In this work, the principal concern will be with the coupling reaction and it is anticipated that the other reactions referred to above will be considered further when products of the RX-R'Li reactions are discussed.

Living organisms are capable of producing novel terpenoids with both remarkable ease and great selectivity. Many of these natural products exhibit significant biological activity useful for treatment of human diseases, but isolation of highly sought chemicals often results in only minute quantities. Consequently, extraction of these potential therapeutics from natural sources becomes an unrealistic method for obtaining enough material for a thorough biological evaluation, and so synthesizing these compounds becomes essential. Synthesis of terpenoids as potential therapeutics requires exceptional selectivity, especially when corresponding isomers elicit a contrasting biological response. The necessity for such selective syntheses along with the inherent structural complexities of terpenoids, often presents a number of significant challenges for the synthetic chemist. Isolation of the terpenoids pawhuskins A–C and petalostemumol from Dalea purpurea was reported by Belofsky in 2004, and of the collected compounds pawhuskin A was found to exhibit the most significant activity in an opioid receptor assay in vitro. Natural pawhuskin A was extracted from “Purple Prairie Clover” in only a 39 mg quantity and therefore syntheses of the natural product along with several analogues were pursued. Two of the synthesized analogues demonstrated greater potency than pawhuskin A, and interestingly these two isomeric derivatives were found to be selective for two different opioid receptors. However, the synthetic route utilized to form these two derivatives was not very selective for either isomer, and thorough purification proved challenging. Ergo, an alternative approach was sought to ensure the purity of these potential therapeutics. Parallel syntheses affording high selectivity for the key isomeric intermediates as well as a third regioisomer have been developed. The new isomeric intermediate also allowed the synthesis of two new analogues. This work is described in this report along with the formation of additional pawhuskin derivatives. The activity of these analogues as opioid receptor modulators also will be discussed.

Sulfoxide-ligand exchange (SLE) and asymmetric halogen-metal exchange (AHME) processes were separately examined for the enantioselective synthesis of functionalized alpha-haloalkylmetal (carbenoid) reagents. Carbenoids derived from SLE were used to effect stereospecific reagent-controlled homologation (StReCH) of boronic esters and those generated via AHME were engaged in Darzens-type chemistry with aldehydes. Abstract for Part 1. Scalemic syn alpha-chloroalkylsulfoxides p-TolS(O)CHClR [R = allyl, (1,3-dioxolan-2-yl)methyl, proparygyl, and 2-(benzyloxy)ethyl] were prepared from the corresponding thioethers by Jackson-Ellman-Bolm catalytic enantioselective sulfoxidation [cat. VO(acac)₂, tert-leucinol derived chiral Schiff base ligand, aq. H₂O₂, CHCl₃; 76-80% yield, >98% ee] followed by non-racemizing chlorination mediated by N-chlorosuccinimide in the presence of potassium carbonate (84-86% yield, syn:anti ≥ 20:1). The corresponding anti diastereoisomers were accessed from their syn epimers by sodium hexamethyldisilazide mediated deprotonation (THF, –78 °C) followed by treatment with either CH₃OH or CD₃OD to yield alpha-[¹H] or alpha-[²H] isotopomers, respectively (88% yield, anti:syn ≥ 17:1). Allyl and (1,3- dioxan-2-yl)methyl substituted chlorosulfoxides reacted with R'Li (t-BuLi or PhLi, THF, –78 °C) to give the expected products of SLE [p-TolS(O)R' and LiCHClR or LiCDClR]; however, neither the benzylether nor propargyl substituted substrates gave wholly satisfactory results under the same reaction conditions. The functionalized carbenoid reagents so obtained, 1-chloro-3-butenyllithium and 1-chloro-2-(1,3- dioxolan-2-yl)ethyllithium, were applied to the StReCH of B-(2-chloropyrid-5-yl) pinacol boronate but only the latter gave acceptable yields of chain extended products. The anti alpha-[²H]-chlorosulfoxide dioxolanyl bearing carbenoid precursor gave superior results to the analogous syn or anti alpha-[¹H]-chlorosulfoxides for StReCH of the B-pyridyl boronate [79% conversion, ≥ 89% ee (99% stereofidelity), vs. ≤ 68% conversion for non-deuterated chlorosulfoxides]. The origin of this isotope effect was traced to a deleterious proton transfer pathway between the alpha- chloroalkyllithium reagent and its chlorosulfoxide precursor. Sequential double iterative StReCH of B-(2-chloropyrid-5-yl) pinacol boronate with two separate portions of (S)-1-[²H]-1-chloro-2-(1,3-dioxolan-2-yl)ethyllithium (generated via SLE with phenyllithium) followed by oxidative work-up (with KOOH) gave (1R,2R)-1,2- [²H]₂-2-(2-chloropyrid-5-yl)-1,2-bis[(1,3-dioxolan-2-yl)methyl]ethanol (40% yield, ≥ 98% ee, dr = 85:15). Substitution of the (R)-configured carbenoid for its antipode in the second StReCH stage above gave the unlike (1S,2R)-isomer of the same pyridylethanol derivative (49% yield, ≥ 98% ee, dr = 79:21). The unlike diastereoisomer was advanced to the trifluoroacetamide of (1R,2R)-1,2-[2H]2-1- amino-2-(2-chloropyrid-5-yl)cyclohex-4-ene (6 steps, 5% overall yield); the non- deuterated isotopomer of this compound was previously advanced to the analgesic alkaloid (–)-epibatidine by Corey and co-workers. Abstract for Part 2. Scalemic planar chiral N,N-dialkyl 2-iodoferrocene carboxamides envisioned as recyclable precursors to ferrocenyl metal reagents for AHME, were prepared from ferrocene carboxylic acid by a three step sequence of: acid chloride formation [(COCl)₂ and cat. DMF)], aminolysis (with R₂NH, R = Me, Et, i-Pr; 65- 80% yield over 2 steps), and sec-butyllithium/(–)-sparteine mediated enantioselective directed ortho-metallation (DoM) followed by iodinolysis (87% yield, ≥ 96% ee). Attempts to access more elaborate 5-substituted 2-iodoferrocene carboxamides via DoM/iodinolysis of ortho-substituted ferrocene carboxamides (Me, Ph, or SiMe₃ substituents) mostly failed; however, analogous trisubstituted ferrocene oxazolines could be synthesized. Treatment of N,N-diisopropyl 2-iodoferrocene carboxamide (298, ≥ 96% ee) with n-BuLi (THF, –78 °C) resulted in complete conversion to the corresponding lithioferrocene (327) via I/Li interchange; subsequent iodinolysis initiated reverse Li/I exchange and returned iodoferrocene 298 without diminished enantiomeric excess, establishing configurational stability for the lithiated ferrocene intermediate. Prochiral (RCHI₂) and racemic (RCHICl) geminal dihalide substrates for AHME studies were prepared by electrophilic quench of dihalomethylsodiums with either Ph(CH₂)₃I or Me₃SiCl (50-78% yield). Of the four dihalides so produced, only prochiral substrate Me₃SiCHI₂ engaged in I/Li exchange with scalemic lithioferrocene 327 resulting in regeneration of its precursor iodoferrocene 298 and the formation of a putative chiral carbenoid Me₃SiCHLiI. Trapping of the carbenoid with aldehydes RCHO (R = Ph, 4-MeOC₆H₄, Ph(CH₂)₂, c-C₆H₁₁) in the presence of Me₂AlCl gave the expected epoxysilane products (35-40% yield, cis:trans ≥ 2:1) but without discernable enantiomeric excess. Hypotheses to account for the apparent lack of stereoinduction in this AHME cycle are presented. Comparable experiments using analogous magnesiated ferrocenes failed to produce putative carbenoid species from the same set of geminal dihalide substrates. / Graduation date: 2012

Nos últimos anos, houve um aumento considerável dos estudos envolvendo o núcleo indolizínico, um entre os milhares de heterociclos existentes, sendo 2012 o ano de maior destaque, com 102 publicações. Esse crescente interesse é atribuído principalmente à busca por novos substratos funcionalizados que apresentem características medicinais e biológicas. Todavia, as indolizinas ainda são pouco exploradas se comparadas a outros núcleos heterocíclicos, principalmente no que diz respeito a sua funcionalização por emprego de reagentes organometálicos. Desta forma, o objeto deste trabalho foi o estudo da reatividade de diversas indolizinas perante diferentes organometálicos, por meio de reações de metalação dirigida, troca iodo-magnésio e acoplamento cruzado de Negishi com o intuito de construir indolizinas polifuncionalizadas. Assim sendo, inicialmente foi estudada a reatividade de bases organometálicas diante de algumas indolizinas e as reações de seus intermediários organometálicos com uma variedade de eletrófilos. Para tanto, as indolizinas foram divididas por posicionamento das funcionalizações, ou seja, indolizinas funcionalizadas na posição 1 do anel (-CO2Et, -CO2tBu e CN), indolizinas funcionalizadas na posição 2 do anel (-CO2Et, CN) e indolizinas funcionalizadas nas posições 1 e 3 do anel. Na sequência, foram estudadas as reações de troca iodo-magnésio diante das indolizinas funcionalizadas nas posições 1 e 3 e, por último, as reações de metalação dirigida com os substratos 2-arilindolizínicos seguidas por reações de acoplamento cruzado de Negishi. As moléculas sintetizadas nesta última etapa, por terem apresentado fortes propriedades fluorescentes, foram submetidas a um estudo minucioso sobre essas características. Essas estratégias sintéticas desenvolvidas no presente trabalho foram altamente eficientes, permitindo o preparo de uma série de compostos com grande diversidade estrutural, sendo sintetizadas 64 indolizinas polifuncionalizadas inéditas e 11 indolizinas polifuncionalizadas já descritas na literatura por meio de outras metodologias, com rendimentos variando de 15% a 87%. / In recent years, there has been a considerable increase in studies involving the indolizinic core, one of thousands of existing heterocycles, with 2012 being the most outstanding year, with 102 publications. This growing interest is mainly attributed to the search for new functionalized substrates that have medicinal and biological characteristics. However, indolizines are unexplored when compared to other heterocycles, particularly regarding their functionalization with the use of organometallic reagents. Thus, the object of this work was the reactivity study of several indolizines with different organometallics by means of directed metalation reactions, iodine-magnesium exchange and Negishi cross-coupling, in order to build functionalized poly-indolizines. Therefore, initially, it was investigated the reactivity of organometallic bases upon some indolizines and the reactions of their organometallic intermediates with a variety of electrophiles. To achieve this, indolizines were divided according to their function position, i.e. indolizines functionalized at position 1 of the ring (-CO2Et, CN and -CO2tBu), indolizines functionalized at position 2 of the ring (-CO2Et, CN) and functionalized at positions 1 and 3 of the ring. Furthermore, the iodine-magnesium exchange reactions of indolizines functionalized at positions 1 and 3 were studied and, finally, directed metalation reactions with 2-aryl indolizinic substrates followed by Negishi cross-coupling reactions were performed. The ultimate products of such reactions showed strong fluorescent properties and, for this reason, were subject of detailed studies on these characteristics. The synthetic strategies developed in this research were highly efficient, enabling the preparation of a large number of compounds with structural diversity, having been synthesized 64 novel poly-functionalized indolizines and 11 known poly-functionalized indolizines, with yields ranging from 15% to 87%.

O núcleo quinolínico constitui uma das classes de heterociclos nitrogenados de maior destaque, pois são amplamente encontradas em produtos naturais, além de comporem a lista dos considerados esqueletos \"privilegiados\", relacionados com as diversas classes terapêuticas como: anticâncer, anticolinesterásicos, antimaláricos, etc. Diante das abordagens sintéticas de funcionalização de anéis heteroaromáticos, o uso de espécies organometálicas ocupa, hoje, uma posição central na química orgânica sintética, principalmente na formação de novas ligações carbono-carbono. Dessa forma, o presente trabalho explorou essencialmente a reatividade de quinolinas frente à reagentes organometálicos tais como alquil-lítio, amidetos de lítio, turbo-Grignard e amidetos mistos de magnésio e lítio. Inicialmente, foi estudada a funcionalização da 4,7- dicloroquinolina através da reação de metalação dirigida frente aos diferentes reagentes disponíveis. Em seguida, foi desenvolvida uma metodologia de troca iodo-magnésio para a 7-cloro-4-iodoquinolina visando a obtenção de derivados funcionalizados na posição C4 bastante estratégica para atividade antimalárica. Neste estudo foi utilizado o reagente turbo-Grignard para etapa de troca, seguida da reação com eletrófilos. Os compostos obtidos tiveram sua atividade antimalárica avaliada pelo grupo do Dr. Adrian M. Pohlit do Instituto Nacional de Pesquisas da Amazônia (INPA). A metodologia de troca iodomagnésio do turbo-Grignard frente à 7-cloro-4-iodoquinolina também foi aplicada para a obtenção de outros derivados por reações de acoplamento cruzado de Negishi, e na rota sintética de um híbrido molecular planejado com potencial atividade antimalárica. Além disso, foi estudada a reação de troca halogênio-metal da 3-bromoquinolina frente a reagentes de lítio seguida da reação com aldeídos. Por fim, algumas das estruturas sintetizadas também tiveram avaliação da atividade anticâncer realizada pelo grupo da Prof. Dra. Letícia Lotufo da Universidade Federal do Ceará. Portanto, foram demonstradas neste trabalho estratégias simples e eficientes utilizando reagentes organometálicos para funcionalização de quinolinas de interesse sintético e medicinal. / The quinoline unit is one of most important nitrogen heterocycle classes since it is found in a large number of natural products. Moreover, it is considered a privileged scaffold presenting a variety of pharmacologic activities such as: anti-cancer, anticholinesterase, antimalarial and others. Among the available aromatic heterocycle functionalization approaches, the organometallic chemistry have a prominent position mainly on the construction of new carbon-carbon bonds. In this context, this work have explored the quinoline reactivity against organometallic reagents like alkyl-lithium, lithium amides, turbo-Grignard and magnesium lithium amides. Initially, the functionalization of 4,7- dichloroquinoline was studied through the direct metalation reaction of the substrate with several available organometallic reagents. Afterwards, a new iodo-magnesium exchange methodology for the 7-chloro-4-iodoquinoline was developed in order to obtain C-4 functionalized quinoline derivatives. The turbo-Grignard was the reagent of choice in iodo-magnesium exchange reactions that were subsequently reacted with different electrophiles. The antimalarial activity of the compounds obtained in this study was evaluated by Dr. Adrian M. Pohlit group of National Institute of Amazon Research (INPA). The developed iodo-magnesium exchange methodology was further applied in Negishi cross-coupling reactions and on a synthetic study of a planned molecular hybrid with potential antimalarial activity. In addition, the halogen-metal exchange reaction on 3-bromoquinoline was studied using alkyl-lithium reagents with subsequent reaction with aldehydes. Finally, the anti-cancer activity of some of structures obtained in this work was evaluated by Prof. Dra Letícia Lotufo group of Federal University of Ceará

Stereochemistry is important aspect of chemistry that customarily includes the study of the relative spatial arrangement of atoms within molecules (static stereochemistry), and the study of the stereochemical requirements and outcomes of chemical reactions (dynamic stereochemistry). These two branches complement each other in modern stereochemistry. Chiral organometallics feature prominently in organic synthesis as reactive intermediates. The possibility of exploring their stereochemistry in synthesis is associated with the configurational stability of the metal-bearing stereogenic center. We were interested in the configurational stability of lithiated and magnesiated nitriles. We developed a new series of lithio-cyclopropylnitriles bearing chelating groups for intramolecular coordination, as a possible strategy to impart configurational stability. Although this strategy has not yet been successful, using density functional theory (DFT) method, we addressed the effect of chelating groups on racemization via the "conducted tour" mechanism. We then explored metal-bromine exchange on enantiopure bromonitrile as alternative route to metalated nitriles. In this way, we demonstrated that magnesiated 2,2-diphenyl cyclopropylnitrile is configurationally stable on the macroscopic timescale. No other metallated nitrile has ever demonstrated configurational stability on this timescale. In contrast, bromine-lithium exchange of 1-bromo-2,2-diphenyl-cyclopropylnitrile demonstrated fast racemization under the same conditions. Another major project focused on conformational control of acyclic molecules. Using X-ray crystallography and NMR spectroscopy, we found that the 2,6-disubstituted aryl group eclipses its geminal hydrogen, and induces an antiperiplanar relationship of the geminal and vicinal hydrogens. Interestingly, anti-nitrile aldols or syn-ketone aldols bearing 2,6-disubstituted aryl groups demonstrate unanticipated remote effects on acyclic conformation: the 2,6-disubstituted aryl group prefers to be in a gauche position to the largest vicinal group. The minimization of allylic 1,3-strain and syn-pentane-like interaction works together in establishing this conformational preference. / Ph. D.

Carbenoides são intermediários altamente reativos que desempenham um papel fundamental em estratégias sintéticas modernas. Essas espécies são muito semelhantes aos carbenos no estado singleto, visto que possuem um caráter ambifílico e reagem por um mecanismo concertado, levando a produtos estereoespecíficos. Estudos preliminares demonstraram a versatilidade de um carbenoide misto de magnésio e lítio (ClCH2 MgCl·LiCl) na reação com diversos aldeídos aromáticos, alifáticos e heterocíclicos. Desta maneira, o objetivo deste trabalho foi estudar a quimiosseletividade de tal reagente e investigar a aplicação deste na síntese diasterosseletiva do (2S,3S)-N-Boc-3amino-1,2-epóxi-4-fenilbutano e seu diastereoisômero de configuração (2R,3S). Para a primeira parte do trabalho, selecionamos alguns aldeídos contendo grupos funcionais, tais como, ésteres, nitrilas, cetonas, amida, entre outros. De maneira geral, o carbenoide de magnésio mostrou-se muito eficiente e quimiosseletivo, levando a 14 cloridrinas funcionalizadas em bons rendimentos isolados, contudo, quando grupos doadores de elétrons estavam presentes na posição 4 do anel, o aldeído apresentou uma diminuição de reatividade e impossibilitou a obtenção do produto desejado. Por fim, estudos preliminares visando à preparação dos epóxidos de configuração (2S,3S) e (2R,3S) foram também realizados e os resultados são discutidos de forma detalhada no texto. / Carbenoids are a class of highly reactive intermediate compounds that play a key role in modern synthetic strategies. These species show a state very similar to that of singlet state carbenes since they have an ambiphilic character and react by a concerted mechanism, something that allows them to afford stereospecific products. Previous studies demonstrated the versatility of a mixed magnesium and lithium carbenoid (ClCH 2 MgCl·LiCl) in the reaction with a number of aromatic, aliphatic and heterocyclic aldehydes. In this way, the objective of this work was to study the chemoselectivity of such reagent and investigate its application in the diastereoselective synthesis of (2S,3S)-N-Boc-3-amino-1,2-epoxy-4-phenylbutane and its diastereoisomer of configuration (2R,3S). For the first part of the work we selected some aldehyde containing functional groups such as esters, nitriles, ketones and amide, among others. In summary, the magnesium carbenoid proved to be very efficient and chemoselective, leading to 14 functionalized chlorohydrins in good isolated yields. Nevertheless, when electron donating groups were present at the position 4 of the substrates ring, the resulting aldehyde showed a decrease in reactivity, which precluded us to obtain the desired product. Finally, preliminary studies aiming the preparation of the epoxides of configuration (2S,3S) and (2R,3S) were also investigated and the results are discussed in detail in the text.

Carbenoides são intermediários altamente reativos que desempenham um papel fundamental em estratégias sintéticas modernas. Essas espécies são muito semelhantes aos carbenos no estado singleto, visto que possuem um caráter ambifílico e reagem por um mecanismo concertado, levando a produtos estereoespecíficos. Estudos preliminares demonstraram a versatilidade de um carbenoide misto de magnésio e lítio (ClCH2 MgCl·LiCl) na reação com diversos aldeídos aromáticos, alifáticos e heterocíclicos. Desta maneira, o objetivo deste trabalho foi estudar a quimiosseletividade de tal reagente e investigar a aplicação deste na síntese diasterosseletiva do (2S,3S)-N-Boc-3amino-1,2-epóxi-4-fenilbutano e seu diastereoisômero de configuração (2R,3S). Para a primeira parte do trabalho, selecionamos alguns aldeídos contendo grupos funcionais, tais como, ésteres, nitrilas, cetonas, amida, entre outros. De maneira geral, o carbenoide de magnésio mostrou-se muito eficiente e quimiosseletivo, levando a 14 cloridrinas funcionalizadas em bons rendimentos isolados, contudo, quando grupos doadores de elétrons estavam presentes na posição 4 do anel, o aldeído apresentou uma diminuição de reatividade e impossibilitou a obtenção do produto desejado. Por fim, estudos preliminares visando à preparação dos epóxidos de configuração (2S,3S) e (2R,3S) foram também realizados e os resultados são discutidos de forma detalhada no texto. / Carbenoids are a class of highly reactive intermediate compounds that play a key role in modern synthetic strategies. These species show a state very similar to that of singlet state carbenes since they have an ambiphilic character and react by a concerted mechanism, something that allows them to afford stereospecific products. Previous studies demonstrated the versatility of a mixed magnesium and lithium carbenoid (ClCH 2 MgCl·LiCl) in the reaction with a number of aromatic, aliphatic and heterocyclic aldehydes. In this way, the objective of this work was to study the chemoselectivity of such reagent and investigate its application in the diastereoselective synthesis of (2S,3S)-N-Boc-3-amino-1,2-epoxy-4-phenylbutane and its diastereoisomer of configuration (2R,3S). For the first part of the work we selected some aldehyde containing functional groups such as esters, nitriles, ketones and amide, among others. In summary, the magnesium carbenoid proved to be very efficient and chemoselective, leading to 14 functionalized chlorohydrins in good isolated yields. Nevertheless, when electron donating groups were present at the position 4 of the substrates ring, the resulting aldehyde showed a decrease in reactivity, which precluded us to obtain the desired product. Finally, preliminary studies aiming the preparation of the epoxides of configuration (2S,3S) and (2R,3S) were also investigated and the results are discussed in detail in the text.