Oxygen mediated oxidative couplings of flavones in alkaline water.

Catalyzed oxidative C-C bond coupling reactions play an important role in the chemical synthesis of complex natural products of medicinal importance. However, the poor functional group tolerance renders them unfit for the synthesis of naturally occurring polyphenolic flavones. We find that molecular oxygen in alkaline water acts as a hydrogen atom acceptor and oxidant in catalyst-free (without added catalyst) oxidative coupling of luteolin and other flavones. By this facile method, we achieve the synthesis of a small collection of flavone dimers and trimers including naturally occurring dicranolomin, philonotisflavone, dehydrohegoflavone, distichumtriluteolin, and cyclodistichumtriluteolin. Mechanistic studies using both experimental and computational chemistry uncover the underlying reasons for optimal pH, oxygen availability, and counter-cations that define the success of the reaction. We expect our reaction opens up a green and sustainable way to synthesize flavonoid dimers and oligomers using the readily available monomeric flavonoids isolated from biomass and exploiting their use for health care products and treatment of diseases.

Late-Stage C(sp2 )-H Functionalization: A Powerful Toolkit To Arm Natural Products for In Situ Proteome Profiling?

The comprehensive investigation of target interactions from native cellular environments is of paramount importance for natural products and related bioactive compounds in drug discovery and chemical biology. Current chemoproteomic tools, such as in situ proteome profiling can do so effectively, but rely heavily on "tagged" probes that are accessible through traditional organic synthesis at the reactive sites of a compound, which may often be required for target binding. Late-stage functionalization may resolve such limitations by tagging compounds in a single step at biologically inert C-H bonds. Herein, recent advances in late-stage C(sp2 )-H functionalization of (hetero)arenes, which are present in many natural products, are summarized, and new toolkits for more widespread use of such strategies to install natural products with next-generation "minimalist" linkers for in situ proteome profiling are suggested.

Photoinduced site-selective alkenylation of alkanes and aldehydes with aryl alkenes.

The dehydrogenative alkenylation of C-H bonds with alkenes represents an atom- and step-economical approach for olefin synthesis and molecular editing. Site-selective alkenylation of alkanes and aldehydes with the C-H substrate as the limiting reagent holds significant synthetic value. We herein report a photocatalytic method for the direct alkenylation of alkanes and aldehydes with aryl alkenes in the absence of any external oxidant. A diverse range of commodity feedstocks and pharmaceutical compounds are smoothly alkenylated in useful yields with the C-H partner as the limiting reagent. The late-stage alkenylation of complex molecules occurs with high levels of site selectivity for sterically accessible and electron-rich C-H bonds. This strategy relies on the synergistic combination of direct hydrogen atom transfer photocatalysis with cobaloxime-mediated hydrogen-evolution cross-coupling, which promises to inspire additional perspectives for selective C-H functionalizations in a green manner.

Visible light driven deuteration of formyl C-H and hydridic C(sp3)-H bonds in feedstock chemicals and pharmaceutical molecules.

Deuterium labelled compounds are of significant importance in chemical mechanism investigations, mass spectrometric studies, diagnoses of drug metabolisms, and pharmaceutical discovery. Herein, we report an efficient hydrogen deuterium exchange reaction using deuterium oxide (D2O) as the deuterium source, enabled by merging a tetra-n-butylammonium decatungstate (TBADT) hydrogen atom transfer photocatalyst and a thiol catalyst under light irradiation at 390 nm. This deuteration protocol is effective with formyl C-H bonds and a wide range of hydridic C(sp3)-H bonds (e.g. α-oxy, α-thioxy, α-amino, benzylic, and unactivated tertiary C(sp3)-H bonds). It has been successfully applied to the high incorporation of deuterium in 38 feedstock chemicals, 15 pharmaceutical compounds, and 6 drug precursors. Sequential deuteration between formyl C-H bonds of aldehydes and other activated hydridic C(sp3)-H bonds can be achieved in a selective manner.

Asymmetric Synthesis of 1,4-Dicarbonyl Compounds from Aldehydes by Hydrogen Atom Transfer Photocatalysis and Chiral Lewis Acid Catalysis.

Enantioenriched 1,4-dicarbonyl compounds are versatile synthons in natural product and pharmaceutical drug synthesis. We herein report a mild pathway for the efficient enantioselective synthesis of these compounds directly from aldehydes through synergistic cooperation between a neutral eosin Y hydrogen atom transfer photocatalyst and a chiral rhodium Lewis acid catalyst. This method is distinguished by its operational simplicity, abundant feedstocks, atom economy, and ability to generate products in high yields (up to 99 %) and high enantioselectivity (up to 99 % ee).

Diastereodivergent asymmetric Michael-alkylation reactions using chiral N,N'-dioxide/metal complexes.

A diastereodivergent asymmetric Michael-alkylation reaction between 3-chloro-oxindoles and ß,γ-unsaturated-α-ketoesters has been achieved using L-RaPr2 /Sc(OTf)3 and L-PrPr2 /Mg(OTf)2 metal complexes as catalysts. Both rel-(1R,2S,3R) and rel-(1S,2S,3R) chiral spiro cyclopropane oxindoles were constructed in good yields, diastereoselectivities and ee values. The diastereodivergent control may originate from different alkylation pathways after the Michael addition, with either intramolecular trapping of the aza-ortho-xylylene intermediate or direct SN2 substitution.

Ni-catalyzed two-component reductive dicarbofunctionalization of alkenes via radical cyclization.

A reductive dicarbofunctionalization reaction of alkenes has been developed and applied to the preparation of substituted carbo- and heterocycles. The reaction conditions avoid the use of air-sensitive organometallic reagents, and are compatible with a broad range of bromo-electrophiles and a wide variety of substituents to give cyclic products in excellent yields.

Asymmetric synthesis of spiro-epoxyoxindoles by the catalytic Darzens reaction of isatins with phenacyl bromides.

The asymmetric Darzens reaction between phenacyl bromides and N-protected isatins was developed to synthesize potentially bioactive spiro-epoxyoxindoles. The optically active products were obtained in moderate to good yields and enantioselectivities catalyzed by chiral N,N'-dioxide-Co(acac)2 complexes. A retro-aldol process accompanying the ring-closure step was observed in the process. A chiral control step was determined to be the initial aldol addition.

Magnesium(II)-catalyzed asymmetric hetero-Diels-Alder reaction of Brassard's dienes with isatins.

The first catalytic asymmetric hetero-Diels-Alder reaction of Brassard's dienes with isatins was realized using Mg(II)/N,N'-dioxide complexes as catalysts, affording the corresponding chiral spirolactones bearing tetrasubstituted centers in up to 99% yield with up to 99% ee and >99 : 1 dr within 3 hours. In the mechanism, based on the operando IR experiments, a predominant Diels-Alder pathway was found in the reaction. A possible transition state model was also proposed.

Iron-catalyzed asymmetric haloamination reactions.

The first iron(III)/N,N'-dioxide-catalyzed asymmetric haloamination of 3-alkylidene- and 3-arylidene-indolin-2-ones was developed, affording the corresponding chiral oxindole derivatives bearing vicinal haloamine substituents with excellent results (up to 99% yield, 99% ee, >19 : 1 dr). This iron catalyst also exhibits perfect enantioselectivity for chalcone derivatives. The cooperative activation of the substrate and the reagent in concert guarantees the high stereoselectivity.

Asymmetric catalytic 1,3-dipolar cycloaddition reaction of nitrile imines for the synthesis of chiral spiro-pyrazoline-oxindoles.

A new 1,3-dipolar cycloaddition of nitrile imines with 3-alkenyl-oxindoles was catalyzed by a new chiral Mg(ClO(4))(2) complex of an N,N'-dioxide ligand. The reaction is so far the sole catalytic synthesis of spiro-pyrazoline-oxindole derivatives. A wide variety of substrates were explored to obtain good yields (up to 98%) and excellent enantioselectivities (up to 99%). This cycloaddition expands the scope of propargyl anion type 1,3-dipole in the construction of 2-pyrazoline subunit.

Catalytic asymmetric conjugate allylation of coumarins.

A catalytic asymmetric conjugate allylation was successfully developed to synthesize potential pharmacologically active 4-allyl-2-oxochroman skeletons. A dual activation strategy was employed by using N,N'-dioxide-Yb(OTf)(3) to activate coumarins and using (CuOTf)(2)•C(7)H(8) to activate tetraallyltin via transmetalation, respectively. Good yields and enantioselectivities were obtained under mild conditions.

Indium(III)-catalyzed asymmetric hetero-Diels-Alder reaction of Brassard-type diene with aliphatic aldehydes.

A highly diastereo- and enantioselective hetero-Diels-Alder (HDA) reaction of a Brassard-type diene with aliphatic aldehydes has been developed. The chiral N,N'-dioxide L2/In(OTf)(3) complex was efficient toward the obtention of the corresponding ß-methoxy-γ-methyl α,ß-unsaturated δ-lactones in good yields (up to 86%) as well as dr and ee values (up to 97:3 cis/trans and 94% ee). In addition, the product 4a could be easily transformed into the methyl-protected epi-prelactone B by hydrogenation.

N,N'-dioxide-Cu(OTf)(2) complex catalyzed highly enantioselective amination reaction of N-acetyl enamide.

The N,N'-dioxide-Cu(OTf)(2) complexes were applied in the asymmetric amination reaction of N-acetyl enamides with dialkyl azodicarboxylate, giving the corresponding products in good yields with high enantioselectivities (up to 91% ee). Precursors of vicinal diamine were readily obtained with excellent diastereoselectivities (>95:5) by NaBH(4) reduction.