Synthesis of Chonemorphol A, Chonemorphol C, and Ecdysantheroside A Aglycone From Simple Steroids

High-oxidation-state steroids, often with appealing medicinal value, are challenging synthetic targets. Introducing the desired oxidation states is often difficult. Herein, we report a 1,3-dipolar cycloaddition reaction strategy to enable the quick construction of complex steroids bearing adjacent oxidized angular methyl and tertiary hydroxy groups through difunctionalization of a tetrasubstituted olefin. To maximize the effectiveness of this synthetic strategy, a five-step synthetic sequence was devised to prepare the desired intermediate from commercially available steroids. The new chemistry not only promoted stereospecific relocation of the original angular methyl group in steroids from C13 to C17 but also enabled the oxidation of this methyl group and the creation of a tetrasubstituted double bond between C13 and C14. Using an uncommon alkoxynitrile oxide as the 1,3-dipole, difunctionalization of the tetrasubstituted double bond was carried out smoothly by a 1,3-dipolar cycloaddition reaction, with installation of two adjacent tetrasubstituted stereogenic centers at C13 and C14 in one step. Based on the above synthetic design, we have synthesized chonemorphol C from epiandrosterone in 8 steps, as well as ecdysantheroside A aglycone and chonemorphol A from 3β-acetoxyandrost-5-en-17-one in 10 steps and 14 steps, respectively.