Academic literature on the topic 'Multistep synthesis'

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.

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

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.

A versatile continuous-flow synthesis of highly functionalized 1,2,4-oxadiazoles starting from carboxylic acids is reported. This process was applied to the multistep synthesis of imidazo[1,2-a]pyridin-2-yl-1,2,4-oxadiazoles, using a three reactor, multistep continuous-flow system without isolation of intermediates. This continuous-flow method was successfully combined with a single-step liquid–liquid microextraction unit to remove high boiling point polar solvents and impurities and provides the target compounds in high purity with excellent overall yields.

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.

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.

Au cours de ce travail, nous nous sommes intéressés à la synthèse d'un analogue de Milnacipran, une molécule commercialisée sous le nom d'Ixel pour son activité anti-dépresseur. Il s'agit d'un cyclobutane trisubstitué portant deux centres stéréogènes contigus. L'objectif est de développer une voie de synthèse efficace et transposable à la version énantiosélective.Nous avons également travaillé sur la formulation nanométrique d'épiPodophyllotoxines, un produit naturel biologiquement active. Nous avons imaginé une architecture moléculaire permettant à la molécule de s'auto-assembler en micelle, ainsi elle peut être transportée de manière efficace au tumeur cancéreux. Les études in vitro et in vivo ont apporté des résultats prometteurs vis-à-vis du potentiel thérapeutique de notre nano-objet. Enfin nous avons étudié au cours de cette thèse deux méthodologies: la réactivité des époxydes en milieu alcalin fort et les dérivés d'organobismuth pour les réactions d'oxydation. Ces derniers ont été exploités afin d'oxyder des hydroxylamines en nitrone dans des conditions douces, permettant de réaliser le tandem oxydation/cycloaddition 1,3 dipolaire in situ avec des alcynes tendus
My PhD thesis mainly involves the enantioselective synthesis of the Milnacipran's analog, a trisubstituted cyclobutane bearing two contiguous stereogenic centers. We have devised a conventional approach which consists of an intramolecular SN2 cyclization. After an acidic treatment, the key intermediate lactone was isolated with an ee > 99%, which was converted to the Milnacarre with no erosion of the ee value. We have also interested in the nanometric formulation of Podophyllotoxine derivatives. The natural product was designed to bear a hydrophilic and hydrophobic side chain. Its micellar solution was evaluated in vitro, in vivo and the obtained resuls were shown to be promising.We have also studied two methodologies: the reactivity of glycidyl ether toward alkyllithium reagents and oxydation of hydroxylamines to nitrone using triphenylbismuth carbonate. We observed in the former case an original rearrangement of the substrate to a vicinal diol, while in the latter case we have developped a mild condition to perform an tandem oxydation/1,3-dipolar cycloaddition in situ with a strained alkyne

U radu je ostvarena totalna sinteza novih acikličnih tiazolnih C-nukleozide sa dvostrukom  vezom i 2′,3′-dideoksi funkcijom u šećernoj komponenti. Ostvarena višefazna sinteza  pomenutih acikličnih analoga tiazofurina zasnovana je na D-arabinozi kao hiralnom prekursoru. Ispitana je in vitro citotoksična aktivnost novosintetizovanih nukleozida prema ćelijskim linijama K562, HL-60, HT-29, MCF-7, MDA-MB-231, HeLa, Raji, PC3, Jurkat, Hs 294T i MRC-5, kao i provera ćelijskih mehanizama koji su u osnovi  uočenog citotoksičnog potencijala novosintetisanih analoga u odnosu na tiazofurin kao referentno jedinjenje.
A total synthesis of new acyclic thiazole C-nucleozides bearing a double bond or 2′,3′-dideoxy functionality in the sugar moiety was achieved in this work. The multi-step synthesis of the mentioned thiazofurin analogues is based on  D-arabinose as a chiral precursor. In vitro cytotoxic activity of newly synthesized compounds was evaluated against the following cell lines: K562, HL-60, HT-29, MCF-7, MDA-MB-231, HeLa, Raji, PC3, Jurkat, Hs 294T and MRC-5. A study of cell mechanisms underlaying the significant cytotoxic potential of these molecules was caried out and the results were compared to thiazofurin that servad as a referent compound in all biological testings.

De par leur grande diversité chimique et leur implication dans de nombreux mécanismes biologiques, les molécules phosphorées font l'objet de nombreuses recherches scientifiques. Depuis près de 30 ans, plusieurs composés phosphorés ont été développés et utilisés pour leurs propriétés médicinales ou phytosanitaires. Les dérivés de type phosphinates ou phosphonates se sont révélés être des composés de choix, grâce à leur grande stabilité chimique et enzymatique. Par ailleurs, les sucres et leurs analogues ont largement démontré leur potentiel biologique en raison de leur implication dans de nombreux processus biologiques. Dans ce contexte, il a été envisagé de développer des analogues de sucres phosphorés possédant un atome de phosphore endocyclique. Il s'agit de structures totalement inédites obtenues à partir de précurseurs phosphorés simples et par des réactions de type : P-alkylation, Pudovik, ouverture d'époxyde, cyclisation par transacétalisation ou transestérification. Grâce à des synthèses en 4 à 7 étapes, deux familles de phosphinosucres ont été préparées ainsi qu'une famille de phosphonosucres en tant qu'analogues de sucre. En parallèle, la synthèse d'analogues de nucléosides phosphorés a également été étudiée par introduction de nucléobases sur les analogues de sucres phosphorés précédemment cités. Ces travaux ont mis en jeu des réactions issues à la fois de la chimie de nucléosides mais également de la chimie du phosphore, permettant d'accéder à des analogues de nucléosides totalement inédits dont l'activité antivirale a pu être évaluée. Enfin, une nouvelle famille de phosphonates nucléosidiques acycliques a été synthétisée en 6 ou 7 étapes en série pyrimidique. Deux prodrogues dérivées de la cytosine et de l'uracile ont également été préparées avec des groupements enzymolabiles de type Bis-(S-acyl-2-thioéthyle). L'ensemble des analogues de nucléotides synthétisés ont été évalués pour leurs propriétés antivirales contre les virus de l'hépatite C et du SIDA. Ainsi, à travers ce projet, trois grandes familles de nouvelles molécules phosphorées ont été développées : les hétérocycles phosphorés oxygénés en tant qu'analogues de sucres, des analogues de nucléosides phosphorés, une nouvelle classe de phosphonates nucléosidiques acycliques
According to their wide chemical diversity and their implication in many biological processes, phosphorus compounds are intensively studied by organic chemists. Since 30 years, many phosphorus molecules have been developed and used for their biological properties in medicine or agrochemistry. Chemically and enzymatically stable compounds, phosphonates and phosphoninates are potential derivatives for drug design. Besides, sugars are an important biological family involved in numerous biological pathways which have widely revealed a high therapeutic potential. In this context, the first objective of these works was to develop sugar analogues with an endocyclic phosphorus atom (phosphasugars) to synthesize unpublished families of phosphinosugars and phosphonosugars. Their synthesis were carried out in 4 to 7 steps, using as key reactions : P-alkylation, Pudovik, epoxyde ring-opening reaction, cyclisation by transacetalisation or transesterification. Moreover, these phosphasugars were extended to the synthesis of new nucleoside analogues by introducing nucleobase on phosphasugar moiety. The antiviral activity of these new compounds was evaluated. Finally, a new class of acyclic nucleoside phosphonates was prepared in pyrimidinyl series. Different nucleotide analogues and prodrugs were synthesized in 6-7 steps with uracil, thymine and cytosine and evaluated against HCV and HIV

La neuraminidase humaine 1 (hNEU1) est une glycosidase impliquée dans de nombreux processus physiologiques majeurs tel que la signalisation cellulaire ou la régulation de certains récepteurs membranaires. Son inhibition sélective constitue actuellement un challenge qui pourrait conduire à des avancées pharmacologiques importantes avec de potentielles applications thérapeutiques. En partenariat avec l’unité MEDyC (UMR URCA/CNRS 7369), nous avons initié un projet de recherche dédié à la conception, la synthèse et l’évaluation biologique de nouveaux inhibiteurs sélectifs de la hNEU1.Après avoir validé la structure des molécules cibles et un schéma rétrosynthétique, la première partie du travail de thèse a été consacrée à la synthèse d’un aldofuranose convenablement fonctionnalisé et protégé. Puis, à l’aide d’une séquence réactionnelle en deux étapes utilisant les compétences spécifiques développées au sein de notre laboratoire, l’aldofuranose a été transformé en un dithioacétal de cétène cyclique possédant la structure de la molécule cible. Dans une seconde partie, une étude méthodologique visant à déterminer les conditions expérimentales optimales pour l’introduction de divers électrophiles sur la position 1 de l’hétérocycle soufré a été effectuée. Les résultats expérimentaux obtenus montrent que cette transformation est dépendante des substituants présents dans la structure de l’hétérocycle soufré. Une étude théorique originale a été réalisée pour mieux comprendre les mécanismes réactionnels sous-jacents. En conclusion, le travail de synthèse effectué ouvre des perspectives encourageantes pour l’obtention des molécules cibles et leur évaluation
Human neuraminidase 1 (hNEU1) is a glycosidase involved in a number of major physiological processes, such as cell signaling and the regulation of membrane receptors. Its selective inhibition currently represents a challenge that could lead to major pharmacological advances with potential therapeutic applications. In partnership with the MEDyC unit (UMR URCA/CNRS 7369), we have initiated a research project dedicated to the design, synthesis and biological evaluation of new selective hNEU1 inhibitors.After validating the structure of the target molecules and a retrosynthetic scheme, the first part of the thesis work was dedicated to the synthesis of a suitably functionalized and protected aldofuranose. Then, using a two-step reaction sequence based on the specific skills developed in our laboratory, the aldofuranose was transformed into a cyclic ketene dithioacetal with the structure of the target molecule. In the second part, a methodological study was carried out to determine the optimum experimental conditions for the introduction of various electrophiles on position 1 of the sulfur heterocycle. The experimental results obtained show that this transformation is dependent on the substituents present in the structure of the sulfur heterocycle. An original theoretical study was then achieved to provide a better understanding of the reaction mechanism. In conclusion, the synthetic work accomplished has led to encouraging prospects for obtaining and evaluating the target molecule

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2008.
Includes bibliographical references (leaves 174-184).
This thesis focused on advancing the microchemical field from single device based demonstrations to systems that can perform multi-step series and parallel synthesis. Few examples of micro-separators and micro-pumps suited for miniaturized lab-on-a-chip systems for organic syntheses exist, so the first half of this thesis developed systems for these micro-unit-operations, while the second half demonstrated multistep microchemical operations enabled by these systems. In-line continuous separation devices are developed that enabled removal of unreacted reagents/byproducts, making it possible to realize a series of reactions without leaving the microreactor environment. Differences in surface forces and preferential wettability characteristics of fluoropolymers are used for phase separation. Such microseparators are used to demonstrate 100% separation of two phase flows of hexane and water, toluene and water, dichloromethane and water, and hexane and methanol. Integrated liquid-liquid extraction devices are microfabricated that performed two -phase contacting by segmented flow, followed by separation - resulting in single stage extraction. Single stage extraction of N,N-dimethylformamide from dichloromethane to water, and from diethyl ether to water is demonstrated. The development of separators allows microreactors to be connected to microseparators to form microreactor networks enabling reactions and separations in succession. The starting reagents are loaded in syringes and syringe pumps push fluid through the train of microdevices. However, this pumping scheme is limited by pressure constraints at the pump drives as well as the microseparators. Therefore, there is a need to develop in-line pumps to sustain the microdevice network. Pressure-driven flow is employed for the operation of micropumps. An enclosure with the liquid is pressurized with helium gas, causing the liquid to flow. The dynamics of pressurizing and de-pressurizing an enclosure are modeled and confirmed by experiments. Active and passive control schemes to provide constant flowrate of the liquid are developed and implemented. Different schemes are developed to use the gas pressure to manipulate the flow path of liquids.
(cont.) In one scheme, two enclosures are used together to perform as an in-line pump. The in-line pumps also acted as a buffer to prevent any disturbance propagation, and allowed the upstream and downstream to operate at different flowrates. The pump concept is demonstrated at two scales - 1) microfabricated silicon chips of 40 microliter volume and 2) using glass shell vials of 10000 microliter volume. These pumps are used along with two microseparators to demonstrate two-stage countercurrent and cross-flow liquid-liquid extraction of N,Ndimethylformamide from dichloromethane to water starting with 4.4 mole percent mixture. The in-line pumps also allowed recirculation with a constant flowrate that enabled long residence time reactions. As an example, peptide synthesis from amino acids, using the Merrifield technique is implemented. Specifically, the pentapeptide, Leuenkephalin is synthesized on different resins simultaneously as an example. A new design for the silicon microreactor for packed bed reactions is developed to enable larger catalyst loadings and offer manageable pressure drops across the packed bed even when the solid loading increased in volume during operation, as is the case with the peptide synthesis experiments. These microchips are also used to study "click chemistry" reactions to synthesize drug-candidate molecules. The packed bed microreactor experiments give higher conversions and better selectivities than batch experiments after the same amount of reaction time as the microreactor experiments provide increased relative catalyst concentration, and reduce side reactions that otherwise reduce selectivity. As an example of multi -step synthesis involving reactions and separations, the synthesis of carbamates starting from azoyl chloride and sodium azide, using the Curtius rearrangement of isocyanates is performed. This example also demonstrates parallel synthesis of analogous carbamates by introducing branching in the synthesis sequence after the isocyanate production to form microreactor networks. The second reaction involved heat decomposition of the organic azide, and performs faster when catalyzed using solid acid zeolite catalyst in a packed bed microreactor.
(cont.) Continuous operation of the microdevice network for ~ 7-10 days at flowrates of 1-5 [mu]l/min show no change in performance. The microreactor based synthesis is run at higher temperatures than conventional batch scale reactions due to the inherent safety in microreactor based production. The multiple-carbamate-synthesis microreactor network consists of five microreactors and two separators. This demonstration is the first multi-step organic synthesis involving reactions and separations, and showcased the major contributions from this thesis. The development of micro-unit-operations in this thesis has advanced the microchemical field from single device based demonstrations to systems that can perform continuous-flow multi-step series and parallel chemical synthesis.
by Hemantkumar Sahoo.
Ph.D.

Les océans occupent plus de 70 % de la surface de la Terre et représentent l'une des composantes les plus riches de la biosphère terrestre. Les différents organismes marins qui s'y trouvent produisent une large diversité de métabolites spécialisés aux propriétés biologiques d'intérêt.Dans ces travaux de thèse, nous nous sommes intéressés à trois volets principaux : (i) l'extraction, le fractionnement, l'isolement et la caractérisation structurales de métabolites spécialisés à partir de l'éponge méditerranéenne Crambe crambe et d'une éponge appartenant à l'ordre verongida échantillonnée à Djibouti, (ii) la synthèse de métabolites isolés lors de travaux antérieurs, l'acide peroxyacarnoïque E et les bolascidines A - D, sélectionnés pour leurs propriétés biologiques et leurs singularités structurales, et (iii) l'évaluation des propriétés biologiques des composés naturels et synthétiques.L'étude d'une éponge échantillonnée à Djibouti a conduit à 3 dérivés de la bromotyrosine, la psammapline A, la psammapline A1 et la bisaprasine. Les différentes bromotyrosines isolées ainsi que la 4-O-sulfatocyclobispsammapline A, isolée lors de travaux antérieurs de l'éponge Hexadella racovitzai, ont été évalués pour leurs propriétés biologiques, notamment antioxydantes. Les travaux menés sur l'éponge Crambe crambe ont conduit à l'isolement et à la caractérisation de trois alcaloïdes guanidiques cycliques, les crambescines A1 462, A2 448 et C1 480. Ces dernières se sont avérées actives vis-à-vis de la déoxyhypusine synthase (DHPS), une enzyme clé impliquée dans la voie de l'hypusination. L'acide peroxyacarnoïque E, isolé précédemment de l'éponge Clathria rugosa, s'est révélé cytotoxique vis-à-vis de plusieurs lignées cellulaires tumorales en activant des voies de nécrose régulées telles que la nécroptose ou la ferroptose. Nous avons échafaudé une stratégie de synthèse convergente en 13 étapes afin d'accéder à ce composé en quantité suffisante. La formation de l'endoperoxyde, considérée comme l'étape clé de la stratégie de synthèse envisagée, a fait l'objet de plusieurs tentatives. Enfin, les travaux antérieurs d'isolement et de caractérisations structurales menés sur l'ascidie Polysyncraton sp. ont conduit à quatre nouvelles molécules de type bolaamphiphiles, les bolascidines A - D. Nous avons conçu une stratégie de synthèse convergente en 15 étapes pour accéder à ces composés ainsi qu'à leurs dérivés en quantités suffisantes. La synthèse du fragment central ainsi que celle de la chaîne alkyle polyinsaturée ont fait l'objet de plusieurs tentatives
Oceans occupy over 70% of the Earth's surface and represent one of the richest components of the terrestrial biosphere. The various marine organisms found there produce a wide variety of specialized metabolites with biological properties of interest.In this work, we focused on three main tasks: (i) the extraction, fractionation, isolation and structural characterization of specialized metabolites from the Mediterranean sponge Crambe crambe, and a sponge belonging to the order verongida sampled in Djibouti, (ii) the synthesis of metabolites isolated in previous work, peroxyacarnoic acid E, and bolascidins A - D, selected for their biological properties and structural singularities, and (iii) the evaluation of the biological properties of natural and synthetic compounds.The study of a sponge sampled in Djibouti led to the identification of three bromotyrosine derivatives, psammaplin A, psammaplin A1, and bisaprasine. Isolated bromotyrosines, as well as 4-O-sulfatocyclobispsammaplin A, previously isolated from the sponge Hexadella racovitzai, were evaluated for their biological properties, notably as antioxidants. The study performed on the Crambe crambe sponge led to the isolation and characterization of three cyclic guanidine alkaloids, crambescines A1 462, A2 448, and C1 480. These were found to be active against deoxyhypusine synthase (DHPS), a key enzyme involved in the hypusination pathway. Peroxyacarnoic acid E, previously isolated from the sponge Clathria rugosa, exhibited cytotoxicity against several tumor cell lines by activating regulated necrosis pathways, such as necroptosis or ferroptosis. We developed a 13-step convergent synthesis strategy to access this compound in sufficient quantity. The synthesis of the endoperoxide, considered as the key step in the proposed synthetic strategy, was the subject of several attempts. Finally, previous isolation and structural characterization work on the ascidian Polysyncraton sp. led to four new bolaamphiphilic compounds, bolascidins A - D. We designed a 15-step convergent synthesis strategy to access these compounds and their derivatives in sufficient quantities. Several attempts were made to synthesize the central fragment and the polyunsaturated alkyl chain

Abstract For the scalable production of commercial products based on vertically aligned carbon nanotubes (VACNTs), referred to as CNT forests, key manufacturing challenges must be overcome. In this work, we describe some of the main challenges currently facing CNT forest manufacturing, along with how we address these challenges with our custom-built rapid thermal processing chemical vapor deposition (CVD) reactor. First, the complexity of multistep processes and reaction pathways involved in CNT growth by CVD limits the control on CNT population growth dynamics. Importantly, gas-phase decomposition of hydrocarbons, formation of catalyst particles, and catalytic growth of CNTs are typically coupled. Here, we demonstrated a decoupled recipe with independent control of each step. Second, significant run-to-run variations plague CNT growth by CVD. To improve growth consistency, we designed various measures to remove oxygen-containing molecules from the reactor, including air baking between runs, dynamic pumping down cycles, and low-pressure baking before growth. Third, real-time measurements during growth are needed for process monitoring. We implement in situ height kinetics via videography. The combination of approaches presented here has the potential to transform lab-scale CNT synthesis to robust manufacturing processes.

In recent years, a large number of nano-size semiconductors have been investigated for their potential applications in photovoltaic cells, optical sensor devices, and photocatalysts [1, 2, 3]. Nano-size semiconductor particles have many interesting properties due mainly to their size-dependent electronic and optical properties. Appropriately, many speciality of nanomaterials such as CdS and ZnS semiconductor particles, and other metal oxides such as ZnO and lithium-titanate oxide (LTO) have been prepared. However, most of them were prepared with toxic reactants and/or complex multistep reaction processes. Particularly, it is quite difficult to produce LTO nanoparticles, since it typically requires wearisome conditions such as very high temperature over 1000 °C, long producing times, and so on. To overcome such problems, various core/shell type nanocrystals were prepared through different methods such as the hydrothermal synthetic method, microwave, and sonochemistry. Also many coating methods on inorganic oxide nanoparticles were tried for the preparations of various core-shell type nanocrystals. Sonoluminescence (SL) is a light emission phenomenon associated with the catastrophic collapse of a gas bubble oscillating under an ultrasonic field [4]. Light emission of single bubble sonoluminescence (SBSL) is characterized by picosecond flashes of the broad band spectrum extending to the ultraviolet [5, 6]. The bubble wall acceleration has been found to exceed 1011 g at the moment of bubble collapse. Recently observed results of the peak temperature and pressure from the sonoluminescing gas bubble in sulfuric acid solutions [9] were accurately predicted by the hydrodynamic theory for sonoluminescence phenomena [7, 10, 11, 12], which provides a clue for understanding sonochemical reactions inside the bubble and liquid layer adjacent to the bubble wall. Sonochemistry involves an application of sonoluminescence. The intense local heating and high pressure inside the bubbles and liquid adjacent bubble wall from such collapse can give rise to unusual effects in chemical reactions. The estimated temperature and pressure in the liquid zone around the collapsing bubble with equilibrium radius 5 μm, an average radius of bubbles generated in a sonochemical reactor at a driving frequency of 20 kHz with an input power of 179 W, is about 1000 °C and 500 atm, respectively. At the proper condition, a lot of transient bubbles are generated and collapse synchronistically to emit blue light when high power ultrasound is applied to liquid, and it is called multibubble sonoluminescence (MBSL). Figure 1 shows an experimental apparatus for MBSL with a cylindrical quartz cell, into which a 5 mm diameter titanium horn (Misonix XL2020, USA) is inserted [13]. The MBSL facilitates the transient supercritical state [14].in the liquid layer where rapid chemical reactions can take place. In fact, methylene blue (MB), which is one of a number of typical textile dyestuffs, was degraded very fast at the MBSL condition while MB does not degrade under simple ultrasonic irradiation [13]. MBSL has been proven to be a useful technique to make novel materials with unusual properties. In our study, various metal oxides such as ZnO powder [15], used as a primary reinforcing filler for elastomer, homogeneous Li4Ti5O12 nanoparticles [16], used for electrode materials, and core/shell nanoparticles such as CdS coating on TiO2 nanoparticles [17] and ZnS coating on TiO2 nanoparticles [18], which are very likely to be useful for the development of inorganic dye-sensitized solar cells, were synthesized through a one pot reaction under the MBSL condition. Figure 2 shows the XRD pattern of ZnO nanoparticles synthesized from zinc acetate dehydrate (Zn(CH3CO2)2 · 2H2O, 99.999%, Aldrich) in various alcohol solutions with sodium hydroxide (NaOH, 99.99%, Aldrich) at the MBSL condition. The XRD patterns of all powers indicate hexagonal zincite. The XRD pattern for the ZnO nanoparticles synthesized is similar to the ZnO powder produced by a modified sol-gel process and subsequent heat treatment at about 600 °C [19] as shown in Fig.3. The average particle diameter of ZnO powder is about 7 nm. A simple sonochemical method for producing homogeneous LTO nanoparticles, as shown schematically in Fig. 4. First, LiOH and TiO2 nanoparticles were used to prepare LiOH-coated TiO2 nanoparticles as shown in Fig.5. Second, the resulting nanoparticles were thermally treated at 500 °C for 1 hour to prepare LTO nanoparticles. Figure 6 shows a high resolution transmission electron microscope image of LTO nanoparticles having an average grain size of 30–40 nm. All the nanoparticle synthesized are very pure in phase and quite homogeneous in their size and shape. Recently we succeeded in synthesizing a supported nickel catalyst such as Ni/Al2sO3, MgO/Al2O3 and LaAlO3, which turned out to be effective for methane decomposition [20]. Sonochemistry may provide a new way to more rapidly synthesize many specialty nanoparticles with less waste [21]. This clean technology enables the preparation of new materials such as colloids, amorphous particles [22], and various alloys.

Objectives. To review the evidence from the past 10 years on the effectiveness of structured protocols for the handoff between clinicians of responsibility for a patient’s care on clinical safety outcomes. Methods. We searched PubMed, EMBASE, PSNet, CINAHL, and a narrowly focused search for unpublished reports from January 2013 to June/July 2024 for systematic reviews and primary studies of structured protocols for handoffs within the same inpatient unit (i.e., not transferring to a different level of care or a different institution) that reported patient clinical outcomes, such as medical errors, adverse events, medication errors, mortality, length of stay. Risk of bias was assessed with the Cochrane Risk of Bias Tool or a modification of the National Institutes of Health pre-post study tool, a narrative synthesis was performed, and certainty of evidence was assessed using criteria used by Making Healthcare Safer II and the National Academy of Medicine. Findings. We retrieved 789 citations, of which 16 articles were eligible for review (2 systematic reviews and 14 articles of 13 primary studies). Four studies were randomized controlled trials and the remainder were pre-post studies. Two studies were performed in Argentina, one each was performed in Taiwan, Canada and Germany, and the rest were performed in the United States. Six studies were single site studies, and the remainder were multisite. Almost all studies were conducted in academic teaching hospitals and assessed physician-to-physician handoffs. Two systematic reviews and two new original research studies (one a randomized controlled trial) provided low-certainty evidence that use of the SBAR tool (situation, background, assessment, recommendation) can improve patient safety clinical outcomes. Ten studies (of 9 implementations; 2 studies were randomized controlled trials) provided moderate-certainty evidence that the I-PASS tool (illness severity, patient summary, action list, situation awareness and contingency plans, and synthesis to receiver) can improve patient safety clinical outcomes. Many co-interventions and implementation strategies are used in conjunction with the I-PASS mnemonic. No multisite evidence was found for any other structured handoff tool. Conclusions. Use of the structured handoff tool I-PASS probably improves patient clinical outcomes and use of the SBAR tool may improve patient clinical outcomes, with I-PASS having a stronger certainty of evidence. Data come primarily from academic teaching hospitals, and the usefulness of any tool in nonacademic teaching settings is understudied.