An activated O → N acyl transfer auxiliary: Efficient amide-backbone substitution of hindered 'difficult' peptides

Journal of Organic Chemistry

Volumn 65, Issue 18, 2000, Pages 5460-5468

  Miranda, Les P ^a,b   Meutermans, Wim D F ^a   Smythe, Mark L ^a   Alewood, Paul F ^a  

^a UNIVERSITY OF QUEENSLAND   (Australia)

^b CARLSBERG LABORATORY   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

9 FLUORENYLMETHYL CHLOROFORMATE; AMINO ACID; GLYCINE; PHENYLALANINE; SYNTHETIC PEPTIDE; VALINE; AMIDE; PEPTIDE;

ACYLATION; ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; MASS SPECTROMETRY; PEPTIDE ANALYSIS; PEPTIDE SYNTHESIS; REVERSED PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; CHEMISTRY;

ACYLATION; AMIDES; PEPTIDES;

EID: 0033624589     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo991340+     Document Type: Article

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68. The following experiment confirms this. A 30 min HBTU mediated coupling of Fmoc-Val onto (Hmb)Val-Ala-Gly-Phe-WANG resin, followed by TFA cleavage showed near complete acylation by MS. However, when the same resin was first treated with piperidine (to remove all O-acylation) prior to TFA cleavage, only nonacylated product was observed.
69. To be able to make the appropriate on-resin comparisons between Hnb and Hmb we have carried out all N-acylation experiments in parallel using identical experimental conditions. HBTU/DMF coupling chemistry at room temperature was employed in this study as it is effective and commonly used in contemporary Fmoc- and Boc-SPPS. It must also be noted that in the very hindered acylation reactions reported here, higher yields can be achieved by the optimization of coupling variables such as the activation method, solvent, temperature, and time.
70. 65 However, in this study less than 1% of this side reaction was observed during cleavage from trityl resin. In practice, this type of side reaction can be avoided by first carrying out on-resin auxiliary photolysis prior to TFA treatment.
71. Diacylation (N and O) yields were used as a gauge for O-acylation. Determined by TFA resin cleavage after acylation with Boc-amino acids without prior base treatment and quantification of the di-acylation product by RP-HPLC peak integration after identification by ES-MS.
72. Throughout the synthesis and handling of the Hnb-substituted peptide care was taken to avoid premature photolysis of the Hnb auxiliary by minimizing exposure to sun and room light. We recommend that the reaction vessel and other glassware used in manipulations be covered with aluminum foil or another type of nontranslucent material.
73. It is expected the Hnb auxiliary can be introduced during SPPS in a preformed manner similar to commercially available N,O-bisFmoc-N-(Hmb)amino acids derivatives.