Solid-Phase Synthesis of “Mixed” Peptidomimetics Using Fmoc-Protected Aza-β³-amino Acids and α-Amino Acids

Abstract

[structure: see text] A solid-phase fluorenylmethyloxycarbonyl (Fmoc)-based synthesis strategy is described for "mixed" aza-beta3-peptides as well as a convenient general approach for their required building blocks, the aza-beta3-amino acid residues (aza-beta3-aa). These monomers allow the synthesis of relatively large quantities of pure mixed aza-beta3-peptides. The required Fmoc-substituted aza-beta3-amino acids are accessible by convenient synthesis, and a number of monomers including those containing side chains with functional groups have been synthesized. The method was applied toward the solid-phase synthesis of aza-beta3-peptide mimetics of a biologically active histone H4 sequence.

A Review on Azapeptides: The Promising Peptidomimetics

“…4. Exploring their valuable significance the solid phase synthesis of "mixed "peptidomimetics was reported using Fmocprotected Aza-β 3 -amino acids and α-amino acids [30]. Growth hormone releasing peptide (GHRP-6)…”

Smac-Derived Aza-Peptide As an Aminopeptidase-Resistant XIAP BIR3 Antagonist

“…Compound (5) was synthesized from 1-(tertbutoxycarbonyl)-1-methylhydrazine (3), using the previously reported synthesis protocol by Busnel et al [22] and others [23][24][25]. The synthesis comprises two steps, an initial Fmocprotection of the primary amino function of the hydrazine, followed by Boc removal of the secondary amine functionality (Scheme 1).…”

One-Pot Synthesis of Fmoc- and Boc-Protected Aza-Methionine Precursors from 2-Methylthioacetaldehyde Dimethyl Acetal

“…In most cases, these protected monoalkylhydrazines have been prepared by the reductive alkylation of mono-protected hydrazines such as Fmoc-or Boc-hydrazines with aldehydes. [3][4][5][6][7][8][9] However, this straightforward route cannot be used in the case of compounds that bear nucleophilic heteroatoms in the substituent group R, as these heteroatoms destabilize the corresponding aldehydes making them prone to undergo the self-condensation. Therefore these precursors of azaanalogs of several natural amino acids including methionine, so far have not been reported in the literature.…”

“…Indeed Freeman et al 6 were unable to synthesize the aza-arginine precursor by this method because of the instability of the required aldehyde; even their attempt to use 3-(di-Boc)guanidinopropionaldehyde diethyl acetal failed to generate the corresponding aldehyde required for the condensation. To overcome these difficulties, we have developed a one-pot synthesis of 2-(methylthio)ethylhydrazones (6) directly from the commercially available and stable 2-(methylthio)acetaldehyde dimethyl acetal (5), without the need for preliminary preparation of the appropriate aldehyde. This method was used for the synthesis of both Fmoc-and Boc-protected precursors of aza-methionine (7a and 7b) starting from 2-(methylthio)acetaldehyde dimethyl acetal (5).…”