Epoxymorphinans

Fig. 10 17-nitrogen substituents of 4,5-epoxymorphinan derivatives and their opioid activities... 

Morphine, the naturally occurring enantiomorph, may be described as a 4,5-epoxymorphinan with the full systematic name 7,8-didehydro-4,5-epoxy-17-methyl-(5a,6a)-morphinan-3,6-dioh Some of the structural... 

Morphine has a B/C cis ring fusion, and formal inversion of the C-14 chiral center leads to a series of analgesically active B/C trans-4,5-epoxymor-phinans. Japanese workers013,114) have described a preparation of B/C trans-4,5-epoxymorphinans by the hydroboration of 8-dihydrodesoxycodeine, and the same group has synthesized B/C trans-morphine and B/C trans-codeine... 

Epoxymorphinan oxiranes with and without a 14/3-OH substituent and related structures have been described previously 201 but without biological data. Other 6-substituted 4,5-epoxymorphinans have been reported. 202 Those with a 14-OH group, including many receptor affinity binding agents, are discussed elsewhere in this book (p. 61). 

Another 4,5-epoxymorphinan with a rigid C-ring has been prepared(22t>) and described as 7,14-cyclodihydrocodeinone (137), where the cyclopropane ring is within the C-ring. The hasubanan-6-one hydrochloride (135) was reacted with dimethyl sulfate to give 136, which rearranged in base to 7,14-cyclodihydrocodeinone (137). The photolysis of these compounds has been described/221 No biological data were reported. 

The proposal03 that there could be a lipophilic site on some opioid receptors that received the alkyl portion of the C-7 substituent of 6,14-endo-ethenotetrahydrooripavines and their ethano- analogs and that such a site is reflected in the solid-state conformation of leucine enkephalin/228 has stimulated work on simpler 4,5-epoxymorphinans. 

A group at Miles Laboratories has been particularly active in this regard, having synthesized many 7- and 8-alkyl derivatives of 4,5-epoxymorphinans. They generated 229 a series of 8/3-alkyldihydrocodeinones (143) by the conjugate addition of lithium dialkylcuprates to codeinone (52) according to Scheme 2.19. Three products were isolated, the 8/3-alkyldihydrocodcinone, 143 (54%) ... 

Halomorphides and halocodides were considered in the section on 6-substituted 4,5-epoxymorphinans (p. 39). Much of that chemistry and the references relating to a-halomorphides (6-substituted) applies to the (3-halomorphides (8-halogen substituted). 

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