glycinyl dipeptides. Alkylation of the semicarbazone of the resulting protected aza-glycinyl dipeptides using tetraethylammonium hydroxide and propargyl bromide provided an efficient entry into the aza-propargylglycinyl peptide building blocks, which have served previously in various reactions including Sonogashira cross-couplings, dipolar cycloadditions and intramolecular exo-dig cycloadditions to furnish a variety of azapeptide building blocks.

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

“…N ′‐Propargyl N ‐(Fmoc)hydrazine 13 was synthesized by alkylation of carbazate 12 , which was prepared by acylation of hydrazine with fluoren‐9‐ylmethyl chloroformate (Scheme ) . Methylidene carbazate alkylation has typically necessitated protection to ensure regio‐selectivity and to avoid bis‐alkylation . Alkylation of N ‐(Fmoc)hydrazine 12 with a bromoacetate linked to Wang resin has however provided mono‐alkylation, likely due to pseudo‐dilution and the steric bulk of the supported electrophile .…”

“…Moreover, propynal is not readily amenable to the common reductive amination strategies used to prepare N ′‐alkyl carbazates . Alkylations of carbazates, semicarbazones, and hydrazides with halides and alcohols have provided propargyl hydrazine derivatives but often require significant protection, and substituted propargyl alcohols …”

Diversity‐Oriented Synthesis of Cyclic Azapeptides by A3‐Macrocyclization Provides High‐Affinity CD36‐Modulating Peptidomimetics

“…[24] As ap roof-of-concept, A 3 -macrocyclization was used to prepare cyclic azatripeptide 9 with e-N-methyl-lysine at the peptide C-terminal and azaPra at its iÀ2position (Scheme 1). [25] Propargylation using Cs 2 CO 3 and proparyl bromide gave azaPra 5a in good conversion as verified by LC-MS analysis of ac leaved resin aliquot. Acylation of 3a with carbazate prepared from benzophenone hydrazone and N,N'-disuccinimidyl carbonate (DSC) provided semicarbazone 4a.…”

“…Acylation of 3a with carbazate prepared from benzophenone hydrazone and N,N'-disuccinimidyl carbonate (DSC) provided semicarbazone 4a. [25] Propargylation using Cs 2 CO 3 and proparyl bromide gave azaPra 5a in good conversion as verified by LC-MS analysis of ac leaved resin aliquot. After o-NBS group removal with 2-mercaptoethanol and DBU, macrocycle 7a was prepared by treating e-Nmethylamine 6a with CuI (20 mol %) and 37 %a queous formaldehyde in DMSO at RT for 24 h, [17] as verified by LC-MS analysis.E longation of 7a to cyclic aza-GHRP-6 9 was achieved by semicarbazone removal with hydroxylamine hydrochloride in pyridine, [16] acylationo fs emicarbazide 8a using the symmetric anhydride from treating Fmoc-Ala-OH with DIC,a nd standard solid-phase peptide synthesis, [26] followed by deprotection and resin cleavage.M acrocycle 9 was isolated in 3.5 %overall yield after HPLC purification.…”

Solid‐phase synthesis of C‐terminal azapeptides

“…Benzhydrylidene‐aza‐glycinamide Rink resin 1 was synthesized by activation of benzophenone hydrazone with DSC (Figure ) and coupling of the activated benzhydrylidene‐carbazate to the amine of the Rink resin. Qualitative completion of the reaction was ascertained by a negative Kaiser test; moreover, formation of benzhydrylidene‐aza‐glycinamide was validated by cleavage of a resin aliquot with a freshly made solution of TFA/H 2 O/triethylsilane (TES; 95/2.5/2.5), removal of the resin by filtration, and analysis of the residue by LC‐MS, which indicated one single peak (retention time (R.T.) = 4.97 min, 50–90% MeOH in water containing 0.1% formic acid (FA) over 10 min) having the desired molecular ion (ESI‐MS m / z calcd for C 14 H 14 N 3 O [M + H] + 240.1, found 240.1).…”