Total Synthesis of Rameswaralide Utilizing a Pharmacophore-Directed Retrosynthetic Strategy.
J Am Chem Soc
; 144(40): 18575-18585, 2022 10 12.
Article
em En
| MEDLINE
| ID: mdl-36166374
ABSTRACT
A pharmacophore-directed retrosynthetic strategy was applied to the first total synthesis of the cembranoid rameswaralide in order to simultaneously achieve a total synthesis while also developing a structure-activity relationship profile throughout the synthetic effort. The synthesis utilized a Diels-Alder lactonization process, including a rare kinetic resolution to demonstrate the potential of this strategy for an enantioselective synthesis providing both the 5,5,6- and, through a ring expansion, 5,5,7-tricyclic ring systems present in several Sinularia soft coral cembranoids. A pivotal synthetic intermediate, a tricyclic epoxy α-bromo cycloheptenone, displayed high cytotoxicity with interesting selectivity toward the HCT-116 colon cancer cell line. This intermediate enabled the pursuit of three unique D-ring annulation strategies including a photocatalyzed intramolecular Giese-type radical cyclization and a diastereoselective, intramolecular enamine-mediated Michael addition, with the latter annulation constructing the final D-ring to deliver rameswaralide. The serendipitous discovery of an oxidation state transposition of the tricyclic epoxy cycloheptenone proceeding through a presumed doubly vinylogous, E1-type elimination enabled the facile introduction of the required α-methylene butyrolactone. Preliminary biological tests of rameswaralide and precursors demonstrated weak cytotoxicity; however, the comparable cytotoxicity of a simple 6,7-bicyclic ß-keto ester, corresponding to the CD-ring system of rameswaralide, to that of the natural product itself suggests that such bicyclic ß-ketoesters may constitute an interesting pharmacophore that warrants further exploration.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Produtos Biológicos
/
Antozoários
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Alcaloides
Limite:
Animals
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article