Enantio- and Diastereoselective Synthesis of Duocarmycine-Based Prodrugs for a Selective Treatment of Cancer by Epoxide Opening
| Autor: | Stephan Rühl, Heiko J. Schuster, Roland Pfoh, Lutz F. Tietze, Sonja M. Hampel |
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| Rok vydání: | 2008 |
| Předmět: |
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Molecular Indoles Stereochemistry Molecular Conformation Epoxide Antineoplastic Agents Stereoisomerism Alkylation Crystallography X-Ray 010402 general chemistry 01 natural sciences Catalysis Duocarmycins chemistry.chemical_compound Neoplasms Amide Prodrugs 010405 organic chemistry Chemistry Organic Chemistry Total synthesis General Chemistry Prodrug Pyrrolidinones 3. Good health 0104 chemical sciences Enantiopure drug Cyclization Epoxy Compounds Amine gas treating |
| Zdroj: | Chemistry - A European Journal. 14:895-901 |
| ISSN: | 1521-3765 0947-6539 |
| Popis: | For the enantio- und diastereoselective synthesis of the prodrug 2, the N-tert-butyloxycarbonyl-protected amine 7 was alkylated with the enantiopure epoxide 14 to give the amide 10. A regio- and facial-selective metal-mediated cyclisation by using a cuprate led to 17 with an inversion of configuration at C10. Subsequent transformation of the hydroxy group in 17 by using the Appel procedure afforded (1S,10R)-9 with an unusual double inversion owing to neighbouring-group participation of the N-tert-butoxycarbonyl group. (1S,10R)-9 is the key intermediate in the synthesis of the prodrug 2, which has been developed for a selective treatment of cancer based on the antibody-directed enzyme prodrug therapy as an analogue of the natural antibiotic duocarmycine SA (1). |
| Databáze: | OpenAIRE |
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