Phosphine-Catalyzed Crossed Rauhut-Currier-Type Coupling and [3 + 2]-Cycloaddition of 2-Alkylidene-3-oxindoles with Alkenes and Allenes to Access β,γ-Unsaturated Enones and Polycyclic Oxindoles.

Dihydroazepino[1,2-]indole diones are tricyclic -acyl-2-alkylidene-3-oxindole enones that readily engage in tertiary phosphine-catalyzed intermolecular coupling reactions with acceptor-substituted alkenes. In these reactions, the tricyclic α-substituted enones undergo an α-alkylation with concomitant formation of a quaternary stereocenter, as well as the installation of a new double bond within the seven-membered azepane ring. The organocatalytic reaction constitutes a special case of the crossed intermolecular Rauhut-Currier reaction as the presence of the α-substituent in the enones prohibits the formation of an α,β-unsaturated product, but instead, skipped β,γ-unsaturated enones are obtained.

Visible light-induced iridium(III)-sensitized [2 + 2] and [3 + 2] photocycloadditions of 2-cyanochromone with alkenes.

2-Cyanochromone (1) readily undergoes visible light-induced photocycloadditions with diverse alkene partners mediated by (Ir[dF(CF)ppy](dtbpy))PF as the photosensitizer. While mono-, di- and trisubstituted styrenes and acrylonitriles as the reactants lead to [2 + 2] cycloadducts with good regiocontrol and high diastereoselectivity, the use of trialkyl-substituted alkenes allows for the isolation of cyclopentenone-fused chromones resulting from a [3 + 2] cycloaddition process in moderate yields.

Synthesis of azepane-fused pyrano[3,2-]indoles by Lewis acid-catalysed oxa Diels-Alder reactions.

The dihydroazepino[1,2-]indole diones 3 are tricyclic oxindole-type enones which are readily accessible by catalytic photooxygenation of cyclohepta[]indoles 1 followed by dehydration. Lewis acid-catalysed oxa Diels-Alder reactions of enones 3 with enol ethers 4 were developed that lead to novel tetracyclic azepane-fused pyrano[3,2-]indoles 5, with high stereoselectivity and under mild reaction conditions.

Photocatalytic Azetidine Synthesis by Aerobic Dehydrogenative [2 + 2] Cycloadditions of Amines with Alkenes.

Photocatalytic dehydrogenative [2 + 2] cycloadditions between amines and alkenes were developed that allow for the stereoselective and high-yielding synthesis of functionalized azetidines. The oxidative formal Aza Paternò-Büchi reactions are induced by photoredox-catalyzed aerobic oxidation of dihydroquinoxalinones as the amines, and in the presence of structurally diverse alkenes intermolecular [2 + 2] cyclization to dihydro-1-azeto[1,2-]quinoxalin-3(4)-ones occurs. The utility of the method is illustrated by the selective conversion of amino acid derived dihydroquinoxalinones , including oxidation-prone lysine and tryptophan derivatives.

Spirooxindol-1,3-oxazine Alkaloids: Highly Potent and Selective Antitumor Agents Evolved from Iterative Structure Optimization.

Spirooxindole-1,3-oxazines are a small and structurally unique class of spirooxindole alkaloids. To date, only four of these compounds have been isolated from natural sources, and their biological properties remained unknown thus far. Dioxyreserpine is a synthetic spirooxindole-1,3-oxazine, that can readily be prepared from the Rauvolfia alkaloid (-)-reserpine by catalytic photooxygenation.

A short total synthesis of (±)-mersicarpine visible light-induced cascade photooxygenation.

A short total synthesis of the alkaloid (±)-mersicarpine is presented. As the key step, a visible light-induced catalytic cascade photooxygenation was utilized, to convert a 3,3-disubstituted tetrahydrocarbazole intermediate, in one step, into a perhydropyrido[1,2-]indole dione as the immediate precursor to the natural product. The synthesis of mersicarpine was achieved with an overall yield of 12% over 13 steps.

Lewis Acid-Catalyzed Carbofunctionalization of Uncommon ,-Diacyliminium Ions: Controlling Regio- and Enantioselectivity.

The tricyclic azepino[1,2-]indole acetates , readily accessible by visible-light-driven catalytic photooxygenation of cyclohepta[]indoles , are convenient precursors to novel and uncommon cyclic ,-diacyliminium ions . We report here the first Lewis acid-catalyzed C-C bond forming reactions of these species with TMSCN and silyl enol ethers as nucleophiles and utilizing TIPSOTf as well as Sc(OTf) as catalysts. Employing Sc(OTf)/pybox complexes as a chiral catalyst system, regio- and enantioselective asymmetric alkylations with silyl enol ethers were achieved.

Value-added chemicals from biomass-derived furans: radical functionalisations of 5-chloromethylfurfural (CMF) by metal-free ATRA reactions.

Biomass-derived 5-chloromethylfurfural (CMF), a congener of the well-known carbohydrate-based platform chemical 5-hydroxymethylfurfural (HMF), can efficiently be functionalised by radical transformations of its benzylic chloromethyl group. We report here the first examples of these radical reactions by way of metal-free, triethylborane/oxygen-induced atom transfer radical addition (ATRA) reactions between CMF and styrenes, which proceed with high yield and selectivity. The key intermediate, the 2-formyl-5-furfuryl radical derived from CMF, and its radical addition reactions were studied with regard to its electronic structure, i.

Photoinduced iodine-mediated tandem dehydrogenative Povarov cyclisation/C-H oxygenation reactions.

We report metal-free, photoinduced aerobic tandem dehydrogenative Povarov cyclisation/C-H oxygenation reactions between N-aryl glycine esters and α-substituted styrenes, which efficiently lead to 4,4-disubstituted dihydroquinoline-3-ones under mild conditions. The reactions are mediated by iodine along with visible light irradiation, which allows for the in situ generation of the essential Brønsted acid HI, to catalyse the key imine [4+2]-cycloaddition.

Visible-Light Cascade Photooxygenation of Tetrahydrocarbazoles and Cyclohepta[b]indoles: Access to C,N-Diacyliminium Ions.

Tetrahydrocarbazoles and perhydrocyclohepta[b]indoles undergo a catalytic cascade singlet oxygenation in alkaline medium, which leads to chiral tricyclic perhydropyrido- and perhydroazepino[1,2-a]indoles in a single operation. These photooxygenation products are new synthetic equivalents of uncommon C,N-diacyliminium ions and can be functionalized with the aid of phosphoric acid organocatalysis.

Ligand Substitution of Ru -Alkylidenes to Ru(bpy) : Sequential Olefin Metathesis/Photoredox Catalysis.

Ruthenium(II) alkylidene complexes such as the Grubbs' 1st and 2nd generation catalysts undergo a ligand substitution with 2,2'-bipyridine, which readily leads to the common photoredox catalyst Ru(bpy) . The application of this catalyst transformation in sequential olefin metathesis/photoredox catalysis is demonstrated by way of ring-closing metathesis (RCM)/photoredox ATRA reactions.

Visible-Light-Mediated Aerobic Tandem Dehydrogenative Povarov/Aromatization Reaction: Synthesis of Isocryptolepines.

A metal-free, photoinduced aerobic tandem amine dehydrogenation/Povarov cyclization/aromatization reaction between N-aryl glycine esters and indoles leads to tetracyclic 11H-indolo[3,2-c]quinolines under mild conditions and with high yields. The reaction can be performed by using molecular iodine along with visible light, or by combining an organic photoredox catalyst with a halide anion. Mechanistic studies reveal that product formation occurs through a combination of radical-mediated oxidation steps with an iminium ion or N-haloiminium ion [4+2]-cycloaddition, and the N-heterocyclic products constitute new analogues of the antiplasmodial natural alkaloid isocryptolepine.

Visible-Light Catalytic Photooxygenation of Monoterpene Indole Alkaloids: Access to Spirooxindole-1,3-oxazines.

Few natural oxindole alkaloids possess an exceptional spiro-[(1,3)oxazinan-3,6'-oxindole] core structure, which results from an unusual oxidative indole rearrangement. The Rauvolfia alkaloid reserpine can be converted into the spirooxindole-1,3-oxazines dioxyreserpine and trioxyreserpine through efficient visible-light catalytic photooxygenation with anthraquinone photocatalysts. A mechanistic investigation sheds new light on the photooxidative rearrangement of reserpine and related monoterpene indole alkaloids, and the spirooxindole-1,3-oxazine products can be valorized by reductive ring opening, to obtain cis-decahydroisoquinolines as new enantiopure synthetic building blocks, as demonstrated for dioxyreserpine.

"Super-Reducing" Photocatalysis: Consecutive Energy and Electron Transfers with Polycyclic Aromatic Hydrocarbons.

Donation welcome: Recent developments in visible-light photocatalysis allow the utilization of increasingly negative reduction potentials. Successive energy and electron transfer with polycyclic aromatic hydrocarbons enables the catalytic formation of strongly reducing arene radical anions, classical stoichiometric reagents for one-electron reduction in organic synthesis.

A Photoredox-Induced Stereoselective Dearomative Radical (4+2)-Cyclization/1,4-Addition Cascade for the Synthesis of Highly Functionalized Hexahydro-1H-carbazoles.

A stereoselective synthesis of functionalized hexahydrocarbazoles was developed based on an unprecedented photoredox-induced dearomative radical (4+2)-cyclization/1,4-addition cascade between 3-(2-iodoethyl)indoles and acceptor-substituted alkenes. The title reaction simultaneously generates three C-C bonds and one C-H bond, along with three contiguous stereogenic centers. The hexahydro-1H-carbazole products are highly valuable intermediates for the synthesis of novel antibiotics, as well as unnatural ring homologues of polycyclic indoline alkaloids.

Photoassisted oxidation of ruthenium(II)-photocatalysts Ru(bpy)3(2+) and Ru(bpz)3(2+) to RuO4: orthogonal tandem photoredox and oxidation catalysis.

Common photoredox catalysts Ru(bpy)3(2+) and Ru(bpz)3(2+) are rapidly converted into Ruthenium(viii)-oxide through continuous visible light irradiation in the presence of NaIO4 or H5IO6. This hitherto unreported photoassisted catalyst oxidation was utilized in the development of tandem catalytic protocols which combine a photoredox reaction with a subsequent RuO4-mediated oxidation. The new concept was demonstrated through one-pot radical cation Diels-Alder (RCDA)/1,5-diene cyclisation sequences.

Iridium(III) Photocatalysis: A Visible-Light-Induced Dearomatizative Tandem [4+2] Cyclization to Furnish Benzindolizidines.

A photocatalytic dearomatizative tandem [4+2] cyclization between N-(2-iodoethyl)indoles and a variety of alkenes leads to tri- and tetracyclic benzindolizidines with high diastereoselectivity and yield. The intermolecular annulation reaction is performed under visible-light irradiation and employs [Ir(ppy)3] or [Ir(dtbbpy)(ppy)2] PF6 as photocatalysts, in combination with tertiary amines as electron and hydrogen atom donors.

A visible light photocatalytic cross-dehydrogenative coupling/dehydrogenation/6π-cyclization/oxidation cascade: synthesis of 12-nitroindoloisoquinolines from 2-aryltetrahydroisoquinolines.

A visible light-induced photocatalytic dehydrogenation/6π-cyclization/oxidation cascade converts 1-(nitromethyl)-2-aryl-1,2,3,4-tetrahydroisoquinolines into novel 12-nitro-substituted tetracyclic indolo[2,1-a]isoquinoline derivatives. Various photocatalysts promote the reaction in the presence of air and a base, the most efficient being 1-aminoanthraquinone in combination with K3 PO4 . Further, the 12-nitroindoloisoquinoline products can be accessed directly from C1-unfunctionalized 2-aryl-1,2,3,4-tetrahydroisoquinolines by extending the one-pot protocol with a foregoing photocatalytic cross-dehydrogenative coupling reaction, resulting in a quadruple cascade transformation.

Tandem organocatalysis and photocatalysis: an anthraquinone-catalyzed indole-C3-alkylation/photooxidation/1,2-shift sequence.

Quinones exhibit orthogonal ground- and excited-state reactivities and are therefore highly suitable organocatalysts for the development of sequential catalytic processes. Herein, the discovery of an anthraquinone-catalyzed thermal indole-C3-alkylation with benzylamines is described, which can be combined sequentially with a new visible-light-driven catalytic photooxidation/1,2-shift reaction. The one-flask tandem process converts indoles into 3-benzylindole intermediates, which are further transformed into new fluorescent 2,2-disubstituted indoline-3-one derivatives.

A gram-scale batch and flow total synthesis of perhydrohistrionicotoxin.

The total synthesis of the spiropiperidine alkaloid (-)-perhydrohistrionicotoxin (perhydro-HTX) 2 has been accomplished on a gram scale by employing both conventional batch chemistry as well as microreactor techniques. (S)-(-)-6-Pentyltetrahydro-pyran-2-one 8 underwent nucleophilic ring opening to afford the alcohol 10, which was elaborated to the nitrone 13. Protection of the nitrone as the 1,3-adduct of styrene and side-chain extension to the unsaturated nitrile afforded a precursor 17, which underwent dipolar cycloreversion and 1,3-dipolar cycloaddition to give the core spirocyclic precursor 18 that was converted into perhydro-HTX 2.

Sugars, alkaloids, and heteroaromatics: exploring heterocyclic chemistry with alkoxyallenes.

As master craftsmen, modern synthetic chemists are challenged to achieve remarkable feats of efficiency and elegance toward molecular targets. The nature of this pursuit necessitates the collection of synthetic repertoires that are tried and true. With methodologies and pathways increasingly scrutinized, the adept chemist must seek out propitious tools to incorporate into the arsenal.