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. / text

Externally initiated o-tolyl initiated poly(3-hexylthiophene) (P3HT) was synthesized according to Grignard metathesis polymerization at varying chain length to compare number average molecular weights (Mn) obtained by gel permeation chromatography (GPC) and 1H NMR end group analysis. The extent of overestimation by GPC (1.3) was determined to be lower than previously reported for low Mn polymers. However, an apparent GPC quantification limit was observed as NMR Mn correlated well to predicted results. Static light scattering studies on high Mn polymers provided evidence that the true molecular weight was more similar to GPC-derived Mn. Despite nearly 100% external initiation efficiency, at a certain Mn limit new uninitiated chains may be synthesized. It is suggested that the synthesis of externally initiated P3HT should be limited to Mn below 40 kDa to ensure fully externally initiated chains. A proposal for the synthesis of externally initiated macrocyclic P3HT will also be discussed.

This thesis deals with the development and application of new synthetic methodology in organic chemistry. The first part describes the development of a new protocol for the synthesis of 3-pyrrolines by means of a microwave-assisted ring-expansion reaction of 2-vinylaziridines. In addition, this methodology is implemented as a key-step in a formal total synthesis of the antibiotic (-)-anisomycin. In the second part, a new methodology for the synthesis of arylglycines from Weinreb amides is described. In this procedure, a Grignard reagent is added to the iminium ion formed from the Weinreb amide upon treatment with a base. When a chiral amide is used, the nucleophilic addition proceeds with high diastereoselectivity. Finally, an easy and straightforward synthesis of α-amino amides via a base-mediated rearrangement of modified Weinreb amides into N,O-acetals is presented. Subsequent arylation, alkylation, alkenylation or alkynylation of this intermediate affords the corresponding α-amino amides in excellent yields. Furthermore, a more generalized protocol for the α-arylation of Weinreb amides lacking an α-amino moiety is also discussed. / QC 20100719

This thesis describes the synthesis of novel ligands that include enantiomerically pure acetal and oxazoline moieties. These ligands are utilised in a number of metalmediated asymmetric syntheses. All asymmetric acetals and pyridine based acetals are synthesised in good yield in a single step from their corresponding enantiomerically pure diols. C2 symmetric bisacetals are investigated as ligands in the organolithium and Grignard additions to benzaldehyde with promising results. C2 symmetric bisacetals and pyridine based acetals are tested for their ability to induce asymmetry in copper(l) catalysed cyclopropanation of styrene using ethyl diazoacetate and the lanthanide(lII) catalysed Diels-Alder cycloaddition involving Danishefsky's diene with little success. Enantiomerically pure phosphinooxazoline ligands are available in good yield in two steps from their corresponding enantiomerically pure aminoalcohols. Enantiomerically pure acetal substituted pyridines and phosphinooxazoline ligands are considered in the rhodium (I) catalysed hydrosilylation of ketones. Reaction conditions for the more successful phosphinooxazoline ligands are optimised. Using these ligands a range of enantiomerically enriched alcohols is presented in good yield and enantiomeric excess. Novel phosphinooxazoline ligands are applied to the palladium(O) catalysed allylic substitution reaction with excellent enantioselectivities of the substitution product.

First chapter of the thesis describes the desymmetrization of the bis-dimethyl amide 1 derived from tartaric acid with vinyl Grignard reagents and subsequent reduction of the resultant -keto amides 2a-c to the -hydroxy amides 3a-c. Application of the -hydroxy amides 3a-c in the total synthesis of bio-active natural products such as gabosines, crassalactone C and anamarine is described in the subsequent sections. In section A of the first chapter, application of the -hydroxy amides 3a-b to the total synthesis of gabosine A 4, gabosine F 5 and gabosine H 6 was described. Key strategy in the synthesis was the use of ring closing metathesis (RCM) reaction. Incidentally, the total synthesis of gabosine H 6 was not only accomplished for the first time but the synthesis also ascertained the absolute stereochemistry of the natural product. During the course of the synthesis of gabosine A 4, an unprecedented formation of a unique 14-membered macrocycle 7 was observed. Incisive studies were conducted to elucidate the reaction sequence for the formation of the macrocyle 7. It was found that the formation of the macrocycle 7 was through a tandem cross-metathesis/intramolecular hetero Diels-Alder reaction. Section B of chapter 1 delineated the utility of the -hydroxy amide 3a in the total synthesis of (–)-crassalactone C 8a. Crassalactone C 8a is a cinnamoyl derivative of styryllactone natural product goniofufurone and was found to possess marginal in vitro cytotoxic activity. Pivotal strategies in the synthesis include the use of bis-cinnamoyl ester 10a in the ring closing metathesis reaction which also evades the selective cinnamoylation of the benzylic hydroxy group. Section C of Chapter 1 deals with the total synthesis of (+)-anamarine 11. While the - hydroxy amide 3a was employed to synthesize an important intermediate 12 enroute to the synthesis of anamarine, to mitigate the number of steps in the synthesis, the -hydroxy amide 13 was employed for the synthesis of (+)-anamarine 11. Key reactions in the total synthesis include the use of 1,3-dithiane as a surrogate for the methyl group, Brown’s allylation and ring closing metathesis. In second chapter of the thesis, formal total synthesis of iriomoteolide 3a 16 is presented. Iriomoteolide 3a 16 is a unique 15-membered marine macrolide isolated by Tusda’s group from the Amphidinium strain HYA024, with impressive in vitro cytotoxic activity against human lymphoma cell line DG-75 (IC50 0.08 g/mL) and Raji cells (IC50 0.05 g/mL). Salient features of the synthesis include the synthesis of the chiral aldehyde 19 from the oxazolidinone 17 and the use of -keto phosphonate 20 derived from D-(–)-tartaric acid in the Horner-Wadsworth-Emmons olefination reaction to construct the C1-C10 fragment 23 of iriomoteolide 3a 16. Synthesis of the C10-C18 fragment 29 was accomplished from the butyrolactone 24 using Keck allylation and olefin cross metathesis reactions as key steps. Ring closing metathesis of the ester 30, followed by selective deprotection of the primary TBS group afforded the key intermediate 31, the transformation of which to iriomoteolide 3a 16 is known in literature.

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.

<p>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 za&scaron;tićene 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-5<br />u 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 (&minus;)-enantiomera goniofufurona, 7-epi-goniofufurona i krasalaktona C, dva nova konformaciono ograničena analoga (+)- i (&minus;)-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 vi&scaron;e 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.</p> / <p> Enantiodivergent total syntheses of both (+)- and (&minus;)-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&nbsp;<br /> phenyl magnesium bromide to a protected dialdose, followed by a stereospecific furano-lactone ring formation by condensation of a partially protected lactole with Meldrum&rsquo;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 (&minus;)-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.</p>

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.

Dans ce travail, il est montré que les alkyl/vinyl/aryl lithiens et magnésiens réagissentavec les acides C-1(F/OMe) naphtoïques en l'absence de catalyseur métallique. Cette nouvelleréaction de substitution nucléophile aromatique permet potentiellement de préparer n’importequel biaryle tout en s'affranchissant des étapes de protection et de déprotection de la fonctionacide (CO2H). Les alkyllithiens linéaires et ramifiés réagissent avec la même efficacité que lesalkylmagnésiens même à basse température (–78 °C). Le déplacement d'un fluor ou d'unméthoxy s'effectue avec la même facilité. L'absence d'ortho-lithiation est confirmée par lepiégeage du milieu réactionnel en fin de réaction par l'iodométhane (après addition de n-BuLi,s-BuLi et t-BuLi). Le bromure de vinylmagnésium requiert un chauffage au reflux du THF.La méthode étudiée permet de préparer extrêmement facilement des 1- et 2-phénylnaphtalènes, 1,1’-binaphtalènes et 2,2’-binaphtalènes. Dans les exemples où lesaryllithiens donnent des rendements moyens-faibles en produits de couplage, les réactifs deGrignard sont beaucoup plus efficaces. Le o-tolyllithium, le bromure de o-tolylmagnésium, lebromure de (4-méthoxyphényl)magnésium, le bromure de (2,5-diméthylphényl)magnésium etle bromure de benzo[d][1,3]dioxol-5-ylmagnésium déplacent facilement le groupefluoro/méthoxy en ortho du groupe CO2M pour donner les produits de substitutioncorrespondants alors que la réaction du bromure de (2,6-diméthoxyphényl)magnésium estmoins efficace sans doute en raison de l'encombrement stérique causé par les deux groupesortho-méthoxy. L'acide 1-(2-méthoxyphényl)-2-naphtoïque est un produit particulièrementintéressant. La déprotection du groupe méthoxy suivie d'une cyclisation est réalisée par BBr3pour donner la 6H-naphtho[2,1-c]chromén-6-one qui est isolée avec un rendement de 97 %.Cette lactone est utile pour la préparation de composés atropoisomères optiquement actifsaprès ouverture énantiosélective du cycle lactone selon la technique mise au point parBringmann. / Alkyl as well as aryl substitution can be readily accomplished in generally excellentyields via a nucleophilic mode by displacement of an ortho-fluoro or methoxy group inunprotected naphthoic acids with lithium and Grignard reagents in the absence of a metalcatalyst.Alkyllithium reagents typically gave good-to-excellent yields, whether primary,secondary, or tertiary at –78 °C. Displacement of a fluoro or a methoxy group occurs withequal efficacy. The absence of ortho-lithiation was confirmed by quenching the reactionproduct with MeI after addition of n-BuLi, s-BuLi and t-BuLi. Alkyl Grignard reagentsEtMgBr and n-BuMgBr proved to be very reactive at –78 °C while vinyl magnesium bromiderequired refluxing in THF.The method provides excellent latitude with respect to the synthesis of 1- and 2-phenylnaphthalenes, 1,1’-binaphthalenes, and 2,2’-binaphthalenes. In those instances wherethe aryllithium reagents gave poor yields of coupling products, the corresponding Grignardreagents proved to be much more effective. o-Tolyllithium, o-tolylmagnesium bromide, (4-methoxyphenyl)magnesium bromide, (2,5-dimethylphenyl)magnesium bromide andbenzo[d][1,3]dioxol-5-ylmagnesium bromide smoothly displaced the fluoro/methoxy grouportho to the CO2M group to give the corresponding substitution products while reaction of(2,6-dimethoxyphenyl)magnesium bromide proceeded with less efficiency presumably due tosteric effects imparted by the two ortho-methoxy groups. Particularly useful is 1-(2-methoxyphenyl)-2-naphthoic acid which allows for further elaboration after the coupling isperformed. Deprotection of the methoxy group followed by cyclization was realized withBBr3 to afford 6H-naphtho[2,1-c]chromen-6-one which was isolated in 97% yield. Thislactone is the starting building block for the preparation of optically active atropisomers byenantioselective ring opening.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.