An Activated O N Acyl Transfer Auxiliary: Efficient Amide-Backbone Substitution of Hindered "Difficult" Peptides

Miranda, L. P., Meutermans, W. D. F., Smythe, M. L. and Alewood, P.F. (2000) An Activated O N Acyl Transfer Auxiliary: Efficient Amide-Backbone Substitution of Hindered "Difficult" Peptides. Journal of Organic Chemistry, 65 18: 5460-5468. doi:10.1021/jo991340+

Author Miranda, L. P.
Meutermans, W. D. F.
Smythe, M. L.
Alewood, P.F.
Title An Activated O N Acyl Transfer Auxiliary: Efficient Amide-Backbone Substitution of Hindered "Difficult" Peptides
Journal name Journal of Organic Chemistry   Check publisher's open access policy
ISSN 0022-3263
Publication date 2000-09-08
Sub-type Article (original research)
DOI 10.1021/jo991340+
Volume 65
Issue 18
Start page 5460
End page 5468
Total pages 9
Place of publication USA
Publisher American Chemical Society
Language eng
Subject C1
780103 Chemical sciences
250302 Biological and Medical Chemistry
Abstract Overcoming the phenomenon known as difficult synthetic sequences has been a major goal in solid-phase peptide synthesis for over 30 years. In this work the advantages of amide backbone-substitution in the solid-phase synthesis of difficult peptides are augmented by developing an activated N-alpha-acyl transfer auxiliary. Apart from disrupting troublesome intermolecular hydrogen-bonding networks, the primary function of the activated N-alpha-auxiliary was to facilitate clean and efficient acyl capture of large or beta-branched amino acids and improve acyl transfer yields to the secondary N-alpha-amine. We found o-hydroxyl-substituted nitrobenzyl (Hnb) groups were suitable N-alpha-auxiliaries for this purpose. The relative acyl transfer efficiency of the Hnb auxiliary was superior to the 2-hydroxy-4-methoxybenzyl (Hmb) auxiliary with protected amino acids of varying size. Significantly, this difference in efficiency was more pronounced between more sterically demanding amino acids. The Hnb auxiliary is readily incorporated at the N-alpha-amine during SPPS by reductive alkylation of its corresponding benzaldehyde derivative and conveniently removed by mild photolysis at 366 nm. The usefulness of the Hnb auxiliary for the improvement of coupling efficiencies in the chain-assembly of difficult peptides was demonstrated by the efficient Hnb-assisted Fmoc solid-phase synthesis of a known hindered difficult peptide sequence, STAT-91. This work suggests the Hnb auxiliary will significantly enhance our ability to synthesize difficult polypeptides and increases the applicability of amide-backbone substitution.
Keyword Chemistry, Organic
Solid-phase Synthesis
Chemical Synthesis
Q-Index Code C1
Additional Notes Do not use DOI link - returns an error message.

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 43 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 49 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 13 Aug 2007, 21:57:17 EST