Enantioselective Total Synthesis of the Key Synthetic Precursor of Third-Generation Oral Contraceptive Etonogestrel

A concise enantioselective synthesis of a key synthetic precursor of the third-generation oral contraceptive etonogestrel (ENG) is described. The key steps were highlighted by improvements for the direct synthesis of the 9,11-olefin 3d from the known and readily available chiral precursor 20, stereoselective hydroboration-oxidation sequence which afforded 11α-and 11β-diastereomeric alcohols 21a-b, and subsequent introduction of exocyclic double bond at the C-11 position of the steroid core by acid-catalyzed Peterson olefination of 11β-TMS tertiary carbinol 23. The synthesis was completed by classical Birch reduction of exocyclic olefin 24 and subsequent catalytic Oppenauer oxidation of thus formed deprotected 1,4-dihydro derivative 25. The chemistry was scaled up to produce multigram quantities of ENG precursor 4 of high chemical and optical purity suitable for further transformation en route to ENG 2. The scale-up process provided a detailed description of the preparation of multi hundredgram scale quantities of intermediates used in the synthesis of 4. Moreover, the presented methodology represents to the best of our knowledge the shortest synthetic approach to 4.