Synthesis of 20-alkyl-8-thiathevinols, opiate agonists derived from 8-thiathevinone, the cycloadduct of thebaine and 2-oxopropanethial

Abstract

The cycloadduct 7 has been prepared from thebaine 1 and the transient thioaldehyde EtO₂C–CH₂S formed in situ from the Bunte salt EtO₂C–CH₂SSO₃Na. The thermal isomerisation of the adduct 7 to give the regioisomer 8 has been reinvestigated. Prolonged heating gave an equilibrium mixture of the adduct 8 and the major, rearrangement product 9. Base-catalysed epimerisation of the adduct 7 gave the 7β-isomer 11, believed to be a transient co-product in the thermal isomerisation of the original adduct 7. Similarly, thebaine 1 and 2-oxopropanethial 18, generated from either the Bunte salt McCOCH₂SSO₃Na or the thiotosylate 16 and triethylamine, gave the cycloadduct 8-thiathevinone 3, the sulphur analogue of thevinone 2, the known cycloadduct of thebaine and but-3-en-2-one. 8-Thiathevinone 3 isomerised thermally to give the corresponding, 7-thia regioisomer.

8-Thiathevinone 3 has been converted with Grignard reagents into a series of (20R)-and (20S)20-alkyl-8-thiathevinols 5. The reactions were not stereoselective, unlike those of thevinone 2, and the tertiary alcohols 5 were accompanied by the secondary alcohols 19 and 20, products of ‘Grignard reduction’. The analgesic potency, in guinea-pig ileum preparations, of the alkylthiathevinols 5 depended upon the C-20 configuration and the alkyl chain length. The (20R)-epimers were the more potent, the maximum potency being observed for the (20R)-20-pentyl derivative 5h, which was equipotant with N-normorphine. Generally, the thiathevinols were much less potent than the corresponding thevinols. 8-Thiathevinone 3 also reacted with alkyllithium reagents to give (20R)-alkylthiathevinols, but the reactions were accompanied by a base-catalysed rearrangement to give the ketoacetal 27.