Difficult Sequences and On-Resin Aggregation
Hydrophobic or beta-branched stretches form interchain beta-sheets on the bead, collapsing resin solvation so reagents cannot reach the N-terminus and both deprotection and coupling stall. Remedies include chaotropic solvent mixtures (DMSO, NMP, DMF/DCM), elevated temperature, lower resin substitution, and backbone amide protection.
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Hydrophobic or beta-branched stretches form interchain beta-sheets on the bead, collapsing resin solvation so reagents cannot reach the N-terminus and both deprotection and coupling stall. Remedies include chaotropic solvent mixtures (DMSO, NMP, DMF/DCM), elevated temperature, lower resin substitution, and backbone amide protection.
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