Stereocontrolled Synthesis of the Fully Glycosylated Monomeric Unit of Lomaiviticin A.
J Am Chem Soc
; 144(35): 16199-16205, 2022 09 07.
Article
em En
| MEDLINE
| ID: mdl-35998350
ABSTRACT
We describe a stereocontrolled synthesis of 3, the fully glycosylated monomeric unit of the dimeric cytotoxic bacterial metabolite (-)-lomaiviticin A (2). A novel strategy involving convergent, site- and stereoselective coupling of the ß,γ-unsaturated ketone 6 and the naphthyl bromide 7 (92%, 151 diastereomeric ratio (dr)), followed by radical-based annulation and silyl ether cleavage, provided the tetracycle 5 (57% overall), which contains the carbon skeleton of the aglycon of 3. The ß-linked 2,4,6-trideoxy-4-aminoglycoside l-pyrrolosamine was installed in 73% yield and with 151 ßα selectivity using a modified Koenigs-Knorr glycosylation. The diazo substituent was introduced via direct diazo transfer to an electron-rich benzoindene (4 â 27). The α-linked 2,6-dideoxyglycoside l-oleandrose was introduced by gold-catalyzed activation of an o-alkynyl glycosylbenzoate (75%, >201 αß selectivity). A carefully orchestrated endgame sequence then provided efficient access to 3. Cell viability studies indicated that monomer 3 is not cytotoxic at concentrations up to 1 µM, providing conclusive evidence that the dimeric structure of (-)-lomaiviticin A (2) is required for cytotoxic effects. The preparation of 3 provides a foundation to complete the synthesis of (-)-lomaiviticin A (2) itself.
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Base de dados:
MEDLINE
Assunto principal:
Fluorenos
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article