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 ch iral intermediate (-)-8 is described. The critical reaction is the inv ersion of C-5 in 11a and 11b by an intramolecular cyclization reaction induced by nucleophilic reagents as shown in structure 13a. The key i ntermediate 22 was prepared in 26.5 % yield in five steps. Diastereose lectivity is high in all but one of the steps, the Reformatsky reactio n, which leads to equal amounts of 11a and 11b. The design of 6 is bas ed on the dioxabicycloheptane nucleus characteristic of TXA2 (1), whic h has been stabilized by fluorination. To this nucleus the two side ch ains are attached in cis orientation, and the omega-chain is modified as reported for the receptor antagonist (-)-5, which in turn is an ana logue 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 nanomola r affinity. These findings lend support to the view of a single TXA2/P GH2 receptor.