The Cyclic Nitronate Route to Pharmaceutical Molecules: Synthesis of GSK’s Potent PDE4 Inhibitor as a Case Study
| Autor: | Alexey Yu. Sukhorukov, Sema L. Ioffe, Evgeny V Pospelov, Ivan S. Golovanov |
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| Rok vydání: | 2020 |
| Předmět: |
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Molecular Stereochemistry C–H functionalization Molecular Conformation Pharmaceutical Science Chemistry Techniques Synthetic Nitroalkene Ring (chemistry) Article Analytical Chemistry lcsh:QD241-441 Acylation chemistry.chemical_compound lcsh:Organic chemistry epimerization Oxazines Drug Discovery medicine Physical and Theoretical Chemistry total synthesis Density Functional Theory Organic Chemistry Acetal Enantioselective synthesis Total synthesis Stereoisomerism pyrrolidines Vinyl ether Nitro Compounds PDE4 inhibitors chemistry Chemistry (miscellaneous) anchimeric assistance Molecular Medicine Nitronate Phosphodiesterase 4 Inhibitors medicine.drug |
| Zdroj: | Molecules, Vol 25, Iss 3613, p 3613 (2020) Molecules Volume 25 Issue 16 |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules25163613 |
| Popis: | An efficient asymmetric synthesis of GlaxoSmithKline&rsquo s potent PDE4 inhibitor was accomplished in eight steps from a catechol-derived nitroalkene. The key intermediate (3-acyloxymethyl-substituted 1,2-oxazine) was prepared in a straightforward manner by tandem acylation/(3,3)-sigmatropic rearrangement of the corresponding 1,2-oxazine-N-oxide. The latter was assembled by a (4 + 2)-cycloaddition between the suitably substituted nitroalkene and vinyl ether. Facile acetal epimerization at the C-6 position in 1,2-oxazine ring was observed in the course of reduction with NaBH3CN in AcOH. Density functional theory (DFT) calculations suggest that the epimerization may proceed through an unusual tricyclic oxazolo(1,2)oxazinium cation formed via double anchimeric assistance from a distant acyloxy group and the nitrogen atom of the 1,2-oxazine ring. |
| Databáze: | OpenAIRE |
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