Organosulfur compounds have been used by humans for centuries and played a pivotal role in shaping our history. The chemistry presented herein deals primarily with three distinct organic transformations involving organosulfur species. The three transformations are used in tandem to complete the synthesis of natural products. The first chapter examines a new diastereoselective alkylation reaction of sulfenate anions with stereoinduction provided by chiral amino iodides. A series of β-amino sulfoxides are accessed in good yields and selectivities from alkylations with the corresponding lithium arene- and E-1-alkenesulfenate anions. The relative reactivity of different electrophiles towards a selection of lithium sulfenate anions was also evaluated by performing competition experiments. In the second chapter 1,2-dibromotetrachloroethane (C2Br2Cl4) was evaluated as a more economical halogenating agent for the in-situ Ramberg-Bäcklund rearrangement (RBR). A series of trans-stilbenoids were successfully synthesized using this protocol in excellent yields. The new RBR system also worked well for dialkyl and cyclic substrates, but the reaction was plagued by polyhalogenation for hexyl benzyl sulfone. The methodology was extended to the formal total synthesis of natural polyphenol E-resveratrol. Chapter three investigates asymmetric aza-Michael reactions of chiral β-amino sulfoxides/sulfones to synthesize thiomorpholine S-oxides and S,S-dioxides, respectively. Remarkably, cyclizations of the β-amino sulfoxides provide the trans- 3,5-substituted heterocycles, while the β-amino sulfones provide the complementary cis-3,5-substituted heterocycles. The aza-Michael chemistry was exploited along with the sulfenate and RBR protocols to access two ant venom alkaloids. / NSERC

Ce travail de thèse porte dans une première partie sur le développement d’une réaction de type Reformatsky asymétrique appliquée à la synthèse de motifs « 2-méthyl-1,3-aminoalcools » syn, syn et syn, anti. Cette réaction met à l’honneur la chimie des sulfoxydes chiraux dont la présence sur le substrat permet de construire trois centres asymétriques contigus. En effet, dans une première étape, une réaction de type Reformatsy entre un précurseur chiral, un γ-bromo-β-cétosulfoxyde et différentes imines permet de former les deux premiers centres asymétriques. La sélectivité favorise de composé syn. Cette réaction est très sélective avec des sélectivités syn/anti allant jusqu’à 100/0. Ensuite, une réduction diastéréosélective des β-cétosulfoxydes obtenus à l’issue de la réaction de Reformatsky permet de former le troisième centre asymétrique avec une diastéréosélectivité totale. Ainsi, l’utilisation du DIBAL-H seul permet d’obtenir l’aminoalcool 1,3-syn alors que l’utilisation du système DIBAL-H/Yb(OTf)3 permet d’accéder à l’aminoalcool 1,3-anti avec dans les deux cas une diastéréosélectivité totale pour cette étape de réduction.Dans une deuxième partie, ce travail de thèse présente des avancées vers la synthèse totale du (+)-triènomycinol, une molécule naturelle à forte activité cytotoxique. Il s’agit d’un macrolactame à 21 chaînons comportant une partie triènique, une liaison peptidique, une stéréotriade syn, anti et un centre asymétrique isolé. La stratégie proposée consiste à construire tous les centres asymétriques en utilisant la chimie des sulfoxydes chiraux. En effet, la stéréotriade a été construite en utilisant la réaction dévloppée dans la première partie, à savoir une réaction de type Reformatsky asymétrique couplée à une réduction diastéréosélective à l’aide du système DIBAL-H/Yb(OTf)3. Le centre stéréogène isolé a lui aussi été construit grâce à la chimie des sulfoxydes chiraux, par réduction diastéréosélective d’un β-cétosulfoxyde à l’aide de DIBAL-H. Cette molécule a été découpée en deux fragments, un fragments « ouest » et un fragment « est » qui ont été couplés. De nombreuses étapes ont au préalable été mises au point sur un composé modèle. Par manque de temps et de matière, la synthèse totale du (+)-triènomycinol n’a pu être achevée. / In a first part, the aim of this PhD thesis was to develop an asymmetric Reformatsky type reaction for the synthesis of “2-methyl-1,3aminoalcohol” moieties. This reaction is based on the chemistry of chiral sulfoxides. Indeed, in a first step, an asymmetric Reformatsky type reaction between a γ-bromo-β-ketosulfoxide and different imines allows us to build two contiguous stereogenic centers. This reaction is very selective with a syn/anti selectivity reaching up to 100/0. In a second step, the β-ketosulfoxides obtained after the Reformatsky-type reaction were diastereoselectively reduced using either DIBAL-H or the system DIBAL-H/Yb(OTf)3 to afford the third stereogenic center with a total diastereoselectivity. To sum up, the use of DIBAL-H allowed us to obtain the aminoalcohol 1,3-syn, whereas the use of the system DIBAL-H/Yb(OTf)3 allowed us to synthesize the aminoalcohol 1,3-anti with a perfect diastereoselectivity in both cases.In a second part, this PhD thesis focused on the total synthesis of natural cytotoxic molecule, (+)-trienomycinol. This molecule is a macrolactam containing a syn, anti stereotriad, an isolated stereogenic center and a trienic unit. The proposed strategy was based on the use of chiral sulfoxides. The stereostriad was built using the strategy developed in the first part, the asymmetric Reformatsky reaction followed by a diastereoselective reduction with the system DIBAL-H/Yb(OTf)3. The isolated stereocenter was obtained by diastereoselective reduction of a β-ketosulfoxide with DIBAL-H. This molecule was divided into two parts: the “west” part and the “east” part which were coupled together. Many steps were first optimized on a model compound. Due to a lack of time and quantity, the total synthesis of (+)-trienomycinol could not be achieved.

O presente trabalho investiga alguns sulfóxidos β-tia-substituidos quanto à sua basicidade relativa e quanto à sua reatividade em relação aos compostos de Grignard aromáticos. O conjunto de compostos investigados foi o seguinte: metil n-propil sulfóxido, metil metiltiometil sulfóxido, etil butil sulfóxido, etil etiltiometil sulfóxido, etil feniltiometil sulfóxido, fenil feniltiometil sulfóxido e 1,3-ditiolano-1-óxido. É apresentada, inicialmente, uma revisão bibliográfica sôbre dois itens: 1. basicidade de sulfóxidos, e 2. reações de sulfóxidos com compostos de Grignard. São apresentados os valores de constantes de associação para dois sulfóxidos β-tia-substituídos e dois não substituídos correspondentes. Estes valores foram calculados a partir de medidas dos deslocamentos químicos dos prótons do fenol em sistemas ternários sulfóxido -fenol-tetracloreto de carbono, pelo dos métodos de Carper e de Mathur. São apresentadas as reações de quatro sulfóxidos com alguns compostos de Grignard aromáticos, tais como os brometos de fenil-, p-anisil-, p-tolilmagnésio, e descritos os métodos de análise dos compostos formados. São descritas as preparações de cincos sulfóxidos e de alguns produtos autênticos. São fornecidos os resultados de algumas experiências de reações de um sulfóxido β-tia-substituído com brometo de fenilmagnésio em presença de base. É apresentada uma discussão na qual se procura interpretar tanto os resultados da literatura como os nossos. Os resultados obtidos demonstram que: a) Há diminuição de basicidade nos sulfóxidos β-tia-substituidos, em comparação com os não substituidos correspondentes. b) A reação dos sulfóxidos β-tia-substituidos com compostos de Grignard aromáticos fornece os mercaptais dos aldeidos aromáticos correspondentes. c) A reação dos sulfóxidos β-tia-substituidos com reagentes de Grignard e impedida por bases fortes. Os rendimentos dos mercaptais são muito mais baixos do que na ausência de base. d) A fixação do organomagnesiano ocorre inicialmente no grupo sulfinila. Um mecanismo envolvendo um estado de transição cíclico é sugerido para explicar a migração preferencial do anel aromático proveniente do composto de Grignard. / This thesis investigates some β-thia-substituted sulphoxides concerning their relative basicity and reactivity toward aromatic Grignard reagents. The following compounds were investigated: methyl n-propyl sulphoxide, methyl methylthiomethyl sulphoxide, ethyl n-butyl sulphoxide, ethyl ethylthiomethyl sulphoxide, ethyl phenylthiomethyl sulphoxide, phenyl phenylthtomethyl sulphoxide and 1,3-dithiolane-l-oxide. A literature review, containing two topics, is presented: 1) basicity of sulphoxides, 2) reactions of sulphoxides with Grignard reagents. The data of the association constants for two β-thiasubstituted and two corresponding unsubstituted sulphoxides are presented. These values were calculated from the chemical shifts of the phenol protons, measured in the ternary systems sulphoxide -phenol-carbon tetrachloride, by methods of Mathur and Carper. The reactivity of four sulphoxides with some Grignard reagents, such as phenyl-, p-anisyl-, and p-tolylmagnesium bromides including the analyses of the resulting products is presented. The preparation of five sulphoxides and of some authentic products are described. Some experiments, in which the Grignard reaction is performed in basic conditions, are reported. The obtained results are discussed in the light of the literature data. It is shown that: a) There is a decrease in basicity going from the unsubstituted sulphoxides to the corresponding β-thia-substituted ones. b) The reaction of β-thia-substituted sulphoxides lead to the corresponding aromatic aldehydes mercaptals. c) The reaction of the β-thia-substituted sulphoxides is inhibited by the presence of a base. The yields of mercaptals are much lower than in the absence of base. d) The attachment of the Grignard reagent occurs, initially, at sulphinyl group. A mechanism, envolving a cyclic transition state, is suggested, in order to explain the preferential migration of the aromatic ring, which belonged originally to the Grignard reagent.

<p>One-step photoinitiated free radical carbonylation was employed for the rapid (5–7 min) labelling of aliphatic carboxylic acids, esters, and amides with a short-lived positron emitter ¹¹C (t_½ = 20.3 min) at the carbonyl position. The labelled compounds were synthesized from alkyl iodides (0.05–0.1 mmol), [¹¹C]carbon monoxide, and appropriate nucleophiles. Decay-corrected radiochemical yields were up to 74%; conversion of [¹¹C]carbon monoxide reached 85–90%; specific radioactivity was 158–192 GBq/mmol. The labelled compounds were identified and characterized using HPLC, LC-MS, and ¹H and ¹³C NMR. The effects of solvents, additives, photoirradiation, temperature, and reaction time were studied and discussed.</p><p>[<i>carbonyl-</i>¹¹C]Amides were synthesized using amines in 1–2 equiv. to iodides, exploiting solvent effects to control reactivity. [<i>carboxyl-</i>¹¹C]Acids were synthesized using water as a nucleophile, in binary and ternary aqueous solvent mixtures; the addition of TBAOH or KOH was necessary to obtain high radiochemical yields. [<i>carbonyl-</i>¹¹C]Esters were synthesized using primary and secondary alcohols, <i>tert-</i>butanol, and phenol. Bases were KOH, BuLi, LiHDMS.</p><p>The effects of photosensitizers were studied and exploited to accelerate the labelling of carboxylic acids and esters resulting in 75–85% decay-corrected radiochemical yields under mild conditions without the use of bases.</p><p>A mild procedure for the ¹¹C-carboxylation of alkyl iodides using DMSO as an oxygen nucleophile was developed. This method is expected to be suitable in the macroscale synthesis of carboxylic acids using isotopically unmodified carbon monoxide.</p><p>Radical carbonylation was applied to improve the synthesis of an extensively used PET tracer, [<i>carbonyl</i>-¹¹C]WAY-100635. The tracer was synthesized in one step, whereas a common approach via Grignard reagents requires three steps.</p><p>In addition, several (¹³C)compounds were synthesised using the described methods.</p><p>Free radical carbonylation may be used for the ¹¹C-carbonylation of alkyl iodides, whereas transition-metal carbonylation – of aryl halides and triflates. Thus, the two carbonylation methods are complementary with respect to the scope of synthetic targets.</p>

One-step photoinitiated free radical carbonylation was employed for the rapid (5–7 min) labelling of aliphatic carboxylic acids, esters, and amides with a short-lived positron emitter 11C (t½ = 20.3 min) at the carbonyl position. The labelled compounds were synthesized from alkyl iodides (0.05–0.1 mmol), [11C]carbon monoxide, and appropriate nucleophiles. Decay-corrected radiochemical yields were up to 74%; conversion of [11C]carbon monoxide reached 85–90%; specific radioactivity was 158–192 GBq/mmol. The labelled compounds were identified and characterized using HPLC, LC-MS, and 1H and 13C NMR. The effects of solvents, additives, photoirradiation, temperature, and reaction time were studied and discussed. [carbonyl-11C]Amides were synthesized using amines in 1–2 equiv. to iodides, exploiting solvent effects to control reactivity. [carboxyl-11C]Acids were synthesized using water as a nucleophile, in binary and ternary aqueous solvent mixtures; the addition of TBAOH or KOH was necessary to obtain high radiochemical yields. [carbonyl-11C]Esters were synthesized using primary and secondary alcohols, tert-butanol, and phenol. Bases were KOH, BuLi, LiHDMS. The effects of photosensitizers were studied and exploited to accelerate the labelling of carboxylic acids and esters resulting in 75–85% decay-corrected radiochemical yields under mild conditions without the use of bases. A mild procedure for the 11C-carboxylation of alkyl iodides using DMSO as an oxygen nucleophile was developed. This method is expected to be suitable in the macroscale synthesis of carboxylic acids using isotopically unmodified carbon monoxide. Radical carbonylation was applied to improve the synthesis of an extensively used PET tracer, [carbonyl-11C]WAY-100635. The tracer was synthesized in one step, whereas a common approach via Grignard reagents requires three steps. In addition, several (13C)compounds were synthesised using the described methods. Free radical carbonylation may be used for the 11C-carbonylation of alkyl iodides, whereas transition-metal carbonylation – of aryl halides and triflates. Thus, the two carbonylation methods are complementary with respect to the scope of synthetic targets.

O presente trabalho investiga alguns sulfóxidos &#946;-tia-substituidos quanto à sua basicidade relativa e quanto à sua reatividade em relação aos compostos de Grignard aromáticos. O conjunto de compostos investigados foi o seguinte: metil n-propil sulfóxido, metil metiltiometil sulfóxido, etil butil sulfóxido, etil etiltiometil sulfóxido, etil feniltiometil sulfóxido, fenil feniltiometil sulfóxido e 1,3-ditiolano-1-óxido. É apresentada, inicialmente, uma revisão bibliográfica sôbre dois itens: 1. basicidade de sulfóxidos, e 2. reações de sulfóxidos com compostos de Grignard. São apresentados os valores de constantes de associação para dois sulfóxidos &#946;-tia-substituídos e dois não substituídos correspondentes. Estes valores foram calculados a partir de medidas dos deslocamentos químicos dos prótons do fenol em sistemas ternários sulfóxido -fenol-tetracloreto de carbono, pelo dos métodos de Carper e de Mathur. São apresentadas as reações de quatro sulfóxidos com alguns compostos de Grignard aromáticos, tais como os brometos de fenil-, p-anisil-, p-tolilmagnésio, e descritos os métodos de análise dos compostos formados. São descritas as preparações de cincos sulfóxidos e de alguns produtos autênticos. São fornecidos os resultados de algumas experiências de reações de um sulfóxido &#946;-tia-substituído com brometo de fenilmagnésio em presença de base. É apresentada uma discussão na qual se procura interpretar tanto os resultados da literatura como os nossos. Os resultados obtidos demonstram que: a) Há diminuição de basicidade nos sulfóxidos &#946;-tia-substituidos, em comparação com os não substituidos correspondentes. b) A reação dos sulfóxidos &#946;-tia-substituidos com compostos de Grignard aromáticos fornece os mercaptais dos aldeidos aromáticos correspondentes. c) A reação dos sulfóxidos &#946;-tia-substituidos com reagentes de Grignard e impedida por bases fortes. Os rendimentos dos mercaptais são muito mais baixos do que na ausência de base. d) A fixação do organomagnesiano ocorre inicialmente no grupo sulfinila. Um mecanismo envolvendo um estado de transição cíclico é sugerido para explicar a migração preferencial do anel aromático proveniente do composto de Grignard. / This thesis investigates some &#946;-thia-substituted sulphoxides concerning their relative basicity and reactivity toward aromatic Grignard reagents. The following compounds were investigated: methyl n-propyl sulphoxide, methyl methylthiomethyl sulphoxide, ethyl n-butyl sulphoxide, ethyl ethylthiomethyl sulphoxide, ethyl phenylthiomethyl sulphoxide, phenyl phenylthtomethyl sulphoxide and 1,3-dithiolane-l-oxide. A literature review, containing two topics, is presented: 1) basicity of sulphoxides, 2) reactions of sulphoxides with Grignard reagents. The data of the association constants for two &#946;-thiasubstituted and two corresponding unsubstituted sulphoxides are presented. These values were calculated from the chemical shifts of the phenol protons, measured in the ternary systems sulphoxide -phenol-carbon tetrachloride, by methods of Mathur and Carper. The reactivity of four sulphoxides with some Grignard reagents, such as phenyl-, p-anisyl-, and p-tolylmagnesium bromides including the analyses of the resulting products is presented. The preparation of five sulphoxides and of some authentic products are described. Some experiments, in which the Grignard reaction is performed in basic conditions, are reported. The obtained results are discussed in the light of the literature data. It is shown that: a) There is a decrease in basicity going from the unsubstituted sulphoxides to the corresponding &#946;-thia-substituted ones. b) The reaction of &#946;-thia-substituted sulphoxides lead to the corresponding aromatic aldehydes mercaptals. c) The reaction of the &#946;-thia-substituted sulphoxides is inhibited by the presence of a base. The yields of mercaptals are much lower than in the absence of base. d) The attachment of the Grignard reagent occurs, initially, at sulphinyl group. A mechanism, envolving a cyclic transition state, is suggested, in order to explain the preferential migration of the aromatic ring, which belonged originally to the Grignard reagent.

Unsaturated sugars constitute as an important category of carbohydrate precursors in synthesis. Specifically, 1,2- and 2,3-unsaturated glycosides are excellent intermediates to derivatize monosaccharides and as building blocks in organic synthesis. For example, a major utility of 1,2-unsaturated sugars, namely glycals, is the addition reactions to afford 2-deoxy glycosides under acidic conditions and rearrangement reactions to produce 2,3-unsaturated glycosides. Lewis acids favour the formation of 2,3-unsaturated glycosides, whereas, Brønsted acids lead to normal addition products. A mixture of both the product is obtained often, depending on the nucleophiles and the stereochemistry of glycal. Chapter 1 of the thesis describes (i) reactivities of glycals under acidic condition and (ii) a general survey of reactions involving on C2-C3 carbons of monosaccharides. Glycals are useful precursors to derive a number of functionalized monosaccharide derivatives. A well-known acid catalyzed reaction of glycals is their conversion to 2,3¬unsaturated glycosides, known as the Ferrier products. In a research programme, reactivity switching and selective activation of C-1 or C-3 of 2,3-unsaturated thioglycosides under acid catalyzed condition was undertaken. Thioglycosides are excellent glycosyl donors and can be activated easily. In identifying the reactivities of 2,3-unsaturated thioglycosides, obtained through Ce(IV)-mediated reaction of a glycal, it was intended to study the glycosylation reaction and also the reactivity control of C1-C3 carbons during a glycosylation reaction. Experiments showed that a reactivity switching was possible through activation of either C-1 or C-3. Thus, C-1 glycosylation with alcohol acceptors occurred in the presence of NIS/TfOH, without the acceptors reacting at C-3. On the other hand, reaction of 2,3-unsaturated thioglycosides with alcohols mediated by triflic acid alone led to a transposition of C-1 ethylthio-moiety to C-3 intramolecularly, to form 3-ethylthio-glycals. Resulting glycals underwent glycosylation with alcohols to afford 3-ethylthio-2-deoxy glycosides. However, when thiol was used as an acceptor, only a stereoselective addition at C-3 resulted, so as to form C-1, C-3 dithio-substituted 2-deoxypyranosides. Oxocarbenium ion is the reactive intermediate during activation of a glycosyl donor, and in the case of a 2,3-unsaturated thioglycosides, the oxocarbenium ion may stabilize further by the presence of a C2-C3 unsaturation. Reaction of a nucleophile with allylic oxocarbenium ion may lead to two regio-isomers. Initially, NIS/TfOH was attempted on 2,3–unsaturated sugar with various alcohols and it was found that C-1 was the preferred reactive centre (Scheme 1) Scheme 1 In order to optimize the reaction for selective nucleophilic attack at C-3, further study was continued by using stoichiometric TfOH, in presence of acceptors alcohols with the intension to activate the double bond. The reaction led to the formation of 2-deoxy O-glycosides with the concomitant transposition of C-1 ethylthio-moiety to C-3 (Scheme 2). Scheme 2 An important observation was that the transposition of thioethyl group from C-1 to C-3 was highly regioselective. For example, with thiocresol as the nucleophile, there was an addition across the C-2-C-3 double bond to afford C-1, C-3-dithio derivative (Scheme 2). Thus, hard-soft nature of the nucleophiles, as well as, carbon centres helped to rationalize the reactivites. It was also observed that the intramolecular transposition of thioethyl group is highly stereo-controlled by equatorial C-4 acetoxy group. Thus, thioethyl nucleophile approached selectively at C-3 and afforded trans-diequatorial products. This rationalization was further confirmed through (i) reaction of benzyl protected 2,3-unsaturated thioglycoside, wherein a C-3 epimeric mixture was observed in 1:1 ratio; (ii) galactosyl derivative under similar reaction condition afforded anomeric mixture of 3-(4-methylphenylthio)-O-glycosides, with trans-diaxial orientation of substituent at C-3 (Scheme 3). Scheme 3 These reactions confirmed the role of C-4 substituent on the carbocation at C-3, through the presence or absence of a neighbouring group participation. In summary, in Chapter 2 the selective activation of either anomeric carbon or C-3 with proper choice of activation and reactivity control at each carbon will be described. Thioglycosides are excellent glyosyl donor and their glycosylation reactions were well explored. Upon indentifying the intramolecular transposition of thioalkyl/aryl functionality from C-1 to C-3, further investigations was undertaken to utilize the newly formed carbon sulfur bonds at C-3. Realizing a potential for such 3-alkyl/aryl thio 2-deoxy sugar, the Pummerer rearrangement was investigated. For this purpose, the thioalkyl/aryl moiety at C-3 was oxidized first to a sulfoxide. The resulting sulfoxide was allowed to undergo Pummerer rearrangement to afford vinyl sulfide (Scheme 4), resulting from the elimination of HOAc in the thioacetal formed in situ. Having implemented Pummerer rearrangement on a sugar substrate, synthetic utility of the rearrangement product, namely vinyl sulfide was undertaken. An effort to implement conjugate addition reaction was undertaken, which required the conversion of vinyl sulfide to vinyl sulfoxide in the first step. The conjugate addition reactions were first conducted with alkoxide nucleophiles. The reaction showed that addition of nucleophiles occurred from axial face to furnish manno-configured derivatives as a single diastereomer at sulfinyl sulfur in a moderate yield along with O-deacetylated product. It was also found that O-benzyl protected sugar vinyl sulfoxide was totally resistant to the conjugate addition reaction (Scheme 4). Scheme 4 In order to find the influence of the substituents in sulfoxide moiety in the addition of nucleophiles, additional study was conducted in which a less hindered thioethyl moiety was installed in place of p-tolylthio moiety. To install ethylthio moiety, a similar sequence of reaction was undertaken as described previously in Scheme 4. Conjugate addition reaction with alkoxide nucleophiles was conducted and analysis of the reaction showed that the addition of alkoxides remained similar, leading to the formation of manno-configuration of substituents (Scheme 5). Scheme 5 The configuration of the Michael adducts were ascertained from 1H NMR, as well as 2D NMR spectroscopies. H-1 of all adducts appeared as an apparent singlet, consistent with very small J1,2 values. Aryl vinyl sulfoxide afforded conjugate addition product at much higher ratio than corresponding alkyl vinyl sulfoxide. Thus, among aryl and alkyl vinyl sulfoxides, conjugate addition occurred better with the aryl vinyl sulfoxide, indicating a strong electronic effect of aryl group in stabilizing the conjugate anion which would form in situ during nucleophilic addition with vinyl sulfoxide. Therefore, p-tolylthio substituted vinyl sulfoxide served as a more efficient Michael acceptor when compared to the thioethyl substituted vinyl sulfoxide. Asymmetric environment of vinyl sulfoxides play a vital role during the reaction. Vinyl sulfoxides can exist in two stereochemically distinct conformation which makes the vinyl group electronically dissimilar. In one of the conformer S-O and C-C bonds are coplanar, whereas in the other conformation, these two bonds are opposite to each other. It is agreed generally that vinyl sulfoxides generally try to adopt the most reactive conformer during the reaction in which the C-C and S-O bonds are syn to each other. Thus, the preference for an axial attack would originate from a face anti to the lone pair of electrons on the sulfur of sulfoxide functionality, leading to the formation of the product with manno-configuration. As O-deacetylated vinyl sulfoxide was obtained along with the Michael adducts, it was assumed that one of the epimers of vinyl sulfoxide appeared to be more reactive when compared to the other. Chapter 3 describes implementation of a Pummerer rearrangement in order to synthesize a sugar vinyl sulfoxide and its conjugate addition reactions with alkoxide nucleophiles. The nucleophilic addition reactions of vinyl sulfoxide with other nucleophiles were studied further. The effect of the substituents of chiral sulfoxides in conjugate addition reactions was also incorporated in the course of reactions. Reactions of amines, carbon and sulfur nucleophiles were undertaken with p-tolylthio-substituted vinyl sulfoxides. The reactions showed formation of the addition-elimination products (Scheme 6). All primary amines, carbon and sulfur nucleophiles afforded C-2 axial epimer, namely, threo-epimer exclusively, wherein secondary amines furnished the equatorial vs axial epimer in 3:1 ratio. Scheme 6 In order to assess the course of the reaction, vinyl sulfoxide presenting a p-cumenethio¬moiety was installed in place of p-tolylthio moiety. Conjugate addition reactions were performed with both primary as well as secondary amines that showed formation of the C-2 epimeric mixtures. With both the primary and secondary amines C-2 equatorial epimer was found to be as the major product (Scheme 7). Scheme 7 In conjugate addition of vinyl sulfoxides, nucleophiles approach the olefinic face preferentially, which is anti to the electron rich sulfur lone pair of electrons and syn to the bulky aryl group. Therefore, C-2 axial epimer was observed as most favourable product. However, secondary amines remarkably influenced the pattern as well as selectivity of the reaction. Steric considerations were likely to dictate the overall reactivity with secondary amines which was even more pronounced when using p-cumenethio-substituted vinyl sulfoxide. Chapter 4 describes the conjugate additions as well as remote effect of aryl substituent on the selectivity of addition of amines on sugar sulfoxide In summary, the Thesis establishes: A new reactivity of switching and a selective activation of 2,3-unsaturated thioglycoside; A Pummerer rearrangement route in order to synthesize sugar vinyl sulfide for the first time, which on selective oxidation furnish a sugar vinyl sulfoxide, a useful precursor for conjugate addition reactions; An assessment of the stereoelectronic, as well as, steric effect of the chiral vinyl sulfoxide with various nucleophiles in conjugate addition reactions; Influence of the protecting groups were also studied in conjugate addition reactions. Overall the study presented in the Thesis provides a new insight to unsaturated sugars. The salient features of the present findings also showed that the intermediates such as C-3 substituted thioalkyl/aryl glycosides, vinyl sulfides, a variety of new C-2 substituted vinyl sulfoxides are also the potential sites for many types of modifications in monosaccharides. (For structural formula pl see the pdf file)

Esta tese descreve, em três diferentes capítulos, a preparação de quatro produtos naturais com atividade biológica reconhecida. O primeiro se refere à síntese de dois ácidos carboxílicos diacetilênicos, os ácidos monitipóricos A e B, isolados dos ovos do coral duro Montipora digitada e que apresentam atividade citotóxica e antibacteriana. Estas sínteses foram alcançadas utilizando-se reações de acoplamento de acetilenos e eterificação por CTF. Reações de transposição de ligação tripla e redução de acetileno terminal por semi-hidrogenação com Lindlar/H2, ou hidroteluração/transmetalação Te-Li, são discutidas. O segundo capítulo descreve a síntese do virol C, um diol poliacetilênico análogo à cicutoxina, isolado como um dos componentes tóxicos da planta Cicuta virosa. Para isso utilizou-se química de sulfóxidos para indução de quiralidade na formação do estereocentro C-10. A união dos fragmentos se deu por reações de Wittig e acoplamento de acetilenos mediado por cobre(I). O último capítulo é dedicado à descrição das tentativas de obtenção do éster metílico do ácido pinélico, um ácido triidroxioctadecenóico derivado do ácido linoléico. É produzido por certas variedades de arroz, como agente de defesa contra o fungo Pyricularia orizae</i< e é relacionado com a qualidade da cerveja, além de ser isolado da planta medicinal Pinellia ternata, como um potente adjuvante para a vacina nasal contra influenza. As tentativas de síntese deste produto foram baseadas em diveras abordagens retrospectivas, onde a última apresenta reações de redução estereosseletiva de &#946;-ceto-sulfóxidos, acoplamento-cruzado entre fragmentos vinílicos e diidroxilação de Sharpless. / This thesis describes, in three different chapters, the synthesis of four natural products with recognized biological activity. The first refers to the synthesis of two diacetylenic carboxylic acids, montiporic acids A and B, which were isolated from eggs of hard coral Montipora digitata and have presented cytotoxic and antibacterial activity. These synthesis were achieved through reactions of acetylenic coupling and etherification on FTC conditions. Reactions of triple bond transposition and terminal acetylene reduction with Lindlar/H2 hydrogenation or hydrotelluration/transmetalation Te-Li are discussed. The second chapter describes the synthesis of Virol C, a polyacetilenic diol analogous of cicutoxin, isolated as a toxic component of Cicuta virosa. The chemistry of sulfoxides was used, in order to achieve the desired configuration. The union of fragments was archieved by Witting and acetylenic coupling reactions.The last chapter describes the attempts to get the methylic ester of pinellic acid, a trihyroxyoctadecenoic acid, based from linoleic acid. Pinellic acid was produced bu some species of rice, as a chemical defense against the fungus Pyricularia orizae; it is related with the quality of beers; and its isolated from Pinellia ternata, (a medicinal plant), as a powerful adjuvant against influenza. The atempts of the synthesis was based on several retrosynthetic approaches, where the last one users a stereo selective reduction of &#946;-ketosulfoxide, cross-coupling between vinyllic fragments and Sharpless dihydroxylation.

La chiralité axiale est une propriété importante de composés biologiquements actifs, de matériaux avancés et plus particulièrement de ligands utilisés en catalyse asymétrique. En effet de nombreuses structures biaryliques atropisomériques ont montré un excellent pouvoir d’induction asymétrique. Ainsi le contrôle de l’atropisomérie et le développement de nouvelles méthodes synthétiques permettant la synthèse de composés à chiralité axiale optiquement purs attire l’attention de la communauté scientifique. Au cours de ce travail une nouvelle stratégie vers l’obtention de biaryles à chiralité axiale atropenrichis a été explorée. L’utilisation de sulfoxydes énantiopurs, jouant à la fois le rôle de groupe directeur et d’auxiliaire de chiralité, dans une stratégie de fonctionnalisation de liaisons C-H par catalyse homogène au palladium, a permis l’obtention efficace de nombreux composés biaryliques hautement atropenrichis . Les méthodologies développées ont ensuite été appliquées à la synthèse formelle d’un composé naturel bioactif à chiralité axiale, la (-)-steganone, ainsi qu’à la synthèse de ligands doublement atropisomériques inédits. / Axial chirality is an important property of biologically active compounds, advanced materials and more importantly of ligands used in asymmetric catalysis. Indeed, numerous atropisomeric biaryls have demonstrated an excellent asymmetric induction capacity. Thus, the control of atropisomery and the development of original synthetic methodologies allowing the synthesis and the obtention of optically pure axially chiral compounds is an important goal for the scientific community. In this work, a new strategy for the synthesis of atropenriched axially chiral biaryls was explored. The use of enantiopur sulfoxides playing the role of both, a directing group and a chirality auxiliary, in a palladium catalyzed C-H functionalization, allowed the efficient construction of numerous highly atropenriched biaryl compounds. The developed methodologies were furthermore applied to the formal synthesis of an axially chiral and bioactive compound, (-)-steganone, as well as the synthesis of doubly atropisomeric unprecedented ligands. These ligands displayed an excellent potential for asymmetric induction in homogenous asymmetric hydrogenation.

Esta tese descreve, em três diferentes capítulos, a preparação de quatro produtos naturais com atividade biológica reconhecida. O primeiro se refere à síntese de dois ácidos carboxílicos diacetilênicos, os ácidos monitipóricos A e B, isolados dos ovos do coral duro Montipora digitada e que apresentam atividade citotóxica e antibacteriana. Estas sínteses foram alcançadas utilizando-se reações de acoplamento de acetilenos e eterificação por CTF. Reações de transposição de ligação tripla e redução de acetileno terminal por semi-hidrogenação com Lindlar/H2, ou hidroteluração/transmetalação Te-Li, são discutidas. O segundo capítulo descreve a síntese do virol C, um diol poliacetilênico análogo à cicutoxina, isolado como um dos componentes tóxicos da planta Cicuta virosa. Para isso utilizou-se química de sulfóxidos para indução de quiralidade na formação do estereocentro C-10. A união dos fragmentos se deu por reações de Wittig e acoplamento de acetilenos mediado por cobre(I). O último capítulo é dedicado à descrição das tentativas de obtenção do éster metílico do ácido pinélico, um ácido triidroxioctadecenóico derivado do ácido linoléico. É produzido por certas variedades de arroz, como agente de defesa contra o fungo Pyricularia orizae</i< e é relacionado com a qualidade da cerveja, além de ser isolado da planta medicinal Pinellia ternata, como um potente adjuvante para a vacina nasal contra influenza. As tentativas de síntese deste produto foram baseadas em diveras abordagens retrospectivas, onde a última apresenta reações de redução estereosseletiva de &#946;-ceto-sulfóxidos, acoplamento-cruzado entre fragmentos vinílicos e diidroxilação de Sharpless. / This thesis describes, in three different chapters, the synthesis of four natural products with recognized biological activity. The first refers to the synthesis of two diacetylenic carboxylic acids, montiporic acids A and B, which were isolated from eggs of hard coral Montipora digitata and have presented cytotoxic and antibacterial activity. These synthesis were achieved through reactions of acetylenic coupling and etherification on FTC conditions. Reactions of triple bond transposition and terminal acetylene reduction with Lindlar/H2 hydrogenation or hydrotelluration/transmetalation Te-Li are discussed. The second chapter describes the synthesis of Virol C, a polyacetilenic diol analogous of cicutoxin, isolated as a toxic component of Cicuta virosa. The chemistry of sulfoxides was used, in order to achieve the desired configuration. The union of fragments was archieved by Witting and acetylenic coupling reactions.The last chapter describes the attempts to get the methylic ester of pinellic acid, a trihyroxyoctadecenoic acid, based from linoleic acid. Pinellic acid was produced bu some species of rice, as a chemical defense against the fungus Pyricularia orizae; it is related with the quality of beers; and its isolated from Pinellia ternata, (a medicinal plant), as a powerful adjuvant against influenza. The atempts of the synthesis was based on several retrosynthetic approaches, where the last one users a stereo selective reduction of &#946;-ketosulfoxide, cross-coupling between vinyllic fragments and Sharpless dihydroxylation.