Halogen (fluorine, chlorine, bromine, iodine) or chalcogen (sulfur, seleno)-containing heterocycles are widely recognized as key building blocks in many natural products and bioactive targets. Catalytic asymmetric halogenation/chalcogenation of carbon-carbon unsaturated bonds via onium ion transformations are efficient methods to obtain diverse chiral heterocyclic backbones. In the past few years, catalytic enantioselective versions of halo/thio/seleno-functionalizations with various halogen and chalcogen electrophiles have experienced constant development. This review highlights those advances in preparing functionalized heterocycles promoted by chiral organocatalysts or metal-based catalysts. 

Recent advances in catalytic asymmetric syntheses of functionalized heterocycles via halogenation/chalcogenation of carbon‐carbon unsaturated bonds

Electrophilic halogenation of alkenes is a powerful transformation offering a convenient route for the construction of valuable functionalized molecules. However, as a highly important reaction in this field, catalytic asymmetric intermolecular iodinative difunctionalization remains a formidable challenge. Herein, we report that an efficient Lewis basic chiral sulfide-catalyzed approach enables this reaction. By this approach, challenging substrates such as γ,γ-disubstituted allylic sulfonamides and 1,1-disubstituted alkenes with an allylic sulfonamide unit undergo electrophilic iodinative difunctionalization to give a variety of iodine-functionalized chiral molecules in good yields with excellent enantio- and diastereoselectivities. A series of free phenols as nucleophiles are successfully incorporated into the substrates. Aside from phenols, primary and secondary alcohols, fluoride, and azide also serve as efficient nucleophiles. The obtained iodinated products are a good platform molecule, which can be easily transformed into various chiral compounds such as α-aryl ketones, chiral secondary amines, and aziridines via rearrangement or substitution. Mechanistic studies revealed that the chiral sulfide catalyst displays a superior effect on control of the reactivity of electrophilic iodine and the enantioselective construction of the chiral iodiranium ion intermediate and catalyst aggregates might be formed as a resting state in the reactions.

Asymmetric Intermolecular Iodinative Difunctionalization of Allylic Sulfonamides Enabled by Organosulfide Catalysis: Modular Entry to Iodinated Chiral Molecules.

Asymmetric Synthesis of Halocyclized Products by Using Various Catalysts: A State‐of‐the‐Art Review

Electricity-driven asymmetric catalysis is an emerging powerful tool in organic synthesis. However, asymmetric induction so far has mainly relied on forming strong bonds with a chiral catalyst. Asymmetry induced by weak interactions with a chiral catalyst in an electrochemical medium remains challenging due to compatibility issues related to solvent polarity, electrolyte interference, etc. Enabled by a properly designed phase-transfer strategy, here we have achieved two efficient electricity-driven catalytic asymmetric bromocyclization processes induced by weak ion-pairing interaction. The combined use of a phase-transfer catalyst and a chiral phosphate catalyst, together with NaBr as the bromine source, constitutes the key advantages over the conventional chemical oxidation approach. Synergy over multiple events, including anodic oxidation, ion exchange, phase transfer, asymmetric bromination, and inhibition of Br2 decomposition by NaHCO3, proved critical to the success. 

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Electricity-driven asymmetric bromocyclization enabled by chiral phosphate anion phase-transfer catalysis

A domino reaction sequence of cyclopropanation/ring-opening/iminium cyclization of tryptamine derivatives with donor-acceptor diazo compounds is developed to furnish pyrroloindolines, creating three consecutive stereogenic centers in a single step. The copper-catalyzed reaction provides pyrroloindolines at room-temperature with good substrate scope.

Copper-catalyzed cascade reaction of tryptamines with diazo compounds to access hexahydropyrroloindoline derivatives.

Halocyclization of olefinic substrate enables establishment of cyclic skeletons via intramolecular halonium-induced nucleophilic addition, which have been well utilized as a practical strategy for constructing cyclic skeleton in natural product synthesis. Recently, the renaissance and rapid evolution of organocatalysis accelerate the development of catalytic asymmetric halocyclization. In this context, natural product synthesis powered by catalytic asymmetric halocyclization has also received considerable progresses in recent years. In seom cases, these newly developed protocols enable more concise synthetic routes for accessing enantioenriched natural products. To this end, this review summarized the applications of catalytic asymmetric halocyclization in natural product synthesis.

The Applications of Catalytic Asymmetric Halocyclization in Natural Product Synthesis

Herein, we disclosed a catalytic asymmetric dearomatization (CADA) of tryptamine via tandem [4 + 2] cycloaddition/cyclization with o-azaxylylene in situ generated from functionalized 3-bromooxindole promoted by chiral N,N′-dioxide/Ni(BF4)2. A variety of dimeric tryptamine derivatives with meso-contiguous quaternary carbon centers were obtained with good to excellent enantioselectivities and diastereoselectivities from Na-unprotected or protected tryptamines. A formal asymmetric synthesis of hodgkinsine B was also executed to showcase its synthetic potential.

The catalytic asymmetric dearomatization of tryptamine for accessing meso-contiguous quaternary carbon centers of oligomeric cyclotryptamine alkaloids: a formal synthesis of hodgkinsine B

Zhiqiang Zhou

Papers

The Applications of Catalytic Asymmetric Halocyclization in Natural Product Synthesis

The catalytic asymmetric dearomatization of tryptamine for accessing meso-contiguous quaternary carbon centers of oligomeric cyclotryptamine alkaloids: a formal synthesis of hodgkinsine B