Polypropionates represent a large family of natural products and several strategies have been developed for their synthesis. The aldol reaction is one of the most important tools for the construction of polypropionate natural products. The Ward group has developed an approach to polypropionate natural products based on sequential aldol reactions of thiopyran building blocks. The Thiopyran Route to Polypropionates (TR2P) involves the stepwise aldol reactions of 15 and 16 to rapidly access stereochemically complex tetrapropionate and hexapropionate synthons in a few steps. The current work describes the effort to prepare enantioenriched 17-AA and/or 17-SA through chiral transition metal based Lewis acids (176) and chiral organocatalysts (48, 179) with chelating Lewis acids. The preparation of non-Felkin tetrapropionate and hexapropionate synthons through the use of a weak base in conjunction with a Lewis acid was developed.

Dioxanones (1) are ketal- or acetal protected forms of 1,3-dihydroxyacetone (DHA). The thesis presents the stereoselective aldol transformations of dioxanones and applications to the synthesis of natural and higher carbohydrates listed in Scheme 1.<p> The field of organocatalysis has recently gained much popularity among the chemical research community. In our group, a set of conditions are developed to perform stereoselective aldol reactions on dioxanone substrate. Cs-symmetrical dioxanones have superior diasteroselectivities than C2v-symmetrical dioxanones (de up to 88% from 34%) and presence of mild Lewis acid (LiCl) or Brønsted acid additives (PyPTS) enhance the enantioselectivity into synthetically useful ranges (from 60 up to 96 % ee).<p> The first aldol addition of dioxanone (1) to desired aldehydes (possessing masked carbonyl functionality), followed by reduction of the corresponding aldol adduct and upon unmasking the aldehyde functionality (i.e dithiane or dimethoxy acetal hydrolysis) resulted in furanose (II) and pyranose (III) forms of D-ribose.<p> A new protocol was developed for the synthesis of biologically important deoxyiminosugars such as L-1-deoxymannojirimycin (DMJ, IV), L-1-deoxyidonojirimycin (DIJ, V) and N-isopropyl DIJ (IV) from readily available dioxanone (1) precursor. The key steps include diastereoselective proline-catalyzed syn-aldol transformation and a reductive amination / cyclization.<p> D-glycero-D-manno-2-octulose (VII), a higher-carbon sugar isolated from opium poppies has been synthesized in enantiomerically pure form. The short synthetic sequence involved two proline-catalyzed aldol addition reactions of dioxanone (1) to appropriate aldehydes. Here, we developed a complete dioxanone methodology towards the higher monosaccharide in a stereocontrolled fashion.<p> The enantioselective stereodivergent first total synthesis of DD- and LL-glycero-β-alloheptopyranose (IX, ent-IX) was accomplished from readily available non-chiral starting materials. The short synthetic sequence involves enamine and enolate mediated aldol reactions at α and α' positions of dioxanone (1) hence demonstrated the complementary nature of organocatalysis and organometallic methods.

Polypropionates represent a large family of natural products and several strategies have been developed for their synthesis. The aldol reaction is one of the most important tools for the construction of polypropionate natural products. The Ward group has developed an approach to polypropionate natural products based on sequential aldol reactions of thiopyran building blocks. The Thiopyran Route to Polypropionates (TR2P) involves the stepwise aldol reactions of 15 and 16 to rapidly access stereochemically complex tetrapropionate and hexapropionate synthons in a few steps. The current work describes the effort to prepare enantioenriched 17-AA and/or 17-SA through chiral transition metal based Lewis acids (176) and chiral organocatalysts (48, 179) with chelating Lewis acids. The preparation of non-Felkin tetrapropionate and hexapropionate synthons through the use of a weak base in conjunction with a Lewis acid was developed.

Expanding the uses of the NCAL and finding the spectrum of substrates best suited for such a transformation has been the main effort of my research. Previous studies had focused on aldedydes as the requisite functionality that would provide the needed electrophilicity in order to complete the aldol; however, recent advancements have introduced ketones as a viable carbonyl. With an established protocol in hand, I set out to explore various substrates that could yield Beta-lactones in good to moderate yields such as amino acid derivatives, diones, and large cyclic formations as well as simple, straight chain acids with varying groups Alpha to the ketone. In general, I was able to establish a basic framework of substrates that are highly and/or moderately susceptible towards the NCAL and current studies continue to further expand the scope. In addition to making Beta-lactones, I investigated alkyl cuprates as soft nucleophiles to afford addition at the Beta carbon yielding a variety of acids. Substrates for cuprate additions have been expanded to bulkier and multi-cyclic Beta-lactones and applied to the synthesis of a Merck IND intermediate. Additions to bi- and tri-chloro Beta-lactones due to the presence of the resulting moity in natural products are currently being studied.

The development of new, efficient methods for the formation of carbon-carbon bonds using transition metal catalysis has broad applications in the field of organic chemistry and is the key to efficient chemical synthesis. Many efforts had been made to develop efficient ways to make these linkages particularly with the aid of metals such as Rh, Pd, Ni, Ru and Cu. Our group is primarily focused on exploring how these transition metals can activate typically inert functional groups, paving way to new synthetic routes to construct more complex molecules. Chapter 1 describes attempts that were conducted to achieve hydroacylation between an aldehyde and a non-conjugated alkene via a metal hydride intermediate. The use of RuHCl(CO)(PPh3)3 proved to be the most efficient catalyst for this transformation thus far. Mechanistic investigations were conducted to explore different possibilities to enable this transformation. This chapter also identifies a new self-aldol domino reaction, which consists of a self-aldol condensation of an aldehyde, followed by oxidation and decarbonylation giving rise to a ketone product. Finally, the use of a simple and direct method to access deuterated aldehydes using RuHCl(CO)(PPh3)3 as a catalyst and D2O as a deuterium source is outlined. Chapter 2 describes a novel Suzuki-Miyaura system that couples esters and boronic esters to form the corresponding ketone product. It was found that an NHC-based Pd catalyst is crucial in the transformation wherein it activates the C(acyl)-O bond of the ester. It is notable that this transformation takes place with the absence of decarbonylation. Reactivity under water in the presence of surfactants was also discovered. Results in aqueous media were demonstrated to be milder than in organic conditions, while achieving similar yields. This system was also applied to coupling of esters and anilines.

Polyketides are a group of complex natural products that can inhibit the growth of bacteria, viruses, fungi, and tumor cells. Most polyketides are very difficult to extract from bacteria. Therefore, numerous syntheses of polyketide-related synthons have been attempted. <p> However, controlling the stereochemistry of the polyketide poses the most challenging task for researchers. The aim of this report is to discuss control of the stereochemistry of the polyketide-related synthons in asymmetric aldol reactions. Several important methodologies for stereochemical control in the aldol reaction exist. The first approach is to control the enolate geometry and the aldehyde (or ketone) geometry. The second approach is to use a chiral auxiliary and chiral ligands. The third approach is to use a chiral catalyst, which is the most efficient method if the catalyst operates with complete efficiency. Proposed transition states are also described to explain the resulting stereochemistry of the aldol adduct. / Master of Science

Orientador: Ronaldo Aloise Pilli / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-18T11:54:19Z (GMT). No. of bitstreams: 1 Drekener_RobertaLopes_D.pdf: 4694535 bytes, checksum: 998a5a4160bc1a4929a466c8dcfe2462 (MD5) Previous issue date: 2011 / Resumo: Neste trabalho descrevemos os avanços sintéticos para obtenção das Criptomoscatonas D1 (41) e D2 (42), isoladas da Cryptocarya mandioccana, para as quais não se encontram sínteses descritas na literatura e suas estruturas tridimensionais ainda não foram elucidadas. As estratégias de síntese propostas para os isômeros 41 e 42 foram baseadas em utilizar como etapa chave a reação aldólica com indução remota 1,5-anti. A primeira proposta envolveu a síntese da metil cetona (R)-153 em 8 etapas e baixo rendimento global (4,2%). Uma nova proposta sintética foi formulada e resultou na síntese da metil cetona (+/-)-157 em 3 etapas e 54% de rendimento. Esta abordagem possibilitou a construção do esqueleto carbônico de 41 e 42, de maneira diastereosseletiva. A etapa aldol utilizando a metil cetona (+/-)-157 foi realizada com sucesso, levando a formação de um aduto diastereoisomérico preferencial (+/-)-162. Já o centro estereogênico em C2' foi formado via redução 1,3-sin empregando-se metodologia de Narasaka para a obtenção de (+/-)-165a e 1,3-anti com a utilização da metodologia de Evans para obtenção de (+/-)-165b. Após manipulações de grupos protetores e de grupos funcionais, os ésteres a,b-insaturados (+/-)-169a e b foram obtidos com a ligação dupla com geometria Z através de metodologia de Horner-Wadsworth-Emmons, com modificação de Still-Gennari. A etapa de remoção do grupo acetonídeo levando aos ésteres a,b-insaturados (+/-)-170a e b foi realizada em meio ácido brando, sendo a ciclização do anel lactônico destes produtos realizada na presença de óxido de dibutilestanho, com excelentes rendimentos em ambas as etapas. Esta abordagem permitiu a formação do composto (+/-)-171a em 6,7% de rendimento e do composto (+/-)-171b em 7,6% de rendimento, a partir do trans-cinamaldeído. A etapa de remoção do grupo protetor p-metoxibenzila, não foi alcançada utilizando-se DDQ ou ZrCl4. Desta forma, embora as sínteses dos compostos 41 e 42 não tenham sido finalizadas e, portanto, a estereoquímica dos produtos naturais da família das Criptomoscatonas D não tenha sido esclarecida, este trabalho permitiu mapear a síntese racêmica destes dois compostos de uma maneira eficiente, contribuindo para que estudos futuros possam definir as estruturas desses produtos naturais / Abstract: Natural compounds of the 5,6-dihydropyranone family, isolated from the genus Cryptocarya (Laureacae), have attracted scientific interest due to their biological activities. Among these compounds, we highlight Cryptomoscatone D1 (41) and D2 (42), isolated from C. mandiocanna, for which a definitive proof of structure is still lacking. In this work, we describe our synthetic efforts toward these compounds. The synthetic strategies proposed for the syntheses of isomers 41 and 42 were based on a key aldol reaction with 1,5-anti remote induction. The first approach involved the synthesis of methyl ketone (R)-153 in 8 steps, however in low overall yield (4.2%). The second synthetic approach led to the synthesis of methyl ketone (+/-)-157, in three steps and 54% overall yield. The aldol step involving methyl ketone (+/-)-157 successfully led to the formation of the diastereoisomer (+/-)-162. The stereogenic center at C2'in (+/-)-165a was established via Narasaka's 1,3-syn reduction while Evans 1,3-anti reduction afforded (+/-)-165b. After manipulation of the protecting and functional groups, a,b-unsaturated esters (+/-)-169a and b were obtained with the desired Z double bond via the Still-Gennari modification of the Horner-Wadsworth-Emmons olefination reaction. Cleavage of the acetonide leading to the a, b-unsaturated d-hydroxyesters (+/-)-170a and b was achieved under mild acidic conditions, and cyclization was performed in the presence of dibutyltin oxide, in excellent yields for both steps. This approach allowed the formation of compound (+/-)-171a in 6.7% yield and compound (+/-)-171b in 7.6% yield, from trans-cinnamaldehyde. Removal of p-methoxybenzyl ether failed using DDQ or ZrCl4 methodologies. Although our studies did not elucidate the structures of Cryptomoscatone D1 (41) and D2 (42), they are a valuable contribution for future efforts aimed to unambiguously establish the structure of these natural products / Doutorado / Quimica Organica / Doutor em Ciências

Orientador: Luiz Carlos Dias / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T11:30:26Z (GMT). No. of bitstreams: 1 Ferreira_MarcoAntonioBarbosa_M.pdf: 7153235 bytes, checksum: e612e11ed109a87cf51fbc6e47852412 (MD5) Previous issue date: 2008 / Resumo: ADIÇÃO DE ENOLATOS DE BORO DE METILCETONAS A ALDEÍDOS. A presenca de um b-heteroatomo em enolatos de boro de metilcetonas tem forte influência na estereoquímica das reações aldólicas correspondentes. As reações aldólicas mediadas por enolatos de boro de metilcetonas com P = PMB com aldeídos aquirais conduziram a altos níveis de estereoindução remota 1,5-anti. No caso das metilcetonas com P = TBS e P = t-Bu, a adição dos enolatos de boro correspondentes a aldeídos quirais conduziu a uma mistura dos diastereoisômeros favorecendo os adutos de aldol 1,5-syn. A natureza do substituinte nos anéis aromáticos não teve influência significativa na estereoquímica das reações aldólicas, levando a resultados similares. LIGAÇÕES DE HIDROGÊNIO INTRA E INTERMOLECULARES DE ÉTERES ALQUÍLICOS E DE SILÍCIO: ESTUDO TEÓRICO E EXPERIMENTAL. Investigou-se o impacto eletrônico do grupo protetor P (TBS ou PMB) no equilíbrio conformacional dos álcoois (R)-metil substituídos 139 (P = TBS) e 140 (P = PMB). A análise conformacional e experimentos de H NMR para os álcoois 139 e 140 refletiram a tendência para a existência de confôrmeros apresentando ligação de hidrogênio. Mostrou-se que a magnitude da ligação de hidrogênio de éteres alquílicos e de silício são dependentes de diversas propriedades, como interação de orbitais, hibridização e energia dos pares de elétrons não ligantes do oxigênio, e não apenas pela ocupância eletrônica do átomo aceptor / Abstract: ADDITION OF BORON ENOLATES OF METHYLKETONES TO ALDEHYDES. The presence of a b-heteroatom substituent in the boron enolates of methylketones has a strong influence in the stereochemical outcome of the corresponding aldol reactions. The boron-mediated aldol reactions of methylketones with P = PMB were found to proceed with high degrees of remote 1,5-anti stereoinduction. In the case of methylketones with P = TBS and P = t-Bu, the corresponding boron enolates additions to aldehydes gives a mixture of aldol adducts favoring the 1,5-syn adducts. The nature of the substituent at the aromatic ring does not influence the stereochemical outcome, as p-OMe and p-NO2 lead to similar results.INTRA AND INTERMOLECULAR HYDROGEN BONDS IN ALKYL AND SILYL ETHERS: EXPERIMENTAL AND THEORETICAL ANALYSIS. We have investigated the electronic impact of the P protecting group (TBS or PMB) in the conformational equilibrium of (R)-methyl substituted alcohols 139 (P = TBS) and 140 (P = PMB). The conformational analysis and H NMR experiments for alcohols 139 and 140 reflect the tendency for the existence of hydrogen-bonded conformations. We showed that the extents of the hydrogen bonds in silyl and alkyl ethers are determined by several properties, such as orbital interactions, lone pair hybridizations, and lone pair energies, and not just by the electronic occupancy of the acceptor atom / Mestrado / Quimica Organica / Mestre em Química

A variety of organometallic-fused heterocycles and acene quinones were prepared and characterized. This work was divided into three parts: first, the synthesis of 5,5-fused heterocyclic complexes of tricarbonylmanganese and (1’,2’,3’,4’,5’-pentamethylcyclopentadienyl)ruthenium; second, the synthesis of 1,2-diacylcyclopentadienyl p-cymene complexes of ruthenium(II); and third, synthesis of cyclopentadienyl-fused polyacenequinone complexes of ruthenium, iron and manganese. The first examples of the convenient, versatile and symmetric cyclopentadienyl-fused heterocycle complexes of (1’,2’,3’,4’,5’-pentamethylcyclopentadienyl)ruthenium(II) and tricarbonylmanganese(I) were synthesized starting from (1,2-dicarbophenoxycyclopentadienyl)sodium. The sodium salt was transmetalated using [MnBr(CO)5] and 1/4 [Ru(μ3-Cl)(Cp*)]4 to give [Mn(CO)3{η5-C5H3(CO2Ph)2-1,2}] and [Ru{η5-C5H3(CO2Ph)2-1,2}(Cp*)]. The diester complexes were saponified under basic conditions to obtain the corresponding dicarboxylic acids. The dicarboxylic acids were used to synthesize unique cyclopentadienylmetal complexes including diacyl chlorides, anhydrides, thioanhydrides and p-tolyl imides of ruthenium and manganese. Similarly, a series of 1,2-diacylcyclopentadienyl-p-cymene cationic complexes of ruthenium were synthesized using thallium salt of 2-acyl-6-hydroxyfulvene and [Ru(η6-p-cymene)(μ-Cl)Cl]2 in a 2:1 ratio with an intension of converting them into heterocycle-fused cationic sandwich complexes. However, our attempts of ring closing on 1,4-diketons with sulfur or selenium were unsuccessful. A methodology involving the synthesis of metallocene-fused quinone complexes was employed starting from pentamethylruthenocene-1,2-dicarboxylic acids. The diacyl chloride was prepared in situ from the dicarboxylic acids and used for Friedel-Crafts acylation. We observed single-step room-temperature diacylation of aromatics, including benzene, o-xylene, toluene, 1,4-dimethoxybenzene and ferrocene with pentamethylruthenocene-1,2-diacyl chloride to obtain the corresponding quinone complexes. Similarly, we synthesized mononuclear and binuclear γ-quinones by aldol condensation of 1,2-diformylcyclopentadienylmetal complexes with cyclohexane-1,4-dione or 1,4-dihydroxyarenes. The third methodology involves the Friedel-Crafts acylation of ferrocene with 2-carbomethoxyaroyl chlorides followed by saponification, carbonyl reduction, and ring closing by second Friedel-Crafts acylation to give Ferrocene-capped anthrone-like tricyclic and tetracyclic ketones. The oxidation of the ketones gave [3,4-c]-fused α-quinone complexes of iron. The oxidative and reductive coupling, enolization and C-alkylation of the anthrone complex were studied. Solvolysis of α-carbinol gave α-ferrocenylcarbenium salt, which underwent dimerization on treatment with non-nucleophilic base. We were successful to trap the in situ generated trimethylsilylenol ether of ferrocene-anthrone using dienophiles like N-phenylmaleimide or dimethylacetylenedicarboxylate under Diels-Alder conditions.

The cobalt-catalysed alkylative aldol cyclisations of α,β-unsaturated amides with an appendant ketone were studied using a range of trialkylaluminium reagents. Investigations revealed that Co(acac)2·2H2O acts as an effective precatalyst for this transformation and the reaction provides β-hydroxylactam products containing three contiguous stereocentres with high levels of diastereoselection. The substrate scope of the reaction was explored and attempts were made to develop an asymmetric variant of this process. Two plausible reaction mechanisms have been proposed; the first invokes a π-allylcobalt species as a key intermediate in the reaction mechanism and the second involves a radical-mediated pathway. A stereochemical rationale for the observed relative stereochemistry of the β-hydroxylactam products has been discussed. II. Rhodium-Catalysed Carbometallations of Ynamides in the Preparation of Multisubstituted Enamides A highly stereo- and regioselective rhodium-catalysed carbozincation of ynamides using organozinc reagents has been disclosed. A careful examination of ligand effects on the rhodium catalyst yielded a complementary set of hydrozincation conditions. The alkenylzinc intermediates produced during the course of these reactions have been harnessed in further transformations with electrophilic species and in cross-couplings, thus providing access to multisubstituted enamides in a stereo- and regioselective fashion. Additionally, a rhodium-catalysed tandem carbometallation−conjugate addition with ortho-boronate substituted cinnamic acid derivatives has been described. The enamide−indene products were obtained in good yields and regioselectivities. Preliminary work has been undertaken on an asymmetric variant of this transformation and the initial results have been reported.