RESUMEN
Clavilactones A, B, and D are epidermal growth factor receptor tyrosine kinase inhibitors that were isolated from cultures of the fungus Clitocybe clavipes. Here, we report full details of the total synthesis of these clavilactones. A key feature of our synthetic approach is a ring-opening/ring-closing metathesis strategy that allows the concise transformation of a cyclobutenecarboxylate into a γ-butenolide. Coupled with enantioselective Ti/BINOL-catalyzed alkynylation of a multisubstituted benzaldehyde and ring-closing metathesis of a diene-bearing silylene acetal to construct the 10-membered carbocycle, this strategy enabled the total synthesis of the natural enantiomers (+)-clavilactone A and (-)-clavilactone B. In addition, the correct structure of clavilactone D was determined by the synthesis of two newly proposed structures. This research resulted in the asymmetric synthesis of the revised (+)-clavilactone D.
RESUMEN
A structural revision of clavilactoneâ D, a potent inhibitor of protein tyrosine kinases, was achieved by total syntheses of two newly proposed structures. The syntheses relied on ring-opening/ring-closing metathesis, which transformed a cyclobutenecarboxylate into a γ-butenolide. The syntheses confirmed that the correct structure of clavilactoneâ D has an amino group at C-3 instead of a hydroxy group at C-2 in the originally proposed structure.
Asunto(s)
Productos Biológicos/síntesis química , Lactonas/síntesis química , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , 4-Butirolactona/análogos & derivados , 4-Butirolactona/síntesis química , 4-Butirolactona/química , Basidiomycota/química , Productos Biológicos/química , Ciclobutanos/síntesis química , Ciclobutanos/química , Lactonas/química , Inhibidores de Proteínas Quinasas/química , EstereoisomerismoRESUMEN
The enantioselective total synthesis of natural enantiomers of clavilactones A and B has been achieved. A key feature of the synthesis is the use of a ring-opening/ring-closing metathesis, which allows the one-pot transformation of a strained cyclobutenecarboxylate into a γ-butenolide.