Synthesis of potentially cytotoxic steroidal lactones

A review of the biological properties and the synthesis of α-methylene-γ- and -δ-lactones is presented. Cholesterol (201) was converted into 4-oxa-3-oxo-5α-cholestane (203) and the α-methylene moiety was introduced by α-hydroxymethylenation, diethylamination and elimination of diethylamine after hydrogenation to give 2-methylene-4-oxa-3-oxo-5α-cholestane (225). The same sequence of reactions was employed to prepare 17β-hydroxy-2-methylene-4-oxa-3-oxo-5α-androstane (238) and its 17-yl acetate (239) from androst-5-en-3β-ol-17-one (228). Reactions of the above α-methylene lactones with L-cysteine gave the cysteine–lactone adducts in a Michael-type addition. Reaction of the lactone (203) with phenyl magnesium bromide gave 4-oxa-3-phenyl-5α-cholest-2-ene (278). On epoxidation this compound gave an unusual rearranged product. 3-hydroxy-4-oxa-3-phenyl-5α-cholestan-2-one (281) which on treatment with ethanol/hydrochloric acid formed 3-ethoxy-4-oxa-3-phenyl-5α-cholestan-2-one (282). Oxidation of the rearranged product (281) with lead tetra acetate gave 5-benzoyloxy-2,3-seco-5α-cholestan-2-oic acid (299) which on esterification gave the methyl ester (300). The oxidised product (299). after hydrolysis. was cyclised to give A-nor-3-oxa-5α-cholestan-2-one (274). [Continues.]