Solvation effects in solid-phase peptide synthesis

Abstract

The success of solid-phase peptide synthesis is highly dependent on the accessibility of the growing resin-bound peptide chain to reagents. To maximize this accessibility, the relationship between solvent properties and peptide-resin solvation has been explored. The tridecapeptide [Lys 9 ]-α-conotoxin G I (from Conus geographus), which contains nine side-chain-protected residues, was used to study solvation effects of protected peptide-resins. Efficient solvation of (aminomethyl)copoly(styrene-1% DVB) and peptide-copoly(styrene-1% DVB) could be directly correlated to solvent Hildebrand and hydrogen-bonding solubility prameters (δ and δ h , respectively). Solvation was also highly dependent on the side-chain protecting group strategy (benzyl (Bzl), tert-butyl (tBu), or p-methoxybenzyl (Mob)) utilized. The most efficient solvation by a single solvent occurred with NMP, regardless of side-chain protection, although the relative solvation is greater for the Bzl-based versus tBu-based side-chain-protected conotoxin-resin. Mixed-solvent systems with optimized δ and δ h values, such as 45% THF/NMP and 20% TFE/DCM, offered grater solvation than single solvents for the Bzl and tBu side-chain-protected conotoxin-resins. Solvation results for Mob side-chain-protected conotoxin-resin suggested that replacement of the tBu side-chain protecting group by the Mob group improves solvation by single solvents, such as NMP, while still providing the weak acid lability desired for side-chain deprotection following solid-phase peptide synthesis utilizing Fmoc chemistry