5-Allyl-9-oxobenzomorphans. Part 4. Synthesis of 3-hydroxy-8-oxyisomorphinans, 5-allyl-9α-hydroxy-6,7-benzomorphans, and related tetrahydrofuranobenzomorphans

Abstract

A series of 3-hydroxy-8-oxyisomorphinans (11, 16) has been synthesized from the corresponding 5-allyl-9p-hydroxy-6,7-benzomorphans (7, 12) via a hydroboration, oxidation, mesylation, and cyclization sequence of reactions. Selective reduction of and methylmagnesium iodide addition to 5-allyl-2'-methoxy-2-methyl-9-oxo-6,7-benzomorphan (1) gave the respective 9a-hydroxy-6,7-benzomorphans (17). These were transformed to a number of 2-substituted-5-allyl-2',9~-dihydroxy-6,7-benzomorphans (22) and corresponding methyltetrahydrofurano analogs (24).

Analgesics and narcotic antagonists in the benzomorphan and 8-oxamorphinan series. 5

“…5-Allyl-2-cyclobutylmethyl-2,,9a-dihydroxy-6,7-benzomorphan (2c) was prepared in three steps from 5-allyl-9ahydroxy-2'-methoxy-6,7-benzomorphan and cyclobutanecarboxylic acid chloride in 68% overall yield by the procedure given previously for the preparation of 2b. 1 The product distilled at 165 °C (0.02 mm). Anal.…”

“…In conclusion, for the cyclopropylmethyl substituent on nitrogen, present and previous results can be summarized as follows, (a) Introduction of 14-OH in morphinans and 9-OH in benzomorphans, regardless of the stereochemistry of the hydroxyl group, decreases analgesic activity relative to the parent compounds, while antagonist activity is enhanced in both series with ß orientation of OH. (b) Substitution of 14-H with CH3 in 8-oxamorphinan enhances antagonist and decreases analgesic activity, (c) Formation of the tetrahydrofuran ring adversely affects analgesic and narcotic antagonist potency levels, (d) Formation of the tetrahydropyran ring gives a reverse effect, i.e., the more potent 9/3-hydroxybenzomorphans 1 give less potent oxaisomorphinans 4, whereas the less potent 9a isomers 2 give more potent oxamorphinans 6.…”