γ-Amino Alcohols via Energy Transfer Enabled Brook Rearrangement.

In the long-standing quest to synthesize fundamental building blocks with key functional group motifs, photochemistry in the recent past has comprehensively established its attractiveness. Amino alcohols are not only functionally diverse but are ubiquitous in the biologically active realm of compounds. We developed bench-stable bifunctional reagents that could then access the sparsely reported γ-amino alcohols directly from feedstock alkenes through energy transfer (EnT) photocatalysis. A designed 1,3-linkage across alkenes is made possible by the intervention of a radical Brook rearrangement that takes place downstream to the EnT-mediated homolysis of our reagent(s). A combination of experimental mechanistic investigations and detailed computational studies (DFT) indicates a radical chain propagated reaction pathway.

Double Strain-Release [2π+2σ]-Photocycloaddition.

In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small ring units have the additional merit of loaded strain at their core, making them suitable reactants as they can capitalize on this intrinsic driving force. With the introduction of cyclobutenone as a strained precursor to ketene, the photocycloaddition with another strained unit, bicyclo[1.1.0]butane (BCB), enables the reactivity of both π-units in the transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes the synthesis of diverse heterobicyclo[2.1.1]hexane units, a pharmaceutically relevant bioisostere. The effective reactivity under catalyst-free conditions with a high functional group tolerance defines its synthetic utility. Experimental mechanistic studies and density functional theory (DFT) calculations suggest that the [2π+2σ]-photocycloaddition takes place via a triplet mechanism.

Photoredox-Enabled Dearomative [2π + 2σ] Cycloaddition of Phenols.

Dearomative photocycloaddition of monocyclic arenes is an appealing strategy for comprehending the concept of "escape from flatland". This brings the replacement of readily available planar aromatic hydrocarbon units with a 3D fused bicyclic core with sp3-enriched carbon units. Herein, we outline an intermolecular approach for the dearomative photocycloaddition of phenols. In order to circumvent the ground-state aromaticity and to construct conformationally restrained building blocks, bicyclo[1.1.0]butanes were chosen as coupling partners. This dearomative approach renders straightforward access to a bicyclo[2.1.1]hexane unit fused to a cyclic enone moiety, which further contributed as a synthetic linchpin for postmodifications. Mechanistic experiment advocates for a plausible onset from both the reactants, depending on the redox potential.

Energy transfer photocatalysis: exciting modes of reactivity.

Excited (triplet) states offer a myriad of attractive synthetic pathways, including cycloadditions, selective homolytic bond cleavages and strain-release chemistry, isomerizations, deracemizations, or the fusion with metal catalysis. Recent years have seen enormous advantages in enabling these reactivity modes through visible-light-mediated triplet-triplet energy transfer catalysis (TTEnT). This tutorial review provides an overview of this emerging strategy for synthesizing sought-after organic motifs in a mild, selective, and sustainable manner. Building on the photophysical foundations of energy transfer, this review also discusses catalyst design, as well as the challenges and opportunities of energy transfer catalysis.

Combinatorial Ligand Assisted Simultaneous Control of Axial and Central Chirality in Highly Stereoselective C-H Allylation.

The significance of stereoselective C-H bond functionalization thrives on its direct application potential to pharmaceuticals or complex chiral molecule synthesis. Complication arises when there are multiple stereogenic elements such as a center and an axis of chirality to control. Over the years cooperative assistance of multiple chiral ligands has been applied to control only chiral centers. In this work, we harness the essence of cooperative ligand approach to control two different stereogenic elements in the same molecule by atroposelective allylation to synthesize axially chiral biaryls from its racemic precursor. The crucial roles played by chiral phosphoric acid and chiral amino acid ligand in concert helped us to obtain one major stereoisomer out of four distinct possibilities.

syn-Selective Difunctionalization of Bicyclobutanes Enabled by Photoredox-Mediated C-S σ-Bond Scission.

Given the importance of cyclic frameworks in molecular scaffolds and drug discovery, it is intriguing to precisely forge and manipulate ring systems in synthetic chemistry. In this field, the intermolecular synthesis of densely substituted cyclobutanes with precise diastereocontrol under simple reaction conditions remains a challenge. Herein, a photoredox strategy for the difunctionalization of bicyclo[1.1.0]butanes (BCBs) under high regio- and syn-selectivity is disclosed. C-S σ-bond cleavage of partially unsaturated sulfur-containing bifunctional reagents in an overall strain-release-driven process enables the thio-alkynylation, -alkenylation, and -allylation of BCBs under mild conditions and demonstrates the generality of this protocol. Mechanistic studies suggest that the intermediacy of cyclic distonic radical cations might be key for the efficient scission of C-S σ-bonds and the origin of diastereoselectivity.

Dearomative ring expansion of thiophenes by bicyclobutane insertion.

Skeletal ring enlargement is gaining renewed interest in synthetic chemistry and has recently focused on insertion of one or two atoms. Strategies for heterocyclic expansion through small-ring insertion remain elusive, although they would lead to the efficient formation of bicyclic products. Here, we report a photoinduced dearomative ring enlargement of thiophenes by insertion of bicyclo[1.1.0]butanes to produce eight-membered bicyclic rings under mild conditions. The synthetic value, broad functional-group compatibility, and excellent chemo- and regioselectivity were demonstrated by scope evaluation and product derivatization. Experimental and computational studies point toward a photoredox-induced radical pathway.

ortho-Selective Dearomative [2π + 2σ] Photocycloadditions of Bicyclic Aza-Arenes.

Dearomative photocycloadditions are valuable chemical transformations, serving as an efficient platform to create three-dimensional molecular complexity. However, the photolability of the original addition product especially within the context of ortho cycloadditions often causes undesired consecutive rearrangements, rendering these ortho cycloadducts elusive. Herein, we report an ortho-selective intermolecular photocycloaddition of bicyclic aza-arenes including (iso)quinolines, quinazolines, and quinoxalines by utilizing a strain-release approach. With bicyclo[1.1.0]butanes as coupling partners, this dearomative [2π + 2σ] cycloaddition enables the straightforward construction of C(sp3)-rich bicyclo[2.1.1]hexanes directly connected to N-heteroarenes. Photophysical experiments and DFT calculations revealed the origin of the [2π + 2σ] selectivity and indicate that, in addition to the originally proposed energy transfer or direct excitation pathways, a chain reaction mechanism is operative depending on the reaction conditions.

Hatemongers ride on echo chambers to escalate hate speech diffusion.

Recent years have witnessed a swelling rise of hateful and abusive content over online social networks. While detection and moderation of hate speech have been the early go-to countermeasures, the solution requires a deeper exploration of the dynamics of hate generation and propagation. We analyze more than 32 million posts from over 6.8 million users across three popular online social networks to investigate the interrelations between hateful behavior, information dissemination, and polarized organization mediated by echo chambers. We find that hatemongers play a more crucial role in governing the spread of information compared to singled-out hateful content. This observation holds for both the growth of information cascades as well as the conglomeration of hateful actors. Dissection of the core-wise distribution of these networks points towards the fact that hateful users acquire a more well-connected position in the social network and often flock together to build up information cascades. We observe that this cohesion is far from mere organized behavior; instead, in these networks, hatemongers dominate the echo chambers-groups of users actively align themselves to specific ideological positions. The observed dominance of hateful users to inflate information cascades is primarily via user interactions amplified within these echo chambers. We conclude our study with a cautionary note that popularity-based recommendation of content is susceptible to be exploited by hatemongers given their potential to escalate content popularity via echo-chambered interactions.

cis-Selective Hydrogenation of Aryl Germanes: A Direct Approach to Access Saturated Carbo- and Heterocyclic Germanes.

A catalytic approach of synthesizing the cis-selective saturated carbo- and heterocyclic germanium compounds (3D framework) is reported via the hydrogenation of readily accessible aromatic germanes (2D framework). Among the numerous catalysts tested, Nishimura's catalyst (Rh2O3/PtO2·H2O) exhibited the best hydrogenation reactivity with an isolated yield of up to 96%. A broad range of substrates including the synthesis of unprecedented saturated heterocyclic germanes was explored. This selective hydrogenation strategy could tolerate several functional groups such as -CF3, -OR, -F, -Bpin, and -SiR3 groups. The synthesized products demonstrated the applications in coupling reactions including the newly developed strategy of aza-Giese-type addition reaction (C-N bond formation) from the saturated cyclic germane product. These versatile motifs can have a substantial value in organic synthesis and medicinal chemistry as they show orthogonal reactivity in coupling reactions while competing with other coupling partners such as boranes or silanes, acquiring a three-dimensional structure with high stability and robustness.

EnT-Mediated N-S Bond Homolysis of a Bifunctional Reagent Leading to Aliphatic Sulfonyl Fluorides.

Sulfur(VI) fluoride exchange (SuFEx) gives rise to a plethora of high-valent sulfur linkages; however, the availability of (aliphatic) sulfonyl fluoride manifolds lag behind, owing to the limited sources of introducing the SO2F moiety via a classical two-electron approach. Recently, radical-based methodologies have emerged as a complementary strategy to increase the diversity of accessible click partners. In this work, synthesis of a bench-stable sulfamoyl fluoride reagent is presented, which may undergo sigma-bond homolysis upon visible-light-induced sensitization to form protected ß-amino sulfonyl fluorides from alkene feedstocks. Notably, this offers an appealing strategy to access various building blocks for peptido sulfonyl fluorides, relevant in a medicinal chemistry context, as well as an intriguing entry to ß-ammonium sulfonates and ß-sultams, from alkenes. Densely functionalized 1,3-sultones were obtained by employing allyl alcohols as substrates. Surprisingly, allyl chloride-derived ß-imino sulfonyl fluoride underwent S-O bond formation and ring closure to yield rigid cyclopropyl ß-imino sulfonate ester under SuFEx conditions. Furthermore, by engaging a thiol-based hydrogen atom donor in the reaction, the reactivity of the same reagent can be tuned toward the direct synthesis of aliphatic sulfonyl fluorides. Mechanistic experiments indicate an energy transfer (EnT)-mediated process. The transient sulfonyl fluoride radical adds to the alkene and product formation occurs upon either radical-radical coupling or hydrogen atom transfer (HAT), respectively.

Chromium/Photoredox Dual Catalyzed Synthesis of α-Benzylic Alcohols, Isochromanones, 1,2-Oxy Alcohols and 1,2-Thio Alcohols.

Herein, a Cr/Photoredox-catalyzed general synthetic strategy to access α-benzylic alcohols, isochromanones, oxy alcohols and thio alcohols is unveiled. Alkylation of aldehydes being a crucial C-C bond forming reaction, designing competent catalytic systems would render an attractive and decorated set of diverse alcohol motifs. Considering the challenges associated with classical organometallic chemistry, the strategy of dual catalysis is applied here to generate diverse alcohol motifs in a mild and efficient manner. The amalgamation of photocatalysis with chromium chemistry is chosen for this purpose to generate an environment with low basicity and thus, high chemoselectivity. With alkyl silanes as preferred coupling partners, this catalytic setup produces a broad substrate scope with an excellent functional group tolerance and displays a facile scale-up as well. Its application towards biologically relevant molecules and product diversification contributes to the synthetic utility of this method.

Intermolecular [2π+2σ]-photocycloaddition enabled by triplet energy transfer.

For more than one century, photochemical [2+2]-cycloadditions have been used by synthetic chemists to make cyclobutanes, four-membered carbon-based rings. In this reaction, typically two olefin subunits (two π-electrons per olefin) cyclize to form two new C-C σ-bonds. Although the development of photochemical [2+2]-cycloadditions has made enormous progress within the last century, research has been focused on such [2π+2π]-systems, in which two π-bonds are converted into two new σ-bonds1,2. Here we report an intermolecular [2+2]-photocycloaddition that uses bicyclo[1.1.0]butanes as 2σ-electron reactants3-7. This strain-release-driven [2π+2σ]-photocycloaddition reaction was realized by visible-light-mediated triplet energy transfer catalysis8,9. A simple, modular and diastereoselective synthesis of bicyclo[2.1.1]hexanes from heterocyclic olefin coupling partners, namely coumarins, flavones and indoles, is disclosed. Given the increasing importance of bicyclo[2.1.1]hexanes as bioisosteres-groups that convey similar biological properties to those they replace-in pharmaceutical research and considering their limited access10,11, there remains a need for new synthetic methodologies. Applying this strategy enabled us to extend the intermolecular [2+2]-photocycloadditions to σ-bonds and provides previously inaccessible structural motifs.

Transition metal catalyzed C-H bond activation by exo-metallacycle intermediates.

exo-Metallacycles have become the key reaction intermediates in activating various remote C(sp2)-H and C(sp3)-H bonds in the past decade and aided in achieving unusual site-selectivity. Various novel exo-chelating auxiliaries have assisted metals to reach desired remote C-H bonds of different alcohol and amine-derived substrates. As a result, a wide range of organic transformations of C-H bonds like halogenation, acetoxylation, amidation, sulfonylation, olefination, acylation, arylation, etc. were accessible using the exo-metallacycle strategy. In this review, we have summarized the developments in C-H bond activation via four-, five-, six-, seven- and eight-membered exo-metallacycles and the key reaction intermediates, including the mechanistic aspects, are discussed concisely.

Accessing C2-Functionalized 1,3-(Benz)azoles through Transition Metal-Catalyzed C-H Activation.

The skeletal presence of 1,3-azoles in a variety of bioactive natural products, pharmacophores, and organic materials demands the derivatization of such heteroarenes regioselectively. Plenty of cross-coupling as well as cyclocondensation reactions have been performed to build up these skeletons but remained commercially unrealizable. A couple of severe drawbacks are faced by these traditional protocols that require a more straightforward strategy to obviate them. Transition metal-catalyzed C-H functionalization has emerged as a superior alternative in that context. 1,3-Azoles and their benzo counterparts have been extensively functionalized exploiting both noble and earth-abundant transition metals. Lately, C-2 functionalization have gained much traction due to the ease of attaining high regioselectivity and installation of synthetically manipulative functionalities. This critical review presents a bird's eye view of all major C-2 functionalization of (benz)azoles catalyzed by a diverse set of metals performed over the past 15 years.

Cobalt-Catalyzed C(sp2)-H Allylation of Biphenyl Amines with Unbiased Terminal Olefins.

Unactivated olefins usually react poorly in conventional alkenylation reactions. Their introduction via C-H activation is limited to aromatic acids. Herein, we disclose a C-H functionalization protocol of aromatic amines with unactivated olefins, which shows exclusive allylic selectivity for the distal ring of the biphenyl system by exploiting a readily available cobalt(II) catalyst. The allylation proceeds smoothly involving a broad set of unbiased olefins and biaryls, giving access to the functionalization of the biphenyl scaffold.

Cloning and Expression of Phytase appA Gene from Shigella sp. CD2 in Pichia pastoris and Comparison of Properties with Recombinant Enzyme Expressed in E. coli.

The phytase gene appAS was isolated from Shigella sp. CD2 genomic library. The 3.8 kb DNA fragment contained 1299 bp open reading frame encoding 432 amino acid protein (AppAS) with 22 amino acid signal peptide at N-terminal and three sites of N-glycosylation. AppAS contained the active site RHGXRXP and HDTN sequence motifs, which are conserved among histidine acid phosphatases. It showed maximum identity with phytase AppA of Escherichia coli and Citrobacter braakii. The appAS was expressed in Pichia pastoris and E. coli to produce recombinant phytase rAppAP and rAppAE, respectively. Purified glycosylated rAppAP and nonglycosylated rAppAE had specific activity of 967 and 2982 U mg(-1), respectively. Both had pH optima of 5.5 and temperature optima of 60°C. Compared with rAppAE, rAppAP was 13 and 17% less active at pH 3.5 and 7.5 and 11 and 18% less active at temperature 37 and 50°C, respectively; however, it was more active at higher incubation temperatures. Thermotolerance of rAppAP was 33% greater at 60°C and 24% greater at 70°C, when compared with rAppAE. Both the recombinant enzymes showed high specificity to phytate and resistance to trypsin. To our knowledge, this is the first report on cloning and expression of phytase from Shigella sp.