TY - JOUR
T1 - Microwave heating in the solid-phase synthesis of N-methylated peptides
T2 - when is room temperature better?
AU - Roodbeen, Renée
AU - Pedersen, Søren Ljungberg
AU - Hosseini, Masood
AU - Jensen, Knud Jørgen
PY - 2012/12
Y1 - 2012/12
N2 - The N-methylation of backbone amides in synthetic peptides is an important method for improving properties such as bioavailability, stability, as well as structural preferences, and is thus an attractive design strategy. However, the synthesis of N-methylated peptides can be challenging as the nucleophile in the acylation step is a sterically hindered secondary amine. In this study, we have systematically evaluated the use of microwave heating, different coupling conditions and the role of steric effects on coupling yields. First, the coupling reagent providing the highest yields was identified by a series of test N-acylation reactions on a selected peptide sequence. Secondly, a comparison of the coupling temperature, that is, room temperature versus microwave heating, with the optimal coupling reagent was performed. Finally, under the optimal conditions, a comprehensive study employing a set of sterically hindered N-methylated amino acids was conducted. Interestingly, incorporation of Fmoc-Arg(Pbf)-OH proceeded with higher yields at room temperature than at elevated temperature as a result of intramolecular Arg lactam formation, which competes with intermolecular amide bond formation. Fmoc-Arg(Boc)2-OH provided even lower coupling yields, due to the complete formation of the Arg lactam product. Our studies have led to a robust, rapid, easy and high-yielding microwave-assisted method using COMU for the incorporation of Fmoc amino acids into challenging, sterically hindered N-methylated amino acid residues in a peptide sequence without the use of harsh reagents.
AB - The N-methylation of backbone amides in synthetic peptides is an important method for improving properties such as bioavailability, stability, as well as structural preferences, and is thus an attractive design strategy. However, the synthesis of N-methylated peptides can be challenging as the nucleophile in the acylation step is a sterically hindered secondary amine. In this study, we have systematically evaluated the use of microwave heating, different coupling conditions and the role of steric effects on coupling yields. First, the coupling reagent providing the highest yields was identified by a series of test N-acylation reactions on a selected peptide sequence. Secondly, a comparison of the coupling temperature, that is, room temperature versus microwave heating, with the optimal coupling reagent was performed. Finally, under the optimal conditions, a comprehensive study employing a set of sterically hindered N-methylated amino acids was conducted. Interestingly, incorporation of Fmoc-Arg(Pbf)-OH proceeded with higher yields at room temperature than at elevated temperature as a result of intramolecular Arg lactam formation, which competes with intermolecular amide bond formation. Fmoc-Arg(Boc)2-OH provided even lower coupling yields, due to the complete formation of the Arg lactam product. Our studies have led to a robust, rapid, easy and high-yielding microwave-assisted method using COMU for the incorporation of Fmoc amino acids into challenging, sterically hindered N-methylated amino acid residues in a peptide sequence without the use of harsh reagents.
U2 - 10.1002/ejoc.201201050
DO - 10.1002/ejoc.201201050
M3 - Journal article
SN - 1434-193X
VL - 2012
SP - 7106
EP - 7111
JO - European Journal of Organic Chemistry
JF - European Journal of Organic Chemistry
IS - 36
ER -