Spirooxindoles have emerged as promising architectures for engineering biologically active compounds. The diastereodivergent construction of unique scaffolds of this type with full control of continuous chiral centers including an all-carbon quaternary stereogenic center is yet to be developed. Here, we report an unprecedented diastereodivergent desymmetric [3 + 3] annulation of oxabicyclic alkenes with enals enabled by N-heterocyclic carbene (NHC)/Rh cooperative catalysis, leading to a series of enantiomerically enriched spirooxindole lactones with excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >95:5 dr). The combined catalyst system comprises a rhodium complex that controls the configuration at the electrophilic carbon and an NHC catalyst that controls the configuration at the nucleophilic oxindole-containing carbon; thus, four stereoisomers of the spirooxindole products can be readily obtained simply by switching the configurations of the two chiral catalysts. Transformations of the chiral spirooxindoles delivered synthetically useful compounds. Importantly, those chiral spirooxindoles arrested mammalian cells in mitosis and exhibited potent antiproliferative activities against HeLa cells. Significantly, both absolute and relative configurations exert prominent effects on the bioactivities, underscoring great importance of catalytic asymmetric diastereodivergent synthesis beyond creating useful tools for the exploration of structure-activity relationships.

Diastereodivergent Desymmetric Annulation to Access Spirooxindoles: Chemical Probes for Mitosis.

The textbook alkene halogenation reaction establishes straightforward access to vicinal dihaloalkanes. However, a robust catalytic method for dihalogenizing electron-deficient olefins in an enantioselective manner is still under development, and its mechanism remains controversial. Herein, we disclose efficient regio-, anti-diastereo-, and enantioselective dibromination, bromochlorination, and dichlorination reactions of enones catalyzed by a chiral N,N'-dioxide/Yb(OTf)3 complex. With the combination of electrophilic halogen and halide salts as halogenating agents, an array of homo- and heterodihalogenated derivatives is achieved in moderate to good enantioselectivities. Moreover, DFT calculations reveal that a novel triplet halo-radical pylon intermediate is probable in accounting for the exclusive regio- and anti-diastereoselectivity.

Enantioselective anti-Dihalogenation of Electron-Deficient Olefin: A Triplet Halo-Radical Pylon Intermediate.

Here, we report an anionic stereogenic-at-cobalt(III) complex catalysis strategy for the enantioselective halocyclization of ortho-alkynylanilines using N-halosuccinimide (NXS) as the halogen source. This protocol provides a distinct atroposelective approach to access the axially chiral ortho-halo-C2-indole skeletons in excellent yields with good to high enantioselectivities (up to 99% yield, 99:1 er).

Stereogenic-at-Cobalt(III) Complex Catalyzed Halocyclization of Alkynes: Enantioselective Access to Axially Chiral ortho-Halo-C2-indoles.

The selective hetero-dihalogenation of alkenes provides useful building blocks for a broad range of chemical applications. Unlike homo-dihalogenation, selective hetero-dihalogenation reactions, especially fluorohalogenation, are underdeveloped. Current approaches combine an electrophilic halogen source with a nucleophilic halogen source, which necessarily leads to anti-addition, and regioselectivity has only been achieved using highly activated alkenes. Here we describe an alternative, nucleophile-nucleophile approach that adds chloride and fluoride ions over unactivated alkenes in a highly regio-, chemo- and diastereoselective manner. A curious switch in the reaction mechanism was discovered, which triggers a complete reversal of the diastereoselectivity to promote either anti- or syn-addition. The conditions are demonstrated on an array of pharmaceutically relevant compounds, and detailed mechanistic studies reveal the selectivity and the switch between the syn- and anti-diastereomers are based on different active iodanes and which of the two halides adds first. 

Diastereodivergent nucleophile–nucleophile alkene chlorofluorination

pdf/recent-advances-in-visible-light-induced-organic-phosphine-rzfu3g3omc.pdf

Recent Advances in Visible-Light-Induced Organic Phosphine- Promoted Deoxygenative Functionalization Reactions

A new strategy is described for the Lewis base-catalyzed bromochlorination of unsaturated systems that is mechanistically distinct from prior methodologies. The novelty of this method hinges on the utilization of thionyl chloride as a latent chloride source in combination with as little as 1 mol % of triphenylphosphine or triphenylphosphine oxide as Lewis basic activators. This metal-free, catalytic chemo-, regio-, and diastereoselective bromochlorination of alkenes and alkynes exhibits excellent site selectivity in polyunsaturated systems and provides access to a wide variety of vicinal bromochlorides with up to >20:1 regio- and diastereoselectivity. The precision installation of Br, Cl, and I in various combinations is also demonstrated by simply varying the commercial halogenating reagents employed. Notably, when a chiral Lewis base promoter is employed, an enantioselective bromochlorination of chalcones is possible with up to a 92:8 enantiomeric ratio when utilizing only 1–3 mol % of (DHQD)2PHAL.

Catalytic Chemo-, Regio-, Diastereo-, and Enantioselective Bromochlorination of Unsaturated Systems Enabled by Lewis Base-Controlled Chloride Release

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Catalytic Chemo-, Regio-, Diastereo-, and Enantioselective Bromochlorination of Unsaturated Systems Enabled by Lewis Base-Controlled Chloride Release