Structural Features in the Seven-Membered vs. Fourteen-Membered Ring Cyclization of Hydroxyamido Ketals Derived from β-Amino Alcohols

Abstract

Hydroxyamido ketals 1 and 3−12, prepared from β-amino alcohols, are obtained either as a single form with a trans (1 and 3−8) or cis (9) conformation in the R = H series or as two cis and trans rotamers in the R ≠ H series (10−12). − The cyclization of these compounds was studied under acidic conditions (PTSA) and over a well defined range of concentrations (c = 0.1−0.2 M). While cis amide 9 and mixtures of cis and trans rotamers 10−12 resulted practically exclusively in the formation of seven-membered ring lactams 22−25, trans compounds 1 and 3−8 afforded fourteen-membered ring bislactams 2, 13−18, the formation of which involves a dimerization. Macrocycles were obtained as three diastereomers in the chiral series 2, 13−16 and as two isomers in the achiral series 17 and 18. Nineteen macrocyclic bislactams have thus been synthesized.