Synthesis of 4-Alkyl-2-chloro Imidazoles Using Intermolecular Radical Additions.

Here, we report an intermolecular radical addition-based reaction sequence that permits preparation of functionalized imidazoles via a 5-step/3-pot procedure. In contrast to traditional, transition-metal mediated protocols, which generally provide access to 2-substituted imidazoles, the strategy described here allows incorporation of a structurally diverse range of complex alkyl side chains at the 4-position. This work demonstrates that intermolecular free-radical addition reactions are a powerful alternative to traditional methods used to synthesize medicinally important heterocyclic frameworks.

A Route to 5,5-Dithiospiroketals and to Long-Chain Monomers from the Biomass.

5,5-Dithiospiroketals are prepared by a double radical addition of α,α'-bisxanthyl acetone to an alkene followed by ionic or thermal cleavage of the xanthate groups and acid-catalyzed ring closure. A modification employs α-chloro-α'-xanthyl acetone to give unsymmetrical derivatives. Reductive removal of the sulfur atoms with Raney nickel furnishes long-chain α,ω-diacids, diols, and diamines. Using biosourced alkenes, monomers and polymers can be obtained where essentially all the carbons are derived from the biomass.

Modular Approach to Substituted Pyridoazepinones.

Pyridoazepinones are potentially interesting structures, yet they are still underexploited in the medicinal chemistry field and hard to obtain synthetically. We present a general and flexible synthetic route to substituted pyridoazepinones, enabled by the xanthate addition-transfer process, which furnishes the target molecules from readily available starting materials in generally good yields. The method shows good functional group tolerance and allows the preparation of pyridoazepinone scaffolds on gram scale.

Asymmetric Synthesis of Merck's Potent hNK1 Antagonist and Its Stereoisomers via Tandem Acylation/[3,3]-Rearrangement of 1,2-Oxazine N-Oxides.

An asymmetric total synthesis of Merck's hNK1 antagonist and three of its stereoisomers was accomplished in 10 steps. The synthesis involves a stereoselective assembly of 1,2-oxazine N-oxide by the [4 + 2]-cycloaddition, site-selective C-H oxygenation using a novel tandem acylation/[3,3]-rearrangement process and the reductive 1,2-oxazine ring contraction into a pyrrolidine ring as key stages. Using this strategy, the fused pyrrolidine subunit was constructed with exceptionally high regio- and stereoselectivities. The approach described here can be used to access enantiopure 3,4-disubstituted prolinols, which are frequently found in pharmaceutically relevant molecules and organocatalysts.

Nucleophilic Halogenation of Cyclic Nitronates: A General Access to 3-Halo-1,2-Oxazines.

In this article, comprehensive studies on the nucleophilic chlorination and bromination of readily available six-membered cyclic nitronates (1,2-oxazine-N-oxides) are reported. Under optimized conditions (POCl3 or (COBr)2 with Hünig's base), 3-halo-substituted 1,2-oxazines, which are difficult to access by other routes, were obtained in good to high yields. The latter were shown to be convenient precursors to other 3-substituted 1,2-oxazine derivatives using Lewis/Brønsted acid-assisted substitution of the halide atom for C-, S-, and N-nucleophiles.

Regioselective single pot C3-glycosylation of strophanthidol using methylboronic acid as a transient protecting group.

This manuscript describes a single pot protocol for the selective introduction of unprotected sugars to the C3 position of the cardiotonic steroid strophanthidol. These reactions proceed with high levels of regiocontrol (>20:1 rr) in the presence of three other hydroxyl functionalities including the C19 primary hydroxyl group and could be applied to different sugars to provide the deprotected cardiac glycosides upon work up (5 examples, 77-69% yield per single operation). The selective glycosylation of the less reactive C3 position is accomplished by the use of traceless protection with methylboronic acid that blocks the C5 and C19 hydroxyls by forming a cyclic boronic ester, followed by in situ glycosylation and a work up with ammonia in methanol to remove the boronic ester and the carbohydrate ester protecting groups.

Acylation of Nitronates: [3,3]-Sigmatropic Rearrangement of in Situ Generated N-Acyloxy, N-oxyenamines.

Acylation of nitronates affords α-acyloxyoxime derivatives via an umpolung functionalization of the α-position. This transformation involves generation of hitherto unknown N-acyloxy, N-oxyenamines and their fast [3,3]-sigmatropic rearrangement driven by the cleavage of the weak N-O bond. The reaction has a broad scope, and it is regioselective in the case of nitronates possessing nonsymmetrically substituted α-positions. Application to the formal total synthesis of clausenamide and cis-clausenamide is presented.

Diastereoselective synthesis and profiling of bicyclic imidazolidinone derivatives bearing a difluoromethylated catechol unit as potent phosphodiesterase 4 inhibitors.

Metal-mediated C-H functionalization of cyclic N-oxides was exploited to access a series of new difluoromethylated analogs of imidazolidinone-based PDE4 inhibitor CMPI in a diastereoselective manner. Among the products synthesized, compounds with fine-tuned activity/selectivity profiles compared to both CMPI and the clinically applied apremilast were identified. From these studies, an unusual fused 1,2-oxazinoimidazolidinone heterocyclic system was suggested as a novel scaffold for the design of potent and selective PDE4 inhibitors. Computational studies suggest that the oxygen atom in the imidazolidinone unit can bind to the metal ion center (most likely Mg2+). DFT calculations of the relative interaction energies of inhibitors with Mg2+ and Zn2+ ions were performed on a model of the bimetal active site of PDE4.

Conjugated nitrosoalkenes as Michael acceptors in carbon-carbon bond forming reactions: a review and perspective.

Despite of their chemical instability and high reactivity, conjugated nitrosoalkenes are useful intermediates in target-oriented organic synthesis. The present review deals with carbon-carbon bond forming reactions involving Michael addition to α-nitrosoalkenes with a particular focus on recent developments in this methodology and its use in total synthesis.