An important side reaction using the thiol, 3,6-dioxa-1,8-octanedithiol (DODT), in 9-fluorenylmethoxycarbonyl-based solid phase peptide synthesis

Paul W R Harris; Renata Kowalczyk; Sung-Hyun Yang; Geoffrey M Williams; Margaret A Brimble

doi:10.1002/psc.2595

An important side reaction using the thiol, 3,6-dioxa-1,8-octanedithiol (DODT), in 9-fluorenylmethoxycarbonyl-based solid phase peptide synthesis

J Pept Sci. 2014 Mar;20(3):186-90. doi: 10.1002/psc.2595. Epub 2013 Dec 18.

Authors

Paul W R Harris¹, Renata Kowalczyk, Sung-Hyun Yang, Geoffrey M Williams, Margaret A Brimble

Affiliation

¹ School of Chemical Sciences, The University of Auckland, 23 Symonds St, Auckland, 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand.

PMID: 24353069
DOI: 10.1002/psc.2595

Abstract

A considerable quantity of an alkylation by-product is observed when using 3,6-dioxa-1,8-octanedithiol as a scavenger during acidic release of peptides containing the thioether amino acid methionine from the solid support. Adjustment of the cleavage conditions by replacement of 3,6-dioxa-1,8-octanedithiol with ethane dithiol or by using methionine sulfoxide as an alternative to methionine resulted in no such impurity. The by-product was detectable by liquid chromatography and mass spectrometry and characterised by NMR spectroscopy of an isolated model peptide. It could be effectively removed in a separate post cleavage step by treatment with dilute aqueous acid at 37 °C.

Keywords: 3,6-dioxa-1,8-ocatanedithiol; alkylation; methionine; peptide cleavage.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ethyl Ethers / chemistry*
Fluorenes / chemistry*
Mass Spectrometry
Solid-Phase Synthesis Techniques / methods*
Sulfhydryl Compounds / chemistry*

Substances

3,6-dioxa-1,8-octanedithiol
9-fluorenylmethoxycarbonyl
Ethyl Ethers
Fluorenes
Sulfhydryl Compounds