Total Synthesis and Olfactory Evaluation of 5β,10‐Dimethyl‐<i>des</i>‐A‐18‐<i>nor</i>‐androstan‐13β‐ol: A Potential Human Pheromone?

Abstract

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 &amp; Co. KGaA, 69451 Weinheim, Germany, 2004)