A general method for removal of a 4-methyl group from triterpenoids. Synthesis of 4β-demethylglycyrrhetinic acid

Abstract

Using 4,4-dimethyl-5α-cholestan-3-one (1) as a model compound, a short high-yielding sequence has been developed for removing a 4-methyl group from triterpenoids. The method makes use of the ‘abnormal’ Beckmann reaction which 3-hydroxyimino-4,4-dimethylsteroids undergo to yield 3,4-seco-nitriles. Epoxidation of the 4-methylene group, followed by treatment of the 3,4-seco-epoxy-nitrile with boron trifluoride in refluxing toluene affords the 4β-demethyl-3-ketone in an overall yield of 40–50%. The general nature of the method has been demonstrated in the conversion of dihydrolanosterol into 4α,14α-dimethyl-5α-cholest-8-en-3-one (17) and 4α,14α-dimethyl-5α-cholestane-3,11-dione (3), and in the synthesis of 3β-hydroxy-11-oxo-24-nor-18β-olean-12-en-30-oic acid (4β-demethylglycyrrhetinic acid)(27) and 3,11-dioxo-24-nor-18β-olean-12-en-30,22β-olactone (31).