Littérature scientifique sur le sujet « Multisteps organic synthesis »

The norbornene skeleton possesses an alkene functionality with a fixed conformation, and represents unique reactivity. The use of norbornene and analogues as substrates is overviewed; reactivities are discussed as well as the role of norbornenes as ligands assisting modern organic transformations.1 Introduction2 Synthesis of Substituted Norbornenes2.1 Preparation of Functionalized Norbornenes by Deprotonation and Substitution Reactions2.2 Preparation of Functionalized Norbornenes under Palladium-Catalyzed­ Reaction Conditions2.3 Alkylation of Norbornene2.4 Multistep Synthesis3 Synthesis of Substituted Norbornanes3.1 Three-Membered-Ring Formation3.2 Formation of Four-Membered Rings3.3 Five- and Six-Membered Ring Formation3.4 Syntheses of Difunctionalized Norbornanes4 Synthesis of Cyclopentanes4.1 Oxidation Reactions4.2 Ring-Opening Cross Metathesis (ROCM)4.3 Ring-Opening Metathesis Polymerization (ROMP)4.4 Palladium-Catalyzed Ring-Opening of Norbornene5 Norbornene-Mediated Reactions5.1 Palladium Insertion into Carbon–Halide Bonds5.2 Palladium Insertion into N–H and C–H Bonds5.3 Norbornene as Ligand in Mediated Reactions6 Conclusion

A direct method was developed for the conversion of benzyl ethers into aryl nitriles by using NH4OAc as the nitrogen source and ­oxygen as the terminal oxidant with catalysis by TEMPO/HNO3; the method is valuable for both the synthesis of aromatic nitriles and for the deprotection of ether-protected hydroxy groups to form nitrile groups in multistep organic syntheses.

Quite extensive synthetic achievements vanish in the online supporting information of publications on functional systems. Underappreciated, their value is recognized by experts only. As an example, we here focus in on the recent synthesis of multicomponent photosystems with antiparallel charge-transfer cascades in co-axial hole- and electron-transporting channels. The synthetic steps are described one-by-one, starting with commercial starting materials and moving on to key intermediates, such as asparagusic acid, an intriguing natural product, as well as diphosphonate “feet”, and panchromatic naphthalenediimides (NDIs), to finally reach the target molecules. These products are initiators and propagators for self-organizing surface-initiated polymerization (SOSIP), a new method introduced to secure facile access to complex architectures. Chemoorthogonal to the ring-opening disulfide exchange used for SOSIP, hydrazone exchange is then introduced to achieve stack exchange, which is a “switching” technology invented to drill giant holes into SOSIP architectures and fill them with functional π-stacks of free choice.

The implementation of automation in the multistep flow synthesis is essential for transforming laboratory-scale chemistry into a reliable industrial process. In this review, we briefly introduce the role of automation based on its application in synthesis viz. auto sampling and inline monitoring, optimization and process control. Subsequently, we have critically reviewed a few multistep flow synthesis and suggested a possible control strategy to be implemented so that it helps to reliably transfer the laboratory-scale synthesis strategy to a pilot scale at its optimum conditions. Due to the vast literature in multistep synthesis, we have classified the literature and have identified the case studies based on few criteria viz. type of reaction, heating methods, processes involving in-line separation units, telescopic synthesis, processes involving in-line quenching and process with the smallest time scale of operation. This classification will cover the broader range in the multistep synthesis literature.

Organic chemistry is the offered after general chemistry and is the course that many find it challenging and difficult. Synthesis is first introduced in organic chemistry I course and is widely considered as one of the topics in which students struggle with and is evident in their performance in the topic. Our method of data collection is a Likert-type and open-ended questionnaire that was distributed at the end organic chemistry I course in an anonymous fashion. The collected data enabled us to examine the challenges students face in learning organic chemistry synthesis. Our findings support the notion that students have many difficulties with multistep organic chemistry synthesis including challenges recalling all of the varied required reactions, the amount of content and topics covered in organic chemistry, conceptual understanding of needed important topics such as mechanisms, acids and bases, nucleophiles and electrophiles, and stereochemistry, and problem-solving competency. Students view organic chemistry synthesis as challenging because of their reliance on memorization of a large number of reactions, reagents, and rules, poor conceptual understanding of the topics, ineffective teaching methods which lacks active learning and student engagement, and the myriad number of possible pathways to solve synthesis problems. Our participants suggest that memorization and rote-learning plays an important role in the learning of multistep organic synthesis, which might cause a hindrance to process of learning and can impede students’ problem-solving ability.

The application of heterogeneous catalysis and green solvents to the set up of widely employed reactions is a challenge in contemporary organic chemistry. We applied such an approach to the synthesis and further conversion of tetrahydropyranyl ethers, an important class of compounds widely employed in multistep syntheses. Several alcohols and phenols were almost quantitatively converted into the corresponding tetrahydropyranyl ethers in cyclopentyl methyl ether or 2-methyltetrahydrofuran employing NH4HSO4 supported on SiO2 as a recyclable acidic catalyst. Easy work up of the reaction mixtures and the versatility of the solvents allowed further conversion of the reaction products under one-pot reaction conditions.

The multistep flow synthesis of complex molecules has gained momentum over the last few years. A wide range of reaction types and conditions have been integrated seamlessly on a single platform including in-line separation as well as monitoring. Beyond merely getting considered as ‘flow version’ of conventional ‘one-pot synthesis’, multistep flow synthesis has become the next generation tool for creating libraries of new molecules. Here we give a more ‘engineering’ look at the possibility of developing a ‘unified multistep flow synthesis platform’. A detailed analysis of various scenarios is presented considering 4 different classes of drugs already reported in the literature. The possible complexities that an automated and controlled platform needs to handle are also discussed in detail. Three different design approaches are proposed: (i) one molecule at a time, (ii) many molecules at a time and (iii) cybernetic approach. Each approach would lead to the effortless integration of different synthesis stages and also at different synthesis scales. While one may expect such a platform to operate like a ‘driverless car’ or a ‘robo chemist’ or a ‘transformer’, in reality, such an envisaged system would be much more complex than these examples.

La mitochondrie est apparue ces dernières années comme une cible thérapeutique d'intérêt. Cet organite des cellules eucaryotes joue un rôle fondamental dans la production énergétique de la cellule. La dérégulation de son fonctionnement est associée à une grande diversité de pathologies telles que des maladies neurodégénératives, métaboliques, cardiovasculaires, cancer et maladies rares mitochondriales. Ainsi, depuis la fin des années 80, différentes stratégies de vectorisation ont été développées, permettant le transport de substances actives à l'intérieur de la mitochondrie. Le nombre grandissant de molécules agissant sur la fonction mitochondriale actuellement en essais clinique ou sur le marché témoigne de l'importance de cet enjeu. Ce projet de thèse a ainsi porté sur la synthèse d'outils pour observer, comprendre et impacter le fonctionnement mitochondrial. Une première partie du projet s'est appliqué à la mise en évidence d'une activité Azoréductase (AzoR) intramitochondriale. Pour cela, des sondes mito-ciblées dont le comportement fluorescent est modulé en présence de l'AzoR ont été conçues, synthétisées, évaluées in vitro et utilisées en imagerie cellulaire de fluorescence afin de démontrer la présence mitochondriale de cette activité enzymatique. Dans la seconde partie de cette thèse, nous nous sommes focalisés sur l'utilisation d'activités enzymatique réductases mitochondriales pour permettre la libération intramitochondriale d'une grande variété de molécules neutres, dans le but ultime de concevoir de nouvelles prodrogues. Pour cela, nous avons conçu, synthétisé et évalué plusieurs plateformes chimiques tripartites (architecture moléculaire composée de trois membres comprenant un déclencheur activable enzymatiquement, un vecteur mitochondrial, et une drogue) qui ont permis le transport de principes actifs puis leur libération sélective à l'intérieur de la mitochondrie grâce à une a activation médiée par deux enzymes, la nitroréductase (NTR) et l'azoréductase (AzoR). Enfin, dans une troisième partie, nous avons abordé la synthèse d'une nouvelle bibliothèque de photosensibilisants mito-ciblées pour une utilisation en thérapie photodynamique
The mitochondria has emerged in recent years as a therapeutic target of interest. This organelle of eukaryotic cells plays a fundamental role in the cell's energy production. The dysregulation of its function is associated with a wide variety of pathologies such as neurodegenerative, metabolic, cardiovascular diseases, cancer and rare mitochondrial diseases. Thus, since the end of the 80s, different vectorization strategies have been developed, allowing the transport of active substances inside the mitochondria. The growing number of molecules acting on mitochondrial function currently in clinical trials or on the market testifies to the importance of this issue. This thesis project focused on the synthesis of tools to observe, understand and impact mitochondrial functioning. A first part of the project focused on the demonstration of intramitochondrial Azoreductase (AzoR) activity. To this end, mito-targeted probes whose fluorescent behavior is modulated in the presence of AzoR have been designed, synthesized, evaluated in vitro and used in fluorescence cell imaging to demonstrate the presence of this enzymatic activity in mitochondria. In the second part of this thesis, we focused on the use of mitochondrial enzyme reductase activities to allow the intramitochondrial release of a wide variety of neutral molecules, with the ultimate goal of designing new prodrugs. To do this, we designed, synthesized and evaluated several tripartite chemical platforms (molecular architecture composed of three members including an enzymatically activable trigger, a mitochondrial vector, and a drug) that allowed both the transport and the release of active coumponds inside the mitochondria thanks to an activation mediated by two enzymes, nitroreductase (NTR) and azoreductase (AzoR). Finally, in a third part, we discussed the synthesis of a new library of mito-targeted photosensitizers intended for applicvations in photodynamic therapy

The task of medicinal chemists in a drug discoveryproject is to synthesize/design analogues to the screening hits, simultaneouslyincreasing target potency and optimizing the pharmacological properties.  This requires a wide selection of moleculesto be synthesized, where both synthetic feasibility and price of startingmaterials are of great importance. In this work, a synthetic pathway from cheapand readily available starting materials to highly modifiable 2,4-disubstitutedpyrrolidines is demonstrated. Previously reported procedures to similarpyrrolidines use expensive catalysts, requires harsh conditions and requiresnon-commercially available starting materials. The suggested pathway herein has demonstrated great possibility forvariation in the 4-position, including fluoro, difluoro, nitrile and alcoholfunctional groups. There are several areas in which the synthesis can beimproved and expanded upon. Improvements can be made by optimizing thedescribed reaction conditions and further expansion of possible modificationsin both 2- and 4-position could be explored.

In recent years, despite the large amount of novel and clinically validated targets identified from the human genome project, the number of new drug launched on the market is decreasing and the overall costs for the development of a drug are rising significantly. Pharmaceutical and biotechnology companies are under a strong pressure to produce a steady stream of innovative, well-differentiated drugs with a reduced cost both for discovery and development. Currently it takes an estimated 10-14 years to develop and market a drug at a cost that exceeds 1 billion dollars. With the aim at increasing the productivity of original and highly pure molecules as potential modulators of therapeutic targets, different and novel technologies, related to synthesis, work-up and isolation, were developed. In particular the so called “Enabling Techniques” have emerged and were studied in a large extent in Academia. Among these new technologies continuous flow organic synthesis is now being investigated widely in fine chemistry and, with the advent of commercially available microreactors, also in pharmaceutical industry. In the framework of my PhD thesis exploring the application of the so called “Enabling Techniques” in a medicinal chemistry laboratory, my efforts were devoted to the evaluation of the benefits that continuous flow chemistry could provide in Drug Discovery programs and in the synthesis of natural products in comparison with traditional synthetic techniques. Flow technologies have recently received a great deal of attention and a fair number of scientific publications have demonstrated their potential for improving productivity in organic synthesis. Established continuous flow chemistry advantages include precise control of temperature, pressure, concentration, residence time and heat transfer. All these aspects significantly affect the reaction outcome improving yield and selectivity. Within my thesis, continuous flow chemistry was firstly applied to the synthesis of hydroxamic acids, a class of well known inhibitors of important biological targets such as metalloproteinases and histone deacetylases. As a part of a medicinal chemistry project, a simple conversion of ester into hydroxamic acids (Scheme 1) was envisaged as a suitable and convenient synthetic method for the preparation of a collection of compounds featuring such privileged substructure. The effects of flow rate, reactor volume and temperature were examined and the optimized reaction conditions were then successfully applied for the preparation of a small collection of ten hydroxamic acids featuring a range of functional groups. Good yields, purity and high reproducibility were observed using this simple protocol. R = Aryl, Alkyl, Heteroaryl, Aminoalkyl; R' = Me, Et Scheme 1. Synthesis of Hydroxamic Acids No racemisation occurred when the reaction was performed on protected amino acids. The yields were comparable and, in some cases, even better than what reported in literature where the same transformation was performed by MW irradiation. Even if the reaction time is relatively longer than with MW, no limitation in scale-up is present using flow chemistry. Based on the good results obtained in the development of the continuous flow synthesis of hydroxamic acids this new methodology was applied to the synthesis of SAHA (suberoylanilide hydroxamic acid). Our two-step sequence entails the conversion of the commercially available methyl suberoyl chloride into methyl suberanilate under Schotten-Baumann conditions, followed by the transformation of ester by aqueous hydroxylamine in presence of sodium methoxide (Scheme 2). Scheme 2. Synthesis of SAHA (suberoylanilide hydroxamic acid) To avoid a time consuming work-up procedure and extensive manual purification of the final compound, an integrated sequential flow synthetic pathway was set-up employing immobilized scavenger. The reaction stream was directly passed through a short packed column containing silica supported quaternary amine for the selective removal of the carboxylic acid by-product. The solution containing the product and traces of the starting material was collected and, after solvent evaporation, crystallization from MeOH afforded SAHA in 84% yield and 99% purity (80% yield over two steps). With the aim at studying the applicability of flow technique also to the synthesis of a natural compound, the continuous flow multi-step synthesis of Dumetorine was undertaken. (+)-Dumetorine, isolated in 1985 from the tubers of Dioscorea dumetorum Pax, shows a notable use in folk medicine and arrow poisons. Its total batch-synthesis was recently published by our group (Scheme 3). Scheme 3. Batch-Total synthesis of Dumetorine The planned synthetic route envisaged a flow process where the synthetic steps were combined into only one continuous sequence minimizing work up and purifications. The reaction crudes had to be processed through packed columns containing immobilized reagents, catalysts, scavengers or catch and release agents. In this way the improvements gained through the precise control of reaction conditions and the reduction in manual handling could be easily evaluated. To synthesize this natural alkaloid, new protocols had to be developed for performing classical reactions under continuous flow conditions. With this aim the flow addition of Grignard reagent to carbonyl compounds was the first reaction that we broadly investigated. In fact, despite many classes of reaction was successfully transferred to continuous flow approach, the addition of Grignard reagents to aldehydes and ketones under flow conditions is up-to-date poorly exemplified in the literature. The optimization of the experimental parameters was investigated by varying the temperature of the stored solution, the residence time and the number of Grignard equivalents. A short column containing polymer supported benzaldehyde was used for the scavenging of the excess of Grignard reagent. The optimized conditions (room teperature; 1.2 Grignard eq; residence time 33 minutes) were successfully applied on different aldehydes and ketones (arylic, heteroarylic, alkylic etc.) for the preparation of a small collection of alcohols (Scheme 5). Good yields (ranging from 88% to 96%), purity and high reproducibility were observed. Scheme4. Flow Grignard addition to carbonyl compounds The protocol was applied to the synthesis of Tramadol, a well known centrally active analgesic used for treating moderate to severe pain (Yield 96%). The developed conditions also allowed the selective addition of Grignard reagents to aldehydes and ketones in the presence of a nitrile function (Scheme 5). Scheme5. Flow Grignard addition to carbonyl compounds in presence of nitriles. In the light of the interesting results concerning the flow addition of Grignard reagent to carbonyl compounds, we started to perform the five-step continuous flow synthesis of (+) Dumetorine reported below (Scheme 6). Scheme 6. Flow-Total synthesis of (+)Dumetorine This synthesis entailed IBX oxidation of primary alcohol, Grignard addition on carbonyl compounds, acylation, ring closing metathesis and Eschweiler-Clarke reductive amination. In the second step the flow addition of suitable Grignard reagent to aldehyde (2) was performed under the previously optimized conditions. The yield of the isolated compound was 90% with a remarkable improvement respect to the batch process. This result is a direct consequence of the efficient mixing and heat dispersion due to the high surface area-to-volume ratios in the PTFE tubing that keeps the temperature constant minimizing the occurrence of side reactions. Compound (5) presents the structural features for ring-closing metathesis and this type of reaction was performed in batch using 2nd generation Grubbs catalyst in good yield. The same result was obtained flowing for short time (less than 20 min) the starting material in presence of dissolved catalyst (both 1st and 2nd generation catalysts were tested) but, in this way, the problem of the final purification by flash chromatography was still present. After a few failing attempts using not commercially available supported Grubbs catalysts of 1st (a) and 2nd (b) generation (Figure 1) , we evaluated the application to flow chemistry of a homogeneous PEG supported Grubbs catalyst in order to increase the performance in RCM maintaining the possibility of a simple catalyst recovery. Figure 1. Supported Grubbs Catalysts prepared A newly synthesized PEG- Supported Hoveyda catalyst (8) was prepared (Scheme 5) in collaboration with Prof. M. Benaglia and Dr. A. Caselli (Università degli Studi di Milano). Using this PEG-supported catalyst, the flow RCM was successfully and we observed the total conversion of (5) in (6). The pure compound (6) was simply obtained by evaporation of the solvent after the precipitation of the catalyst in presence of Et2O. The catalyst easily recovered can be recycled for RCM reactions. Scheme 5. Synthesis of PEG-supported Hoveyda catalyst The Dumetorine batch synthesis was affected by a low yielding acid catalyzed cleavage of Boc protecting group due to a Michael side reaction of the secondary amine on the α-β unsaturated lactone ring. As a consequence, the reductive amination resulted not an easy task to be managed. In order to overcome these problems, we performed the unprecedented flow Eschweiler-Clarke reaction, a particular amination reduction. Under optimized continuous flow conditions, we assessed the concomitant BOC deprotection and N-methylation. The solutions of starting materials and reagents were pumped in the PTFE tubing reactor and then through a column containing SCX cartridge (catch and release purification) obtaining (+)-Dumetorine in high purity and good yield (Overall yield: 29% (65% diastereoisomeric mixture); obtained (+)-Dumetorine amount: 227 mg). So, a flow-based synthesis of (+)-Dumetorine was accomplished; remarkable results were obtained in the Grignard reaction, performed in an efficient and safe manner at room temperature avoiding cryogenic temperature; in the RCM reaction, carried out with a newly synthesised PEG-supported Hoveyda catalyst and finally in the unprecedented flow Eschweiler-Clarke reaction with concomitant BOC deprotection and N-methylation in high yield. This flow total synthesis represents a significant improvement over the existing protocol characterized by lower yield and more steps and the synthetic route was also tested for the preparation of additional analogue derivatives. In fact on the basis of the results that we obtained in the synthesis of (+)-Dumetorine, we applied flow technology to the preparation of its simplified natural congeners (+)-Sedridine (9) and (-)-Sedamine (10). The synthesis of the two natural alkaloids was assessed with good results using protocols (Grignard addition, Eschweiler Clarke reaction) optimized for the preparation of (+)-Dumetorine. Figure 2. (+)-Sedridine (9) and (-)-Sedamine (10) All the results that were assessed in this PhD thesis clearly demonstrate how flow chemistry shows great potentiality in the Medicinal Chemistry field and how that this technique is of great advantage in the assembly of challenging molecules, as natural products, in terms of overall yield reaction time and limitation of handling and purification.

The multistep synthesis of natural products has historically served as a useful and informative platform for showcasing the best, state-of-the-art synthetic methodologies and technologies. Over the last several decades, electrochemistry has proved itself to be a useful tool for conducting redox reactions. This is primarily due to its unique ability to selectively apply any oxidizing or reducing potential to a sufficiently conductive reaction solution. Electrochemical redox reactions are readily scaled and can be more sustainable than competing strategies based on conventional redox reagents. In this chapter, we summarize the examples where electrochemistry has been used in the synthesis of natural products. The chapter is organized by the reaction type of the electrochemical step and covers both oxidative and reductive reaction modes.

When a reactant or a set of reactants undergoes several reactions (at least two) simultaneously, the reaction is said to be a complex reaction. The total conversion of the key reactant, which is used as a measure of reaction in simple reactions, has little meaning in complex reactions, and what is of primary interest is the fraction of reactant converted to the desired product. Thus the more pertinent quantity is product distribution from which the conversion to the desired product can be calculated. This is usually expressed in terms of the yield or selectivity of the reaction with respect to the desired product. From the design point of view, an equally important consideration is the analysis and quantitative treatment of complex reactions, a common example of which is the dehydration of alcohol represented by We call such a set of simultaneous reactions a complex multiple reaction. It is also important to note that many organic syntheses involve a number of steps, each carried out under different conditions (and sometimes in different reactors), leading to what we designate as multistep reactions (normally called a synthetic scheme by organic chemists). This could, for example, be a sequence of reactions like dehydration, oxidation, Diels-Alder, and hydrogenation. This chapter outlines simple procedures for the treatment of complex multiple and multistep reactions and explains the concepts of selectivity and yield. For a more detailed treatment of multiple reactions, the following books may be consulted: Aris (1969) and Nauman (1987). We conclude the chapter by considering a reaction with both catalytic and noncatalytic steps, which also constitutes a kind of complex reaction. Because both chemists and chemical engineers are involved in formulating a practical strategy for accomplishing an organic synthesis, it is important to appreciate the roles of each.

Abstract The use of flow chemistry in the single- and multistep synthesis of active pharmaceutical ingredients has been well demonstrated. The pharmaceutical industry is now taking the next steps towards integration of flow chemistry into large-scale commercialized processes, which can effectively supply patient populations. This chapter details advances in this area, and outlines the data and knowledge required to select, develop, scale, and commercialize an efficient flow process.

Peter Legzdins of the University of British Columbia has described (J. Am. Chem. Soc. 2007, 129, 5372) a stoichiometric tungsten complex that specifically functionalized the primary H of an alkane 1 to give the organometallic 2. Neither the scope of the reactivity of 2 nor the functional group compatibility of this process have as yet been explored. Ruggero Curci of the Università di Bari has reported (Tetrahedron Lett. 2007, 48, 3575) the stereospecific hydroxylation of 1,3-dimethyl cyclohexane 4 to the diol 6. Yasuyuki Kita of Osaka University has developed (Organic Lett. 2007, 9, 3129) conditions for specific benzylic oxidation, converting 7 into 8 with high diastereocontrol. Larry E. Overman of the University of California, Irvine has established (Organic Lett. 2007, 9, 5267) that by using a slow H-atom donor, it was possible to effect intramolecular H abstraction, leading, by oxidation of the intermediate captodatively-stabilized radical, from 9 to the acetate 10. The target C-H of 9 is activated by being adjacent to the ring nitrogen. There are many other ways that nitrogen, easily oxidized, has been used to activate a C-H for bond formation. Takehiko Yoshimitsu and Tetsuaki Tanaka of Osaka University have established (Organic Lett. 2007, 9, 5115) a free-radical route for the homologation of a tertiary amine such as 11 with phenyl isocyanate 12. Chuan He of the University of Chicago has devised (Angew. Chem. Int. Ed. 2007, 46, 5184) an Ag catalyst for the oxidative cyclization of sulfamates such as 15. M. Christina White of the University of Illinois has developed (J. Am. Chem. Soc. 2007, 129, 7274) a ligand system that allows the diastereoselective Pd-mediated allylic oxidation of 16 to 17. The cyclization of 18 to 19 developed (J. Org. Chem. 2007, 72, 8994) by Renhua Fan of Fudan University is thought to be proceeding via H atom abstraction by an intermediate nitrogen radical. The oxidation of the amine 20 to the endocyclic enamine 21 reported (J. Am. Chem. Soc. 2007, 129, 14544) by Maurice Brookhart of the University of North Carolina depended on the ease of oxidative addition of an intermediate alkenyl Co complex into the C-H bond adjacent to the nitrogen. The multistep cyclization of 22 to 23 devised (Organic Lett. 2007, 9, 4375) by Philippe Renaud of the Universität Bern depended on the ease of H atom abstraction adjacent to nitrogen.