16617-07-5Relevant articles and documents
The application of a specific morphinan template to the synthesis of galanthamine
Yamamoto, Naoshi,Okada, Takahiro,Harada, Yukimasa,Kutsumura, Noriki,Imaide, Satomi,Saitoh, Tsuyoshi,Fujii, Hideaki,Nagase, Hiroshi
, p. 5751 - 5758 (2017)
(–)-Galanthamine (4) was synthesized from naltrexone (1) in 18 steps with 3% total yield by overcoming many specific side reactions derived from the 4,5-epoxymorphinan skeleton. The key features are cleavage of the D-ring by the Hofmann elimination and the following the one-pot C9–C10 and C9–14 bond cleavages concomitant with the C9 removal by the OsO4–NaIO4 combination reaction. Then, the treatment with zinc powder in acetic acid led to not only removal of the 2,2,2-trichloroethoxycarbonyl (Troc) group, but also reductive amination of the resulting imine to give the desired 7-membered ring.
Transformation of naltrexone into mesembrane and investigation of the binding properties of its intermediate derivatives to opioid receptors
Konoura, Kazuya,Fujii, Hideaki,Imaide, Satomi,Gouda, Hiroaki,Hirayama, Shigeto,Hirono, Shuichi,Nagase, Hiroshi
, p. 439 - 448 (2015)
We transformed naltrexone (5) with the morphinan skeleton into mesembrane (4) belonging to the Sceletium alkaloids via key intermediate 6, characterized by a cis-fused hydroindole skeleton with a suspended phenyl ring fixed by an epoxy bridge. We then investigated the binding affinities of 4 and the key intermediate 6 derivatives to the opioid receptors. Among the tested compounds, 15′, with a cis-fused hydroindole core, bound to the three opioid receptor types with strong to moderate affinities. The observed differences of binding affinities among the tested compounds were reasonably explained by the conformational analyses of the compounds. The structure-activity relationship (SAR) of the tested compounds like 15′ with the hydroindole structure was completely different from the reported SAR of morphinan derivatives with the hydroisoquinoline skeleton. Compound 15′ with a structure that differs from the morphinans represents a useful fundamental skeleton with a novel chemotype that may contribute to the development of new opioid ligands.
Rapid access to morphinones: removal of 4,5-ether bridge with Pd-catalyzed triflate reduction
Hupp, Christopher D.,Neumeyer, John L.
, p. 2359 - 2361 (2010)
A new synthetic method for the removal of the 4,5-bridged ether moiety of several opioids has been developed. This process offers a faster, simpler synthetic route to obtain the morphinone scaffold in high yields without the need for protection of the ketone moiety.
Syntheses and receptor-binding studies of derivatives of the opioid antagonist naltrexone
Uwai, Koji,Uchiyama, Hiroko,Sakurada, Shinobu,Kabuto, Chizuko,Takeshita, Mitsuhiro
, p. 417 - 421 (2004)
Naltrexone (1), which is a member of the group of competitive opioid antagonists, shows a strong affinity for μ-receptors and its derivatives have been notable as novel receptor anatgonists. In this paper, the preparation of several naltrexone derivatives is described; these were used to investigate the role of the oxygenated functional groups in facilitating binding to a series of the opioid receptors. The derivatives showed affinity for opioid μ-receptors which was similar to that of naltrexone, but these compounds, which had masked hydroxyl functional groups, displayed a moderate activity. These results suggest that every oxygenated functional group in naltrexone (1) plays an important role in binding to the opioid receptor.
Asymmetric synthesis of (-)-naltrexone
Dongbang, Sun,Pedersen, Blaine,Ellman, Jonathan A.
, p. 535 - 541 (2019/01/10)
(-)-Naltrexone, an opioid antagonist used extensively for the management of drug abuse, is derived from naturally occurring opioids. Herein, we report the first asymmetric synthesis of (-)-naltrexone that does not proceed through thebaine. The synthesis starts with simple, achiral precursors with catalytic enantioselective Sharpless dihydroxylation employed to introduce the stereogenic centers. A Rh(i)-catalyzed C-H alkenylation and torquoselective electrocyclization cascade provides the hexahydro isoquinoline bicyclic framework that serves as the precursor to the morphinan core. The acidic conditions used for Grewe cyclization not only provide the morphinan framework, but also cause a hydride shift resulting in the introduction of the C-6 oxo functionality present in (-)-naltrexone. The C-14 hydroxyl group is installed by an efficient two-step sequence of Pd-mediated ketone to enone dehydrogenation followed by C-H allylic oxidation using Cu(ii) and O2, a method that has not previously been reported either for the synthesis or semi-synthesis of opioids. The longest linear sequence is 17 steps, and because the stereogenic centers in the product rely on Sharpless asymmetric dihydroxylation, the route could be used to access either enantiomer of the natural product, which have disparate biological activities. The route also may be applicable to the preparation of opioid derivatives that could not be easily prepared from the more fully elaborated and densely functionalized opioid natural products that have traditionally served as the starting inputs.
