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Application of the ‘Direct Amide Cyclization’ to Peptides Containing an Anthranilic Acid Residue
Author(s) -
Philipova Irena,
Linden Anthony,
Heimgartner Heinz
Publication year - 2005
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200590135
Subject(s) - chemistry , anthranilic acid , oxazolone , azulene , azirine , amide , yield (engineering) , ring (chemistry) , residue (chemistry) , stereochemistry , tripeptide , peptide , combinatorial chemistry , medicinal chemistry , organic chemistry , biochemistry , materials science , metallurgy
The 2,2‐disubstituted 2 H ‐azirin‐3‐amines 7a – 7c were used as amino acid synthons to prepare linear peptides derived from anthranilic acid. These linear peptides, which contain α , α ‐disubstituted α ‐amino acids, were synthesized by using the ‘azirine/oxazolone method’ ( Schemes 2 – 5 ) and were subjected to the acid‐catalyzed ‘direct amide cyclization’. Unfortunately, all attempts to isolate the ten‐membered cyclotripeptides, by starting with different precursors, failed. Instead of the expected cyclotripeptides, the corresponding 1,3a,7‐triazabenz[ e ]azulene‐3,6‐diones 12 and 17 ( Schemes 2 and 3 ) were obtained in up to 44% yield. Most likely, these products were formed by a transannular ring contraction of the desired products, followed by dehydration. In the case of the linear precursor 24 , the 20‐membered cyclodimer 25 was formed in 50% yield, together with traces of the 1,3a,7‐triazabenz[ e ]azulene‐3,6‐dione 27 and the completely unexpected quinazolinone 26 ( Scheme 5 ). In the cases of the linear precursors 30 and 34 , no ring closure was observed under the conditions of the ‘direct amide cyclization’, which indicates the limitations of this method.