COUPLING DIFFICULTY ASSOCIATED WITH INTERCHAIN CLUSTERING AND PHASE-TRANSITION IN SOLID-PHASE PEPTIDE-SYNTHESIS

We have developed a model containing clustered peptide chains to evaluate coupling difficulties associated with interchain interactions in solid phase peptide synthesis. Our results revealed two new findings. First, there was a significant difference in solvation properties between the conventional dispersed and our clustered peptide chain models at a similar level of peptidyl loading. At the completion of an eight-residue peptide, with a peptide content of >61%, the solvated volumes of a dispersed chain model increased 20-30-fold over the initial dry resin and were about 4-5-fold higher than those of the clustered chain model in both polar and nonpolar solvents. The decrease in solvation mimics the effect of higher cross-linking of resin supports, leading to poor swelling ability. Second, there was a polystyrene to polyamide transition when the peptide loading reached approximately 50% of the peptidyl resin. In this transition phase, the swelling and growth of the peptidyl resin reached the lowest point in both polar aprotic and hydrophobic solvents. Furthermore, the phase transition was also the crossover point where the aprotic polar solvent N,N-dimethylformamide provided better resin swellability than the nonpolar solvent dichloromethane. A good correlation between swelling ability and the coupling yield in aprotic polar solvents was also found. A combination of the aprotic polar solvent NMP and coupling at elevated temperature was found to be the most efficient to increase coupling efficiency. Thus, our results provide evidence for coupling difficulties associated with the interchain interactions exacerbated by chain clustering and phase transition.