N-(Fmoc-α-aminoacyl)benzotriazoles: Versatile synthetic reagents from proteinogenic amino acids

Abstract

N-Fmoc-α-amino acids were smoothly converted into stable, crystalline N-(Fmoc-α-aminoacyl)benzotriazoles 2a-r (69-90%). Compounds 2b,g reacted with the chiral derivatizing reagent, (+/-)α-methylbenzylamine (5 or 6), to afford α-(N-Fmoc-amino)acid amides 3a,b and 4a,b (average yield 72 %) with no detectable racemization.

Chiral Acylation with N-(Protected α-Aminoacyl)benzotriazoles for Advantageous Syntheses of Peptides and Peptide Conjugates

“…34 Scheme 2 was found to be more convenient for the preparation of N-(Cbz-and N-(Fmoc-a-aminoacyl)benzotriazoles wherein a mixture of 1 equivalent of a carboxylic acid with 4 equivalents of 1H-benzotriazole and 1-1.2 equivalents of thionyl chloride in tetrahydrofuran or dichloromethane was stirred at 20°C for 2 hours (Table 1). [15][16][17][18][19][20]35 Bis(COBt) compounds corresponding to aspartic acid,…”

Benzotriazole-Mediated Syntheses of Depsipeptides and Oligoesters

“…Recently, we were able to prepare N -Pg(tri- or tetrapeptidoyl)benzotriazoles as advantageous coupling reagents for synthesizing tetra-, penta-, and hexapeptides in solution phase . These N -acylbenzotriazoles are also advantageous for N-, O-, C-, and S-acylation, especially while the corresponding acid chlorides are unstable or difficult to prepare . Cysteine-containing S- Pg(α-aminoacyl)di- and tripeptides were prepared from N- Pg(α-aminoacyl)benzotriazoles via S-acylation without racemization and underwent chemical ligations to generate native peptides .…”

Total Synthesis of Pyrophen and Campyrones A–C

“…Indeed, acyl benzotriazoles have been extensively used as electrophiles in Claisen condensations with enolates to form 1,3-dicarbonyl compounds . Amino acid-derived acyl benzotriazoles have also been utilized in coupling reactions as neutral acylating agents that are resistant to epimerization at the α-stereocenter …”