Synthesis of stable prostacyclin analogues from 2,3-disubstituted bicyclo[3.2.0]heptan-6-ones

Abstract

A short synthesis of 9-deoxy-6,9α-methanoepoxy-Δ⁵-prostaglandin F₁(14) from bicyclo[3.2.0]heptan-6-one (3) is described. The ketone (3) can be converted by known methods into the vinyl ether (8). In the presence of mercury(II) acetate at 100 °C, the 5-hydroxyalk-1-enyl methyl ether (8) undergoes a novel intramolecular vinyl transetherification reaction to give the Δ²-dihydropyran (9). Hydroboration–oxidation of the dihydropyran (9) furnished selectively the tetrahydropyran-3-ol (10). Subsequent elaboration via oxidation, Wittig olefination, and deprotection afforded 9-deoxy-6,9α-methanoepoxy-Δ⁵-prostaglandin F₁(14). The protected bicyclo[3.2.0] heptan-6-one (16) underwent a ring expansion with diazomethane, producing a 1 : 1 mixture of the two homologated ketones (17) and (18). Wittig olefination and deprotection of these ketones provided 15-epi-9-deoxy-6,9α-methano-Δ⁵-prostaglandin F₁(19) and its structural isomer (20). The two bicyclo[3.2.0]heptan-6-ones (3) and (4) also led directly to a series of 9-deoxy-6,9α-cycloprostaglandins F₁via Wittig reactions.