Synthesis of 6-vinyl and 5-vinylproline analogues of ascomycin

6-Vinyl (12) and (5R)- and (5S)-vinylproline (18, 19) analogues of ascomycin are synthesised starting from the known suitably protected (6S)-methoxy-9-hydroxy derivative (4) of ascomycin. The strategy involves hydrolytic cleavage of the Cε–N bond of the pipecolic acid moiety, extension of the amino acid side chain by two or one carbon units, functional group manipulations, Pd-catalysed reinstallation of the Cε–N or Cδ–N bonds, followed by deprotection and oxidation.