A triply convergent total synthesis of a symchiral pyrrolidine-fused prostacyclin analog

Article abstract of DOI:10.1021/jo00114a016

The synthesis of symchiral 1-azatricyclo[6.3.0.0]undeca-5-enyl prostaglandin I₂ analog 34 is reported. Construction of the tricyclic skeleton of 34 was accomplished in two steps by employing a triply convergent approach which utilized vinyl sulfone technology. Introduction of the heterocyclic subunit of 34 was achieved by an S(N)2'-thio-Claisen rearrangement which efficiently coupled a thiolactam moiety to a suitable allylic vinyl sulfone. Annulation of bicyclic vinyl sulfones 20, 23, and 29 was accomplished via a conjugate addition of lithium acetylide 11 to the vinyl sulfone moieties, followed by an intramolecular S(N)2 displacement of a suitable nucleofuge. Competition between intramolecular carbon alkylation and β-elimination of stabilized nitrogen anions from intermediate α-sulfonyl anions 20-i, 23-i, 29-i was discussed. Refunctionalization of the resulting tricyclic skeleton was accomplished by employing standard literature protocols. Compound 34 was found to be essentially inactive as an inhibitor of collagen-induced platelet aggregation, having an IC₅₀ of >10 μM.