Total synthesis of (+)-3-oxacarbacyclin - 1. Retrosynthesis and asymmetric olefination through Horner-Wadsworth-Emmons, Peterson and Martin reactions

The asymmetric Horner-Wadsworth-Emmons (HWE) reaction of the prochiral ketones 8a/b with the phosphonoacetates 10a, ent-10a, 10b and rac-16, which contain 8-phenylmenthol, 8-phenylnormenthol and trans-2-(triphenylsilyl)-cyclohexanol, respectively, as chiral auxiliaries, were studied, The HWE reaction of 8a with the phosphonoenolates Li-10a/b at low temperatures gave the esters 7a/b and 11a/b in high yields with diastereoselectivities up to 97:3. The (E)-configured esters 7a/b serve as starting material for the total synthesis of (+)-3-oxacarbacyclin. Similarly, the reaction of 8b with ent-Li-10a gave the esters ent-7b and ent-11b. in a ratio of 95:5 in 82% yield, The olefination of 8b with rac-16 afforded a mixture of the esters rac-17 and rac-18, of yet unassigned configuration, in a ratio of 70:30. The HWE reactions of 8a/b with Li-10a, ent-Li-10a and rac-Li-10b show linear temperature-diastereoselectivity relationships. The stereochemical course of the HWE reactions can be understood in terms of a selective addition of the chiral (E)-configured phosphonoenolate from its least hindered side to the ketone 8 at the convex side. The asymmetric Peterson reaction of 8b with the silyl enolate Li-20 gave the esters ent-7b and ent-11b in a ratio of 89:11. The diastereomerically pure beta-hydroxy esters 22, rac-25 and 27, which contain 8-phenylmenthol, trans-2-(triphenylsilyl)cyclohexanol and 3-{[(3,5-dimethylphenyl) phenylsulfonyl]amino}isoborneol, respectively, as chiral auxiliaries, were prepared by a highly selective addition of the enolates Li-21, rac-Li-24 and Li-26 to the ketone 8b. The asymmetric Martin dehydration of 22, rac-25 and 27 with the sulfurane 23 proceeds with stereoselectivities ranging from 82:18 to 99:1, Interestingly, the HWE, Peterson and Martin reactions involving 8-phenylmenthol as the chiral auxiliary all proceed with the same sense of asymmetric induction.