Cycloaddition reactions are among the most important tools for the construction of cyclic compounds in organic synthesis, since these reactions are vital to access natural products and biologically active compounds. Organocatalysis plays an increasingly pivotal role in these reactions, often allowing several stereocenters to be selectively created and integrated in the target molecule. Among the large number of efficient types of organocatalysts available, the diarylprolinol silyl ethers have been established as one of the most frequently used in aminocatalysis allowing for novel activation modes and reaction concepts. In this review, we will focus on the different activation modes made available by the diarylprolinol silyl ether system with the aim of highlighting their applicability in asymmetric cycloadditions for the assembly of complex molecular architectures.

Asymmetric cycloaddition reactions catalysed by diarylprolinol silyl ethers.

Asymmetric construction of halogenated quaternary carbon centers under mild reaction conditions remains challenging. Reported here is an unprecedented and highly stereoselective Bronsted base catalyzed [4+2] cycloaddition between either α-chloro- or α-bromoaldehydes and cyclic enones. The key intermediate, an α-halogenated enolate, is susceptible to dehalogenation and can be stabilized and stereochemically controlled using bifunctional tertiary amines. This method provides facile access to a collection of optically pure bicyclic dihydropyrans having three contiguous stereocenters, including a halogen-bearing quaternary carbon center. Of note, the product can be transformed in situ into densely functionalized spirocyclopropanes in a highly efficient and stereoselective manner.

Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of α-Haloaldehydes.

Medium-sized heterocycles exist in a broad spectrum of biologically active natural products and medicinally important synthetic compounds. The construction of medium-sized rings remains challenging, particularly the assembly of different ring sizes from the same type of substrate. Here we report palladium-catalyzed, regiodivergent [5 + 4] and [5 + 2] annulations of vinylethylene carbonates and allylidenemalononitriles. We describe the production of over 50 examples of nine- and seven-membered heterocycles in high isolated yields and excellent regioselectivities. We demonstrate the synthetic utility of this approach by converting a nine-membered ring product to an interesting polycyclic caged molecule via a [2 + 2] transannulation. Mechanistic studies suggest that the [5 + 2] annulation proceeds through palladium-catalyzed ring-opening/re-cyclization from the [5 + 4] adducts.

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Regiodivergent construction of medium-sized heterocycles from vinylethylene carbonates and allylidenemalononitriles

In this review, the recent developments in catalytic asymmetric inverse-electron-demand hetero-Diels-Alder reaction, which is recognized as one of the most powerful routes to construct highly functionalized and enantioenriched six-membered heterocycles, are described The article is organized on the basis of different kinds of electron-deficient heterodienes, including α,β-unsaturated ketones/aldehydes, o-benzoquinones, α,β-unsaturated imines, N-aryl imines, o-benzoqinone imides, and other aza-olefins

Catalytic Asymmetric Inverse-Electron-Demand Hetero-Diels-Alder Reactions.

Organocatalytic Asymmetric Synthesis of Cyclic Compounds Bearing a Trifluoromethylated Stereogenic Center: Recent Developments

Highly enantioselective synthesis of fused bicyclic dihydropyranones via low-loading N-heterocyclic carbene organocatalysis.

Asymmetric synthesis of bicyclic dihydropyrans via organocatalytic inverse-electron-demand oxo-Diels-Alder reactions of enolizable aliphatic aldehydes.

Spiroheterocycles are regarded as a privileged framework because of their wide distribution in various natural products and synthetic molecules and promising bioactivities. This review focuses on the recent advances in the synthesis of spiroheterocycles by using the strategy of N-heterocyclic carbene (NHC) organocatalysis, and is organized based on the stereoselectivity and the reactive intermediates. According to the stereochemistry, this review was divided into two main parts, covering racemic and enantioselective versions. In each part, we firstly describe the synthetic transformations using nucleophilic Breslow intermediates, and then discuss the reactions that employ electrophilic acylazolium or radical cation intermediates. With those distinct catalytic activation modes of NHC organocatlysis, we expect this synthetic protocol will possibly produce new molecules with structural novelty and complexity, which may warrant further research in the field of drug discovery.

Recent Advances in the Synthesis of Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis.

A collection of novel spiroheterocycles with strained aziridine moieties have been facilely synthesized by using easily accessible starting materials under mild reaction conditions. This procedure is robust, scalable and highly diastereoselective, and also features broad substrate scope. In addition, some of the products show promising in vitro biological activity against a spectrum of pathogens, which might be considered as a clue for the discovery of new antimicrobial agents.

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Xiao-Jun Gou

Papers

Highly enantioselective synthesis of fused bicyclic dihydropyranones via low-loading N-heterocyclic carbene organocatalysis.

Asymmetric synthesis of bicyclic dihydropyrans via organocatalytic inverse-electron-demand oxo-Diels-Alder reactions of enolizable aliphatic aldehydes.

Recent Advances in the Synthesis of Spiroheterocycles via N-Heterocyclic Carbene Organocatalysis.

Facile synthesis of novel spiroheterocycles via diastereoselective aziridination of cyclic enones

The Institute of Chemistry of Great Britain and Ireland. Proceedings, 1914. Part III