Evaluation of 1H-Triazole-1-[N,N'-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation
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Evaluation of 1H-Triazole-1-[N,N'-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation. / Wester, Anita; Björkling, Fredrik; Franzyk, Henrik.
In: The Journal of Organic Chemistry, Vol. 86, No. 21, 2021, p. 14371–14380.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Evaluation of 1H-Triazole-1-[N,N'-Bis(tert-butoxycarbonyl)]carboxamidine in Solution-Phase and On-Resin Guanidinylation
AU - Wester, Anita
AU - Björkling, Fredrik
AU - Franzyk, Henrik
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1021/acs.joc.1c00994
DO - 10.1021/acs.joc.1c00994
M3 - Journal article
C2 - 34661410
VL - 86
SP - 14371
EP - 14380
JO - Journal of Organic Chemistry
JF - Journal of Organic Chemistry
SN - 0022-3263
IS - 21
ER -
ID: 282313302