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Enantioselective cyclopropanation of α-carbonyl sulfoxonium ylides (SY) has so far been limited to addition/ring closure reactions on electron-poor olefins. Herein, we report the iridium-catalyzed intramolecular cyclopropanation of SY in the presence of a chiral diene in up to 96% yield and 98% enantioselectivity. Moreover, density functional theory calculations suggest that the re face of the olefin preferably attacks an iridium carbene intermediate in an asynchronous concerted step that is independent of the geometry of the olefin.

(+)-Matrine and (+)-isomatrine are tetracyclic alkaloids isolated from the plant

Hybrid fused two-dimensional/three-dimensional (2D/3D) rings are important pharmacophores in drugs owing to their unique structural and physicochemical properties. Preparation of these strained ring systems often requires elaborate synthetic effort and exhibits low efficiency, thus representing a limiting factor in drug discovery. Here, we report two types of energy-transfer-mediated cascade dearomative [2 + 2] cycloaddition/rearrangement reactions of quinoline derivatives with alkenes, which provide a straightforward avenue to 2D/3D pyridine-fused 6−5−4−3- and 6−4−6-membered ring systems. Notably, this energy-transfer-mediated strategy features excellent diastereoselectivity that bypasses the general reactivity and selectivity issues of photochemical [2 + 2] cycloaddition of various other aromatics. Tuning the aza-arene substitutions enabled selective diversion of the iridium photocatalysed energy transfer manifold towards either cyclopropanation or cyclobutane-rearrangement products. Density functional theory calculations revealed a cascade energy transfer scenario to be operative.

p class="Abstract"span lang="EN-GB"Herein, we present a highly diastereoselective method to furnish acyclic 3-amino-1,5-diol derivatives using a tandem double-aldol-Tishchenko protocol (italicdr/italicup togt;99:1) using a butanone derived sulfinylimine. In most cases only 1 diastereomer predominates, from a possible 16. The reaction is also regioselective. In addition, the highly challenging cyclobutanone and 3-pentanone derivatives are also amenable to a double-aldol-Tishchenko reaction, although theitalicdr/italicvalues are modest. Despite that, clean single diastereoisomers can be isolated, which should prove very useful in medicinal chemistry and other areas. Detailed DFT calculations support the observed stereoselectivities in all cases, providing a rationale for the excellentitalicdr/italicvalues in the butanone series and the moderate values for the 3-pentanone class.o:p/o:p/span/p.

The Carothers equation is often used to predict the utility of a small molecule reaction in a polymerization. In this study, we present the mechanistic study of Pd/Ag cocatalyzed cross dehydrogenative coupling (CDC) polymerization to synthesize a donor-acceptor (D-A) polymer of 3,3'-dihexyl-2,2'-bithiophene and 2,2',3,3',5,5',6,6'-octafluorobiphenyl, which go counter to the Carothers equation. It is uncovered that the second chain extension cross-coupling proceeds much more efficiently than the first cross-coupling and the homocoupling side reaction (at least 1 order of magnitude faster) leading to unexpectedly low homocoupling defects and high molecular weight polymers. Kinetic analyses show that C-H bond activation is rate-determining in the first cross-coupling but not in the second cross-coupling. Based on DFT calculations, the high cross-coupling rate in the second cross-coupling was ascribed to the strong Pd-thiophene interaction in the Pd-mediated C-H bond activation transition state, which decreases the energy barrier of the Pd-mediated C-H bond activation. These results have implications beyond polymerizations and can be used to ease the synthesis of a wide range of molecules where C-H bond activation may be the limiting factor.

Methylene-selective C-H functionalization is a significant hurdle that remains to be addressed in the field of Pd(II) catalysis. We report a Pd(II)-catalyzed synthesis of benzocyclobutenes by methylene-selective C(sp3)-H arylation of ketones. The reaction utilizes glycine as a transient directing group and a 2-pyridone ligand, which may govern the methylene selectivity by making intimate molecular associations with the substrate during concerted metalation-deprotonation. This reaction is shown to be highly selective for intramolecular methylene C(sp3)-H arylation, thus enabling sequential C(sp3)-H functionalization.

In the biosynthesis of the tryptophan-linked dimeric diketopiperazines (DKPs), cytochromes P450 selectively couple DKP monomers to generate a variety of intricate and isomeric frameworks. To determine the molecular basis for selectivity of these biocatalysts we obtained a high-resolution crystal structure of selective Csp2-N bond forming dimerase, AspB. Overlay of the AspB structure onto C-C and C-N bond forming homolog NzeB revealed no significant structural variance to explain their divergent chemoselectivities. Molecular dynamics (MD) simulations identified a region of NzeB with increased conformational flexibility relative to AspB, and interchange of this region along with a single active site mutation led to a variant that catalyzes exclusive C-N bond formation. MD simulations also suggest that intermolecular C-C or C-N bond formation results from a change in mechanism, supported experimentally through use of a substrate mimic.

There have been significant advancements in radical-mediated reactions through covalent-based organocatalysis. Here, we present the generation of iminyl and amidyl radicals via N-heterocyclic carbene (NHC) catalysis, enabling diastereoselective aminoacylation of trisubstituted alkenes. Different from photoredox catalysis, single electron transfer from the deprotonated Breslow intermediate to

Silanes are important in chemistry and material science. The self-redistribution of HSiCl

Compared with the conventional Diels–Alder reaction, the development of selective cross-Diels–Alder reactions between two different conjugated dienes, especially in a catalytic asymmetric manner, has been neglected. We now report a peri- and enantioselective cross-Diels–Alder reaction of 3-alkoxycarbonyl-2-pyrones with unactivated conjugated dienes catalysed by a copper(II)–bis(oxazoline) complex, leading to formal inverse-electron-demand adducts with high enantioselectivity under mild reaction conditions. Computational studies showed that this reaction proceeds through an ambimodal transition state: post-transition-state bifurcation leads to [2+4] and [4+2] adducts with the same enantioselectivity, followed by a facile Cope rearrangement to provide a single observed thermodynamic [2+4] product. This reaction occurs with a wide variety of cyclopentadienes, fulvenes and cyclohexadienes, providing a highly efficient and enantioselective approach to densely functionalized cis-bicyclic scaffolds. The synthetic value of this reaction is demonstrated by the asymmetric synthesis of two biologically important natural products, artemisinic acid and coronafacic acid. Periselective catalytic asymmetric cross-Diels–Alder reactions between two different conjugated dienes remain underdeveloped. Now, the selectivity challenges are overcome in such a reaction of electron-poor 2-pyrones and unactivated conjugated dienes, and an ambimodal transition state is identified.

Summary The first catalytic asymmetric synthesis of N–N axially chiral compounds has been accomplished via a quinidine catalyzed N-allylic alkylation reaction. These N–N axially chiral frameworks are a new addition to the families of axially chiral molecules and to the atropisomerism involving heteroatom(s), e.g., N, O, and S. The reaction takes place smoothly under mild conditions and displays excellent functional group tolerance, allowing facile access to a variety of N–N axially chiral 1-aminopyrroles and 3-aminoquinazolinones in high yields and excellent enantioselectivities. DFT calculations have been applied to understand the origin of enantioselectivity and provide guidance for the design of additional molecules of this type. The investigation of N–N axis atropisomerism holds promise for new discoveries in medicinal chemistry and asymmetric catalysis.

The title compound was made by the reaction of the CpCo-complex of 2,3,7,8-tetrakis(trimethylsilyl) linear [3]phenylene, in which the metal coordinates one of the cyclobutadiene rings, with CpCo(C2H4)2. Because of its relative stability, a syn-dicobalt-bound configuration is indicated rather than its anti alternative.

We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.

The mechanisms by which the complexes CpCoL2 (Cp = C5H5; L = CO or CH2=CH2) mediate the cycloisomerizations of α,δ,ω-enynenes containing allylic ether linkages are probed by DFT methods. The outcomes corroborate experimental results and provide energetic and structural details of the trajectories leading to 3-(oxacyclopentyl or cycloalkyl)furans via the intermediacy of isolable CpCo-η 4-dienes. They comprise initial stereoselective complexation of one of the double bonds and the triple bond, rate-determining oxidative coupling to a triplet 16e cobalta-2-cyclopentene, and terminal double bond docking, followed by stereocontrolled insertion to assemble intermediate cis- and trans-fused triplet cobalta-4-cycloheptenes. A common indicator of the energetic facility of the latter is the extent of parallel alignment of the alkene moiety and its target Co–Cα bond. The cobalta-4-cycloheptenes transform further by β-hydride elimination–reductive elimination to furnish CpCo-η 4-dienes, which are sufficiently kinetically protected to allow for their experimental observation. The cascade continues through cobalt-mediated hydride shifts and dissociation of the aromatic furan ring. The findings in silico with respect to the stereo-, regio-, and chemoselectivity are in consonance with those obtained in vitro.

We report the catalytic generation of a vinyl Pd-oxyallyl that dimerizes regiospecifically to form highly functionalized nonbridged cyclooctanoids. Such compounds are otherwise synthetically challenging, but highly useful in synthesis. This vinyl Pd-oxyallyl species demonstrates both electrophilic and nucleophilic properties. DFT calculations elucidate the mechanism and the origins of the chemoselective cyclooctanoid formation.

Conventional analytic techniques that measure ensemble averages and static disorder provide essential knowledge of the reaction mechanisms of organic and organometallic reactions. However, single-molecule junctions enable the in situ, label-free and non-destructive sensing of molecular reaction processes at the single-event level with an excellent temporal resolution. Here we deciphered the mechanism of Pd-catalysed Suzuki-Miyaura coupling by means of a high-resolution single-molecule platform. Through molecular engineering, we covalently integrated a single molecule Pd catalyst into nanogapped graphene point electrodes. We detected sequential electrical signals that originated from oxidative addition/ligand exchange, pretransmetallation, transmetallation and reductive elimination in a periodic pattern. Our analysis shows that the transmetallation is the rate-determining step of the catalytic cycle and clarifies the controversial transmetallation mechanism. Furthermore, we determined the kinetic and thermodynamic constants of each elementary step and the overall catalytic timescale of this Suzuki-Miyaura coupling. Our work establishes the single-molecule platform as a detection technology for catalytic organochemistry that can monitor transition-metal-catalysed reactions in real time.

The introduction of thianthrene as a linchpin has proven to be a versatile strategy for the C-H functionalization of aromatic compounds, featuring a broad scope and fast diversification. The synthesis of aryl thianthrenium salts has displayed an unusually high para regioselectivity, notably superior to those observed in halogenation or borylation reactions for various substrates. We report an experimental and computational study on the mechanism of aromatic C-H thianthrenation reactions, with an emphasis on the elucidation of the reactive species and the nature of the exquisite site selectivity. Mechanisms involving a direct attack of arene to the isolated O-trifluoracetylthianthrene S-oxide (TT+-TFA) or to the thianthrene dication (TT2+) via electron transfer under acidic conditions are identified. A reversible interconversion of the different Wheland-type intermediates before a subsequent, irreversible deprotonation is proposed to be responsible for the exceptional para selectivity of the reaction.

We report herein a rare example of enantiodivergent aldehyde addition with β-alkenyl allylic boronates via chiral Brønsted acid catalysis. 2,6-Di-9-anthracenyl-substituted chiral phosphoric acid-catalyzed asymmetric allylation using β-vinyl substituted allylic boronate gave alcohols with R absolute configuration. The sense of asymmetric induction of the catalyst in these reactions is opposite to those in prior reports. Moreover, in the presence of the same acid catalyst, the reactions with β-2-propenyl substituted allylic boronate generated homoallylic alcohol products with S absolute configuration. Unusual substrate-catalyst C-H⋅⋅⋅π interactions in the favoured reaction transition state were identified as the origins of observed enantiodivergence through DFT computational studies.

Here we report a nonenzymatic glycosylation reaction that builds axial S-glycosidic bonds under biorelevant conditions. This strategy is enabled by the design and use of allyl glycosyl sulfones as precursors to glycosyl radicals and exploits the exceptional functional group tolerance of radical processes. Our method introduces a variety of unprotected glycosyl units to the cysteine residues of peptides in a highly selective fashion. Through developing the second-generation protocol, we applied our method in the direct glycosylation of complex polypeptides and proteins. Computational studies were performed to elucidate the reaction mechanism.

Synthetic chemistry is built around the formation of carbon–carbon bonds. However, the development of methods for selective carbon–carbon bond cleavage is a largely unmet challenge1–6. Such methods will have promising applications in synthesis, coal liquefaction, petroleum cracking, polymer degradation and biomass conversion. For example, aromatic rings are ubiquitous skeletal features in inert chemical feedstocks, but are inert to many reaction conditions owing to their aromaticity and low polarity. Over the past century, only a few methods under harsh conditions have achieved direct arene-ring modifications involving the cleavage of inert aromatic carbon–carbon bonds7,8, and arene-ring-cleavage reactions using stoichiometric transition-metal complexes or enzymes in bacteria are still limited9–11. Here we report a copper-catalysed selective arene-ring-opening reaction strategy. Our aerobic oxidative copper catalyst converts anilines, arylboronic acids, aryl azides, aryl halides, aryl triflates, aryl trimethylsiloxanes, aryl hydroxamic acids and aryl diazonium salts into alkenyl nitriles through selective carbon–carbon bond cleavage of arene rings. This chemistry was applied to the modification of polycyclic aromatics and the preparation of industrially important hexamethylenediamine and adipic acid derivatives. Several examples of the late-stage modification of complex molecules and fused ring compounds further support the potential broad utility of this methodology. Common aromatic rings, such as anilines, arylboronic acids and aryl halides, can be opened up and converted to alkenyl nitriles through carbon–carbon bond cleavage using a copper catalyst.

We report a computational and experimental study of the reaction of oxadiazinones and strained alkynes to give polycyclic aromatic hydrocarbons (PAHs). The reaction proceeds by way of a pericyclic reaction cascade and leads to the formation of four new carbon-carbon bonds. Using M06-2X DFT calculations, we interrogate several mechanistic aspects of the reaction, such as why the use of non-aromatic strained alkynes can be used to access unsymmetrical PAHs, whereas the use of arynes in the methodology leads to symmetrical PAHs. In addition, experimental studies enable the rapid synthesis of new PAHs, including tetracene and pentacene scaffolds. These studies not only provide fundamental insight regarding the aforementioned cycloaddition cascades and synthetic access to PAH scaffolds, but are also expected to enable the synthesis of new materials.

A kinetic, product, and computational study on the reactions of the cumyloxyl radical with monosubstituted cyclopentanes and cyclohexanes has been carried out. HAT rates, site-selectivities for C-H bond oxidation, and DFT computations provide quantitative information and theoretical models to explain the observed patterns. Cyclopentanes functionalize predominantly at C-1, and tertiary C-H bond activation barriers decrease on going from methyl- and tert-butylcyclopentane to phenylcyclopentane, in line with the computed C-H BDEs. With cyclohexanes, the relative importance of HAT from C-1 decreases on going from methyl- and phenylcyclohexane to ethyl-, isopropyl-, and tert-butylcyclohexane. Deactivation is also observed at C-2 with site-selectivity that progressively shifts to C-3 and C-4 with increasing substituent steric bulk. The site-selectivities observed in the corresponding oxidations promoted by ethyl(trifluoromethyl)dioxirane support this mechanistic picture. Comparison of these results with those obtained previously for C-H bond azidation and functionalizations promoted by the PINO radical of phenyl and tert-butylcyclohexane, together with new calculations, provides a mechanistic framework for understanding C-H bond functionalization of cycloalkanes. The nature of the HAT reagent, C-H bond strengths, and torsional effects are important determinants of site-selectivity, with the latter effects that play a major role in the reactions of oxygen-centered HAT reagents with monosubstituted cyclohexanes.

Strained cyclic allenes, first discovered in 1966 by Wittig and coworkers, have recently emerged as valuable synthetic building blocks. Previous experimental investigations, and computations reported here, demonstrate that the Diels–Alder reactions of furans and pyrroles to 1,2-cyclohexadiene and oxa and aza heterocyclic analogs proceed with endo selectivity. This unprecedented endo selectivity gives the adduct with the allylic saturated carbon of the cyclic allene endo to the diene carbons. The selectivity is very general and useful in synthetic applications. Our computational study establishes the origins of this endo selectivity. We analyze the helical frontier molecular orbitals of strained cyclic allenes and show how secondary orbital and electrostatic effects influence stereoselectivity. The LUMO of carbon-3 of the allene (C-3 is not involved in primary orbital interactions) interacts in a stabilizing fashion with the HOMO of the diene in such a way that the carbon of the cyclic allene attached to C-1 favors the endo position in the transition state. The furan LUMO, allene HOMO interaction reinforces this preference. These mechanistic studies are expected to prompt the further use of long-avoided strained cyclic allenes in chemical synthesis.

The SN2 reaction exhibits the classic Walden inversion, indicative of the stereospecific backside attack of the nucleophile on the stereogenic center. Observation of the inversion of the stereocenter provides evidence for an SN2-type displacement. However, this maxim is contingent on substitution proceeding on a discrete stereocenter. Here we report an SN2 reaction that leads to enantioenrichment of product despite starting from a racemic mixture of starting material. The enantioconvergent reaction proceeds through a dynamic Walden cycle, involving an equilibrating mixture of enantiomers, initiated by a chiral aminocatalyst and terminated by a stereoselective SN2 reaction at a tertiary carbon to provide a quaternary carbon stereocenter. A combination of computational, kinetic, and empirical studies elucidates the multifaceted role of the chiral organocatalyst to provide a model example of the Curtin-Hammett principle. These examples challenge the notion of enantioenriched products exclusively arising from predefined stereocenters when operating through an SN2 mechanism. Based on these principles, examples are included to highlight the generality of the mechanism. We anticipate the asymmetric SN2 dynamic kinetic resolution to be used for a variety of future reactions.

Computational studies with ωB97X-D density functional theory of the mechanisms of the steps in Trauner's biomimetic synthesis of preuisolactone A have elaborated and refined mechanisms of several unique processes. An ambimodal transition state has been identified for the cycloaddition between an o-quinone and a hydroxy-o-quinone; this leads to both (5 + 2) (with H shift) and (4 + 2) cycloaddition products, which can in principle interconvert via α-ketol rearrangements. The origins of periselectivity of this ambimodal cycloaddition have been investigated computationally with molecular dynamics simulations and tested further by an experimental study. In the presence of bicarbonate ions, the deprotonated hydroxy-o-quinone leads to only the (5 + 2) cycloaddition adduct. A new mechanism for a benzilic acid rearrangement resulting in ring contraction is proposed.

We report a dramatic effect on product outcomes of the lithium ion enabled amino-Cope-like anionic asymmetric cascade when different γ-dienolate heteroatom substituents are employed. For dienolates with azide, thiomethyl, and trifluoromethylthiol substituents, a Mannich/amino-Cope/cyclization cascade ensues to form chiral cyclohexenone products with two new stereocenters in an

We examine the theoretical underpinnings of the seminal discoveries by Reiner Sustmann about the ambiphilic nature of Huisgen's phenyl azide cycloadditions. Density functional calculations with ωB97X-D and B2PLYP-D3 reproduce the experimental data and provide insights into ambiphilic control of reactivity. Distortion/interaction-activation strain and energy decomposition analyses show why Sustmann's use of dipolarophile ionization potential is such a powerful predictor of reactivity. We add to Sustmann's data set several modern distortion-accelerated dipolarophiles used in bioorthogonal chemistry to show how these fit into the orbital energy criteria that are often used to understand cycloaddition reactivity. We show why such a simple indicator of reactivity is a powerful predictor of reaction rates that are actually controlled by a combination of distortion energies, charge transfer, closed-shell repulsion, polarization, and electrostatic effects.

Sequentially snipping off fluorines It is often useful in pharmaceutical or agrochemical research to modify the properties of carbon compounds by appending one or more fluorine atoms. However, the methods used to prepare mono-, di-, or trifluorocarbon centers tend to differ from each other in inconvenient ways. Yu et al. developed a radical reaction that can successively remove one or two fluorine atoms from trifluoromethyl groups adjacent to amides or esters. The mechanism relies on a spin-center shift after attack at the carbonyl oxygen by a boryl radical. Science , this issue p. 1232