Synthesis of Levonorgestrel: A New Strategy to Construct the Key 13β-Ethyl Steroid Precursor

Levonorgestrel, a representative 13β-ethyl progestin, poses a synthetic challenge due to the construction of its 13β-ethyl precursor. Herein, we report the chemical synthesis of the common 13β-ethyl precursor, (13S,14S)-13-ethyl-3-methoxy-6,7,11,12,13,14,15,16-octahydro-17H-cyclopenta[a]phenanthren-17-one, in seven or eight steps from inexpensive 3-bromoanisole or 3-methoxybenzaldehyde. Key transformations include a Hajos–Wiechert-type reaction to introduce the chiral ethyl group, a Friedel–Crafts cyclization to form the B ring, and regio- and stereoselective hydrogenation. Starting from this 13β-ethyl precursor, levonorgestrel was subsequently obtained in four steps, including an ethylenediamine-mediated Birch reduction.