Evaluation of 1H-Triazole-1-[N,N'-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation.
J Org Chem
; 86(21): 14371-14380, 2021 11 05.
Article
em En
| MEDLINE
| ID: mdl-34661410
ABSTRACT
Several guanidines and guanidinylated peptides have substantial potential as therapeutics, but efficient guanidinylation reagents are vital for easy access to these compounds. Presently, pyrazole-1-carboxamidine type reagents are commonly used in the transformations of amines into corresponding guanidines. Here, we report a comparative study of the utility of 1H-triazole-1-[N,N'-bis(tert-butoxycarbonyl)]carboxamidine, which was synthesized in two steps and readily upscaled to gram amounts. It exhibited excellent performance in solution-phase reactions, rapidly converting a set of representative aliphatic primary and unhindered secondary amines as well as aniline into the corresponding bis(tert-butoxycarbonyl)-protected guanidines. To enable a direct assessment of the reactivity of guanidinylation reagents, conversions were performed in deuterated solvents (d7-DMF or d8-THF), allowing for continuous analysis of the reaction mixtures by 1H and 13C NMR. Likewise, 1H-triazole-1-[N,N'-bis(tert-butoxycarbonyl)]carboxamidine proved to be a versatile reagent in solid-phase conversions, for example, a resin-bound test peptide (KFFKFFK) was fully guanidinylated in only 2 h by using 2 equivalents of the reagent per free amino group. Also, 1H-triazole-1-[N,N'-bis(tert-butoxycarbonyl)]carboxamidine proved capable of completely guanidinylating more sterically hindered N-terminal residues (e.g., N-methyl amino acids or a peptoid) in resin-bound peptides. Its superior reactivity and stability demonstrated under heating conditions make 1H-triazole-1-[N,N'-bis(tert-butoxycarbonyl)]carboxamidine a valuable guanidinylation reagent both in solution- and solid-phase synthesis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Triazóis
/
Técnicas de Síntese em Fase Sólida
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article