Approches to the synthesis of steroidal &-Methylene Lactones
Chagonda, Lameck, Shoriwa
MetadataShow full item record
A brief review of the biological properties and the synthesis of a-methylene-y- and 6-lactones is presented. Estrone 69_ was converted to estrololactone-methyl ether 71 which was a~foimylated with ethyl formate, diethylaminated, hydrogenated and underwent $-elimination to the 3-methoxy-l6-methylene-17-oxo-l7a-oxa- D-homo-estra-1,3,5(10)-triene 75 which was reduced to the 16-methyl lactone 77 and thiolated to the thiol-adduct 76. The estrololactone 70a was a-formylated, acetylated, diethylaminated, hydrogenated and underwent |3-elimination to the 3-acetoxy-l6-methylene-l7-oxo-l7a-oxa- D-homo-estra-1,3,5(10)-triene ^9 which was hydrolysed to the 3-hydroxy- 16-methylene lactone 78. The reaction of the estrololactone methyl ether 71 with triphenylphosphonium ethyl bromide gave 3-methoxy-l6-isopropylidene- -17-oxo-l7a-oxa-D-homo-estra-1,3,5(10)-triene 100. Cholesterol 109 was first converted to 3-oxo-4-oxa-5a_cholestane 119 and eventually to 2-methylene-4-oxa-3-oxo-5a-cholestane 122 through similar procedures. The lactone 122 was thiolated to the ethyl and phenyl thiol-adducts 123 and 124 respectively. Baeyer-Villiger oxidation of the steroidal arylidene 17-ketones 128 (a, b and c) and alkylidene 17-ketones 129 (a and b) with trifluoro- peracetic acid gave isomeric 16a- and g-epoxides 130 and 152 respectively. Similar oxidation of the p-methoxybenzylidene ketone 128d gave the epoxy- enol lactone 145 and (3-diketones 142 and 148. Baeyer-Villiger oxidation of the arylidene ketones 128 (a, b, c and d) with 40-45% peracetic acid gave a-acetoxyketo-acids 153. The a-acetoxyketo-acid 153d was esterified with diazomethane to the methyl ester 154 d. Reduction of the benzylidene ketones 128 (a and d) gave reduced mixtures which were oxidised with Jones' reagent to the ketones 163. The benzylidene ketone 163a was oxidised with45% peracetic acid to the lactone 166a, which was brominated and dehydrobrominated to the benzylidene lactone 170 which was hydrolysed to 3(3-hydroxy-l6-benzylidene-17- -oxo-17a-oxa-D-homo-5a-androstane 171. The reduced ketone 165d was oxidised with UO-US% peracetic acid to the lactone 166d which was not treated further. The oxidation of the 16-isopropyl ketone 161 with peracetic acid was unsuccessful. Reaction of 3-hydroxybenzylidene ketone 127awith thiophenol gave the thiol-adduct 174 but trifluoroperacetic acid oxidation of it did not give the expected benzylidene lactone 176. The 38-hydroxy-5a-androstan-l7-one 126a was o-silylated with trimethylchlorosilane to the silyl enol ether 178 but condensation with butyraldehyde in the presence of titanium chloride did not give the desired 8“hydroxylactone 181. The lithium enolate 18? of the 3^-hydroxy-l7-oxo-l7a-oxa-D-homo-5a_androstone 188 with butyraldehyde and zinc chloride did not give the3(3-hydroxylactone 190. The lithium enolate of the 3-methoxy-l7-oxo-l7a-oxa-D-homo-estra- -1,3,5(10)-triene 71_ was however deuterated to the lactone 191. The cytotoxic activity (LD^Q) was determined by a tissue culture technique on HeLa S3 cells and preliminary results show considerable activity for the 3-acetoxy-l6-methylene lactone 99^ (0.14 pg/ml), the 3-methoxy-l6-methylene lactone 75 and its thiol-adduct 76 (0.24 jjg/ml) and the 3-hydroxy-16-methylene-lactone 78 (0.50 jjg/ml); the 3-acetoxy- -16-acyloxy-methylene lactone 94, the 3-methoxy-l6-methyl lactone 77, the 3-methoxy-l6-isopropylidene lactone 100 and the benzylidene lactones 170 and 171 are inactive (> 10.00 pg/ml).