Synthesis of macrolide prostaglandin analogs

Abstract

Prostaglandin analogs of the E- and F2 alpha-functional type, which are constrained to conformations in which the side-chains are close in space and specifically aligned in the terminal portions by covalent bonding, have been synthesized. These analogs are 1, (omega-1)-macrolides. The syntheses proceeded from aldehyde intermediate I via the Emmon's condensation with dimethyl n-(dimethyl-t-butylsilyloxy)2-oxoalkylphosphonate anions (II a or b). The macrolide closures were performed using 2, 2'-dipyridyl disulfide. For the synthesis of 9-ketoprostaglandin macrolides, a free 9-hydroxy is available for oxidation after macrolide closure, so long as the 9-position is protected as the acetate rather than benzoate. Chiroptical data revealed that the conformations of the macrolide prostaglandins are unchanged (relative to the natural unconstrained prostaglandins) in the vicinity of the five-membered ring and the allyl alcohol unit by the formation of the macrolide linkage.