TIN-a combinatorial compound collection of synthetically feasible multicomponent synthesis products.

The synthetic feasibility of any compound library used for virtual screening is critical to the drug discovery process. TIN, a recursive acronym for \u27TIN Is Not commercial\u27, is a virtual combinatorial database enumeration of diversity-orientated multicomponent syntheses (MCR). Using a \u27one-pot\u27 synthetic technique, 12 unique small molecule scaffolds were developed, predominantly styrylisoxazoles and bis-acetylenic ketones, with extensive derivatization potential. Importantly, the scaffolds were accessible in a single operation from commercially available sources containing R-groups which were then linked combinatorially. This resulted in a combinatorial database of over 28 million product structures, each of which is synthetically feasible. These structures can be accessed through a free Web-based 2D structure search engine or downloaded in SMILES, MOL2, and SDF formats. Subsets include a 10% diversity subset, a drug-like subset, and a lead-like subset that are also freely available for download and virtual screening ( http://mmg.rcsi.ie:8080/tin )

PALLADIUM-CATALYZED DECARBOXYLATIVE ALLYLATIONS OF ESTER ENOLATE EQUIVALENTS AND PALLADIUM-CATALYZED CYCLIZATIONS VIA CO2 AND SILYL ACTIVATION

Palladium-catalyzed decarboxylative allylation (DcA) has received much attention as an alternative C-C bond formation method to traditional metal-catalyzed cross-coupling reactions. Among various nucleophilic partners that undergo DcA, ester enolates are reported to be difficult to allylate and often demand harsher conditions. Herein we report the development of a mild and fast method that provides access to various types of α-allylated amides and esters via decarboxylative allylation of ester enolate equivalents. These amide and ester products undergo further transformations such as hydrolysis, reduction and nucleophilic addition reactions without pre-functionalization. Also enantioselective DcA and diastereoselective DcA of α,α-disubstituted amide enolates are extensively studied and reported. Rapid and efficient synthesis of complex molecules via multicomponent reactions (MCR) is a viable alternative method to time- and resource-consuming stepwise synthesis. In general, multicomponent reactions assemble three or more different reactive components into a multisubstituted product in a one-pot, batch-wise process. Also, this process allows the formation of multiple new bonds in a single operation. Herein we report the development of one-pot, three-component and four-component double decarboxylative allylation reactions to produce α- and γ-allylated amides. In these MCRs, benzylic amide enolates exhibited remarkable success over alkyl amide enolates due to stability differences between two nucleophiles. In the progress of transition metal-catalyzed allylation reactions, it is of great interest to activate allylic alcohols in situ to obtain π-allyl intermediates instead of using pre-activated allyl sources. Due to the inherently poor leaving ability of the hydroxyl group several attempts to activate allyl alcohols have been made using Lewis acids such as Ti(OPri)4, BEt3, BPh3, and SnCl2. Compared to these methods, activation of allyl alcohol using CO2, an inexpensive and readily available gas, is an economical choice. CO2 activates the allylic alcohol in 2-(1-hydroxyallyl)phenol substrate allowing formation of π-allyl palladium intermediate followed by intramolecular etherification to synthesize benzopyrans. Furthermore, we report a successful attempt to activate allyl alcohols by an adjacent silyl group to obtain benzopyrans

Probing the Structure and Photophysics of Porphyrinoid Systems for Functional Materials

Porphyrins (Pors) and their many cousins, including phthalocyanines (Pcs), corroles (Cors), subphthalocyanines (SubPcs), porphyrazines (Pzs), and naphthalocyanines (NPcs), play amazingly diverse roles in biological and non-biological systems because of their unique and tunable physical and chemical properties. These compounds, collectively known as porphyrinoids, can be employed in any number of functional devices that have the potential to address the challenges of modern society. Their incorporation into such devices, however, depends on many structural factors that must be well understood and carefully controlled in order to achieve the desired behavior. Self-assembly and self-organization are key processes for developing these new technologies, as they will allow for inexpensive, efficient, and scalable designs. The overall goal of this dissertation is to elucidate and ultimately control the interplay between the hierarchical structure and the photophysical properties of these kinds of systems. This includes several case studies concerning the design and spectroscopic analysis of supramolecular systems formed through simple, scalable synthetic methods. We also present detailed experimental and computational studies on some porphyrin and phthalocyanine compounds that provide evidence for fundamental changes in their molecular structure. In addition to their impact on the photophysics, these changes also have implications for the organization of these molecules into higher order materials and devices. It is our hope that these findings will help to drive chemists and engineers to look more closely at every level of hierarchical structure in the search for the next generation of advanced materials

Zn(II)-porphyrin metallacyles: versatile building units for the self-assembling of discrete 3D multi-component systems with tunable geometries and properties

il progetto di ricerca descritto nel presente lavoro di tesi si \ue8 focalizzato sulla progettazione, sintesi e caratterizzazione di strutture 3D supramolecolari ottenute mediante appropriata combinazione di leganti piridinici con pannelli metallaciclici di zinco porfirine. La versatilit\ue0 dell'approccio sintetico perseguito, ha permesso, a seguto di un astuto e pensato design delle unit\ue0 di base molecolari, di ottenere efficientemente una libreria di elaborate strutture supramolecolari tridimensionali, di modulabile forma e dimensione del sistema desiderato, regolandone le proprieta fotoindotti inter-componente e/o introducendo nuove funzionalit\ue0 derivanti dall'organizzazione geometrica di un preciso numero di centri metallici attivi. Parte del lavoro \ue8 stato dedicato ad una approfondita investigazione sulla possibilit\ue0 di ottenere strutture eterometalliche di ordine discreto, mediante autoassemblaggio di un metallaciclo di zinco porfirine in combinazione con appropriati leganti clatrochelati piridinici, tramite una collaborazionecon il gruppo di Prof. K. Severin (EPFL di Losanna). Lo scopo finale \ue8 di ottenere facilmente, mediante un approccio sintetico modulare, sistemi funzionali di ordine superiore contenenti un definito numero di ben organizzati centri metallici attivi (cio\ue8 magneticamente, cataliticamente o redox attivi). Ci si \ue8 inoltre concentrati sulla sintesi di architetture supramolecolari discrete aventi dimensioni e geometria modulabile e recanti un numero variabile di unit\ue0 porfiriniche, ottenute per semplice mescolamento di due o tre diversi moduli porfirinici. Scegliendo in modo appropriato i connettori piridinici, cio\ue8 variandone il numero di centri basici donatori e/o giocando sulla loro posizione relativa, strutture molecolari di dimensioni implememntate diventano facilmente ottenibili. Progettando in modo studiato le unit\ue0 molecolari di base, in termini di lablit\ue0/inerzia e discriminazione di tipo hard/soft, queste si autoassembleranno a formare in modo quantitativo tramite la formazione di legami di coordinazione complementari. Le strutture multi-porfiriniche cos\uec ottenute costituiscono un telaio ben ordinato di unit\ue0 cromoforiche coinvolti in processi fotoindotti di trasferimento di energia e di trasferimento di carica. Infine parte del lavoro di ricerca \ue8 stato svolto durante un periodo di 6 mesi trascorsi presso il laboratorio del Dr. Romain Ruppert dell\u2019Universit\ue0 di Strasburgo. Il progetto aveva lo scopo di sintetizzare dei dimeri di zinco porfirine connesse mediante coordinazione a un catione di Pd(II), e di studiare la loro possibile applicazione ed utilizzo come piattaforme fotoattive alternative per l\u2019autoassemblaggio di sistemi discreti suprmaolecolari a forma di sandwich. Da un punto di vista fotofisico il nuovo dimero presenta interessanti propriet\ue0 in quanto \ue8 presente una forte comunicazione elettroinica fra le due porfirne attraverso il ponte metallico di Pd(II). D\u2019altro canto, da un punto di vista di sintesi supramolecolare, il dimero presenta le caratteristiche richieste: due punti di ancoraggio costituiti dai due centri di Zn(II), un buon grado di inerzia del legame esociclico e una sufficiente coplanarit\ue0 a disposizione rigida delle componenti.The research carried out during this PhD project and reported in this Thesis is focused on the design, preparation and characterization of multi-component supramolecular 3D architectures obtained by appropriate paneling multitopic pyridyl ligands with flat Zn-porphyrin metallacycles. The versatility of the synthetic approach pursued, allowed to efficiently construct libraries of elaborated 3D structures, tuning the shape and dimension of the target systems, modulating the inter-component photo-induced properties and/or introducing new functions deriving from the geometrical organization of a precise number of active metal centers, by cleverly tailoring the molecular building blocks. In Chapter 1, a general introduction on key role of porphyrins as functional and structural building unit for the assembly of artificial discrete supramolecular structures is presented, together with the main designing concepts of the metal mediated self-assembling synthetic strategy. Few examples of elegant multiporphyrin architectures and their application are reported. Finally, the modular synthetic approach pursued during this research project is described. In Chapter 2, a thourough investigation on the possibility to produce new hetero-multimetallic ordered discrete structures, by self-assembling of a zinc-porphyrin metallacycle (1Zn) with dipyridyl clathrochelate metalloligands (provided by the group of Prof. K. Severin, EPFL, Lausanne, CH), is discussed. In particular, linear FeII metal containing ligands with terminal 4-pyridyl groups, lengthes between 1.5 and 3.2 nm, and containing either one or two clatrochelate cores were chosen. The final aim is the easy access, by a modular approach, to higher order functional systems comprising defined numbers and spacial organizations of metal-active centers (e.g. magnetically, redox or catalytically active). Chapter 3 reports on the metal mediated assembling of a linear dipyridyl diazadioxa[8]circulene (Circ, provided by the group of Prof. M. Pittelkow, University of Copenhagen, DK) with either 1Zn and of a cis-protected diphosphines PtII complex. Circ is a flat and conjugated compound presenting a central antiaromatic cyclooctatetraene core. The designing idea was to endow the ligand in structures, enforcing conformations which could enable, to find experimental evidences of the antiaromaticity, by observation of deshielding effect due to the diatropic ring current of the COT core. Discussion of their structural analysis in solution and in the solid state is described. The work described in Chapter 4 focused on the synthesis of giant 3D discrete supramolecular architectures, with tuned dimensions, geometry and varied number of porphyrin units, obtained by simple mixing different (metallo)porphyrin modules. By appropriate tailoring of the meso-4\u2019pyridylporphyrin connectors, i.e. increasing the number of basic donor sites and/or playing on their relative disposition, larger molecular architectures become easily available. Cleverly designed molecular building units, in terms of lability/inertness and hard/soft metal-to-ligand discriminations, quantitatively self-connect by formation of mutual coordination bonds. The obtained discrete multi-porphyrin structures constitute a spatially-ordered lattice of chromophores featuring photoinduced antenna-effect and charge transfer processes. Pursuing a modular synthetic approach, a library of fascinating In Chapter 5, Is reported the work performed during a six-month internship in the laboratories of Dr. Romain Ruppert, University of Strasbourg (FR), is devoted at investigating and tackling the possibility to employ a PdII-linked Zn(II)-porphyrin dimer (ZnPdZn), as alternative photo-active platforms for the assembling of discrete supramolecular sandwich structures

Technological Innovations in Photochemistry for Organic Synthesis: Flow Chemistry, High-Throughput Experimentation, Scale-up, and Photoelectrochemistry

[Image: see text] Photoinduced chemical transformations have received in recent years a tremendous amount of attention, providing a plethora of opportunities to synthetic organic chemists. However, performing a photochemical transformation can be quite a challenge because of various issues related to the delivery of photons. These challenges have barred the widespread adoption of photochemical steps in the chemical industry. However, in the past decade, several technological innovations have led to more reproducible, selective, and scalable photoinduced reactions. Herein, we provide a comprehensive overview of these exciting technological advances, including flow chemistry, high-throughput experimentation, reactor design and scale-up, and the combination of photo- and electro-chemistry

Stereodivergent Synthesis of Enantioenriched Five- and Six-Membered Cyclic-1,3-diols and Applications Toward Library Synthesis

Abstract This work describes the development of methods to access synthetically useful chiral diols in enantiomerically pure form. First chapter describes the development of a stereodivergent approach for enantioenriched synthesis of 2-cyclopentene-1,3-diol that was later converted to 4-hydroxy-2-cyclopentenones (4-HCPs), which are highly privileged synthetic building blocks with numerous applications in natural product syntheses and pharmaceuticals. The present approach enables the gram scale synthesis of 4-HCPs with chemically diverse protecting groups, in a stereodivergent manner. In chapter 2, we describe the development of a unified strategy for the stereodivergent synthesis of enantioenriched 1,3-dihydroxy substituted six-membered carbo- and heterocyclic rings. The previously known approaches for accessing these compounds involve multiple synthetic steps and one or more enzymatic steps. We developed a purely synthetic approach to synthesize enantioenriched carbo- and heterocyclic six-membered 1,3-diols from a common, highly economical commercial available starting material. In Chapter 3, we described the development of a small-molecule library of stereochemically diverse compounds by integrating enantioenriched carbo- and heterocyclic 1,3-diols, and natural α-amino acids

Development of a New General Click Chemistry and Applications in Bioconjugation: Part I: Rewiring Bacteria Cell Surfaces with Bio-Orthogonal Chemistry Part II: A Novel General Dialdehyde Click Chemistry for Primary Amine Conjugation

The ability to tailor cell surfaces with non-native molecules is critical to advance the study of cellular communication, cell behavior, and for next-generation therapeutics. There has been tremendous effort to tailor mammalian cell surfaces with organic functional groups; however, there are few reliable and non-invasive methods for re-wiring the bacterial cell surface. Current methods to re-engineer bacteria surfaces rely on complicated, slow, and often expensive molecular biology and metabolic manipulation methods with limited scope on the type of molecules installed onto the surface. In the first part of this report, we introduce a new straightforward method based on liposome fusion to re-engineer Gram-negative bacteria cell surface with bio-orthogonal groups that can subsequently be conjugated to a range of molecules (biomolecules, small molecules, probes, proteins) for further studies and programmed behavior of bacteria. This method is fast, efficient, inexpensive, and useful for installing a broad scope of ligands and biomolecules to Gram-negative bacteria surfaces. The development of methods to conjugate a range of molecules to primary amine functional groups have revolutionized the fields of chemistry, biology and material science. Due to its abundance, the primary amine is the most convenient functional group handle in molecules for ligation to other molecules for a broad range of applications that affect all scientific fields. Current conjugation methods with primary amines include the use of activated carboxylic acids, isothiocyanates, Michael addition type systems and reaction with ketones or aldehydes followed by in situ reductive amination. In the second part, we introduce a new traceless, high yield, fast; click chemistry method based on the rapid and efficient trapping of amine groups via a functionalized dialdehyde group. The click reaction occurs in mild conditions in organic solvents or aqueous media, proceeds in high yield. Moreover, no catalyst or activating group is required and the only by-product is water. The dialdehyde headgroup was used for applications in cell surface engineering and for tailoring surfaces for material science applications. We anticipate broad utility of the general dialdehyde click chemistry to primary amines in all areas of chemical research ranging from polymers, bioconjugation to material science and nanoscienc

Palladacycles with Palladium-Bonded Stereogenic Carbons: Tools for Exploring Reaction Pathways in Organometallic Chemistry

While reactions with organopalladium intermediates often give useful organic products, little is known about how the ligand sphere impacts the reactivity of these intermediates. To explore the interactions between the auxiliary ligand and the other substitutents on the metal center, we performed synthetic and structural studies on both polymer-bound palladacycles and a new organometallic scaffold, the palladapyrrolidinone. In the case of palladacycles on solid-phase, we observed that the precise characteristics of the polymer-bound ligand had a large impact on the reactivity of the complex. In the case of the palladapyrrolidinones, we observed that the shape and size of the ligand sphere had a large impact on the diastereoselective formation of a sp3-C stereocenter bound to a palladium center. We found that a chiral non-racemic ligand had little impact on the stereoselectivity. In conclusion, the ligand sphere has a distinct impact on both the reactivity and stereoselectivity of reactions involving palladacycles

I. Microwave-Influenced Diversity-Oriented Synthesis Of Biologically Relevant Small & Natural-Product-Like Molecules Via Multicomponent Coupling Reactions Ii. Synthetic Studies Toward The Total Synthesis Of The Repeating Tetrasaccharide Unit Of Zwitterionic Polysaccharide Ps A1

Microwave-influenced diversity-oriented synthesis of biologically relevant small and natural-product-like molecules via multicomponent coupling reactions (MCCRs) have been investigated. Cheap, readily available starting materials in conjunction of microwave irradiation and employment of environmentally benign solvent (e.g. water) provided a common platform that allowed to access a wide array of structurally and skeletally diverse molecules. The investigation allowed us to establish a new paradigm of diversity-activity relationships (DARs) by tuning reacting components of the MCCRs and proved that in contrary to the conventional use of microwave as a rate accelerating tool, it can be used to influence reactivity of molecules. The method was also extended to develop new protecting groups (PGs, PDMAB, PMNPAB) that can be useful in carbohydrate as well as other areas of synthetic organic chemistry. Additionally, the new p-N,N-diemethylaminobenzyl (PDMAB) PG was employed to develop an alkoxide-based neutral glycosylation and further extended to study entirely neutral glycosylation via oxocarbenium ion. We also investigated the total synthesis of the repeating tetrasaccharide unit of zwitterionic polysaccharide PS A1 using different strategies. PS A1 is known to modulate T-cell response via MHC-II pathway and shown to prevent tumor growth. The synthesis is quite challenging and we have been able to construct the trisaccharide unit of the repeating tetrasaccharide unit of PS A1