Methodological studies in solid phase synthesis : Linkers and applications of multi-component condensations

Sammanfattning: Solid phase synthesis has become an increasingly important tool in the synthesis of oligopolymers and small organic molecules. This thesis covers three important areas in the solid phase synthesis technique: linker strategies, reduction methods and novel routes to complex heterocycles. The synthesis of the OMPPA [4-(3-hydroxy-4-metylpentyl)phenyl acetic acid] linker is described. This linker is compatible with the Boc/Bzl protective group strategy, and yields peptide acids upon cleavage from solid support. The OMPPA linker is stable towards “low-acid” treatment and is self-scavenging during final cleavage of the peptide product from solid support. These properties are beneficial for peptide purity and yields.The synthesis of the HMPPA [3-(4-hydroxymethylphenylsulfanyl)propanoic acid] linker is described. This safety catch linker is compatible with both Fmoc/tBu- and Boc/Bzl protective group strategies in solid phase peptide synthesis. The HMPPA linker is stable towards super acids yet final cleavage from solid support is performed by a relatively mild reductive acidolysis method, yielding peptide acids. It is suggested that this linker may be useful when synthesizing cyclic peptides on solid support. A new facile method for reducing cystine moieties is described. Adding metallic zinc to cystine containing peptides and proteins dissolved in slightly acidic aqueous and/or non-aqueous solutions, results in rapid disulfide reduction. This method is compatible with functional groups commonly present in peptides and proteins. The solid phase synthesis of oxygen-bridged tetrahydropyridones via a multi-component condensation reaction is described. Expected products were obtained in reasonable yields using both aromatic- and aliphatic ketones. This class of compounds has the general physico-chemical properties that are typical for drugs with high pharmacological activity.