Practical Asymmetric Synthesis of a γ-Secretase Inhibitor Exploiting Substrate-Controlled Intramolecular Nitrile Oxide−Olefin Cycloaddition
| Autor: | Antony J. Davies, Karel M. J. Brands, Sarah E. Brewer, Robert D. Wilson, Jeremy P. Scott, Andrew D. Gibb, Faye J. Sheen, Ulf-H. Dolling, David Hands, Stephen P. Keen, Robert A. Reamer, Steven F. Oliver |
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| Rok vydání: | 2006 |
| Předmět: |
Molecular Structure
Intramolecular reaction Nitrile Chemistry Stereochemistry Organic Chemistry Enantioselective synthesis Oxides Stereoisomerism Alkenes Amino Alcohols Chemical synthesis Cycloaddition chemistry.chemical_compound Intramolecular force Nitriles Stereoselectivity Amyloid Precursor Protein Secretases Enzyme Inhibitors Isoxazole Tartrates |
| Zdroj: | The Journal of Organic Chemistry. 71:3086-3092 |
| ISSN: | 1520-6904 0022-3263 |
| DOI: | 10.1021/jo060033i |
| Popis: | A practical asymmetric synthesis of the gamma-secretase inhibitor (-)-1 is described. As the key transformation, a highly diastereoselective intramolecular nitrile oxide cycloaddition forms the hexahydrobenzisoxazole core of 3 in four operations. Other aspects of the route include a highly stereoselective reduction of an isoxazole to form a cis-gamma-amino alcohol, an efficient chemical resolution, a dianion cyclization to construct a sultam ring, and the alpha-alkylation of a sultam with excellent diastereoselectivity. In each instance, the relative stereochemistry was evolved by way of substrate-based induction with > or = 96% ds. Kilogram quantities of the targeted drug candidate (-)-1 were obtained, without recourse to chromatography, by way of 10 isolated intermediates and in 13% overall yield. |
| Databáze: | OpenAIRE |
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