Flexible and Convergent Enantioselective Total Synthesis of (R)‑Juglanaloids A and B: Two Phthalide Spiro Alkaloids with Potential Alzheimer’s Disease Inhibitory Activity

Juglanaloids A and B are recently isolated natural products characterized by an unprecedented spiro bicyclic isobenzofuranone-tetrahydrobenzazepinone framework and a promising antiamyloid activity. Here reported is a straightforward convergent total synthesis of these natural products, which were ob...

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Published in:Journal of organic chemistry 2024-05, Vol.89 (10), p.7255-7262
Main Authors: Khettar, Ibrahim, Sinibaldi, Arianna, Schettini, Rosaria, Gorini, Giorgio, Siddiqa, Ayesha, Litta, Antonella Dentoni, De Riccardis, Francesco, Izzo, Irene, Sala, Giorgio Della
Format: Article
Language:English
Subjects:
Alkaloids - chemical synthesis
Alkaloids - chemistry
Alkaloids - pharmacology
Alzheimer Disease - drug therapy
Benzofurans - chemical synthesis
Benzofurans - chemistry
Benzofurans - pharmacology
Molecular Structure
Spiro Compounds - chemical synthesis
Spiro Compounds - chemistry
Spiro Compounds - pharmacology
Stereoisomerism
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Summary:Juglanaloids A and B are recently isolated natural products characterized by an unprecedented spiro bicyclic isobenzofuranone-tetrahydrobenzazepinone framework and a promising antiamyloid activity. Here reported is a straightforward convergent total synthesis of these natural products, which were obtained in high enantiomeric purity (94% and >99% ee for juglanaloids A and B, respectively) through an eight-step longest linear sequence, based on an efficient and reliable enantioselective phase-transfer-catalyzed alkylation step. Considering the interesting biological activity of juglanaloids, this convenient, highly enantioselective, flexible, and predictable synthetic strategy promises to be a powerful tool for accessing potentially bioactive spiro bicyclic phthalide-tetrahydrobenzazepinone derivatives.
ISSN:0022-3263
1520-6904
1520-6904
DOI:10.1021/acs.joc.4c00740