Preparation and applications of xanthenylamide (XAL) handles for solid-phase synthesis of C-terminal peptide amides under particularly mild conditions

Y. Han, S. L. Bontems, P. Hegyes, M. C. Munson, C. A. Minor, S. A. Kates, F. Albericio, George Barany

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)6326-6339
Number of pages14
JournalJournal of Organic Chemistry
Volume61
Issue number18
DOIs
StatePublished - Jan 1 1996

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Amides
Peptides
Trifluoroacetic Acid
Acids
Methylene Chloride
Alkylation
Prothrombin
Oxytocin
Carboxylic acids
Tryptophan
Proteins

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Preparation and applications of xanthenylamide (XAL) handles for solid-phase synthesis of C-terminal peptide amides under particularly mild conditions. / Han, Y.; Bontems, S. L.; Hegyes, P.; Munson, M. C.; Minor, C. A.; Kates, S. A.; Albericio, F.; Barany, George.

In: Journal of Organic Chemistry, Vol. 61, No. 18, 01.01.1996, p. 6326-6339.

Research output: Contribution to journalArticle

Han, Y. ; Bontems, S. L. ; Hegyes, P. ; Munson, M. C. ; Minor, C. A. ; Kates, S. A. ; Albericio, F. ; Barany, George. / Preparation and applications of xanthenylamide (XAL) handles for solid-phase synthesis of C-terminal peptide amides under particularly mild conditions. In: Journal of Organic Chemistry. 1996 ; Vol. 61, No. 18. pp. 6326-6339.
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