Abstract
Tentoxin is a naturally occurring phytotoxic cyclic tetrapeptide excreted by fungi of the Alternaria alternata family. The four total syntheses of tentoxin published to date give poor total yields, mainly owing to two difficulties, the introduction of the dehydro amino acid and more especially the cyclization step. Here we describe a method that stereospecifically introduces Zโdehydrophenylalanine (ฮ^Z^Phe) by a modified Erlenmeyer aldolization reaction. The linear tetrapeptide, BocโR^1^AlaโLeuโR^2^ฮ^Z^PheโGlyโOMe (R^1^, R^2^: CH~3~, ^14^CH~3~), the precursor of tentoxin, was obtained in a 72% yield from BocโLeuโGlyโOH. This linear tetrapeptide, labelled with carbonโ14, was used for a comparative study of four cyclization reagents DPPA, DCCโPfpOH, HBTU and HATU. This last was the most effective and gave tentoxin in a 81% cyclization yield. The activated ester formed with this reagent displayed an enhanced capacity for cyclization, permitting cyclization in concentrated medium (10 mM). This new synthetic route gave tentoxin in a 60% yield from BocโLeuโGlyโOH and offers a means of achieving the synthesis of hitherto elusive analogues. Copyright ยฉ 2002 European Peptide Society and John Wiley & Sons, Ltd.