Total synthesis of a novel antiulcer agent via a modification of the intramolecular Wadsworth-Emmons-Wittig reaction

• Published in: Journal of the American Chemical Society Vol. 107; no. 26; pp. 7967 - 7974
• Main Authors: Aristoff, Paul A, Johnson, Paul D, Harrison, Allen W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.12.1985; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja00312a028

A convergent synthesis of the novel, potent antiulcer agent U-68,215 (3), a benzindene prostacyclin analogue, is described. U-68,215 is prepared via a cyclopentane annulation sequence in optically pure form in 14 steps and 12% yield from 5-methoxy-2-tetralone (8a). The key step in the synthesis involves the coupling of the phosphonate reagent 6 (the chirality of which was derived from a Sharpless resolution of an allylic alcohol precursor) with the enol lactone 7a (prepared in 50% overall yield from 8a) to produce enone 5 via a modified intramolecular Wadworth-Emmons-Wittig reaction. Hydrogenation of 5 followed by an unusual one-pot equilibrium-reduction sequence generates the four centers around the cyclopentane ring with complete stereocontrol.