Application of the ‘Direct Amide Cyclization’ to Peptides Containing an Anthranilic Acid Residue

✍ Scribed by Irena Philipova; Anthony Linden; Heinz Heimgartner

• Book ID: 102260216
• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: German
• Weight: 408 KB
• Volume: 88
• Category: Article
• ISSN: 0018-019X
• DOI: 10.1002/hlca.200590135

✦ Synopsis

Abstract

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.