Total Synthesis of (+/-)-3-Deoxy-7,8-dihydromorphinone

Article abstract of DOI:10.1021/jo00348a022

The total synthesis of (+/-)-3-deoxy-7,8-dihydromorphinone (1), starting from readily available <3,5-bis(benzyloxy)phenyl>acetic acid (4) is described.The amide 6, obtained from acid 4 and m-methoxyphenethylamine was converted by Bischler-Napieralski cyclization to the dihydroisoquinoline hydrochloride 7.Birch reduction of 7 gave the dihydroxydihydroanisole 8, which was acid cyclized in situ and then converted to (+/-)-2,4-bis<(methoxycarbonyl)oxy>-17-(methoxycarbonyl)morphinan-6-one (10).The conversion of 7 to 10 was carried out without isolation of intermediates.Hydrolysis with THF/Et2NH gave the 4-hydroxy compound 14.Reaction of 14 with cupric bromide followed by treatment with NaOH/CHCl3 and hydrolysis gave 4,5-epoxy-2-hydroxymorphinan-6-one (16).The 2-oxygen function was removed by Li/NH3 reduction of the phosphate ester 18 obtained by acylation of the ketal 17 with diethyl chlorophosphate.LAH reduction of the ketal 19 followed by acid hydrolysis gave the title compound (+/-)-3-deoxy-7,8-dihydromorphinone (1) in an overall yield (from 4) of 27percent.