Synthetic Approach to the AB Ring System of Ouabain

• Published in: Journal of organic chemistry Vol. 68; no. 7; pp. 2572 - 2582
• Main Authors: Jung, Michael E, Piizzi, Grazia
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 04.04.2003; Amer Chemical Soc
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Cardiotonic Agents - chemical synthesis; Catalysis; Chemistry; Chemistry, Organic; Cyclization; Exact sciences and technology; Indicators and Reagents; Molecular Structure; Organic chemistry; Ouabain - chemical synthesis; Oxidation-Reduction; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; REDUCTION; CONVERSION; MODEL; Ester; Epoxide; Ouabain; Bicyclic compound; Alcohol; Robinson annelation; Polyol; Chemical synthesis; Enone; Ring cleavage
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo020454+

Several novel hydroxylated cis-decalin derivatives, potential intermediates for the synthesis of the AB ring system of the important cardiotonic steroid ouabain, have been synthesized from commercially available starting materials. The first step in the preparation of these highly functionalized intermediates is a Robinson annulation of the β-keto ester 6 and the 4-silyl-3-buten-2-one 5 to furnish the octalone 4 with good diastereoselectivity in fair yield (due to competition with a novel silicon-to-carbon phenyl migration). Reduction of the epoxy alcohol 3 (derived from 4 in two high-yielding steps) with LiAlH4 gave a mixture of the desired triol 11 along with the product of an unusual reductive opening at the tertiary carbon, namely the triol 12. A plausible mechanism for this unusual reduction is presented as are possible methods for avoiding it. In particular, reduction of the corrresponding epoxy ketone 15 with aluminum amalgam proceeded in good yield to give the hydroxy ketone 16. Also reduction of the epoxide ester having the inverted stereochemistry at C3 afforded the desired tertiary alcohol 33 in good yield. Another approach using the β,γ-unsaturated ketal 38 permitted the formation of the tertiary alcohol 40. Fleming oxidation of the related, very functionalized silane 39 afforded the desired 1β-alcohol 41 in fair yield. Finally a novel rearrangement was observed when the epoxy alcohol 24 was treated with DIBAL to effect loss of the angular hydroxymethyl group to produce the tetrasubstitued alkene 29 in high yield.