(-)-4-Hydroxymorphinanones: their synthesis and analgesic activity

Manmade, A.; Dalzell, Haldean C.; Howes, John F.; Razdan, Raj K.

doi:10.1021/jm00144a013

Cited by 20 publications

(8 citation statements)

References 6 publications

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“…We envisioned that with readily available inputs, an intramolecular C–H activation, alkenylation, electrocyclization, and reduction sequence could provide rapid access to fused bicyclic cores that in just a few additional steps could be taken on to diverse morphinan products. To demonstrate this approach, we reported total syntheses of the enantiomer of the semisynthetic opioid agonist (+)-ketorfanol , and the more complex opioid antagonist (−)-naltrexone, , which is widely used to treat opioid addiction.…”

Section: Asymmetric Synthesis Of (+)-Ketorfanol and (−)-Naltrexonementioning

confidence: 99%

“…We envisioned that with readily available inputs, an intramolecular C−H activation, alkenylation, electrocyclization, and reduction sequence could provide rapid access to fused bicyclic cores that in just a few additional steps could be taken on to diverse morphinan products. To demonstrate this approach, we reported total syntheses of the enantiomer of the semisynthetic opioid agonist (+)-ketorfanol 44,45 and the more complex opioid antagonist (−)-naltrexone, 4,46 which is widely used to treat opioid addiction. Rh(I)-catalyzed C−H activation and alkenylation of imine 42 afforded azatriene 43, which underwent in situ torquoselective 6π electrocyclization to give a single diastereomer of hexahydroisoquinoline 44 as determined by 1 H NMR analysis (Scheme 6).…”

Section: Asymmetric Synthesis Of (+)-Ketorfanolmentioning

confidence: 99%

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Rhodium-Catalyzed C–H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles

2021

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Metrics & MoreArticle Recommendations CONSPECTUS: Nitrogen heterocycles are present in approximately 60% of drugs, with nonplanar heterocycles incorporating stereogenic centers being of considerable interest to the fields of medicinal chemistry, chemical biology, and synthetic methods development. Over the past several years, our laboratory has developed synthetic strategies to access highly functionalized nitrogen heterocycles with multiple stereogenic centers. This approach centers on the efficient preparation of diverse 1,2-dihydropyridines by a Rh-catalyzed C−H bond alkenylation/electrocyclization cascade from readily available α,β-unsaturated imines and alkynes. The often densely substituted 1,2-dihydropyridine products have proven to be extremely versatile intermediates that can be elaborated with high regioselectivity and stereoselectivity, often without purification or even isolation. Protonation or alkylation followed by addition of hydride or carbon nucleophiles affords tetrahydropyridines with divergent regioselectivity and stereoselectivity depending on the reaction conditions. Mechanistic experiments in combination with density functional theory (DFT) calculations provide a rationale for the high level of regiocontrol and stereocontrol that is observed. Further elaboration of the tetrahydropyridines by diastereoselective epoxidation and regioselective ring opening furnishes hydroxysubstituted piperidines. Alternatively, piperidines can be obtained directly from dihydropyridines by catalytic hydrogenation in good yields with high face selectivity.When trimethylsilyl alkynes or N-trimethylsilylmethyl imines are employed as starting inputs, the Rh-catalyzed C−H bond alkenylation/electrocyclization cascade provides silyl-substituted dihydropyridines that enable a host of new and useful transformations to different heterocycle classes. Protonation of these products under acidic conditions triggers the loss of the silyl group and the formation of unstabilized azomethine ylides that would be difficult to access by other means. Depending on the location of the silyl group, [3 + 2] cycloaddition of the azomethine ylides with dipolarophiles provides tropane or indolizidine privileged frameworks, which for intramolecular cycloadditions yield complex polycyclic products with up to five contiguous stereogenic centers. When different types of conditions are employed, loss of the silyl group can result in either rearrangement to cyclopropyl-fused pyrrolidines or to aminocyclopentadienes. Mechanistic experiments supported by DFT calculations provide reaction pathways for these unusual rearrangements.The transformations described in this Account are amenable to natural product synthesis and drug discovery applications because of the biological relevance of the structural motifs that are prepared, short reaction sequences that rely on readily available starting inputs, high regiocontrol and stereocontrol, and excellent functional group compatibility. For example, the methods have been applied to efficient asymmetric s...

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Section: Asymmetric Synthesis Of (+)-Ketorfanol and (−)-Naltrexonementioning

confidence: 99%

Section: Asymmetric Synthesis Of (+)-Ketorfanolmentioning

confidence: 99%

Rhodium-Catalyzed C–H Alkenylation/Electrocyclization Cascade Provides Dihydropyridines That Serve as Versatile Intermediates to Diverse Nitrogen Heterocycles

2021

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“…Isolated from the opium poppy latex, morphine ( 1 ) and its congeners are among the oldest and most extensively studied alkaloid natural products known to date (Figure 1). [1] Given their potent neurological and immunological activity, morphine alkaloids and the unnatural semisynthetic opioids, such as ketorfanol, [2a] oxycodone, [2b] and naltrexone, [2c] have found various important therapeutic applications, including acting as pain killers or treating opioid abuse and alcohol dependence. Besides the biological importance, these compounds also exhibit very intriguing chemical structures, such as a unique poly‐bridged/fused ring system, a quaternary center, a basic tertiary amine moiety, and a 1,2,3,4‐tetrasubstituted arene, which have posted significant challenges for their preparation.…”

Section: Introductionmentioning

confidence: 99%

Deconstructive Asymmetric Total Synthesis of Morphine‐Family Alkaloid (−)‐Thebainone A

2021

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Herein, we describe the development of ad econstructive strategy for the first asymmetric synthesis of (À)thebainone A, capitalizing on an enantioselective CÀCb ond activation and aC ÀOb ond cleavage reaction. The rhodiumcatalyzeda symmetric "cut-and-sew" transformation between sterically hindered trisubstituted alkenes and benzocyclobutenones allowed efficient construction of the fused A/B/C rings and the quaternary center of the natural product. The newly optimizedconditions show broad substrate scope and excellent enantioselectivity (up to 99.5:0.5 er). Taking advantage of boron-mediated ether bond cleavage,w ec ompleted the synthesis of the morphine alkaloid (À)-thebainone Ab yt wo complementary routes. Figure 1. Morphine and related alkaloids.

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“…1). 1 Extensive modifications to the naturally occurring opioids have also been investigated in endeavors to increase potency and in vivo efficacy and have led to the discovery of semi-synthetic opioids such as (–)-ketorfanol ( 4 )2 and the extensively prescribed (–)-oxycodone ( 5 ) 3. However, despite the medical importance of naturally occurring and semi-synthetic opioid agonists, undesired side effects such as addictive properties and the potential for fatal overdoses are enormous societal problems.…”

Section: Introductionmentioning

confidence: 99%