SYNTHESIS OF A THROMBOXANE-A(2) RECEPTOR ANTAGONIST POSSESSING THE DIOXABICYCLOHEPTANE NUCLEUS OF TXA(2)

The synthesis of the TXA2/PGH2 receptor antagonist 6 from the known chiral intermediate (-)-8 is described. The critical reaction is the inversion of C-5 in 11a and 11b by an intramolecular cyclization reaction induced by nucleophilic reagents as shown in structure 13a. The key intermediate 22 was prepared in 26.5 % yield in five steps. Diastereoselectivity is high in all but one of the steps, the Reformatsky reaction, which leads to equal amounts of 11a and 11b. The design of 6 is based on the dioxabicycloheptane nucleus characteristic of TXA2 (1), which has been stabilized by fluorination. To this nucleus the two side chains are attached in cis orientation, and the omega-chain is modified as reported for the receptor antagonist (-)-5, which in turn is an analogue of PGH2 (3). These changes in the side chains have the effect of converting the powerful agonist 2 (DFTXA2) into a receptor antagonist devoid of agonist activity, which binds to the receptor with nanomolar affinity. These findings lend support to the view of a single TXA2/PGH2 receptor.