5-Hydroxytryptophan as a building block in oligopeptides using Fmoc/tBu SPPS

Abstract

One of the initial steps in the development of therapeutic agents is the identification of lead compounds that bind to the target of interest. Use of combinatorial libraries allows the screening of thousands to millions of compounds. To optimize the characteristics of the first generation of compounds, many of their analogues need to be synthesized. In this sense, 5-hydroxytryptophan closely resembles tryptophan. Both, however, are sensitive to oxidation and alkylation during solid-phase peptide synthesis. In an effort to overcome these side reactions during oligopeptide synthesis, we prepared N α-Fmoc-N in-Boc-5-O-benzyl-5-hydroxytryptophan. To evaluate its properties, this building block was incorporated in a pentagastrin analogue using Fmoc/tBu chemistry. After deprotection and cleavage from the support, the products were purified and identified. The fully deprotected peptide was the main compound, contaminated by its 5-O-benzylated analogue. The relative amount of the latter decreased using longer deprotection times.