Synthesis of macrolide prostaglandin analogs

Prostaglandin analogs of the E- and F2α-functional type, which are constrined 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, (ω-1)-macrolides. The syntheses proceed from aldehyde intermediate I via the Emmon's condensation with dimethyl n-(dimethyl-t-butyl-silyloxy) 2-oxoalkylphosphonate anions (IIa 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 uncosntrained prostaglandins) in the vicinity of the five-membered ring and the allyl alcohol unit by the formation of the macrolide linkage.