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Here, we report a mild approach to the construction of the difluoroalkyl bicyclopentane and bicycloheptane (CF2-BCP and CF2-BCHep) units, as the structural surrogates of para- and meta-substituted aryl ketones and aryl ethers. The chemistry is orchestrated by the key activity of a dihydrobenzoacridine photocatalyst (PC). Depending by the nature of the substrate, the PC engages in catalytic electron-donor acceptor (EDA) complex or promotes the direct reduction of the substrate (Ered up to -1.9 V vs SCE) through a single-electron transfer (SET) mechanism. These two convergent manifolds leads to the generation of the reactive R-CF2 radical that reacts trough a strain-release atom-transfer-radical addition (ATRA) process with the [1.1.1]- or [3.1.1]-propellane. The method is general and tolerant of a variety of functional groups, such as sulfones, amines, amides or alkynes (30 examples, yields up to 90%), and extendable to complex bioactive molecules, including aminoacids, dipeptides or carbohydrates. The structural features of the CF2-BCP hybrid bioisostere were investigated in the solid state by single crystal X-ray analysis. Finally, we synthesised a CF2-BCP analogue of a Leukotriene A4 (LTA4) hydrolase inhibitor, replacing the original aryl ether motif. Interestingly, in-silico docking studies indicated that this new molecule maintains the same arrangement and key interactions within the enzyme pocket.

The conjugation of photoactive benzophenone with diphenylalanine yielded a self-assembling photocatalyst that was probed in the E → Z photoisomerisation of stilbene derivatives.

Photocatalysis has become a prominent tool in the arsenal of organic chemists to develop and (re)imagine transformations. However, only a handful of versatile organic photocatalysts (PCs) are available, hampering the discovery of new reactivities. Here, we report the design and complete physicochemical characterization of 9-aryl dihydroacridines (9ADA) and 12-aryl dihydrobenzoacridines (12ADBA) as strong reducing organic PCs. Punctual structural variations modulate their molecular orbital distributions and unlock locally or charge-transfer (CT) excited states. The PCs presenting a locally excited state showed better performances in photoredox defunctionalization processes (yields up to 92%), whereas the PCs featuring a CT excited state produced promising results in atom transfer radical polymerization under visible light (up to 1.21

A mild light-driven protocol for the direct alkylation of phenols is reported. The process is driven by the photochemical activity of a halogen-bonded complex formed upon complexation of the in situ generated electron-rich phenolate anion with the α-iodosulfone. The reaction proceeds rapidly (10 min) under microfluidic conditions, delivering a wide variety of ortho-alkylated products (27 examples, up to 97% yield, >20:1 regioselectivity, on a gram scale), including densely functionalized bioactive phenol derivatives.

By conducting in-depth mechanistic investigations to rationalize reaction manifolds, chemists can expand the generality of synthetic processes and discover novel reactivities. The challenge is to use the resulting information to control the selectivity of a given synthetic process. A particular challenge for organic chemists is to use an external stimulus to switch a reactivity on or off. Here, we mechanistically investigated light-driven [2+2] heterocycloadditions (Paternò-Büchi reactions) between indoles and ketones. We used ground-state UV-Vis absorption and transient absorption spectroscopy (TAS) at ns and fs timescale, together with DFT and TD-DFT calculations. We found that the reaction can proceed via an exciplex or electron-donor-acceptor (EDA) complex manifold, which are key intermediates in determining the reaction’s stereoselectivity. We used this discovery to control the reaction’s diastereoselectivity, gaining access to previously inaccessible diastereoisomeric variants. When moving from 370 to 456 nm irradiation, the EDA complex is increasingly favored, and the diastereomeric ratio dr (en-do:exo) moves from >99

Carbon nanodots stand as the missing link between the molecular and the nanoscale world, owing to the unique molecular-like behavior emerging from their synthetic precursors. A converging set of analytical and spectroscopic data yields a precise inventory of the surface reactive groups of amine-rich carbon dots (NCDs-1). As a result, NCDs-1 provide a multi-functional nano-platform that is able to covalently activate carbonyl groups, form iminium-ions and enamine intermediates, and efficiently promote diverse aminocatalytic transformations in water. Remarkably, the catalytic activity of carbon dots can also govern the stereoselectivity in the bond-forming event. Indeed, the use of chiral carbon dots (NCDs-7) as catalysts affords the final aldol products with significant enantiomeric excess. The successful implementation of carbon nanostructures into chemical roles so far restricted to molecular systems opens new avenues for advanced applications where the nanoscale and the molecular realms will merge and complement each other. What is the breakthrough expected for the next-generation nanomaterial? The programming of its structure and functions using “green” synthetic and up-scaling protocols? Low toxicity and application in advanced technology platforms? In this vision, carbon nanodots are a potential game-changer among all other forms of nanomaterials. Carbon nanodots are obtained under hydrothermal conditions from a blend of molecular reagents whose properties turn out to be encoded within the final material. Herein, we show that amine-rich carbon nanodots display a prominent molecular behavior in terms of (1) acid-base properties, (2) distribution of amino domains with different chemical environments, probed by 19F-tagging NMR spectroscopy, (3) formation of enamine and iminium catalytic intermediates, and (4) asymmetric catalysis. Carbon nanodots can, therefore, bridge the gap between homogeneous and heterogeneous catalysis, by transferring key molecular prerogatives at the horizon of nanoscale materials. A detailed characterization of nitrogen-rich carbon dots (NCDs) has been instrumental in unlocking their potential as novel colloidal organocatalysts in water media. As a result of their multi-functional properties, diverse aminocatalytic transformations of carbonyl compounds are efficiently mediated by NCDs under iminium-ion and enamine activation pathways. These include conjugate additions and aldol reactions occurring with remarkable efficiency (up to 96% yield) and complete diastereocontrol (d.r. >20:1) and are amenable to asymmetric catalysis applications in the presence of chiral NCDs.

We describe an efficient photocatalytic procedure for the direct iodosulfonylation of terminal olefins 3 with α-iodo phenylsulfones 4. Specifically, the process uses the simple, robust, and fully recyclable phenol derivative 6e as the precatalytic system and occurs with visible-light irradiation (450 nm). Mechanistic investigations proved the key role of the in situ generated photocatalyst, namely phenolate anion 7e, which has shown high catalytic activity and considerable stability toward the operating conditions. Importantly, this photocatalytic transformation provides a wide variety of densely functionalized alkyl iodides 5 (23 examples, up to 95% yield). Finally, the synthetic potential of this photochemical transformation was demonstrated by scaling up the process under microfluidic conditions (up to 0.67 mmol h–1) while accessing a series of relevant product manipulations.

The utilization of carbon dioxide as a raw material represents nowadays an appealing strategy in the renewable energy, organic synthesis, and green chemistry fields. Besides reduction strategies, carbon dioxide can be exploited as a single-carbon-atom building block through its fixation into organic scaffolds with the formation of new C-C bonds (carboxylation processes). In this case, activation of the organic substrate is commonly required, upon formation of a carbanion C−, being sufficiently reactive toward the addition of CO2. However, the prediction of the reactivity of C− with CO2 is often problematic with the process being possibly associated with unfavorable thermodynamics. In this contribution, we present a thermodynamic analysis combined with density functional theory calculations on 50 organic molecules enabling the achievement of a linear correlation of the standard free energy (ΔG0) of the carboxylation reaction with the basicity of the carbanion C−, expressed as the pKa of the CH/C− couple. The analysis identifies a threshold pKa of ca 36 (in CH3CN) for the CH/C− couple, above which the ΔG0 of the carboxylation reaction is negative and indicative of a favorable process. We then apply the model to a real case involving electrochemical carboxylation of flavone and chalcone as model compounds of α,β-unsaturated ketones. Carboxylation occurs in the β-position from the doubly reduced dianion intermediates of flavone and chalcone (calculated ΔG0 of carboxylation in β = −12.8 and −20.0 Kcalmol-1 for flavone and chalcone, respectively, associated with pKa values for the conjugate acids of 50.6 and 51.8, respectively). Conversely, the one-electron reduced radical anions are not reactive toward carboxylation (ΔG0 > +20 Kcalmol-1 for both substrates, in either α or β position, consistent with pKa of the conjugate acids < 18.5). For all the possible intermediates, the plot of calculated ΔG0 of carboxylation vs. pKa is consistent with the linear correlation model developed. The application of the ΔG0 vs. pKa correlation is finally discussed for alternative reaction mechanisms and for carboxylation of other C=C and C=O double bonds. These results offer a new mechanistic tool for the interpretation of the reactivity of CO2 with organic intermediates.

Herein is reported the asymmetric allylic benzylation of Morita-Baylis-Hillman (MBH) carbonates with 2-methylbenzophenone (MBP) derivatives as nonstabilized photogenerated C-nucleophiles. The dual activation of both reaction partners, chiral Lewis-base activation of the electrophile and light activation of the nucleophile, enables the stereoselective installation of benzyl groups at the allylic position to forge tertiary and quaternary carbon centers.

Twelve naphthochromenone photocatalysts (PCs) were synthesized on gram scale. They absorb across the UV/Vis range and feature an extremely wide redox window (up to 3.22 eV) that is accessible using simple visible light irradiation sources (CFL or LED). Their excited-state redox potentials, PC*/PC.- (up to 1.65 V) and PC.+ /PC* (up to -1.77 V vs. SCE), are such that these novel PCs can engage in both oxidative and reductive quenching mechanisms with strong thermodynamic requirements. The potential of these bimodal PCs was benchmarked in synthetically relevant photocatalytic processes with extreme thermodynamic requirements. Their ability to efficiently catalyze mechanistically opposite oxidative/reductive photoreactions is a unique feature of these organic photocatalysts, thus representing a decisive advance towards generality, sustainability, and cost efficiency in photocatalysis.

The first light-driven method for the alpha-trifluoromethoxylation of ketones is reported. Enol carbonates, in particular Boc derivatives, react with N-trifluoromethoxy-4-cyano-pyridinium triflimide (2a) using the photoredox-catalyst 4-CzIPN (5 mol-%) under irradiation at 456 nm affording the corresponding α-trifluoromethoxy ketones in up to 50% isolated yield and virtually complete chemoselectivity. As shown by 35 examples, representing a great variety of substrates, the reaction is general and proceeds rapidly under batch (1h) and flow conditions (2 min). Mechanistic investigations reveal that a radical-chain propagation is operative, as efficiently orchestrated by the activity of the organic photoredox catalyst. Diverse products manipulations, including ketone reduction and reductive amination, demonstrate the synthetic potential of the disclosed method to accessing elusive trifluoromethoxylated potentially bioactive ingredients.

A variety of highly functionalised N-containing polycycles (35 examples) are synthesised from simple indoles and aromatic ketones through a mild visible-light Paternò–Büchi process. Tetrahydrooxeto[2,3-b]indole scaffolds, with up to three contiguous all-substituted stereocenters, are generated in high yield (up to >98%) and excellent site- regio- and diastereocontrol (>20 : 1). The use of visible light (405 or 465 nm) ensures enhanced performances by switching off undesired photodimerisation side reactions. The reaction can be easily implemented using a microfluidic photoreactor with improved productivity (up to 0.176 mmol h−1) and generality. Mechanistic investigations revealed that two alternative reaction mechanisms can account for the excellent regio- and diastereocontrol observed., A scalable visible-light [2 + 2]-heterocycloaddition process allows the dearomatisation of indoles to complex biorelevant polycycles.

The first light-driven method for the α-trifluoromethoxylation of ketones is reported. Enol carbonates react with N-trifluoromethoxy-4-cyano-pyridinium, using the photoredox catalyst 4-CzIPN under 456 nm irradiation, affording the α-trifluoromethoxy ketones in ≤50% isolated yield and complete chemoselectivity. As shown by 29 examples, the reaction is general and proceeds very rapidly under batch (1 h) and flow conditions (2 min). Diverse product manipulations demonstrate the synthetic potential of the disclosed method in accessing elusive trifluoromethoxylated bioactive ingredients., Organic Letters, 23 (18), ISSN:1523-7060, ISSN:1523-7052

Herein we report an effective synthetic method for the direct assembly of highly functionalized tetracyclic pharmacophoric cores. Coumarins and chromones undergo diastereoselective [4 + 2] cycloaddition reactions with light-generated photoenol intermediates. The reactions occur by aid of a microfluidic photoreactor (MFP) in high yield (up to >98%) and virtually complete diastereocontrol (>20:1 dr). The method is easily scaled-up to a parallel setup, furnishing 948 mg of product over a 14 h reaction time. Finally, a series of manipulations of the tetracyclic scaffold obtained gave access to valuable precursors of biologically active molecules.

A large variety of highly functionalized N-containing polycycles (35 examples) are synthetized from simple indoles and aromatic ketones through a mild visible-light-driven [2+2]-heterocycloaddition process. Tetrahydrooxeto[2,3b]indole scaffolds, with up to three contiguous all-substituted stereo-centers are generated in high yield (up to >98%) and excellent site- regio- and diastereocontrol (>20:1). The use of visible light (405 or 465 nm) ensures enhanced performances by switching off undesired photodimerization reactions. Mechanistic investigations revealed that the operative reaction mechanism is dependent by the nature of the used ketone-substrate.

Touched for the very first time! It is herein highlighted how acetaldehyde silyl enol ethers undergo enantioselective Mukaiyama aldol reaction with aliphatic and aromatic aldehydes. The chemistry relies on the use of the highly efficient and substrate-selective imidodiphosphorimidate catalyst, which displays some of the features of enzymatic catalysis.

he photoenolization/Diels–Alder strategy offers straightforward access to synthetically valuable benzannulated carbocyclic products. This historical light-triggered process has never before succumbed to efforts to develop an enantioselective catalytic approach. Herein, we demonstrate how asymmetric organocatalysis provides simple yet effective catalytic tools to intercept photochemically generated hydroxy-o-quinodimethanes with high stereoselectivity. We used a chiral organic catalyst, derived from natural cinchona alkaloids, to activate maleimides toward highly stereoselective Diels–Alder reactions. An unconventional mechanism of stereocontrol is operative, wherein the organocatalyst is actively involved in both the photochemical pathway, by leveraging the formation of the reactive photoenol, and the stereoselectivity-defining event.

Reported herein is a light‐triggered organocatalytic strategy for the desymmetrization of achiral 2‐fluoro‐substituted cyclopentane‐1,3‐diketones. The chemistry is based on an intermolecular aldol reaction of photochemically generated hydroxy‐o‐quinodimethanes and simultaneously forges two adjacent fully substituted carbon stereocenters, with one bearing a stereogenic carbon–fluorine unit. The method uses readily available substrates, a simple chiral organocatalyst, and mild reaction conditions to afford an array of highly functionalized chiral 2‐fluoro‐3‐hydroxycyclopentanones.

Introduction: Aberrant phosphorylation-mediated signaling is a well-established condition involved in the onset and progression of virtually all types of cancer. That not only depends on the over-activation of protein kinases, but also on the lack of the proper counterbalance of protein phosphatases, because of their decreased expression or activity. In turn, this is likely to be due to genetic and epigenetic alterations, or interactions with cellular inhibitors and inhibitory post-translational modifications, respectively. In Large Granular Lymphocyte Leukemia (LGLL), a rare lymphoproliferative disorder characterized by clonal expansion of either cytotoxic T lymphocytes (T-LGLL) or natural killer cells (chronic lymphoproliferative disorder of NK cells, CLPD-NK), constitutive activation of phosphorylation-regulated survival pathways, especially the JAK2/STAT3 axis, but also PI3K/Akt and NF-κB pathways among others, has been found to account for the molecular mechanisms sustaining monoclonal cell proliferation and resistance to apoptosis. Interestingly, since such pathways are modulated by the tyrosine phosphatase SHP-1 under normal conditions, it is conceivable that putative alterations of this phosphatase, and consequent inability to disrupt hyperactive pathways, play a role in LGLL pathogenesis. In this study, we assessed the ability of small molecules inducing the expression and stimulating the activity of SHP-1 to abrogate the survival pathways in LGL by counteracting aberrant signals generated by constitutively activated protein kinases. Methods: Peripheral blood specimens were collected from untreated patients with LGLL (both T-LGLL and CLPD-NK). Peripheral blood mononuclear cells (PBMCs) were isolated by Ficoll-Hypaque (Sigma Aldrich) gradient separation. LGLs were further separated from PBMCs by using immunomagnetic beads (Miltenyi Biotec). LGLs were incubated either with acetyl-11-keto-β-boswellic acid (AKBA), a pentacyclic triterpene capable of inducing SHP-1 expression, or SC-78, a regorafenib-like derivative specifically stimulating SHP-1 activity, or both at increasing concentrations and discrete time points. After such treatments, LGLs underwent annexin V-PI flow cytometry to assess the extent of apoptosis or were lysed to monitor the abundance of SHP-1 and the phosphatase activity thereof. Moreover, the phosphorylation/activation status and the protein level of factors directly involved in the constitutively activated survival pathways of LGLs were evaluated by Western blot analysis. Results: Both AKBA and SC-78 proved effective at eliciting a significant level of apoptosis in the low micromolar range, exhibiting an additive effect when used in combination. Moreover, both compounds activated SHP-1 activity, as demonstrated by in-vitro phosphatase assays. As to the phosphorylation-dependent signals affected by SHP-1 activation, we observed a marked decrease in the phosphorylation status of STAT3, resulting in the downregulation of the STAT3-induced expression of downstream target genes (Mcl-1, survivin, Cyclin D and S1P5), as well as the dephosphorylation of Akt and p65, which confirmed the role of SHP-1 as a functional antagonist of survival pathways in LGLs. Conclusion: Taken together, our results support the newly emerging evidence that the targeted activation of SHP-1, which is already recognized as a tumor suppressor in other tumor cells, may serve as a mechanism countering the aberrant pro-survival signals, thus opening new options for the treatment of LGLL. Disclosures Zambello: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

A catalyst-free, environmentally benign three-component vinylogous Mukaiyama-Mannich reaction of pyrrole-based silyl dienolates is presented, which works effectively in both aqueous and solvent-free environments. Both lipophilic and hydrophilic aldehyde candidates are suitable substrates, allowing access to a rich repertoire of unsaturated vicinal aminolactam structures with virtually complete g-site selectivity and moderate to good anti-diastereoselectivity. The utility of this technology is highlighted by protecting group-free synthesis of densely hydroxylated, sugar-related lactam frameworks. The role of water as an indispensable H-bonding reaction propeller is demonstrated.

Abstract Cascade reactions are powerful tools for rapidly assembling complex molecular architectures from readily available starting materials in a single synthetic operation. Their marriage with asymmetric organocatalysis has led to the development of novel techniques, which are now recognized as reliable strategies for the one-pot enantioselective synthesis of stereochemically dense molecules. In recent years, even more complex synthetic challenges have been addressed by applying the principle of vinylogy to the realm of organocascade catalysis. The key to success of vinylogous organocascade reactions is the unique ability of the chiral organocatalyst to transfer reactivity to a distal position without losing control on the stereo-determining events. This approach has greatly expanded the synthetic horizons of the field by providing the possibility of forging multiple stereocenters in remote positions from the catalyst’s point of action with high selectivity while simultaneously constructing multiple new bonds. This article critically describes the developments achieved in the field of enantioselective vinylogous organocascade reactions, charting the ideas, the conceptual advances, and the milestone reactions that have been essential for reaching highly practical levels of synthetic efficiency.

Densely substituted pyrrole-carboxylates have been prepared in good yields in a highly practical one-pot three-step procedure. The key reaction of this process, which involves an uninterrupted sequence of reactions on-water, is a diastereoselective vinylogous Mukaiyama–Michael addition reaction (VMMcR) of heterocyclic 2-silyloxydienes to 1,2-diaza-1,3-dienes mediated by water itself. Subsequent in situ addition of catalytic aqueous sodium carbonate promotes an intramolecular aza-Michael addition with final ring-opening and aromatization. The superior use of water in the VMMcR as both reaction medium and promoter vis-a-vis deployment of conventional Lewis acids in organic solvents is highlighted, which provides the best results in terms of reaction rate, efficiency, stereoselectivity, and overall practicality.