Azabicycloalkanes as analgetics. II. An improved synthesis of 1-phenyl-6-azabicyclo(3,2,1)octane derivatives.

Takeda, Mikio; Inoue, Hirozumi; Noguchi, K.; Honma, Yasushi; Kawamori, Masatoshi; Tsukamoto, Goro; Yamawaki, Yasuhiko; Saito, Seiichi

doi:10.1248/cpb.24.1514

Cited by 14 publications

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“…Cyclizations of β-aryl ketones to form [3.2.1] bicycles are rare; the few other reports of this transformation require treatment with strong Lewis 9 or Brønsted acids 10 at elevated temperatures. These reactions presumably operate via an electrophilic aromatic substitution mechanism.…”

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confidence: 99%

A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H

2014

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A catalytic, enantioselective formal synthesis of (+)-dichroanone and (+)-taiwaniaquinone H is reported. The all-carbon quaternary stereocenter was constructed by asymmetric conjugate addition catalyzed by a palladium(II) (S)-tert-butylpyridinooxazoline complex. The unexpected formation of a [3.2.1] bicyclic intermediate required the identification of a new route. Analysis of the Hammett constants for para-substituted arenes enabled the rational design of a highly enantioselective conjugate addition substrate that led to the completion of the formal synthesis.

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confidence: 99%

A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H

2014

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“…¡ See ref 1. k Administered as free base in dilute HC1. 1 No effect with doses up to 10 mg/kg. m With marked CNS depression.…”

Section: F¡2mentioning

confidence: 98%

“…h No effect with doses up to 22.5 mg/kg. 1 Hydrobromide. ¡ See ref 1. k Administered as free base in dilute HC1.…”

Section: F¡2mentioning

confidence: 99%

Azabicycloalkanes as analgetics. 3. Structure-activity relations of 1-phenyl-6-azabicyclo[3.2.1]octanes and absolute stereochemistry of (+)-1-(3-hydroxyphenyl)-6-methyl-6-azabicyclo[3.2.1]octane and its 7-endo-methyl derivative

Takeda¹,

Inoue²,

Noguchi³

et al. 1977

J. Med. Chem.

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A series of 53 1-phenyl-6-azabicyclo[3.2.1]octanes (1) has been tested for their analgetic and narcotic antagonist activities. Structure-activity relationships were investigated by varying the structural parameters. The most interesting compound in this series, the 1-(3-hydroxphenyl)-6,7-dimethyl derivative 8, shows the profile of a well-balanced antagonist-analgesic agent with a very mild physical dependence capacity. The absolute stereochemistry of its active enantiomer [(+)8] was established by the x-ray study and the chemical transformation to the phenylmorphan [(+)-II]. (+)-8 was stereochemically correlated also with the active enantiomer of the 7-demethyl derivatives [(+)-7] by chemical transformation and CD measurement. Certain structural and stereochemical correlations between these compounds (7 and 8) and other known antagonist-analgetics are discussed.

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“…There are to date only three synthetic approaches disclosed to these structures (Figure 2A). [7,9] While innovative in design, the routes still suffer from drawbacks including the number of steps and associated low overall yields,product selectivity issues,limited substrate scope and divergence,n otably to access C-substituted derivatives and oxa-and aza-analogues from readily available substrates.Hence,practical syntheses (small number of steps from readily available precursors in high overall yield) of these bridged bicyclicn itrogen scaffolds is highly warranted to speed up the drug discovery process,s till rate limited by organic synthesis. [10] Disconnections based on an uncommon Based on our interest in C(sp 3 )-H functionalization reactions,apractical synthesis was envisioned by combining ad irected C(sp 3 )-H alkenylation with ac onsecutive amination from readily available aminocyclohexane derivatives 1 and 1,1-dibromo-1-alkenes 2 (Figure 2B).…”

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confidence: 99%

Expedient Synthesis of Bridged Bicyclic Nitrogen Scaffolds via Orthogonal Tandem Catalysis

et al. 2021

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Bridged nitrogen bicyclic skeletons have been accessed via unprecedented site‐ and diastereoselective orthogonal tandem catalysis from readily accessible reactants in a step economic manner. Directed Pd‐catalyzed γ‐C(sp3)‐H olefination of aminocyclohexane with gem‐dibromoalkenes, followed by a consecutive intramolecular Cu‐catalyzed amidation of the 1‐bromo‐1‐alkenylated product delivers the interesting normorphan skeleton. The tandem protocol can be applied on substituted aminocyclohexanes and aminoheterocycles, easily providing access to the corresponding substituted, aza‐ and oxa‐analogues. The Cu catalyst of the Ullmann‐Goldberg reaction additionally avoids off‐cycle Pd catalyst scavenging by alkenylated reaction product. The picolinamide directing group stabilizes the enamine of the 7‐alkylidenenormorphan, allowing further product post functionalizations. Without Cu catalyst, regio‐ and diastereoselective Pd‐catalyzed γ‐C(sp3)‐H olefination is achieved.

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Azabicycloalkanes as analgetics. II. An improved synthesis of 1-phenyl-6-azabicyclo(3,2,1)octane derivatives.

Cited by 14 publications

References 0 publications

A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H

A Catalytic, Enantioselective Formal Synthesis of (+)-Dichroanone and (+)-Taiwaniaquinone H

Azabicycloalkanes as analgetics. 3. Structure-activity relations of 1-phenyl-6-azabicyclo[3.2.1]octanes and absolute stereochemistry of (+)-1-(3-hydroxyphenyl)-6-methyl-6-azabicyclo[3.2.1]octane and its 7-endo-methyl derivative

Expedient Synthesis of Bridged Bicyclic Nitrogen Scaffolds via Orthogonal Tandem Catalysis

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