Total Synthesis of (+)‐3‐Oxacarbacyclin 1. Retrosynthesis and Asymmetric Olefination through Horner–Wadsworth–Emmons, Peterson and Martin Reactions

Abstract

Abstract 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 β‐hydroxy esters 22 , rac ‐ 25 and 27 , which contain 8‐phenyl‐menthol, 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.