P. Kraft, K. Popaj
Dec 1, 2004
Citations
0
Influential Citations
10
Citations
Journal
European Journal of Organic Chemistry
Abstract
5β,10-Dimethyl-des-A-18-nor-androstan-13β-ol (Limdrostanol, 11) was suspected to be the underlying parent steroid responsible for the interesting urinous-animalic, woody olfactory properties of the commercial odorant Timberol® (6−9), and the captives Norlimbanol® (7) and Limbanol® (10), and so could constitute a potential human pheromone. We report the first synthesis of 11, starting with treatment of the bis-Grignard reagent of 1,4-dibromobutane (15) with γ-butyrolactone (16), Appel−Lee bromination of the resulting diol 17 with elimination of the tertiary hydroxy group, and transformation of the obtained bromo alkene 18 into the corresponding triphenylphosphonium salt 13. This was subjected to a Schlosser−Wittig reaction with the γ,δ-unsaturated aldehyde 14, prepared in turn by Grignard treatment of ethyl methacrylate (19) and subsequent Saucy−Marbet reaction of the resulting dimethyl carbinol 20 with ethyl vinyl ether (21). Cascade cyclization of the Schlosser−Wittig product 23 with methanesulfonic acid in dichloromethane at 0 °C afforded the tricyclic alkene 24, which was transformed into the target structure 11 by epoxidation with 3-chloroperbenzoic acid and subsequent reduction with lithium triethylborohydride. In addition to 11, the corresponding 14α-isomer 26 was obtained, and the olfactory properties of both are discussed. The high odor thresholds of 11 and 26, as well as the distinct differences in odor with 6−10, make it very unlikely that these des-A-18-nor-androstanols are the underlying odorous principle of 6−10, or that they function as human pheromones. An alternative synthesis of 11 by cyclization of 23 at 0 °C with 0.8 equivalents of methanesulfonic acid in formic acid as terminating nucleophile is also discussed, but gave only unsatisfactory yields. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)