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

A concise diastereoselective synthesis of a key intermediate for the third-generation oral contraceptive etonogestrel is described. The initial first-generation synthesis was conducted on a low-gram scale and afforded 11-methylene-18a-homo-5α-estr-3-one-17β-ol ( 12 ) in 15% overall yield. Key to the route redesign was the simplification of the synthesis by (a) direct introduction of the 9,11 double bond by DDQ oxidation of benzyl-protected 18a-homosteroid, (b) significant improvement of the hydroboration–oxidation step in terms of efficiency, reaction yield, and stereoselectivity, (c) development of a noncryogenic Peterson olefination for installation of a C-11 exocyclic double bond, (d) classical one-pot two-step Birch reduction, and (e) catalytic Oppenauer oxidation. This second-generation process development route was scaled up to afford multigram quantities of the etonogestrel (ENG) precursor 4 with high diastereomeric purity in 10 steps, suitable for further transformation en route to etonogestrel 2 . Moreover, the presented methodology represents, to the best of our knowledge, the shortest synthetic approach to the ENG precursor.