Synthesis of cyclo(amide-ester)s by ring-expansion ofN-(acyl)-lactams

Abstract

The synthesis of cyclo(amide-ester)s based on α-amino acids and e-aminocaproic acid in combination with β-hydroxy acids was achieved by ring-expansion reactions. Three different approaches were followed: (i) According to Shemyakin, e-caprolactam or diketopiperazines were acylated with differently substituted β-benzyloxyacyl chlorides. Removal of the protecting group by hydrogenolysis over a palladium catalyst results in hydroxyacyl incorporation into the e-caprolactam or the diketopiperazine ring and formation of the eleven-membered cyclo(amide-ester)s 1 a–c or the fourteen-membered cyclo(diamide-diester)s 2 a–c. (ii) Alternatively, the cyclo(amide-ester)s 1 a–c were obtained via intramolecular nucleophilic substitution of the halogen atom in N-(3-halogenoacyl)-e-caprolactam by the oxygen atom of the lactam unit followed by reaction with water. (iii) Finally, results on the intramolecular Michael addition in N-(acryloyl)- and N-(crotonyl)-e-caprolactams are presented. The Michael addition was induced by the nucleophilic addition of the lactam oxygen atom to the CC double bond followed by a sequence of reactions, which leads to the cyclo(amide-ester)s 1 a, b.