Microwave heating in solid-phase synthesis: evaluation of reagents and resins for the synthesis of long sequences (#3)
The reagents and resins for solid-phase peptide synthesis (SPPS) were originally developed for applications at ambient temperature. The general adaptation of precise microwave heating in SPPS will require a physico-chemical understanding of the effect of elevated temperatures on reactions and side-reactions as well as on the resins.
We have systematically studied the synthesis of ‘difficult sequences’, glycopeptides, N-methylated peptides, and small proteins using microwave heating. Some intramolecular side-reactions appear to be promoted over intermolecular coupling reactions by elevated temperature.
This has been complemented with NMR studies, which revealed that not only do coupling reagents yield activated esters at different rates, these esters also differ in thermal and hydrolytic stability. Thus, the amount of residual water in the SPPS solvents had a significant effect on electrophilic reagents and intermediates, which became more pronounced at elevated temperature.
A systematic study of the effect solid supports (resins) on the synthesis of long sequences up to 54 AA was conducted.1 2 3
- S. L. Pedersen, A. P. Tofteng, L. Malik, K. J. Jensen, Microwave heating in solid-phase peptide synthesis, Chem. Soc. Rev., 2012, 41, 1826-1844.
- R. Roodbeen, S. L. Pedersen, M. Hosseini, K J. Jensen, Microwave heating in solid-phase synthesis of N-methylated peptides: When is room temperature better? 2012, European Journal of Organic Chemistry, 7106-7111
- A. P. Tofteng, S. L. Pedersen, D. Staerk, K. J. Jensen, Effect of Residual Water and Microwave Heating on Half-Lifes of Reagents and Reactive Intermediates in Peptide Synthesis, Chemistry – European Journal, 2012, 18, 9024-9031.