Tandem anionic oxy‐Cope rearrangement/radical oxygenation reactions provide δ,ϵ‐unsaturated α‐(aminoxy) carbonyl compounds, which serve as convenient precursors to diverse compound classes. Functionalized carbocycles are accessible by very rare all‐carbon 5‐endo‐trig cyclizations, but also common 5‐exo‐trig radical cyclizations, based on the persistent radical effect. The tandem reactions can be further extended by highly diastereoselective allylation or reduction steps to give complex scaffolds.
Pyrazolones [1] are common heterocycles that are present in several pharmacologically active compounds, such as Metamizole (Scheme 1), a powerful analgesic and antipyretic developed by Hoechst AG in 1920. More recently, pyrazol-3-ones were found to be inhibitors of the cluster of differentiation 80 (CD80) protein, and to have potent activity in inhibiting protease-resistant prion protein accumulation, cytokines, and p38 kinases. Pyrazol-3-ones have also been studied as multidrug resistance modulators. [2] Despite the interest in pyrazolones as common structural motifs in pharmacologically active compounds, there are few methods that allow the construction of pyrazolones in asymmetric form. For example, Yuan and co-workers described a highly enantioselective pyrazolone addition to nitrostyrenes catalyzed by thiourea compounds, which gives the resulting chiral pyrazolones in high enantio and diaste-[a] M. Š imek, M. Remeš, Dr. J. Veselý Scheme 1. Biologically active pyrazolones.Scheme 2. Previous organocatalytic methods for pyrazol-3-one developed in our group. TMS = trimethylsilyl.
A unified approach to meroterpenoids applanatumols B, V, W, X, and Y produced by the medicinal fungus Ganoderma applanatum and 2′-epi-spiroapplanatumine O is presented. The key synthetic sequence consists of a tandem anionic ketone allylation/oxy-Cope rearrangement/α-oxygenation furnishing an α-aminoxy ketone and a persistent radical effectbased 5-exo-trig cyclization leading to the trisubstituted cyclopentane core. The relative configuration of applanatumol V has to be revised. Some compounds display significant cytotoxic and antioxidant properties.
A series of peracylated glycosamine-derived thioureas have been synthesized and their behavior as bifunctional organocatalysts has been tested in the enantioselective nucleophilic addition of formaldehyde tert-butyl hydrazone to aliphatic α-keto esters for the synthesis of tertiary azomethyl alcohols. Using the 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-d-glucosamine derived 3,5-bis-(trifluoromethyl)phenyl thiourea the reaction could be accomplished with high yields (75-98%) and moderate enantioselectivities (50-64% ee). Subsequent high-yielding and racemization-free tranformations of both aromatic- and aliphatic-substituted diazene products in a one pot fashion provide a direct entry to valuable azoxy compounds and α-hydroxy-β-amino esters.
An organocatalytic asymmetric allylic amination of Morita–Baylis–Hillman carbonates with aromatic amines in the presence of β-isocupreidine is described. Chiral allylic amines were obtained in almost quantitative yields (90–96%) with moderate enantioselectivity. Recrystallization afforded products in good yields (45–73%) and high optical purity (82–99% ee). This method provides a facile and efficient route to obtain optically active β-lactams, including the building block of the cholesterol-lowering drug Ezetimibe.
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