Photoredox-Catalyzed Strain-Release-Driven Synthesis of Functionalized Spirocyclobutyl Oxindoles.

Spirocyclobutyl oxindoles have garnered substantial attention in drug discovery and pharmaceuticals owing to their wide range of biological activities. Strain-release in small-ring compounds is a powerful strategy to enable efficient access to complex molecules. In this study, we successfully realized a photoredox-catalyzed strain-release radical spirocyclization approach to attain functionalized spirocyclobutyl oxindoles.

Strain-enabled radical spirocyclization cascades: rapid access to spirocyclobutyl lactones and - lactams.

Spirocyclobutane derivatives have gained significant attention in drug discovery programs due to their broad spectrum of biological activities and clinical applications. Ring-strain in organic molecules is a powerful tool to promote reactivity by releasing strain energy, allowing the construction of complex molecules selectively and efficiently. Herein, we report the first strain-enabled radical spirocyclization cascades for the synthesis of functionalized spirocyclobutyl lactones and - lactams, which are finding increasing applications in medicinal chemistry.

A highly diastereoselective strain-release Doyle-Kirmse reaction: access to functionalized difluoro(methylene)cyclopropanes.

Difluoro(methylene)cyclopropanes (F2MCPs) show better anti-cancer properties and chemical reactivities compared to their nonfluorinated analogues. However, catalytic stereoselective methods to access these privileged motifs still remain a challenging goal. The Doyle-Kirmse reaction is a powerful strategy for the concomitant formation of carbon-carbon and carbon-sulfur bonds.

Photocatalyzed Dowd-Beckwith radical-polar crossover reaction for the synthesis of medium-sized carbocyclic compounds.

The Dowd-Beckwith reaction, a ring-expansion of carbonyl compounds alkoxy radicals, is a powerful approach for synthesizing medium to large-sized carbocyclic scaffolds, which takes advantage of existing ring structures and avoids entropic and enthalpic factors that arise from the end-to-end cyclization strategies. However, the Dowd-Beckwith ring-expansion followed by H-atom abstraction is still the dominating pathway, which hampers its synthetic applications, and there currently exist no reports on the functionalization of ring-expanded radicals using non-carbon based nucleophilic reagents. Herein, we report a redox-neutral decarboxylative Dowd-Beckwith/radical-polar crossover (RPC) sequence that delivers functionalized medium-sized carbocyclic compounds with broad functional group tolerance.

Photoinduced Temperature-Regulated Selective Carbene C-H Insertion for the Synthesis of Functionalized Spiro-β-lactones and -lactams.

A temperature-regulated catalyst-free photoinduced selective carbene C-H insertion strategy was realized to efficiently synthesize spiro--lactones and -lactams, which hold considerable promise in drug discovery programs. The reaction shows broad applicability across a range of α-diazo esters and amides with various ring sizes and substituents and has been demonstrated to successfully achieve the late-stage spirocyclization of natural/bioactive compounds. The obtained products could be transformed into spiro-oxetanes, -azetidines, and -cyclopropanes, privileged scaffolds with broad utility in medicinal chemistry.

Amphiphilic Iodine(III) Reagents for the Lipophilization of Peptides in Water.

We report the functionalization of cysteine residues with lipophilic alkynes bearing a silyl group or an alkyl chain using amphiphilic ethynylbenziodoxolone reagents (EBXs). The reactions were carried out in buffer (pH 6 to 9), without organic co-solvent or removal of oxygen, either at 37 °C or room temperature. The transformation led to a significant increase of peptide lipophilicity and worked for aromatic thiols, homocysteine, cysteine, and peptides containing 4 to 18 amino acids.

Highly Diastereoselective Strain-Increase Allylborations: Rapid Access to Alkylidenecyclopropanes and Alkylidenecyclobutanes.

Allylboration of carbonyl compounds is one of the most widely used methods in the stereoselective synthesis of natural products. However, these powerful transformations are so far limited to allyl- or crotylboron reagents; ring-strained substituents in the α-position have not been investigated. Such substrates would lead to an increase in strain energy upon allylboration and as such cause a significant increase in the activation barrier of the reaction.

Low-Temperature Intramolecular [4+2] Cycloaddition of Allenes with Arenes for the Synthesis of Diene Ligands.

The intramolecular [4+2] cycloaddition between arenes and allenes first reported by Himbert gives rapid access to rigid polycyclic scaffolds. Herein, we report a one-pot oxyalkynylation/cycloaddition reaction proceeding under mild conditions (23-90 °C) and providing complex polycyclic architectures with high efficiency, and atom and step economy. The bicyclo[2.

Ring-Expansion Induced 1,2-Metalate Rearrangements: Highly Diastereoselective Synthesis of Cyclobutyl Boronic Esters.

The broad synthetic utility of organoboron compounds stems from their ready ability to undergo 1,2-migrations. Normally, such shifts are induced by α-leaving groups or by reactions of alkenyl boronates with electrophiles. Herein, we present a new strategy to induce 1,2-metalate rearrangements, via ring expansion of vinylcyclopropyl boronate complexes activated by electrophiles.

Ethynylbenziodazolones (EBZ) as Electrophilic Alkynylation Reagents for the Highly Enantioselective Copper-Catalyzed Oxyalkynylation of Diazo Compounds.

Ethynylbenziodoxol(on)e (EBX) cyclic hypervalent iodine reagents are now established reagents for the alkynylation of radicals and nucleophiles, yet they present limited possibilities for further structure and reactivity modification. Herein, the first synthesis is reported for the corresponding ethynylbenziodazolone (EBZ) reagents, in which the oxygen atom in the iodoheterocycle is replaced by a nitrogen atom. The substituent on the nitrogen enables further fine-tuning of the reagent structure and reactivity.

Cyclic Hypervalent Iodine Reagents: Enabling Tools for Bond Disconnection via Reactivity Umpolung.

The efficient synthesis of organic compounds is an important field of research, which sets the basis for numerous applications in medicine or materials science. Based on the polarity induced by functional groups, logical bond disconnections can be deduced for the elaboration of organic compounds. Nevertheless, this classical approach makes synthesis rigid, as not all bond disconnections are possible.

Correction: Community structure informs species geographic distributions.

[This corrects the article DOI: 10.1371/journal.pone.

Enantioselective Copper-Catalyzed Oxy-Alkynylation of Diazo Compounds.

Enantioselective catalytic methods allowing the addition of both a nucleophile and an electrophile onto diazo compounds give a fast access into important building blocks. Herein, we report the highly enantioselective oxyalkynylation of diazo compounds using ethynylbenziodoxol-(on)e reagents and a simple copper bisoxazoline catalyst. The obtained α-benzoyloxy propargylic esters are useful building blocks, which are difficult to synthesize in enantiopure form using other methods.

Cyclic Hypervalent Iodine Reagents for Atom-Transfer Reactions: Beyond Trifluoromethylation.

Hypervalent iodine compounds are privileged reagents in organic synthesis because of their exceptional reactivity. Among these compounds, cyclic derivatives stand apart because of their enhanced stability. They have been widely used as oxidants, but their potential for functional-group transfer has only begun to be investigated recently.

Copper-Catalyzed Oxy-Alkynylation of Diazo Compounds with Hypervalent Iodine Reagents.

Alkynes have found widespread applications in synthetic chemistry, biology, and materials sciences. In recent years, methods based on electrophilic alkynylation with hypervalent iodine reagents have made acetylene synthesis more flexible and efficient, but they lead to the formation of one equivalent of an iodoarene as side-product. Herein, a more efficient strategy involving a copper-catalyzed oxy-alkynylation of diazo compounds with ethynylbenziodoxol(on)e (EBX) reagents is described, which proceeds with generation of nitrogen gas as the only waste.

Fast and highly chemoselective alkynylation of thiols with hypervalent iodine reagents enabled through a low energy barrier concerted mechanism.

Among all functional groups, alkynes occupy a privileged position in synthetic and medicinal chemistry, chemical biology, and materials science. Thioalkynes, in particular, are highly useful, as they combine the enhanced reactivity of the triple bond with a sulfur atom frequently encountered in bioactive compounds and materials. Nevertheless, general methods to access these compounds are lacking.

Synthetic applications of eosin Y in photoredox catalysis.

Eosin Y, a long known dye molecule, has recently been widely applied as a photoredox catalyst in organic synthesis. Low cost and good availability make eosin Y an attractive alternative to typical inorganic transition metal photocatalysts. We summarize the key photophysical properties of the dye and the recent synthetic applications in photoredox catalysis.

The photoredox-catalyzed Meerwein addition reaction: intermolecular amino-arylation of alkenes.

A variety of amides are efficiently accessible under mild conditions by intermolecular amino-arylation using a photo Meerwein addition with visible light. The reaction has a broad substrate scope, tolerates a large range of functional groups, and was applied to the synthesis of a 3-aryl-3,4-dihydroisoquinoline.

The photocatalyzed Meerwein arylation: classic reaction of aryl diazonium salts in a new light.

The use of diazonium salts for aryl radical generation and C-H arylation processes has been known since 1896 when Pschorr first used the reaction for intramolecular cyclizations. Meerwein developed it further in the early 1900s into a general arylation method. However, this reaction could not compete with the transition-metal-mediated formation of C(sp(2))-C(sp(2)) bonds.

Visible-light-mediated α-arylation of enol acetates using aryl diazonium salts.

Visible light mediates efficiently the α-arylation of enol acetates by aryl diazonium salts under mild conditions using [Ru(bpy)(3)]Cl(2) as a photoredox catalyst. The broad scope of the reaction toward various diazonium salts and enol acetates was explored. The application of this reaction in the concise synthesis of 2-substituted indoles was demonstrated.

Visible light photocatalytic synthesis of benzothiophenes.

The photocatalytic reaction of o-methylthio-arenediazonium salts with alkynes yields substituted benzothiophenes regioselectively through a radical annulation process. Green light irradiation of eosin Y initiates the photoredox catalysis. The scope of the reaction was investigated by using various substituted diazonium salts and different alkynes.

Metal-free, visible-light-mediated direct C-H arylation of heteroarenes with aryl diazonium salts.

Visible light along with 1 mol % eosin Y catalyzes the direct C-H bond arylation of heteroarenes with aryl diazonium salts by a photoredox process. We have investigated the scope of the reaction for several aryl diazonium salts and heteroarenes. The general and easy procedure provides a transition-metal-free alternative for the formation of aryl-heteroaryl bonds.

Eosin Y catalyzed visible light oxidative C-C and C-P bond formation.

Eosin Y catalyzes efficiently the visible light mediated coupling of sp(3) C-H bonds adjacent to the nitrogen atom in tetrahydroisoquinoline derivatives in the absence of an external oxidant. Nitroalkanes, dialkyl malonates, malononitrile, and dialkyl phophonates were used as pronucleophiles in this metal-free, visible light oxidative coupling reaction.