Preparation and Applications of Xanthenylamide (XAL) Handles for Solid-Phase Synthesis of C-Terminal Peptide Amides under Particularly Mild Conditions(1-3)

Yongxin Han; Susan L. Bontems; Peter Hegyes; Mark C. Munson; Charles A. Minor; Steven A. Kates; Fernando Albericio; George Barany

doi:10.1021/jo960312d

Preparation and Applications of Xanthenylamide (XAL) Handles for Solid-Phase Synthesis of C-Terminal Peptide Amides under Particularly Mild Conditions(1-3)

J Org Chem. 1996 Sep 6;61(18):6326-6339. doi: 10.1021/jo960312d.

Authors

Yongxin Han¹, Susan L. Bontems, Peter Hegyes, Mark C. Munson, Charles A. Minor, Steven A. Kates, Fernando Albericio, George Barany

Affiliation

¹ Department of Chemistry, University of Minnesota, 207 Pleasant Street S.E., Minneapolis, Minnesota 55455, PerSeptive Biosystems Biosearch Products, 500 Old Connecticut Path, Framingham, Massachusetts 01701, and Department of Organic Chemistry, University of Barcelona, 08028-Barcelona, Spain.

PMID: 11667474
DOI: 10.1021/jo960312d

Abstract

[[9-[(9-Fluorenylmethyloxycarbonyl)amino]xanthen-2(or 3)-yl]oxy]alkanoic acid (XAL) handles have been prepared by efficient four-step routes from 2- or 3-hydroxyxanthone and coupled onto a range of amino-functionalized supports. The resultant XAL supports are the starting points for solid-phase peptide synthesis by Fmoc chemistry. Upon completion of chain assembly, C-terminal peptide amides are released in excellent yields and purities by use of low concentrations [1-5% (v/v)] of trifluoroacetic acid (TFA) in dichloromethane, often without a need for added carbocation scavengers. These cleavage conditions allow retention of all or a significant portion of tert-butyl type and related side-chain protecting groups, which subsequently may be removed fully in a solution process carried out at higher acid concentration. XAL supports are particularly useful for the synthesis of acid-sensitive peptides, including tryptophan-containing sequences that are known to be susceptible to yield- and/or purity-reducing alkylation side reactions. The effectiveness of this chemistry was shown with the syntheses of prothrombin (1-9), acyl carrier protein (65-74), Tabanus atratus adipokinetic hormone, fragments of the protein RHK 1, CCK-8 sulfate, and oxytocin. Furthermore, the application of XAL supports for the preparation of fully protected peptide amides has been demonstrated.