Organocatalytic asymmetric mannich-type reactions: an easy approach to optically active amine derivatives

The topics I came across during the period I spent as a Ph.D. student are mainly two. The first concerns new organocatalytic protocols for Mannich-type reactions mediated by Cinchona alkaloids derivatives (Scheme I, left); the second topic, instead, regards the study of a new approach towards the enantioselective total synthesis of Aspirochlorine, a potent gliotoxin that recent studies indicate as a highly selective and active agent against fungi (Scheme I, right). At the beginning of 2005 I had the chance to join the group of Prof. Alfredo Ricci at the Department of Organic Chemistry of the University of Bologna, starting my PhD studies. During the first period I started to study a new homogeneous organocatalytic aza-Henry reaction by means of Cinchona alkaloid derivatives as chiral base catalysts with good results. Soon after we introduced a new protocol which allowed the in situ synthesis of N-carbamoyl imines, scarcely stable, moisture sensitive compounds. For this purpose we used α-amido sulfones, bench stable white crystalline solids, as imine precursors (Scheme II). In particular we were able to obtain the aza-Henry adducts, by using chiral phase transfer catalysis, with a broad range of substituents as R-group and excellent results, unprecedented for Mannich-type transformations (Scheme II). With the optimised protocol in hand we have extended the methodology to the other Mannich-type reactions. We applied the new method to the Mannich, Strecker and Pudovik (hydrophosphonylation of imines) reactions with very good results in terms of enantioselections and yields, broadening the usefulness of this novel protocol. The Mannich reaction was certainly the most extensively studied work in this thesis (Scheme III). Initially we developed the reaction with α-amido sulfones as imine precursors and non-commercially available malonates with excellent results in terms of yields and enantioselections.3 In this particular case we recorded 1 mol% of catalyst loading, very low for organocatalytic processes. Then we thought to develop a new Mannich reaction by using simpler malonates, such as dimethyl malonate.4 With new optimised condition the reaction provided slightly lower enantioselections than the previous protocol, but the Mannich adducts were very versatile for the obtainment of β3-amino acids. Furthermore we performed the first addition of cyclic β-ketoester to α-amido sulfones obtaining the corresponding products in good yield with high level of diastereomeric and enantiomeric excess (Scheme III). Further studies were done about the Strecker reaction mediated by Cinchona alkaloid phase-transfer quaternary ammonium salt derivatives, using acetone cyanohydrin, a relatively harmless cyanide source (Scheme IV). The reaction proceeded very well providing the corresponding α-amino nitriles in good yields and enantiomeric excesses. Finally, we developed two new complementary methodologies for the hydrophosphonylation of imines (Scheme V). As a result of the low stability of the products derived from aromatic imines, we performed the reactions in mild homogeneous basic condition by using quinine as a chiral base catalyst giving the α-aryl-α-amido phosphonic acid esters as products (Scheme V, top).6 On the other hand, we performed the addition of dialkyl phosphite to aliphatic imines by using chiral Cinchona alkaloid phase transfer quaternary ammonium salt derivatives using our methodology based on α-amido sulfones (Scheme V, bottom). The results were good for both procedures covering a broad range of α-amino phosphonic acid ester. During the second year Ph.D. studies, I spent six months in the group of Prof. Steven V. Ley, at the Department of Chemistry of the University of Cambridge, in United Kingdom. During this fruitful period I have been involved in a project concerning the enantioselective synthesis of Aspirochlorine. We provided a new route for the synthesis of a key intermediate, reducing the number of steps and increasing the overall yield. Then we introduced a new enantioselective spirocyclisation for the synthesis of a chiral building block for the completion of the synthesis (Scheme VI).

Gold Catalyzed Functionalization Of Alkynes And Allenamides

The gold(I)-catalyzed chemoselective dearomatization of β-naphthols is reported through a straightforward approach via [3,3]-sigmatropic rearrangement /allene-cyclyzation cascade processes. Easily accessed naphthyl-propargyl ethers and derivatives in this work are employed as starting materials. Delightfully, an array of deoramatized dyhydrofuryl -naphthalen-2(1H)-ones featured densely functional groups are obtained in high yields (up to 98%) in 10 min reaction time under extremely mild reaction conditions like reagent grade solvent and exposure to air. The potential of accessing to high enantioselectivety on the dearomatized dyhydrofuryl- naphthalen-2(1H)-ones is also approved by the good ee (65%) relying on (R)-xylyl- BINAP(AuCl)2. In addition, complete theoretical elucidation of the reaction pathway is also proposed which addresses a rationale for essential motivation such as regio- and chemoselectivity. Moreover, an efficient gold catalyzed intermolecular dearomatization of substituted β-naphthols with allenamides is presented here. PPh3AuTFA (5 mol %) approves the efficient dearomatively allylation protocol under mild conditions and exhibits high tolerance on substrates scope (24 examples) in good to excellent yield accompanied with high regioselectivity and stereoselectivity. Moreover, the synergistic catalytic system also highlight the synergistic function between the [PPh3Au]+ (π-acid) and TFA− (Lewis base). At last, a new chiral BINOL phosphoric acid silver salt is successfully synthesized and used as the chiral counter anion, which strongly promotes the enantioselectivity (up to 92%). At last but not least, crucially, SmI2 induced enantioselective formal synthesis of strychnine, a complex alkaloid and a classical target used to benchmark new synthetic methods is developed. Enantioselective dearomatising radical cyclisation on to the indole unit and further ET will then give organosamarium that is quenched diastereoselectively by the ester to deliver Strychnine in 7 steps.

Stereoselective Catalytic Processes for the Synthesis of Polycyclic Aromatic Compounds

In this PhD-thesis, two methodologies for enantioselective intramolecular ring closing reaction on indole cores are presented. The first methodology represents a highly stereoselective alkylation of the indole N1-nitrogen, leading to 3,4-dihydro-pyrazinoindol-1-ones – a structural class which is known for its activity on the CNS and therefore of high pharmacological interest concerning related diseases. In this approach, N-benzyl cinchona-alkaloids were used for the efficient catalysis of intramolecular aza-Michael reactions. Furthermore, computational studies in collaboration with the research group Prof. Andrea Bottoni (Department of Chemistry “G. Ciamician”, Bologna) were accomplished in order to get insight into the key interactions between catalyst and substrate, leading to enantiomeric excesses up to 91%. The results of the calculations on a model system are in accordance with the experimental results and demonstrate the high sensibility of the system towards structural modifications. The second project deals with a metal catalyzed, intramolecular Friedel-Crafts (FC)-reaction on indolyl substrates, carrying a side chain which on its behalf is furnished with an allylic alcohol unit. Allylic alcohols are part of the structural class of “π-activated alcohols” – alcohols, which are more easily activated due to the proximity to a π-unit (allyl-, propargyl-, benzyl-). The enantioselective intramolecular cyclization event is catalyzed efficiently by employment of a chiral Au(I)-catalyst, leading to 1-vinyl- or 4-vinyl-tetrahydrocarbazoles (THCs) under the formation of water as byproduct. This striking and novel process concerning the direct activation of alcohols in catalytic FC-reactions was subsequently extended to similar precursors, leading to functionalized tetrahydro-β-carbolines. These two methodologies represent highly efficient approaches towards the synthesis of scaffolds, which are of enormous pharmaceutical interest and amplify the spectra of enantioselective catalytic functionalisations of indoles.

Design and development of new green catalytic methodologies for the synthesis of enantiomerically enriched molecules

The following Ph.D work was mainly focused on catalysis, as a key technology, to achieve the objectives of sustainable (green) chemistry. After introducing the concepts of sustainable (green) chemistry and an assessment of new sustainable chemical technologies, the relationship between catalysis and sustainable (green) chemistry was briefly discussed and illustrated via an analysis of some selected and relevant examples. Afterwards, as a continuation of the ongoing interest in Dr. Marco Bandini’s group on organometallic and organocatalytic processes, I addressed my efforts to the design and development of novel catalytic green methodologies for the synthesis of enantiomerically enriched molecules. In the first two projects the attention was focused on the employment of solid supports to carry out reactions that still remain a prerogative of omogeneous catalysis. Firstly, particular emphasis was addressed to the discovery of catalytic enantioselective variants of nitroaldol condensation (commonly termed Henry reaction), using a complex consisting in a polyethylene supported diamino thiopene (DATx) ligands and copper as active species. In the second project, a new class of electrochemically modified surfaces with DATx palladium complexes was presented. The DATx-graphite system proved to be efficient in promoting the Suzuki reaction. Moreover, in collaboration with Prof. Wolf at the University of British Columbia (Vancouver), cyclic voltammetry studies were reported. This study disclosed new opportunities for carbon–carbon forming processes by using heterogeneous, electrodeposited catalyst films. A straightforward metal-free catalysis allowed the exploration around the world of organocatalysis. In fact, three different and novel methodologies, using Cinchona, Guanidine and Phosphine derivatives, were envisioned in the three following projects. An interesting variant of nitroaldol condensation with simple trifluoromethyl ketones and also their application in a non-conventional activation of indolyl cores by Friedel-Crafts-functionalization, led to two novel synthetic protocols. These approaches allowed the preparation of synthetically useful trifluoromethyl derivatives bearing quaternary stereocenters. Lastly, in the sixth project the first γ-alkylation of allenoates with conjugated carbonyl compounds was envisioned. In the last part of this Ph.D thesis bases on an extra-ordinary collaboration with Prof. Balzani and Prof. Gigli, I was involved in the synthesis and characterization of a new type of heteroleptic cyclometaled-Ir(III) complexes, bearing bis-oxazolines (BOXs) as ancillary ligands. The new heteroleptic complexes were fully characterized and in order to examine the electroluminescent properties of FIrBOX(CH2), an Organic Light Emitting Device was realized.

Catalytic liquid- and gas-phase oxidations for the synthesis of intermediates and specialty chemicals: some examples of industrial relevance

Nowadays, it is clear that the target of creating a sustainable future for the next generations requires to re-think the industrial application of chemistry. It is also evident that more sustainable chemical processes may be economically convenient, in comparison with the conventional ones, because fewer by-products means lower costs for raw materials, for separation and for disposal treatments; but also it implies an increase of productivity and, as a consequence, smaller reactors can be used. In addition, an indirect gain could derive from the better public image of the company, marketing sustainable products or processes. In this context, oxidation reactions play a major role, being the tool for the production of huge quantities of chemical intermediates and specialties. Potentially, the impact of these productions on the environment could have been much worse than it is, if a continuous efforts hadn’t been spent to improve the technologies employed. Substantial technological innovations have driven the development of new catalytic systems, the improvement of reactions and process technologies, contributing to move the chemical industry in the direction of a more sustainable and ecological approach. The roadmap for the application of these concepts includes new synthetic strategies, alternative reactants, catalysts heterogenisation and innovative reactor configurations and process design. Actually, in order to implement all these ideas into real projects, the development of more efficient reactions is one primary target. Yield, selectivity and space-time yield are the right metrics for evaluating the reaction efficiency. In the case of catalytic selective oxidation, the control of selectivity has always been the principal issue, because the formation of total oxidation products (carbon oxides) is thermodynamically more favoured than the formation of the desired, partially oxidized compound. As a matter of fact, only in few oxidation reactions a total, or close to total, conversion is achieved, and usually the selectivity is limited by the formation of by-products or co-products, that often implies unfavourable process economics; moreover, sometimes the cost of the oxidant further penalizes the process. During my PhD work, I have investigated four reactions that are emblematic of the new approaches used in the chemical industry. In the Part A of my thesis, a new process aimed at a more sustainable production of menadione (vitamin K3) is described. The “greener” approach includes the use of hydrogen peroxide in place of chromate (from a stoichiometric oxidation to a catalytic oxidation), also avoiding the production of dangerous waste. Moreover, I have studied the possibility of using an heterogeneous catalytic system, able to efficiently activate hydrogen peroxide. Indeed, the overall process would be carried out in two different steps: the first is the methylation of 1-naphthol with methanol to yield 2-methyl-1-naphthol, the second one is the oxidation of the latter compound to menadione. The catalyst for this latter step, the reaction object of my investigation, consists of Nb2O5-SiO2 prepared with the sol-gel technique. The catalytic tests were first carried out under conditions that simulate the in-situ generation of hydrogen peroxide, that means using a low concentration of the oxidant. Then, experiments were carried out using higher hydrogen peroxide concentration. The study of the reaction mechanism was fundamental to get indications about the best operative conditions, and improve the selectivity to menadione. In the Part B, I explored the direct oxidation of benzene to phenol with hydrogen peroxide. The industrial process for phenol is the oxidation of cumene with oxygen, that also co-produces acetone. This can be considered a case of how economics could drive the sustainability issue; in fact, the new process allowing to obtain directly phenol, besides avoiding the co-production of acetone (a burden for phenol, because the market requirements for the two products are quite different), might be economically convenient with respect to the conventional process, if a high selectivity to phenol were obtained. Titanium silicalite-1 (TS-1) is the catalyst chosen for this reaction. Comparing the reactivity results obtained with some TS-1 samples having different chemical-physical properties, and analyzing in detail the effect of the more important reaction parameters, we could formulate some hypothesis concerning the reaction network and mechanism. Part C of my thesis deals with the hydroxylation of phenol to hydroquinone and catechol. This reaction is already industrially applied but, for economical reason, an improvement of the selectivity to the para di-hydroxilated compound and a decrease of the selectivity to the ortho isomer would be desirable. Also in this case, the catalyst used was the TS-1. The aim of my research was to find out a method to control the selectivity ratio between the two isomers, and finally to make the industrial process more flexible, in order to adapt the process performance in function of fluctuations of the market requirements. The reaction was carried out in both a batch stirred reactor and in a re-circulating fixed-bed reactor. In the first system, the effect of various reaction parameters on catalytic behaviour was investigated: type of solvent or co-solvent, and particle size. With the second reactor type, I investigated the possibility to use a continuous system, and the catalyst shaped in extrudates (instead of powder), in order to avoid the catalyst filtration step. Finally, part D deals with the study of a new process for the valorisation of glycerol, by means of transformation into valuable chemicals. This molecule is nowadays produced in big amount, being a co-product in biodiesel synthesis; therefore, it is considered a raw material from renewable resources (a bio-platform molecule). Initially, we tested the oxidation of glycerol in the liquid-phase, with hydrogen peroxide and TS-1. However, results achieved were not satisfactory. Then we investigated the gas-phase transformation of glycerol into acrylic acid, with the intermediate formation of acrolein; the latter can be obtained by dehydration of glycerol, and then can be oxidized into acrylic acid. Actually, the oxidation step from acrolein to acrylic acid is already optimized at an industrial level; therefore, we decided to investigate in depth the first step of the process. I studied the reactivity of heterogeneous acid catalysts based on sulphated zirconia. Tests were carried out both in aerobic and anaerobic conditions, in order to investigate the effect of oxygen on the catalyst deactivation rate (one main problem usually met in glycerol dehydration). Finally, I studied the reactivity of bifunctional systems, made of Keggin-type polyoxometalates, either alone or supported over sulphated zirconia, in this way combining the acid functionality (necessary for the dehydrative step) with the redox one (necessary for the oxidative step). In conclusion, during my PhD work I investigated reactions that apply the “green chemistry” rules and strategies; in particular, I studied new greener approaches for the synthesis of chemicals (Part A and Part B), the optimisation of reaction parameters to make the oxidation process more flexible (Part C), and the use of a bioplatform molecule for the synthesis of a chemical intermediate (Part D).

Synthesis and application of new ion-tagged ligands and organocatalysts

We report the synthesis and application of some ion-tagged catalysts in organometallic catalysis and organocatalysis. With the installation of an ionic group on the backbone of a known catalyst, two main effects are generally obtained. i) a modification of the solubility of the catalyst: if judicious choice of the ion pair is made, the ion-tag can confer to the catalyst a solubility profile suitable for catalyst recycling. ii) the ionic group can play a non-innocent role in the process considered: if stabilizing interaction between the ionic group and the developing charges in the transition state are established, the reaction can speed up. We describe the use of ion-tagged diphenylprolinol as Zn ligand. The chiral ligand grafted onto an ionic liquid (IL) was recycled 10 times with no loss of reactivity and selectivity, when it was employed in the first example of enantioselective addition of ZnEt2 to aldehydes in ILs. An ammonium-tagged phosphine displayed the capability to stabilize Pd catalysts for the Suzuki reaction in ILs. The ionic phase was recycled 6 times with no detectable loss of activity and very low Pd leaching in the organic phase. This catalytic system was also employed for the functionalization of the challenging substrate 5,11-dibromotetracene. In the field of organocatalysis, we prepared two ion-tagged derivatives of the McMillan imidazolidinone. The results of the asymmetric Diels-Alder reaction between trans-cinnamaldehyde and cyclopentadiene exhibited great dependence on the position and nature of the ionic group. Finally, when O-TMS-diphenylprolinol was tagged with an imidazolium ion, exploiting a silyl ether linker, an efficient catalyst for the asymmetric addition of aldehydes to nitroolefins was achieved. The catalyst displayed enhanced reactivity and the same high level of selectivity of the untagged parent catalyst and it could be employed in a wide range of reaction conditions, included use of water as solvent.

Cinchona alkaloids and BINOL derivatives as privileged catalysts or ligands in asymmetric synthesis

During the last fifteen years organocatalysis emerged as a powerful tool for the enantioselective functionalization of the most different organic molecules. Both C-C and C-heteroatom bonds can be formed in an enantioselective fashion using many types of catalyst and the field is always growing. Many kind of chiral catalysts have emerged as privileged, but among them Proline, cinchona alkaloids, BINOL, and their derivatives showed to be particularly useful chiral scaffolds. This thesis, after a short presentation of many organocatalysts and activation modes, focuses mainly on cinchona alkaloid derived primary amines and BINOL derived chiral Brønsted acids, describing their properties and applications. Then, in the experimental part, these compounds are used for the catalysis of new transformations. The enantioselective Friedel-Crafts alkylation of cyclic enones with naphthols using cinchona alkaloid derived primary amines as catalysts is presented and discussed. The results of this work were very good and this resulted also in a publication. The same catalysts are then used to accomplish the enantioselective addition of indoles to cyclic enones. Many catalysts in combination with many acids as co-catalysts were tried and the reaction was fully studied. Selective N-alkylation was obtained in many cases, in combination with quite good to good enantioselectivities. Also other kind of catalysis were tried for this reaction, with interesting results. Another aza-Michael reaction between OH-free hydroxylamines and nitrostyrene using cinchona alkaloid derived thioureas is briefly discussed. Then our attention focused on Brønsted acid catalyzed transformations. With this regard, the Prins cyclization, a reaction never accomplished in an enantioselective fashion until now, is presented and developed. The results obtained are promising. In the last part of this thesis the work carried out abroad is presented. In Prof. Rueping laboratories, an enantioselective Nazarov cyclization using cooperative catalysis and the enantioselective desymmetrization of meso-hydrobenzoin catalyzed by Brønsted acid were studied.

Au(I) Catalyzed Manipulation of Propargylic Alcohols: A New Route Towards the Synthesis of Indole Alkaloids

In this work we presented several aspects regarding the possibility to use readily available propargylic alcohols as acyclic precursors to develop new stereoselective [Au(I)]-catalyzed cascade reactions for the synthesis of highly complex indole architectures. The use of indole-based propargylic alcohols of type 1 in a stereoselective [Au(I)]-catalyzed hydroindolynation/immiun trapping reactive sequence opened access to a new class of tetracyclic indolines, dihydropyranylindolines A and furoindolines B. An enantioselective protocol was futher explored in order to synthesize this molecules with high yields and ee. The suitability of propargylic alcohols in [Au(I)]-catalyzed cascade reactions was deeply investigated by developing cascade reactions in which was possible not only to synthesize the indole core but also to achieve a second functionalization. Aniline based propargylic alcohols 2 were found to be modular acyclic precursors for the synthesis of [1,2-a] azepinoindoles C. In describing this reactivity we additionally reported experimental evidences for an unprecedented NHCAu(I)-vinyl specie which in a chemoselective fashion, led to the annulation step, synthesizing the N1-C2-connected seven membered ring. The chemical flexibility of propargylic alcohols was further explored by changing the nature of the chemical surrounding with different preinstalled N-alkyl moiety in propargylic alcohols of type 3. Particularly, in the case of a primary alcohol, [Au(I)] catalysis was found to be prominent in the synthesis of a new class of [4,3-a]-oxazinoindoles D while the use of an allylic alcohol led to the first example of [Au(I)] catalyzed synthesis and enantioselective functionalization of this class of molecules (D*). With this work we established propargylic alcohols as excellent acyclic precursor to developed new [Au(I)]-catalyzed cascade reaction and providing new catalytic synthetic tools for the stereoselective synthesis of complex indole/indoline architectures.

Synthesis of new bioactive β-lactam compounds

New biologically active β-lactams were designed and synthesized, developing novel antibiotics and enzymatic inhibitors directed toward specific targets. Within a work directed to the synthesis of mimetics for RGD (Arg-Gly-Asp) sequence able to interact with αvβ3 and α5β1-type integrins, new activators were developed and their Structure-Activity Relationships (SAR) analysis deepened, enhancing their activity range towards the α4β1 isoform. Moreover, to synthesize novel compounds active both against bacterial infections and pulmonary conditions of cystic fibrosis patients, new β-lactam candidates were studied. Among the abundant library of β-lactams prepared, mainly with antioxidant and antibacterial double activities, it was identified a single lead to be pharmacologically tested in vivo. Its synthesis was optimized up to the gram-scale, and pretreatment method and HPLC-MS/MS analytical protocol for sub-nanomolar quantifications were developed. Furthermore, replacement of acetoxy group in 4-acetoxy-azetidinone derivatives was studied with different nucleophiles and in aqueous media. A phosphate group was introduced and the reactivity exploited using different hydroxyapatites, obtaining biomaterials with multiple biological activities. Following the same kind of reactivity, a small series of molecules with a β-lactam and retinoic hybrid structure was synthesized as epigenetic regulators. Interacting with HDACs, two compounds were respectively identified as an inhibitor of cell proliferation and a differentiating agent on steam cells. Additionally, in collaboration with Professor L. De Cola at ISIS, University of Strasbourg, some new photochemically active β-lactam Pt (II) complexes were designed and synthesized to be used as bioprobes or theranostics. Finally, it was set up and optimized the preparation of new chiral proline-derived α-aminonitriles through an enantioselective Strecker reaction, and it was developed a chemo-enzymatic oxidative method for converting alcohols to aldehydes or acid in a selective manner, and amines to relative aldehydes, amides or imines. Moreover, enzymes and other green chemistry methodologies were used to prepare Active Pharmaceutical Ingredients (APIs).

Synthesis and conformational analysis of heteroaromatic atropisomeric systems

The research work reported in this Thesis was held along two main lines of research. The first and main line of research is about the synthesis of heteroaromatic compounds with increasing steric hindrance, with the aim of preparing stable atropisomers. The main tools used for the study of these dynamic systems, as described in the Introduction, are DNMR, coupled with line shape simulation and DFT calculations, aimed to the conformational analysis for the prediction of the geometries and energy barriers to the trasition states. This techniques have been applied to the research projects about: • atropisomers of arylmaleimides; • atropisomers of 4-arylpyrazolo[3,4-b]pyridines; • study of the intramolecular NO2/CO interaction in solution; • study on 2-arylpyridines. Parallel to the main project, in collaboration with other groups, the research line about determination of the absolute configuration was followed. The products, deriving form organocatalytic reactions, in many cases couldn’t be analyzed by means of X-Ray diffraction, making necessary the development of a protocol based on spectroscopic methodologies: NMR, circular dichroism and computational tools (DFT, TD-DFT) have been implemented in this scope. In this Thesis are reported the determination of the absolute configuration of: • substituted 1,2,3,4-tetrahydroquinolines; • compounds from enantioselective Friedel-Crafts alkylation-acetalization cascade of naphthols with α,β-unsaturated cyclic ketones; • substituted 3,4-annulated indoles.

Innovative asymmetric organocatalytic processess: en route to the synthesis of biologically relevant compounds

This doctoral thesis deals with the development of novel organocatalytic strategies for asymmetric transformation. The intrinsic versatility of organocatalysis and the use of different activation modes have been exploited to achieve new catalytic enantioselective processes, towards the synthesis of biologically relevant scaffolds. The most investigated organocatalytic system have been those based on H-bond interaction (such as chiral thioureas or phosphoric acids) as well as the ones based on aminocatalysis. Despite conceptually distinct, the transformations detailed in this Thesis are linked together by simple and recurring modes of activation, induction and reactivity, promoted by the catalysts employed. The chemical diversity of the challenges encountered allows to get a precious overall view on organocatalysis, highlighting that enormous chemical diversity can be created by judicious choice of select catalyst.

Photoredox Catalysis and Nucleophilic Organometallic Reagents – Application in Organic Synthesis

The main purpose of my PhD was the combination of the principles of transition metal catalysis with photoredox catalysis. We focused our attention on the development of novel dual catalytic protocols for the functionalization of carbonyl compounds through the generation of transient nucleophilic organometallic species. Specifically, we focused on the development of new methodologies combining photoredox catalysis with titanium and nickel in low oxidation state. Firstly, a Barbier-type allylation of aromatic and aliphatic aldehydes –catalytic in titanium– in the presence of a blue photon-absorbing dye was developed. Parallelly, we were pleased to observe that the developed methodology could also be extended to the propargylation of aldehydes under analogous conditions. After an extensive re–optimization of all the reaction parameters, we developed an enantioselective and diastereoselective pinacol coupling of aromatic aldehydes promoted by non-toxic, cheap and easy to synthetize titanium complexes. The key feature, that allows the complete (dia)stereocontrol played by titanium, is the employment of a red-absorbing organic dye. The tailored (photo)redox properties of the red-absorbing organic dye [nPr–DMQA+][BF4–] promote the selective reduction of Ti(IV) to Ti(III). Moreover, even if the major contribution in dual photoredox and nickel catalysis is devoted to the realization of cross-coupling-type reactions, we wanted to evaluate different possible scenarios. Our focus was on the possibility of exploiting intermediates arising from the oxidative addition of nickel complexes as transient nucleophilic species. The first topic considered regarded the possibility to perform allylation of aldehydes by dual photoredox and nickel catalysis. In the first instance, a non–stereocontrolled version of the reaction was presented. Finally, after a long series of drastic modification of the reaction conditions, a highly enantioselective variant of the protocol was also reported. All the reported methodologies are supported by careful photophysical analysis and, in some cases, computational modelling.