ABSTRACT
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.
ABSTRACT
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.
Subject(s)
Acetone , Alkenes , Alcohols , Biomass , NickelABSTRACT
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.
ABSTRACT
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.
Subject(s)
Oxazines , Oxides , Acylation , Cycloaddition Reaction , StereoisomerismABSTRACT
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.
ABSTRACT
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.
ABSTRACT
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.