Key Intermediates for introducing a bulky bicyclo[3.3.0]heptane skeleton in the w-side chain to reduce the enzyme inactivation of prostaglandins

In the development of new prostaglandin analogues, the most beneficial modifications for obtaining prostaglandin (PG) analogs with different biological activities have been done in the w-side chain. This chain is introduced, in the well known total stereo-controlled Corey convergent synthesis of PGs, by using a key β-ketophosphonate in an E-HEW-stereoselective olefination with an aldehyde linked to a key cyclopentane intermediate. The concept of PG w-side chain is design in the β-ketophosphonate intermediate. In vivo, the PGs are inactivated by enzyme oxidation of the 15-α-OH group to 15-keto group. By using 15-, 16- substituents or 16-aryloxy substituents, the inactivation was diminished. In this direction, we intend to diminish inactivation by introducing bulky bicyclo[3.3.0]octane or bicyclo[3.3.0]oct-6-ene substituents linked to the C-15 carbon atom. For this goal we synthesize the key β-ketophosphonate intermediates starting from bicyclo[3.3.0]oct(a)ene acids by a two or three step sequence. Two mono-acid β-ketophosphonates, one ester β-ketophosphonate and a bis-β-ketophosphonate compounds were obtained. The ester β-ketophosphonate was used to build the w-side chain of the concepted PG analog. The bis-β-ketophosphonate will create a pseudo PG compound with two PG fragments linked to a bicyclo[3.3.0]octane fragment. The compounds were characterized by elemental analysis, IR and high resolution ¹H- and ¹³C-NMR spectroscopy.