Dissertations / Theses on the topic 'Grignard reactions'

The development of chiral organometallics for asymmetric synthesis is a topic of significant research in the recent past. The most studied in this class are the chiral organolithium reagents with many reported examples. The primary focus of our research is the development of C_α-chiral Grignard reagents, where the metal bearing α-carbon is the sole source of chirality. Examples of such Grignard reagents are rare owing to the problems associated with their synthesis, and their low configurational stability. We have studied these problems in three different modules of this project. Reactions of 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile with carbon electrophiles are first attempted in order to expand the utility of this configurationally stable C_α-chiral Grignard reagent in asymmetric synthesis. This reagent has been shown to be non-reactive towards carbon electrophiles at low temperatures. Consequently, we attempt to enhance the reactivity of this compound through two different approaches, Lewis-base activation and the "ate-complex" generation. The Magnesium/Halogen (Mg/X) exchange reactions have been shown to be extremely useful in the synthesis of complex Aryl, alkenyl (sp²) and alkynyl (sp) Grignard reagents. Examples of Mg/X exchange reactions of Alkyl (sp³) halides are, however, rare. Even more rare are such examples with secondary and tertiary alkyl halides, justifying the relative paucity of chiral Grignard reagents. In this module of our project, we study the Mg/X exchange reactions on secondary alkyl halides possessing a γ-hydroxyl group, as an internal activator for such Mg/X exchange reactions. Enantiomerization pathways of chiral organolithium compounds have been widely studied. However, few such studies have been performed on chiral Grignard reagents. In this module of the project, we studied the solvent assisted enantiomerization mechanism of the C_α-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile. Rate constant for the enantiomerization of this compound was measured in three different ethereal solvents to study the effect of solvent on the configurational stability. Finally, the order of the enantiomerization process with respect to [Et₂O] was studied in order to predict the mechanism of this process in Et₂O solvent. Our kinetic studies on the enantiomerization process provided us with a definitive picture for the enantiomerization of the C_α-chiral 1-magnesio-2,2-diphenyl-cyclopropylcarbonitrile, where solvation of the Grignard reagent preceded an ion-pair separation step which eventually lead to enantiomerization of the Grignard species. However, the precise structure of all the involved solvated intermediates could not be determined as kinetics was not able to distinguish between these intermediates. We next performed computational calculations to study the effect of solvation on the analogous 1-magnesio-cyclopropylcarbonitrile in order to address the unanswered questions from our kinetic studies.
Ph. D.

Organometallic reactions, including allylation, alkylation, aldol and Reformatsky type reactions of carbonyl compounds in aqueous media mediated by Sn, Zn, Mn, and In were studied. The possible mechanism and stereochemistry of these reactions were investigated. The methodology has successfully been applied to the syntheses of 1,3-butadienes, vinyloxiranes, and methylenetetrahydrofurans; and the syntheses of natural product (+)-muscarine, (+)-epimuscarine, (+)-KDN and (+)-KDO.
A novel tellurium reagent, bis(triphenylstannyl)telluride, for organic synthesis was developed. Its application in the preparation of organotellurium compounds, reduction of vic-dihalides and $ alpha$-halo ketones, desulfurization of organic trisulfides and cleavage of organic disulfides was studied. All the reactions with this reagent proceeded under very mild conditions.

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 synthesis of a novel class of antioxidants, namely pyridine annulated heterocyclic nitroxides has been investigated. Two analogues were developed that differed in the structure around the free radical nitroxide. The isolation and characterisation of several side products formed in the reactions gave insight into the reaction mechanism. These findings were exploited in order to improve the overall synthetic yield of the reaction.

O-acyl-N-benzyllactamides are obtained in good yield by reaction of 4-benzyl-5-methyl-1,3-oxazolidine-2,4-diones with Grignards reagents and with lithium alkyls. Three alkanes and two ethers were oxidised with ozone in dichloromethane solution or in aqueous pH 3 suspension. Cyclodecane and cyclododecane were converted into the corresponding cycloalkanones. n-decane was converted into a mixture of isomeric n-decanones and carboxylic acids. An ester was formed from the ethers. Hence, one of the methylene groups of these substrates is generally converted into a carbonyl group. Some of these reactions have preparative value. The oxidation of naphthalene in dichloromethane or acetonitrile with excess ozone gives phthalic aldehyde, 2-formyl benzoic acid and phthalic anhydride. Small amounts of the (E)- and (Z)-isomer of 3-phenyl-(2-formyl)-propenal and are also observed in some cases. The reaction is faster in acetonitrile than in dichloromethane owing to the higher solubility of ozone in the former solvent. The reaction is faster on lowering the temperature because of the increase of the concentration of ozone in solution at lower temperature. With a 1:1 or a 1:2 naphthalene:ozone ratio high conversion and low selectivity for the anhydride is observed. The ozonation of cyclohexane in dichloromethane or acetonitrile gives cycloxexanone, cyclohexanol and acidic material. The influence of solvent, reactant concentration, amount of ozone, temperature, reaction time is studied. A reaction mechanism is proposed based on the results of a simulation of the reaction energetics. The ozonation of N-phenylmorpholine in dichloromethane or acetonitrile produced a lactame and a diformylderivative. These products derive from the attack of ozone at the heterocyclic ring. The reaction mechanism has been investigated by DFT calculations which show that the reaction occurs through the insertion of ozone at the carbon-hydrogen bond of a methylenic group of the morpholine ring. The regioselectivity is due to the to the significantly lower energy barrier calculated for the attack of ozone in α to nitrogen than in α to oxygen. Also, the energy barrier decreases with increasing the polarity of the solvent, accounting for the higher reaction rate observed for the reaction carried out in acetonitrile than in dichloromethane. The ozonation of trans- and cis-decalin in dichloromethane or acetonitrile gives the corresponding 9-hydroxydecalinns, 2- and 3-decalones and acidic material. The influence of solvent, reactant concentration, amount of ozone, temperature, reaction time is studied. A reaction mechanism is proposed based on the results of a simulation of the reaction energetics. The N,N bis(salicylidene)ethylenediaminocobalt(II) catalysed oxidative carbonylation of para-substituted aromatic primary amines at 100 °C in methanol gives carbamates in high yields. In presence of excess dimethylamine also N-aryl-N’,N’-dimethylureas are formed. In methylene chloride moderate yields in isocyanate are obtained. 1-methylbenzylamine gives the carbamate and the urea in high yield. i-propylamine gives only the urea. An α-aminoalcohol gives a 1,3-oxazolidin-2-one. Aliphatic secondary amines react faster and give carbamates in methanol and ureas in methylene chloride. The turnover frequency is also measured in two cases.

Une methode generale de synthese stereospecifique de motifs dieniques 1,5- et 1,6- a ete developpee: la reaction de reactifs de grignard actives par des complexes de nickel adequats sur le dihydrofurane et le dihydropyrane, dont la configuration de la double liaison est preetablie. Elle a permis l'acces rapide et stereoselectif (z=99%) a des alcools homo- et bis-homoallyliques z. A partir du dihydrofurane et en repetant la reaction, on peut obtenir des dienes 1,5 et 1,6- a partir du dihydropyrane. Ces resultats ont ete appliques a la preparation a grande echelle de pheromones d'insectes: l'acetate de (6z,11z)-hexadeca-6,11-dien-1-yle, pheromone d'eudia pavonia, et le (5z,9z)-heptacosa-5,9-diene, pheromone de drosophila melanogaster synthetisee pour la premiere fois pour identification. Une nouvelle synthese efficace et peu couteuse du gossyplure, pheromone du ver rose du cotonnier, melange 1:1 d'acetates de (7z,iie)- et de (7z,11z)-hexadeca-7,11-dien-1-yle a ete proposee. Elle a ete realisee a partir d'un melange 1:1 de (3z)- et (3e)-bromo-3-enes obtenu par isomerisation photochimique (decouverte fortuitement) de l'isomere z. Enfin, une autre potentialite de la reaction etudiee a ete mise en valeur. Elle consiste a privilegier la reaction de beta-elimination d'hydrogene sur des reactifs de grignard appropries (bromure d'isopropylmagnesium). A l'aide d'un complexe de nickel monodente, cette reaction effectuee sur des 6-alkyl-3,4-dihydro-2h-pyranes aboutit a des alcools 5-alkyl-bis-homoallyliques (e=95%)

U disertaciji je ostvarena sineza amida i oksazolina žučnih kiselina, kao i njihovih alkil i alkilidenskih derivata polazeći od holne kiseline. Ipitano je ponašanje različitih okso derivata žučnih kiselina u uslovima Grignard-ove i Wittig-ove reakcije. Ispitana je biološka aktivnost odabranih sintetizovanih jedinjenja
Synhesis of bile acid amide and oxazoline derivatives, and their alkyl and alkylidene derivatives was accomplished starting from cholic acid. Also, chemical behavior of different bile acid oxo derivatives in Grignard and Wittig reaction was investigated. Biological activity  of selected synthesized compounds was evaluated.

Despite the unfavorable pharmacokinetic properties associated with peptides, they are still of great interest in drug development due to a multitude of interesting biological functions. The development of peptidomimetics strives to maintain or improve the biological activity of a peptide concurrently with removing the unwanted properties. This thesis describes two synthetic approaches to peptidomimetics with particular emphasis on secondary structure mimetics. First the design, synthesis and evaluation of two beta-turn mimetics incorporated in the endorphin Leu-enkephalin is presented. The beta-turn mimetics were stabilized by replacement of the intramolecular hydrogen bond with an ethylene bridge, and the amide bond between Tyr and Gly was replaced with an ether linkage. Linear analogues of the two mimetics were also synthesized. The peptidomimetics and their linear analogues were evaluated in a competitive binding assay at two opiate receptors, my and delta. One of the cyclized beta-turn mimetics was found to be a delta receptor antagonist with an IC50 value of 160 nM. Second a synthetic strategy to a beta-strand mimetic using 2-fluoro-4-iodopyridine as scaffold is described. The synthesis involved a Grignard exchange reaction on the pyridine scaffold using an amino acid derivative as electrophile followed by an SNAr reaction using an amine as nucleophile. The synthesis of a tripeptidomimetic of Leu-Gly-Gly and attempts to introduce chiral building blocks at the C-terminal, as well as studies towards elongated mimetics are presented. Two additional studies deal with the synthesis of two classes of potential thrombin inhibitors based on the pyridine scaffold. The first class contain pyridine as central fragment (P2 residue) substituted with a para-amidinobenzylamine group as P1 residue and various benzoyl groups as P3 residues. Three potential thrombin inhibitors were synthesized and found to be microM inhibitors in an enzymatic assay. In the second class, the pyridine ring serves as P3 residue. This class also lacks a strongly basic group in the P1 position. A small library of eight compounds were synthesized and evaluated in the enzymatic assay. Unfortunately, these compounds lacked inhibitory activity.

U radu je ostvarena enantiodivergentna totalna sinteza oba enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C polazeći iz D-glukoze. Ključne faze u sintezi 7-epi-(+)-goniofufurona bile su stereoselektivna adicija fenilmagnezijum bromida na aldehidnu grupu pogodno zaštićene dialdoze, i stereospecifično formiranje furano-laktonskog prstena ciklokondenzacijom odabranog hemiacetalnog derivata sa Meldrum-ovom kiselinom. Sinteza (+)-goniofufurona i (+)-krasalaktona C zahtevala je inverziju konfiguracije na C-5u zajedničkom intermedijeru, koja je efikasno ostvarena u uslovima Mitsunobu-ove reakcije, ili alternativno oksidacijom benzilne hidroksilne grupe u prohiralni keton, uz naknadnu stereoselektivnu redukcijom sa borohidridom. Sličan pristup je zatim primenjen za sintezu neprirodnih (−)-enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C, dva nova konformaciono ograničena analoga (+)- i (−)-goniofufurona (oksetani 36 i ent-36), kao i odgovarajućih 7-deoksigenovanih derivata (31 i ent-31). Takodje je razvijena i prva totalna sinteza prirodnog (+)-krasalaktona B (3) i alternativna sinteza (+)-krasalaktona C (4) polazeći iz D-glukoze. Selektivni pristup molekulima 3, odnosno 4 omogućen je promenom uslova za TBDPS deprotekciju u finalnom intermedijeru 53. Osnovna karakteristika pomenutih pristupa je njihova generalnost i fleksibilnost. Na taj način je omogućena sinteza serije analoga i derivata (+)-goniofufurona, ili 7-epi-goniofufurona, uključujući i do sada nepoznate 7-epi-(+)-krasalaktone B (6) i C (7), 5,7-di-O-cinamoil derivate 8 i 9, 5,7-di-O-izopropilidenske derivate 5 i 10, kao i više lipofilnih derivata (jedinjenja 26, 30, 33, 65, ent-30 i ent-33). Konačno, u drugom delu rada, ispitan je uticaj sintetizovanih stiril-laktona na rast odabranih tumorskih ćelijskih linija in vitro.
Enantiodivergent total syntheses of both (+)- and (−)-enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C have been accomplished starting from D-glucose. The key steps of the synthe-sis of 7-epi-(+)-goniofufurone were a stereo-selective addition of  phenyl magnesium bromide to a protected dialdose, followed by a stereospecific furano-lactone ring formation by condensation of a partially protected lactole with Meldrum’s acid. The synthesis of (+)-goniofufurone and (+)-crassalactone C required a configurational inversion at C-5 in the common intermediate that was efficiently achieved under the standard Mitsunobu conditions, or alternatively through a sequential oxidation of the benzylic hydroxyl group followed by a stereo-selective reduction with borohydride. A similar approach was applied to the synthesis of the unnatural enantiomers of goniofufurone, 7-epi-goniofufurone and crassalactone C, two novel, conformationally constrained analogues of both (+)- and (−)-goniofufurone (oxetanes 34 and ent-34). as well as the corresponding 7-deoxygenated derivatives (31 and ent-31). We have also developed the first total synthesis of (+)-crassalactone B (2) and an alternative synthesis of (+)-crassalactone C (3) starting from D-glucose. Finally, the synthesized styryl-lactones were evaluated for their antiproliferative activity against a panel of human tumor cell lines.

En chimie organique, le développement de méthodes de synthèse robustes et respectueuses de l’environnement a toujours été un défi. De plus, en chimie médicinale, la mise au point de méthodes de synthèse de synthons fluorés de haute valeur ajoutée sont importantes pour avoir accès à des composés bioactifs. Dans ce manuscrit, nous présentons des méthodes efficaces et faciles à mettre en œuvre pour la formation de liaisons carbone-carbone catalysée par le nickel et la formation de liaisons carbone hétéroatome par un réarrangement de β aminoalcools α-trifluorométhylés.Nous avons montré que le couplage croisé entre un éther d’énol méthylique et un réactif de Grignard pouvait être catalysé par un système simple à base de Ni(OAc)2/(O)PPh3 dans des conditions douces (40°C) via l’insertion du nickel dans la liaison C-OMe. Cette méthode a été appliquée à la synthèse d’un composé antitumoral, le DMU-212.La synthèse d’amines α-trifluorométhylées linéaires énantioenrichies a été réalisée selon une réaction de réarrangement régiosélectif de β-aminoalcools α-trifluorométhylés en se basant sur une stratégie établie dans le laboratoire via un intermédiaire aziridinium. Nous avons montré que les produits obtenus pouvaient être engagés dans des réactions de post-fonctionnalisation
In organic chemistry, the development of robust and sustainable synthetic methods has always been a challenge. Moreover, in medicinal chemistry, the development of fluorinated building blocks synthetic methods with high value is important to access bioactive compounds. In this manuscript, we report efficient and easy to carry methods for the formation of carbon-carbon bonds catalyzed by nickel and the formation of carbon-heteroatom bonds by a rearrangement of α-trifluoromethyl-β aminoalcools.We demonstrated that it is possible to perform a cross-coupling reaction of an alkenyl methy ether with a Grignard reagent using a simple catalytic system based on Ni(OAc)2/(O)PPh3 under mild conditions (40°C) via the insertion of nickel into C-OMe bond. This method has been applied to the synthesis of an antitumoral agent, DMU-212.The synthesis of enantioenriched linear α-trifluoromethylamine derivatives is reported consisting in a rearrangement of α-trifluoromethyl-β aminoalcool based on an established strategy in our group via an aziridinium intermediate. We have shown that the synthesized compounds can be involved in post-functionalization reactions

La recherche d'une méthode de synthèse de phénylséléno phosphate d'alkyle (RO)::(2)P(O)CH::(2)SePh a permis de trouver un nouveau réactif de Grignard (ETO)::(2)P(O)CH::(2)MGCL. Les propriétés de ce nouveau réactif ont été étudiées et comparées à celles des autres organométalliques correspondants connus lithiens et cuivreux. Ce réactif de Grignard conduit à une synthèse originale de sélénophosphonates. Utilisation des phosphates d'alkyle comme agents d'alkylation pour la synthèse de dithioesters. Des énephosphoramides fonctionnels ont été obtenus pour la première fois et la réactivité carbonique de l'un d'entre eux a été étudiée

The research described in this thesis originated from an idea to develop new body protection for the sport of fencing. The ultimate goal is to develop body armour which would be flexible, wearable, washable, light and breathable, offer protection from injuries and cover the entire body of a sportsman. A new material which exhibits shear thickening behaviour has been specially developed for this purpose in the process of this investigation. The material was designed and synthesised as a soft polymeric system which is flexible, chemically stable and able to increase the value of its modulus of elasticity upon impact at a high strain rate, while remaining in its soft gel-like elastomeric state when low strain rate deformation is applied. The polymeric system that has been developed is based on interpenetrating polymeric networks (IPN) of immiscible polyurethane/urea-ester/ether and poly(boron)n(dimethylsiloxane)m (where on average m ≈ 16 n). In addition, as the polydimethylsilane (PDMS) based polymeric system strongly tends to phase separation, the siloxane polymeric network was chemically cross-linked to the polyurethane polymeric network through polyurethane chemical cross-link-bridges. In order to introduce polyurethane cross-links to a siloxane-based polymeric network, some of the attached methyl groups in the PDMS polymeric backbone were substituted by ε-pentanol groups. The resulting polymeric system combines properties of an alternating copolymer with IPN. The actual substitution of the methyl groups of PDMS into alternating ε-pentanol groups was performed by Grignard reaction of trifunctional chlorosilane monomers, magnesium and 1,5-dibromopentane. Chemical analytical techniques like FT-IR, 13C NMR and 1H NMR spectroscopy were used to reveal the chemical structure of the synthesised polymeric network. The mechanical and dynamical properties of the obtained polymeric system were analysed by dynamic mechanical analysis (DMA). This part of the investigation indicated that the novel polymeric system exhibited shear thickening behaviour, but only at a narrow diapason of deformations (i.e., deformations between 2 to 3 % of the length of the sample). At this limited diapason of deformation an effective increase of the modulus of elasticity from 6 MPa (at lower frequencies, i.e., up to ≤6 Hz of the applied oscillating stress) to 65 MPa (at frequencies between 12.5 to 25 Hz) was obtained. However, no increase in the modulus of elasticity was recorded at deformations below 1.5 % or above 3.5 % of length of the sample at the same frequencies (0 to 25Hz) of the applied oscillating stress.

博士
國立臺灣大學
化學學系
81
The relatively unreactive aliphatic C-S bonds can be activated by at least three methods. First, in the presence of a reactive benzylic dithioacetal which is bening generated into an allylic double bond with respect to the aliphatic ditioacetal, renders further coupling possible.Second, the regioselective formation of the double bond via b-heteroatom elimination constitutes another pathway to activate C-S bonds such that a further cross- coupling can occur. Third, the chelation interaction between bisdithioacetal and nickel will also assist the cleavage of the C-S bond leading to the cross coupling reactions.

碩士
國立臺灣師範大學
化學研究所
87
The π-facial selectivity in the reactions of 5-substituted-2-dicyanomethyleneadamantanes and 5-aza-2-dicyanomethyleneadamantane N-oxide with the Grignard reagents, CH3MgCl and/or PhCH2MgCl were examined using semiempirical and ab initio calculation. The substituents investigated include -F, -Cl, -Br, -OH, NH2, -OMgCl, -CH3 and -Si(CH3)3. The reactions for all substituents, except the -Si(CH3)3 group, favor syn attack. The calculated syn/anti product ratio for the substituents of -F, -Cl, -Br groups agree well with available experimental results. The results obtained from the PM3, HF and B3LYP methods show that the HF results agree with the experimental results better than the other two methods. In addition, the results of employed NBO analysis show that the stabilization energy due to the hyperconjugative σCα-Cβ→σ*C-Nu interactions at the transition state correlates well withπ-facial selectivity in the reactions of 5-substituted-2-dicyanomethyleneadamantanes with CH3MgCl. The calculated results for the reaction with PhCH2MgCl appear that the strength of the hyperconjugative σCα-Cβ→π*C-C interactions at the transition state plays a significant role in π-facial selectivity for the substituents of -F, -Cl, -Br groups. Besides the hyperconjugation described above, the electrostatic interactions between the benzyl group of PhCH2MgCl and -OH and/or -NH2 groups in the 5-substituted-2-dicyanomethyleneadamantanes are also a significant factor in the π-facial selectivity. The calculations of 5-aza-2-dicyanomethyleneadamantane N-oxide also gave results that structural effects, as found in previous study, affect the syn/anti product ratio significantly in the π-facial selectivity.

博士
國立臺灣大學
化學系
85
Chelation assisted reactions of acetals,ketals and orthoesters with Grignard reagents afford the corresponding ring-opening products in highly regioselectivity. Contiguous diols can thus be differentiated easily by theses procedures. Reactions of orthoesters of myo-inositol with Grignard reagents yield regio- and stereoselective the corresponding products having a free group at C-1. The regioselectivity is rationalized owning to the presence of 2-methoxy group which will serve as an auxiliary to form a chelation complex with magnesium. Myo-inositol derivatives having two free hydroxy group at C-1,3 position can be achieved from reactions with excess Grignard reagents. The reaction of myo-inositol derivatives with excess LAH/AlCl also yields the corresponding C-1,5 diols. Tunable C-chiral diols are prepared from the reactions of bisketals of L-thretiol with different kinds of Grignard reagent. Chiral ketals obtained from the reactions of such C2-chiral diols and α,β- unsaturated ketones under go Simmons-Smith cyclopropanation in highly diastereoselectivity.

碩士
國立臺灣大學
化學系
85
This thesis contains twe parts: In the first part we discuss the substitution reactions of organomagnesium copper reagents, which were prepaired from Grignard reagents, and the loaner of phosgene, S,S-dimethtldithiocarbonate (DMDTC). We can obtain the disubsti- tuted ketones, even monosubstituted thioesters as products. In the second parts we found that magnesium bromide promoted intramolecular cyclization reactions of Grignard reagents and acetals. By using this method, we can easily get the products which contain 3, 4 or 5 memberd rings.

碩士
國立臺灣大學
化學學系
84
Aliphatic substituted dithioacetal cannot react with Grignard reagents under nickel-catalyzed conditions. However, they can couple with Grignard reagents in the presence of the the chel- ation effect of heteroatom in their chains or in the presence of the allylic dithioacetals formation during the reaction. Herein, we describe a new procedure to convert bisdithioacetals to the corresponding homoallylic dithioacetals by reacting with silylmethyl Grignard reagents. Hydoxy Groups will assist the cross-coupling reactions between aliphatic dithioacetals and Grignard reagents to yield olefin- ation products. Because of the coordination of proximal O- and S- atom with nickel, the otherwise unreactive aliphatic C-S bonds can be activated. The competitive chelating ability bet- ween oxygen and sulfur in these reaction is discussed.

碩士
國立臺灣大學
化學學系
81
The NiCl2(PPh3)2 catalyzed cross-coupling reactions of Grignard eagents with dithianes having β-OR or β-SR group at C2 positionead to the regioselective formation of the double bond via β-ORr β-SR elimination process. The rate of β- OR or β-SRlimination appears to be faster than the rates of cyclopropyling opening rearrangement and β-hydride elimination. Variousvidences suggest that the reaction may proceed via orangonickelntermediate from which the β-OR or β-SR group is eliminated.o exchange between nickel and magnesium may occur.

In Michael J. Krische research group we are developing new transition metal catalyzed Carbon-Carbon (C-C) forming reactions focusing on atom economy and byproduct free, environmental friendly approaches. We have developed a broad family of C-C bond forming hydrogenations with relative and absolute stereocontrol which provide an alternative to stoichiometric organometallic reagents in certain carbonyl and imine additions. Inspiring from the group work my goal was to develop new reactions, extend the scope of our group chemistry and their application towards synthesis of biologically active natural products. I have been part of enantioselective Rh catalyzed Aldol reaction of vinyl ketones to different aldehydes. Also, we have found that iridium catalyzed transfer hydrogenation of allylic acetates in the presence of aldehydes or alcohols results in highly enantioselective carbonyl allylation under the conditions of transfer hydrogenative. Based on this reactivity a concise enantio- and diastereoselective synthesis of 1,3-polyols was achieved via iterative chain elongation and bidirectional iterative asymmetric allylation was performed, which enables the rapid assembly of 1,3-polyol substructures with exceptional levels of stereocontrol. The utility of this approach stems from the ability to avoid the use of chirally modified allylmetal reagents, which require multistep preparation, and the ability to perform chain elongation directly from the alcohol oxidation level. This approach was utilized for the total synthesis of (+)-Roxaticin from 1,3-propanediol in 20 longest linear steps and a total number of 29 manipulations. Further, advancements were made in iridium catalyzed C-C bond formation under transfer hydrogenation. While methallyl acetate does not serve as an efficient allyl donor, the use of more reactive leaving group in methallyl chloride compensate for the shorter lifetime of the more highly substituted olefin π-complex. Based on this insight into the requirements of the catalytic process, highly enantioselective Grignard-Nozaki-Hiyama methallylation is achieved from the alcohol or aldehyde oxidation levels. Also, a catalytic method for enantioselective vinylogous Reformatsky- type aldol addition was developed in which asymmetric carbonyl addition occurs with equal facility from the alcohol or aldehyde oxidation level. Good to excellent levels of regioselectivity and uniformly high levels of enantioselectivity were observed across a range of alcohols and aldehydes.
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碩士
國立臺灣師範大學
化學系
84
Reactions of β-nitrostyrene and Grignard Reagents gave 1,4-adducts(nitronates) at -20 ℃.Futher manipulation of the nitronate were demostrated as follows:(1) treatment of the nitronates with 0 ℃ 5% HCl(aq) generated nitroalkanes. (2) tretment of the nitronates with 0 ℃ 85% H2SO4(aq)generated caboxylic acids. (3) tretment of the nitronates with 0℃ conc. HX(aq) generated hydroximoyl halides. Hydroximoyl halides could convert to nitrile oxide in the presence of base such as triethyl amine, followed by 1,3-dipolar cycloaddition with alkenes or alkynes to give 2-isoxazolines or isoxazoles.

碩士
國立臺灣師範大學
化學系
84
1,1-二苯基-2-硝基乙烯及其衍生物與格里納試劑反應,經稀酸水溶液水 解後得到屬於1,4-加成的產物o 例如一級的硝基烷類及 oxime 化合物;但 如果將反應所形成的intermediate-nitronate 加入強酸中,則進行 Nef 或 Meyer reaction, 預期為羰基或酸化合物,但在反應的過程中,卻意外 的捕抓住鹵素離子,而形成中間產物 hydroximoylhalides. hydroximoyl halides 可和鹼作用脫去 HX 而生成 nitrile oxides. nitrileoxides 和烯或炔進行 1,3-dipolar cycloaddition 的反應,得到具有專一性或高 選擇性的 2-isoxazoline 或 isoxazole.由於立體障礙因素,使得 1,1,2-三苯基-2-硝基乙烯與三級丁基或二及異丙基等之立障較大之格里 納試劑反應時,改以自由基的方式進行反應,整個反應過程可知,苯基及烷 基扮演著相當重要的角色o 1,1-Diphenyl-2-nitroethylene and their derivatives can react with Grignandreagents to form 1,4-addition products such as primary nitroalkanes and oximes after workup with dilute aqueous acid solution. On the other hand,if the intermediate-nitronates are added to ice cold 85% H2SO4 or concentratedHX(aq) solution will undergo Nef or Meyer reaction and the expected producted are carbonyl compounds or carpoxylic acids. Surprisingly, the hydroximoyl Halides are formed if the reactive intermediate trap the halogen ions. Hydroximoyl halides will convert into nitrile oxides in the presence of base.It is known that nitrile oxides under 1,3-dipolar cycloaddition with alkenes oralkynes to generate stereospecific or steroselective of 2-isoxalolines orisoxazoles.1,1,2-Triphenyl-2-nitroethylene react with Grignard reagents to give free radical or SET products if the organomagensium halides belong to teritary orsecondary reagents. the different results can be ascribed to the steric effectof the phenyl and bulky alkyl groups.

博士
國立臺灣大學
化學學系
82
The nickel-catalyzed reactions of allylic dithioketals with excess MeMgI give the geminal dimethylation products in good yields. t-Butylstyrenes and related compounds are synthesized stereoselectively. The formation of a chelation complex results in the enhancement of the reactivity of the nickel-catalyzed cross coupling reaction of aliphatic dithioacetals with Grignard reagents. Various neighboring heteroatom substituents can facilitate the olefination of a dithioacetal group giving the corresponding olefins regioselectively. (2S,3S)-1,4-di-tert- alkoxy-2,3-butanediols are obtained from the reactions of (2S,3 S)-threitol bisketals with Grignard reagents. The size of the alkoxy substituents can be easily tuned. The reactions of benzylic acetals, prepared from (2S,3S)-1,4-di-tert-alkoxy-2,3- butanediols and aromatic aldehyde, with aryl or secondary or sterically hindered Grignard reagents give the corresponding alkylative ring- opening products in high diastereoselectivity (%de=92-99%).

博士
國立臺灣大學
化學系
85
Chelation assisted reactions of a neighboring bisacetonide with a Grignard reagent or an aluminum reagent afford the corresponding diols regioselectively. These diols might demonstrate certain unique properties to serve as a ligand in asymmetric reactions because the size of the alkoxy substituents can be easily be tuned by changing the Grignard reagent or by varying the ketal moiety.

碩士
國立中興大學
化學系所
100
Transtion-metal-Catalyzed Cross-Coupling reaction is a powerful strategy for Constracting Carbon-Carbon and Carbon-heteroatom bonds. In the first part of this thesis, the direct meta C-H functionalization of C-H bond of aromatic ring is introduced. The combination of iridium-Catalyzed C-H activation and sequential functionalization of the resulting aryl boronic ester is an excellent approach for regioselection meta C-H functionalization of aromatic C-H bond. The second part of this thesis, although the Grignard reagents have been used as nucleophiles to react with aryl disulfides, leading the corresponding aryl thioethers, these are some drawbacks in these systems. Fisrt, aryl disulfides and thiosulfonates must be prepared in advance. Second, from the atom economic point of view, an equivalent of sulfur moiety will be generated as the byproducts. Thus, it is desirable to develop a convenient method for the synthesis of aryl thioethers through the reaction of Grignard reagents with thiols without the preparation of aryl disulfides. The second of this thesis, the NCS-promoted coupling reaction of Grignard reagents with thiols is reported.

博士
國立臺灣師範大學
化學系
104
Abstract This thesis consists of two independent parts. Independently, each part has its own preface, motivation, discussion, experimental results, and conclusions. Research and discussion for the mechanism of the reaction between the Grignard reagent and β-nitrostyrene derivatives are discussed in the first section. Polar addition or single electron transfer has been a controversial issue in the Grignard reaction pathway. The previous studies showed the Grignard reagent with greater steric-hindered functionality, such as t-BuMgCl in polar solvent including THF, favors the SET reaction route; while the Grignard reactions with less steric crowding in non-polar solvents, such as ether were found to be via the polar addition route. The results of reactions of 1,1,2-triphenyl-2-nitroethane or β-nitrostyrene derivatives with several different kinds of Grignard reagents were discussed in this research work. Under -25℃inTHF, two different products were found to be 1,4-addition product via polar addition route and 1,8-addition product via single transfer electron route. 1,8-Addition product resulting from the Grignard reaction is novel since hitherto was not described. One-pot preparation of Chroman is the subject of the second part of this thesis. This one-pot synthesis was carried out under the following reaction condition to produce 3-nitro-chroman as an exclusive product with excellent yield. As such, salicylicaldehyde and cyclohexylamine along with nitromethane in (4:5:1) mixed in glacial acetic acid (2.0 ml) at 80-90℃for 24 hours. Therefore, a novel method for the preparation of Chroman was invented. Key word: polar addition、Single Electron Transfer、1,1,2-Triphenyl-2-nitroethene、Chroman

Cette thèse se compose en deux parties: Première Partie: La conception et la synthèse d’analogues pyrrolidiniques, utilisés comme agents anticancéreux, dérivés du FTY720. FTY720 est actuellement commercialisé comme médicament (GilenyaTM) pour le traitement de la sclérose en plaques rémittente-récurrente. Il agit comme immunosuppresseur en raison de son effet sur les récepteurs de la sphingosine-1-phosphate. A fortes doses, FTY720 présente un effet antinéoplasique. Cependant, à de telles doses, un des effets secondaires observé est la bradycardie dû à l’activation des récepteurs S1P1 et S1P3. Ceci limite son potentiel d’utilisation lors de chimiothérapie. Nos précédentes études ont montré que des analogues pyrrolidiniques dérivés du FTY720 présentaient une activité anticancéreuse mais aucune sur les récepteurs S1P1 et S1P3. Nous avons soumis l’idée qu’une étude relation structure-activité (SARs) pourrait nous conduire à la découverte de nouveaux agents anti tumoraux. Ainsi, deux séries de composés pyrrolidiniques (O-arylmethyl substitué et C-arylmethyl substitué) ont pu être envisagés et synthétisés (Chapitre 1). Ces analogues ont montré d’excellentes activités cytotoxiques contre diverses cellules cancéreuses humaines (prostate, colon, sein, pancréas et leucémie), plus particulièrement les analogues actifs qui ne peuvent pas être phosphorylés par SphK, présentent un plus grand potentiel pour le traitement du cancer sans effet secondaire comme la bradycardie. Les études mécanistiques suggèrent que ces analogues de déclencheurs de régulation négative sur les transporteurs de nutriments induisent une crise bioénergétique en affamant les cellules cancéreuses. Afin d’approfondir nos connaissances sur les récepteurs cibles, nous avons conçu et synthétisé des sondes diazirine basées sur le marquage d’affinité aux photons (méthode PAL: Photo-Affinity Labeling) (Chapitre 2). En s’appuyant sur la méthode PAL, il est possible de récolter des informations sur les récepteurs cibles à travers l’analyse LC/MS/MS de la protéine. Ces tests sont en cours et les résultats sont prometteurs. Deuxième partie: Coordination métallique et catalyse di fonctionnelle de dérivés β-hydroxy cétones tertiaires. Les réactions de Barbier et de Grignard sont des méthodes classiques pour former des liaisons carbone-carbone, et généralement utilisées pour la préparation d’alcools secondaires et tertiaires. En vue d’améliorer la réaction de Grignard avec le 1-iodobutane dans les conditions « one-pot » de Barbier, nous avons obtenu comme produit majoritaire la β-hydroxy cétone provenant de l’auto aldolisation de la 5-hexen-2-one, plutôt que le produit attendu d’addition de l’alcool (Chapitre 3). La formation inattendue de la β-hydroxy cétone a également été observée en utilisant d’autres dérivés méthyl cétone. Étonnement dans la réaction intramoléculaire d’une tricétone, connue pour former la cétone Hajos-Parrish, le produit majoritaire est rarement la β-hydroxy cétone présentant la fonction alcool en position axiale. Intrigué par ces résultats et après l’étude systématique des conditions de réaction, nous avons développé deux nouvelles méthodes à travers la synthèse sélective et catalytique de β-hydroxy cétones spécifiques par cyclisation intramoléculaire avec des rendements élevés (Chapitre 4). La réaction peut être catalysée soit par une base adaptée et du bromure de lithium comme additif en passant par un état de transition coordonné au lithium, ou bien soit à l’aide d’un catalyseur TBD di fonctionnel, via un état de transition médiée par une coordination bidenté au TBD. Les mécanismes proposés ont été corroborés par calcul DFT. Ces réactions catalytiques ont également été appliquées à d’autres substrats comme les tricétones et les dicétones. Bien que les efforts préliminaires afin d’obtenir une enantioselectivité se sont révélés sans succès, la synthèse et la recherche de nouveaux catalyseurs chiraux sont en cours.
This thesis consists of two parts: Part 1: Design and synthesis of constrained azacyclic pyrrolidine analogues of FTY720 as anticancer agents FTY720 is presently marketed as a drug (GilenyaTM) for the treatment of relapsing-remitting multiple sclerosis. It functions as an immunosuppressant due to its effect on sphingosine-1-phosphate (S1P) receptors. At higher doses, FTY720 also has antineoplastic actions. However, at such doses it induces bradycardia due to the activation of the S1P1 and S1P3 receptors. This limits its potentical to be used as a cancer therapy in humans. Our previous studies have shown that some constrained pyrrolidine analogues of FTY720 have anticancer activity but no activity toward S1P1 and S1P3 receptors. We reasoned that a study of the structure-activity relationships (SARs) could lead to the discovery of new effective antitumor agents. Thus, two series of constrained analogues (O-arylmethyl-substituted pyrrolidines and C-aryl-substituted pyrrolidines) were designed and synthesized (Chapter 1). These analogues showed excellent cytotoxic activity against various human cancer cells (prostate, colon, breast, pancreas and leukemia). Especially, several active analogues, which cannot be phosphorylated by SphK, have the potency to be further studied in the treatment of cancer without inducing bradycardia. Mechanistic studies suggest that these constrained analogues trigger down-regulation of nutrient transporters, which induce a bioenergetic crisis and the cancer cells starve to death. To further investigate their target receptors, we have designed and synthesized diazirine based photo-affinity labeling (PAL) probes (Chapter 2). Aided by the PAL technique, information regarding the target receptor could be obtained through LC/MS/MS protein analysis. These tests are in progress and the preliminary results appear promising. Part 2: Metal coordination-controlled and bifunctional catalysis toward tertiary β-ketols The Barbier and Grignard reactions are classical methods to form carbon-carbon bonds, and generally used to prepare secondary or tertiary alcohols. In an attempt to perform a Grignard reaction with n-butyl iodide under Barbier one-pot conditions, we obtained major product β-hydroxyl ketol from the self-aldol reaction of 5-hexen-2-one, rather than the expected addition alcohol product (Chapter 3). The unusual β-ketol formation was also observed using other methyl ketone substrates. Interestingly, in an intramolecular reaction of a triketone substrate, which is well known to give the Hajos-Parrish ketone, the favored product was a rarely studied β-ketol with the hydroxyl group at axial position. Intrigued by these results, after systematic reaction condition studies, we developed two new methods toward the catalytic synthesis of specific β-ketols by intramolecular cylcization in high yield and selectivity (Chapter 4). The reaction can be catalyzed either by a suitable base and lithium bromide as the additive, through a lithium pre-organized transition state or by a bifunctional catalyst TBD (triazabicyclodecene), through a TBD mediated bidentate transition state. The proposed mechanisms were corroborated by DFT computation. These catalytic reactions were also extended to other triketone and diketone substrates. Although the initial efforts to achieve enantioselectivity were not successful, they merit further study of the synthesis and investigation of new chiral catalysts.