Synthesis of New, Sulphur-Containing Morphinan Analgesics

A new sulphur-containing cycloadduct, 8-thiathevinone, was formed by Diels-Alder reaction of the transient thioaldehyde 2-oxopropanethial with thebaine. The thioaldehyde was best prepared and trapped in situ, from S-(2-oxopropyl) toluene-p-thiosulphonate and triethylamine. Two homologous series of epimeric tertiary alcohols, both series having the 7alpha-configuration, were prepared by the reaction of 8-thiathevinone with Grignard reagents. These alcohols were generally less potent analgesics than those derived from thevinone (the cycloadduct of thebaine and but-1-en-2-one). However, alcohols from one series, believed to have the (20R-configuration, were generally more potent than their epimers. The reaction of 8-thiathevinone with butyl-lithium gave the corresponding diastereomeric tertiary alcohols; while that with propyl-lithium gave an unexpected rearrangement product. The thermal isomerisation of the known cycloadduct of thebaine and ethyl thioxoacetate was reinvestigated. Isomerisation of the 8-thia cycloadduct to give the 7-thia regioisomer was observed, as before, in toluene at 11