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This work reports on dye sensitized photoanodes for C-H activation in organic substrates, assembled by vacuum sublimation of a commercially available quinacridone (QNC) dye in the form of nanosized rods onto Fluorine doped tin oxide (FTO), TiO2 and SnO2 slides. The photoanodes display extended absorption in the visible (450-600 nm) and ultrafast photoinduced electron injection (1 ps, as revealed by transient absorption spectroscopy) of the QNC dye into the semiconductor. The proton-coupled electron-transfer reactivity of QNC is exploited for generating a nitrogen-based radical as its oxidized form, which is competent in C-H bond activation. In particular, the key reactivity parameter is the bond dissociation free energy (BDFE) associated with the N•/N-H couple in QNC of 80.5±2.3 kcalmol-1, which enables hydrogen atom abstraction from allylic or benzylic C-H moieties. A photoelectrochemical response is indeed observed for organic substrates characterized by C-H bonds with BDFE below the 80.5 kcalmol-1 threshold, such as γ-terpinene, xanthene, dihydroanthracene. This work opens a rationale and mechanistically oriented design of dye-sensitized photoelectrodes for selective organic transformations.

Modern photocatalysis has proven its generality for the development and functionalization of native functionalities. To date, the field has found broad applications in diverse research areas, including the total synthesis of natural products. This contribution covers recent reports of total syntheses involving as a key step a photocatalytic reaction. Among the selected examples, the photocatalytic processes proceed in a highly chemo-, regio-, and stereoselective manner, thereby allowing the rapid access to structurally complex architectures under light-driven conditions.

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.

In this Account, we summarize the contributions of our group to the field of photochemistry and photocatalysis. Our work deals with the development of novel synthetic methods based on the exploitation of photoexcited aryl ketones. The application of new technologies, such as microfluidic photoreactors (MFPs), has enhanced the synthetic performance and scalability of several photochemical methods, e.g., Paternò–Büchi and photoenolization/Diels–Alder processes, while opening the way to unprecedented reactivity. In addition, careful mechanistic analysis of the developed methods has been instrumental in disclosing a new family of powerful organic photocatalysts that can mediate several thermodynamically extreme photoredox processes.1 Introduction1.1 Shining Light on Aryl Ketones: From the Historical Background to Recent Synthetic Applications1.2 Preliminary Mechanistic Considerations2 Synthetic Transformations Driven by Triplet State Benzophenones3 Synthetic Transformations Driven by Triplet State o-Alkyl-Substituted Benzophenones4 The Evolution of Aryl-Ketone-Derived Products: Applications in Organophotoredox Catalysis5 Conclusions and Future Directions

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.

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.

In the last decade, photoredox catalysis has unlocked unprecedented reactivities in synthetic organic chemistry. Seminal advancements in the field have involved the use of well-studied metal complexes as photoredox catalysts (PCs). More recently, the synthetic community, looking for more sustainable approaches, has been moving towards the use of purely organic molecules. Organic PCs are generally cheaper and less toxic, while allowing their rational modification to an increased generality. Furthermore, organic PCs have allowed reactivities that are inaccessible by using common metal complexes. Likewise, in synthetic catalysis, the field of photocatalysis is now experiencing a green evolution moving from metal catalysis to organocatalysis. In this feature article, we discuss and critically comment on the scientific reasons for this ongoing evolution in the field of photoredox catalysis, showing how and when organic PCs can efficiently replace their metal counterparts.

The synthesis of a set of new organic photocatalysts (PCs) with a donor-acceptor carbazolyl dicyanobenzene structure is reported. The PCs developed have fine-tailored redox potentials from –1.62 V (PC•+/PC*) to 1.36 V (PC*/PC•–) and were accessed through a straightforward two-step synthesis. The potential of these PCs was demonstrated in synthetically relevant reactions with mechanistically opposite thermodynamic requirements, previously reported only in the presence of precious Ir-based PCs. In addition, the PCs outperformed the yields promoted by the well-established 4CzIPN organic dye in both type of reactions.

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 synthesis of four membered heterocycles usually requires multi-step procedures and prefunctionalized reactants. A straightforward alternative is the photochemical [2+2]-heterocycloaddition between an alkene and a carbonyl derivative, conventionally based on the photoexcitation of this latter. However, this approach is limited by the absorption profile of the carbonyl, requiring in most of the cases the use of high-energy UV-light, that often results in undesired side reactions and/or the degradation of the reaction components. The development of new and milder visible light-driven [2+2]-heterocycloadditions is, therefore, highly desirable. In this Review, we highlight the most relevant achievements in the development of [2+2]-heterocycloadditions promoted by visible light, with a particular emphasis on the involved reaction mechanisms. The open challenges will also be discussed, suggesting new possible evolution, and stimulating new methodological developments in the field.

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.

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.

Asymmetric catalysis is a rapidly evolving field in synthetic chemistry. This is due to the growing needs of stereoselective synthetic routes to access enantiopure natural products and bioactive mo...

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

Organic photocatalysts are emerging as viable and more sustainable tools than metal complexes. Recently, the field of organo-photocatalysis has experienced an explosion in terms of applications, redesign of well-established systems, and identification of novel scaffolds. A rational approach to the structural modification of the different photocatalysts is key to accessing unprecedented reactivity, while improving their catalytic performances. We herein discuss the concepts underpinning the scaffold modification of some of the most recently used photocatalysts and analyze how specific structural changes alter their physicochemical and redox properties.

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.

CO2 is the ultimate renewable carbon source on Earth and the essential C1 building block for carbohydrate biosynthesis in photosynthetic organisms. Modern synthetic chemistry is facing the key challenge of developing fundamental transformations, such as C-C bond formation, in a sustainable and efficient manner from renewable sources. In this Minireview, the most significant methods recently reported for CO2 fixation under transition metal-free conditions are summarized, organized into three different chapters according to the nature of the chemical transformation that forges the new C-C bond. The focus is on the mechanistic aspects of the different CO2 activation modes, with specific attention to those systems that operate under catalytic conditions.

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.

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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.

A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings. The chemistry utilizes, for the first time, remotely enolizable π-extended allylidenemalononitriles as electron-rich 1,3-diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic α,β-unsaturated aldehydes. The generality of the process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-, and 6,5,6-fused ring systems, as well as biorelevant steroid-like 6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism for the key [4+2] addition is proposed as a domino bis-vinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated.

Light-driven reactions of 2-methylbenzophenones (2-MBPs) occur with improved yields (up to >98%) and reaction rates (up to 0.240 mmol h−1) by using a tailored microfluidic photoreactor (MFP). For the first time, coumarins were converted into 4-benzylated chromanones in high yields (50–93%) and diastereoselectivity (up to >20 : 1 dr), thus by-passing their photo-dimerisation end-reaction.

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.

The direct organocatalytic enantioselective benzylation by using toluenes and α,β-unsaturated aldehydes is presented. The reaction is catalyzed by tert-butyldimethylsilyl-protected diphenylprolinol in the presence of a mild organic base and proceeds with excellent yields and enantioselectivities up to >99 % ee. This reactivity is based on a synergistic effect between the iminium ion intermediate and the base-activated toluene. Toluene derivatives having various electron-withdrawing substituents were also applied in this unprecedented transformation. The synthetic potential is demonstrated by manipulations of the products to, for example, biologically active phenylbenzazepines.

Organocatalysis is shown to expand the classical reactivity pattern for conjugate addition reactions. It is demonstrated that the site selectivity can be extended from 1,4- to 1,6-additions for the enantioselective vinylogous additions of methyl-substituted vinylogous lactones to enals and 2,4-dienals. This novel reactivity is demonstrated for methyl-substituted olefinic azlactones and butyrolactones. Their synthetic potential is first highlighted by the development of the organocatalytic regioselective vinylogous 1,4-addition to enals which proceeds with a very high level of double-bond geometry control and excellent enantioselectivity. The concept is developed further for the unprecedented intermolecular enantioselective organocatalyzed vinylogous 1,6-addition to linear 2,4-dienals, by which the site selectivity of the process is extended from the β-position to the remote δ-position of the 2,4-dienal. The organocatalyst controls the newly generated stereocenter six bonds away from the stereocenter of the catalyst with a high level of enantiocontrol, and the products are obtained with full control of double-bonds configuration. The scope of these new reaction concepts is demonstrated for a series of aliphatic and aryl-substituted enals and 2,4-dienals undergoing enantioselective vinylogous reactions with methyl-substituted olefinic azlactones and butyrolactones. Furthermore, mechanistic considerations are presented which can account for the change from 1,4- to 1,6-selectivity. Finally, a number of different transformations of the optically active 1,4- and 1,6-addition products are demonstrated.

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 the 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.