Assembly of the gephyrotoxin ring system via a [4+1] approach to 3-pyrrolines

Pearson, William H.; Poon, Yam-Foo

doi:10.1016/s0040-4039(00)70644-7

Cited by 16 publications

(4 citation statements)

References 27 publications

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“…Mild muscarinic activity was originally reported for this alkaloid, however recent studies have revealed a more complex and interesting array of neurological activities associated with gephyrotoxin. The low abundance of gephyrotoxin in amphibians and its unusual chemical and biological characteristics have led to synthetic interest in several laboratories. − …”

Section: Resultsmentioning

confidence: 99%

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Synthesis of Benzo-Fused 1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction: A Formal Synthesis of Gephyrotoxin

2000

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The intramolecular capture of benzocyclobutyl, benzocyclopentyl, and benzocyclohexyl carbocations 7 by azides produces spirocyclic aminodiazonium ions 8, which undergo 1,2-C-to-N rearrangement with loss of dinitrogen to produce benzo-fused iminium ions resulting from either aryl (9) or alkyl (10) migration to the electron-deficient nitrogen atom. Reduction of the iminium ions affords regioisomeric benzo-fused 1-azabicyclo[m.n.0]alkanes, e.g., benzopyrrolizidines, benzoindolizidines, benzoquinolizidines, or perhydrobenzo[f]pyrrolo[1,2-a]azepines in two regioisomeric versions, anilines (e.g., 11-14) and benzylic amines (e.g., 15-18), the result of aryl and alkyl migrations, respectively. Generally, aryl migration is preferred, despite modeling that shows that the lowest energy aminodiazonium ions are those where the departing dinitrogen is preferentially antiperiplanar to the migrating alkyl group rather than the aryl group. The utility of this methodology was illustrated by a formal synthesis of the alkaloid gephyrotoxin 4. A dependence on the efficiency and regioselectivity of the Schmidt reaction upon subtle changes in the structure of the cation precursor was observed, necessitating the exploration of a variety of substrates. Fortunately, these materials were easily made. Ultimately, the azido-alkene 81 bearing a 2-bromoethyl side-chain was useful for the Schmidt reaction, producing the known benzo-fused indolizidine 49, which had been transformed by Ito et al. into gephyrotoxin 4. The synthesis of 49 required nine steps (five purifications) from commercially available 4-methoxy-1-indanone 60 and proceeded in 22% overall yield.

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Section: Resultsmentioning

confidence: 99%

“…The low abundance of gephyrotoxin in amphibians and its unusual chemical and biological characteristics have led to synthetic interest in several laboratories. [31][32][33][34][35][36][37][38][39] A retrosynthetic analysis of gephyrotoxin is shown in Scheme 6. Ito and co-workers have prepared 49 and converted it to gephyrotoxin 4.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Benzo-Fused 1-Azabicyclo[m.n.0]alkanes via the Schmidt Reaction: A Formal Synthesis of Gephyrotoxin

2000

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“…From here, imine 37 underwent a 6exo-tet cyclization to deliver iminium 38. [23][24][25] Finally, reduction with NaBH 4 afforded the expected (�)-γ-lycorane (�)-11 c (Scheme 6).…”

Section: Cycloaddition Approachesmentioning

confidence: 99%

Synthetic Approaches to α‐, β‐, γ‐, and δ‐Lycoranes

et al. 2023

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Lycorane is a pentacyclic core presented in alkaloids isolated from the Amaryllidaceae family of herbaceous flowering plants. Members of this class of natural products have shown to display important biological properties including analgesic, antiviral, and antiproliferative activities. This review presents the known synthetic routes toward α‐, β‐, γ‐, and δ‐lycoranes. α‐(19 routes), β‐(10 routes), γ‐(38 routes), and δ‐(6 routes).

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“…[141][142][143][144][145][146][147][148][149][150][151] Several total syntheses of racemic pyrrolizidine and indolizidine alkaloids were accomplished in this way. [141][142][143][144][146][147][148][149][150] The enantiodivergent syntheses of trihydroxyheliotridane 6,7-O-acetonide 36 was possible via the chiral azidodiene 35, both enantiomers of which were available from L-and D-erythrose (Scheme 25). 145 A sequence starting from L-glutamic acid and involving the homochiral azidodiene 37 allowed access to (-)-8a-epidesacetoxyslaframine 38 (Scheme 26…”

Section: Intramolecular Cycloadditions Of Alkadienyl Azidesmentioning

confidence: 99%