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.

An efficient total synthesis of the biologically highly active, stable (+)-10,10-difluorothromboxane A2, possessing the absolute configuration of TXA2, from the chiral synthon (-)-5 is described. The key intermediate, the aldehyde 25, is prepared in 16 steps with a total yield of 8.8%, which compares with 1.95% in 14 steps by our previously reported chemical-enzymatic route. Diastereoselectivity is high in all but one of the steps, the Reformatsky reaction, which leads to 13 and 14. However, both epimers have been converted efficiently to 25. The synthesis of the 9beta,11beta diastereomer 46 is also described. As predicted, the geometrically equivalent isomer showed significant binding to the platelet receptor at K(d) = 240 nM. It is, however, only a weak agonist causing aggregation of washed human platelets at 0.7% of the activity of 2. These data are rationalized in terms of an obligatory hydrogen bond between the 9alpha,11alpha-oxetane oxygen of 2 and its receptor to achieve full biological activity.