CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Neste trabalho foram realizadas reaÃÃes de C-alquilaÃÃo via CatÃlise de TransferÃncia de Fase (CTF) com a finalidade de obter os precursores de aminoÃcidos para uma posterior resoluÃÃo cinÃtica enzimÃtica. As reaÃÃes de C-alquilaÃÃo ocorreram a 70 ÂC, vÃrios agentes transferidores de fase foram testados, e o mais promissor foi o cloreto de benziltributilamÃnio (CBTBA). As reaÃÃes se processaram com o uso de 3 mmol do cianoacetoamido acetato de etila, 3 mmol de carbonato de potÃssio, 6 mmol do agente alquilante, cloreto de benzila. ApÃs purificaÃÃo do produto, realizou-se uma reaÃÃo de hidrÃlise total com posterior proteÃÃo dos grupos amino e carboxila resultando em trÃs diferentes compostos rac-33, rac-34 e rac-35. A resoluÃÃo cinÃtica enzimÃtica do rac-33 por reaÃÃo de interesterificaÃÃo usando o butirato de butila (PrCO2Bu) foi inicialmente testada com diversas lipases (Candida antarctica Lipase B e sua isoenzima Candida antarctica Lipase A, ACYLASE I obtida de Aspergillus melleus, PSL-C I, Lipase a partir da Candida rugosa e a LIPOZYME RM IM) variando tempo, temperatura e solvente. A LIPOZYME RM IM foi a Ãnica enzima capaz de promover a reaÃÃo de interesterificaÃÃo e com altos valores de enantiosseletividade (E). As melhores reaÃÃes ocorreram à temperatura de 55 ÂC. A resoluÃÃo do rac-33 a 55 ÂC ocorreu em oito horas e quinze minutos, em sistema sem solvente, com uma conversÃo de 50%, ees >99%, eeP>99% com um alto valor de enantiosseletividade, E>200 (10633), Esquema 3. A resoluÃÃo cinÃtica do 2-acetilamino-3-fenil-propanoato de alila (rac-35) ocorreu em quatro horas e trinta minutos, sem solvente à temperatura de 55 ÂC, resultando em 49% de conversÃo, eeS98%, eeP>99% e E>200 (9278). / In this work reactions of C-alkylation were carried out via Phase Transfer Catalysis (PTC) in order to obtain precursors of amino acids and them to perform enzymatic kinetic resolution. The reactions of C-alkylation occurred at 70 ÂC, several phase transfer agents were tested, and the most promising was the benzyltributylammonium chloride (CBTBA). The reaction were performed using 3 mmol of ethyl cianoacetoamidoacetate, 3 mmol of potassium carbonate, 6 mmol of alkylating agent, benzylchloride. After purification of the product, a reaction of total hydrolysis was carried out with subsequent protection of amino and carboxyl groups resulting in three different compounds rac-33 rac-34 and rac-35. The enzymatic kinetic resolution of rac-33 via interesterification with butyl butyrate (PrCO2Bu) was initially tested with different lipases (Candida antarctica Lipase B and itâs isoenzyme, Lipase Candida antarctica Lipase A, ACYLASE I obtained from Aspergillus melleus, PSL-C I, Lipase from Candida rugosa and Lipozyme RM IM) varying time, temperature and solvent. The Lipozyme RM IM was the only enzyme capable of promoting the reaction of interesterification and with high values of enantioselectivity (E). The best reactions occurred at 55 ÂC. The resolution of rac-33 at 55  C occurred in eight hours and fifteen minutes in system solvent free, with conversion of 50%, eeS>99%, eeP>99% with a high value of enantioselectivity, E > 200 (10633), Scheme 3. The kinetic resolution of allyl 2-acetylamino-3-phenyl-propanoate (rac-35) occurred in four hours and thirty minutes, without any solvent at 55  C, resulting in 49% of conversion, eeS>98%, eeP>99% and E > 200 (9278).

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Neste trabalho descrevemos a sÃntese quimioenzimÃtica do Mesilato de Rasagilina (AzilectÂ), um fÃrmaco utilizado na monoterapia de pacientes com Parkinson no estÃgio inicial. Um dos objetivos deste trabalho foi realizar a introduÃÃo da quiralidade via processos de biocatÃlise. Foram estudadas duas estratÃgias: i) biorreduÃÃo da indanona na presenÃa de uma sÃrie de leveduras e ii) resoluÃÃo cinÃtica do rac-indanol utilizando lipases, em solvente orgÃnico. Na estratÃgia (i) realizamos uma triagem com seis leveduras. Em todos os testes realizados o (S)-indanol foi obtido com baixas conversÃes (9,4-13,2%) e excessos enantiomÃricos de atà 97,6%. Devido aos baixos valores de conversÃo, decidimos aplicar a estratÃgia (ii). ApÃs uma triagem com nove lipases comerciais foi possÃvel verificar que a Amano lipase AK a partir da Pseudomonas fluorescens e a Lipase a partir da Thermomyces lanuginosus imobilizada em immobead-150 foram as mais eficientes na resoluÃÃo cinÃtica do rac-acetato de indanila, em meio aquoso, com razÃo enantiomÃrica de 111,0 e 167,0, respectivamente. Com isso, tais lipases foram selecionadas para a resoluÃÃo cinÃtica do rac-indanol em meio orgÃnico. Os melhores resultados de seletividade e atividade enzimÃtica foram obtidos utilizando hexano como solvente orgÃnico, tempo reacional de 15 minutos e temperatura de 30ÂC para a Amano lipase AK (enzima livre) e 35ÂC para a Thermomyces lanuginosus, com razÃo enantiomÃrica>200 para ambos os casos. Foram realizadas imobilizaÃÃes da Amano AK (enzima livre) em vÃrios suportes e os melhores resultados de seletividade e atividade foram obtidos em hexano como solvente orgÃnico, tempo reacional de 6 horas e temperatura de 30ÂC empregando a Amano lipase AK imobilizada em quitosana 2,5% de baixo peso molecular; alginato de sÃdio 2,5% e a Amano lipase AK imobilizada em quitosana 5,0% de baixo peso molecular. Foi realizado o estudo de reuso das lipases imobilizadas, sendo a Thermomyces lanuginosus imobilizada em immobead-150, a mais eficiente comparada Ãs demais, uma vez que proporcionou excelentes resultados em maiores ciclos reacionais. Posteriormente, empregando uma reaÃÃo de Mitsunobu, o (S)-indanol foi convertido no (R)-azidoindano com rendimento de 70%. Em seguida, o (R)-azidoindano foi submetido a uma reaÃÃo de Staudinger, produzindo a (R)-indanamina com 60% de rendimento. / Here we describe the synthesis of the chemoenzymatic Rasagilina mesylate (AzilectÂ), a drug used in monotherapy in patients with early stage Parkinson. One of the goals of this project was to carry out the introduction of chirality via biocatalysis processes. We studied two strategies: i) bioreduction of indanone in the presence of a series of yeast and ii) kinetic resolution of rac-indanol using lipases in organic solvent. In strategy (i) was conducted a screening with six yeasts. In all tests the (S)-indanol was obtained in low conversions (9.4 to 13.2%) and enantiomeric excesses of up to 97.6%. Due to low conversion rates, we decided to implement the strategy (ii). After screening of nine commercial lipases, was possible to verify that the Amano lipase AK from Pseudomonas fluorescens and Lipase from Thermomyces lanuginosus immobilized on immobead-150 were the most efficient in the kinetic resolution of rac- indanila acetate in aqueous medium with enantiomeric ratio equals 111.0 and 167.0 respectively. Thus, such lipases were selected for the kinetic resolution of rac-indanol in organic media. The best results of enzyme activity and selectivity were obtained using hexane as a solvent, reaction time of 15 minutes and 30ÂC for Amano lipase AK (free enzyme) and 35ÂC for Thermomyces lanuginosus, with enantiomeric ratio equals 200 for both cases. Were held assets of Amano AK (free enzyme) in various media and the best results were obtained selectivity and activity in hexane as organic solvent, reaction time of 6 hours and 30  C using Amano Lipase AK immobilized chitosan in 2.5% low molecular weight; sodium alginate 2.5% and Amano AK lipase immobilized on chitosan 5.0% low molecular weight. The study was conducted reuse of immobilized lipase, Thermomyces lanuginosus being immobilized on immobead-150, the more efficiently compared to the others, since it has provided excellent results in higher reaction cycles. Subsequently, using a Mitsunobu reaction, (S)-indanol was converted to (R)-azidoindano with 70% yield. Then, the (R)-azidoindano was subjected to Staudinger reaction, producing (R)-indanamine in 60% yield.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / The present work is divided into three chapters, in which we report the use of lipases to obtain precursors of α-amino acid, derivatives thiamphenicol and chemoenzymatic synthesis of (S)-dapoxetine. The first chapter refers to the use of the lipase from Rhyzomucor miehei, which by means of kinetic resolution of N-acetyl-α-amino esters was possible to obtain derivatives with high values of enantiomeric excesses. The second section aims at obtaining derivatives of thiamphenicol applying the lipase from Candida rugosa for the reaction of hydrolysis of the diacetate thiamphenicol, and Candida antarctica lipase B by acylation process. Finally, the third section reports the chemoenzymatic synthesis of (S)-dapoxetine in the enantiopure form by kinetic resolution process via transesterification reactions of 3-chloro-1-phenylpropan-1-ol, using lipase from Candida rugosa. / O presente trabalho encontra-se dividido em trÃs capÃtulos, na qual relatamos a utilizaÃÃo de lipases para obtenÃÃo de precursores de α-aminoÃcidos, derivados de tianfenicol e a sÃntese quimioenzimÃtica da (S)-dapoxetina. O primeiro capÃtulo refere-se à utilizaÃÃo da lipase a partir de Rhyzomucor miehei, que por meio de uma resoluÃÃo cinÃtica de N-acetil-α-aminoÃsteres foi possÃvel obter derivados com elevados valores de excessos enantiomÃricos. O segundo capÃtulo visa a obtenÃÃo de derivados do tianfenicol aplicando a lipase a partir da Candida rugosa para a reaÃÃo de hidrÃlise do diacetato de tianfenicol, e a lipase B obtida a partir de Candida antarctica por processo de acilaÃÃo. Por fim, o terceiro capÃtulo relata a sÃntese quimioenzimÃtica da (S)-dapoxetina de forma enantiopura por processo de resoluÃÃo cinÃtica via reaÃÃes de transesterificaÃÃo do 3-cloro-1-fenilpropan-1-ol, usando a lipase obtida a partir da Candida rugosa.

The present work refers to the development of a biocatalytic process of the synthesis of the (S)-Pindolol, a drug used as a beta-blocker in the treatment of hypertension and cardiac arrhythmia. Moreover, this drug is an antagonist of the auto receptor 5-HT1AÂÂ, that favours the combination between medications of the selective serotonin reuptake inhibitors group (SSRIÂs), which can accelerate or increase the therapeutic efficacy of the antidepressants. The initial strategy in the process development includes, as the first step, the enzymatic kinetic resolution of a mixture of the rac - acetato de 1 - (clorometil)-2-(1H-indol-4-iloxi)etila, in the presence of the Pseudomonas fluorescens lÃpase, for obtainment of c = 50%; ee = 94% and E = 115, after 24h. The second step involved the purification and enzymatic hydrolysis of the enatiomerically pure compound acetato de (R)-acetato de 1-(clorometil)-2-(1H-indol-4-iloxi)etila, which served as substrate for the Candida rugosa lipase for production of the enantiomerically pure alcohol (R)-1-cloro-3-(1H-indol-4-iloxi)-2-propanol. From the perspective of the Green Chemistry precepts and sustainability, it was investigated the enzymatic immobilization by covalent bond formation of the enzymatic biocatalysts of the C. rugosa and P. fluorescens lipases. The utilization of the solid supports to enzyme immobilization has many advantages, such as the recovery of the biocatalyst from the reaction medium to be reutilized, limitation of the conformational variations, stability to variation of the reaction medium as the pH variation and temperature variation. The support studied in this work was the functionalized nanosilica by ATPES and glutaraldehyde. The results of the kinetic resolution of the rac - acetato de 1 - (clorometil)-2-(1H-indol-4-iloxi)etila by immobilized enzymes of the P. fluorescens were c = 47%; ee = 97% and E = 150; 12h in 10 cicles of reuse with 97% of ee. While the asymmetric hydrolysis of the (R)-acetato de 1-(clorometil)-2-(1H-indol-4-iloxi) de etila resulted in total substrate consumption for the interval of 12h of reaction and 10 cicles of the reuse. The enantiomerically pure compound (R)-1-cloro-3-(1H-indol-4-iloxi)-2-propanol was purified and submited to the reaction in the presence of the ethanol and excesso f isopropilamine. A white solid, caracterized as (S)-Pindolol, was obtained with 66% of yield. / O presente trabalho refere-se ao desenvolvimento de um processo biocatalÃtico para a sÃntese do (S)-Pindolol, um fÃrmaco utilizado como betabloqueador no tratamento da hipertensÃo e arritmia cardÃaca. AlÃm disso, o referido fÃrmaco à um antagonista do autorreceptor 5-HT1A, o que favorece a combinaÃÃo com fÃrmacos do grupo de inibidores seletivos da recaptaÃÃo da serotonina (ISRS), podendo acelerar ou aumentar a eficÃcia terapÃutica dos antidepressivos. A estratÃgia no desenvolvimento do processo incluiu como etapa chave a resoluÃÃo cinÃtica enzimÃtica do rac-acetato de 1-(clorometil)-2-(1H-indol-4-iloxi)etila, na presenÃa de lipases de Pseudomonas fluorescens, com a obtenÃÃo do acetato de (1R)-(clorometil)-2-(1H-indol-4-iloxi) de etila com conversÃo (c) de 50%; excesso enantiomÃrico (ee) de 94% e enantiosseletividade (E) de 150, apÃs 24h. A segunda etapa chave envolveu a hidrÃlise enzimÃtica do acetato de (1R)-(clorometil)-2-(1H-indol-4-iloxi)etila, na presenÃa da lipase de Candida rugosa para produÃÃo do (R)-1-cloro-3-(1H-indol-4-iloxi)-2-propanol. Sob a perspectiva dos preceitos da QuÃmica Verde e da Sustentabilidade, foi investigada a imobilizaÃÃo enzimÃtica, por formaÃÃo de ligaÃÃo covalente, das lipases de C. rugosa e P. fluorescens em nanossÃlica. A utilizaÃÃo de suportes sÃlidos para imobilizaÃÃo de enzimas possui vantagens, tais como recuperaÃÃo do biocatalisador a partir do meio reacional para serem reutilizadas, limitaÃÃo das variaÃÃes de conformaÃÃo da enzima, estabilidade para variaÃÃes do meio reacional como pH e temperatura. O suporte estudado neste trabalho foi a nanossÃlica funcionalizada com aminopropiltrietoxissilano (ATPES) e glutaraldeÃdo. A resoluÃÃo cinÃtica do rac-acetato de 1-(clorometil)-2-(1H-indol-4-iloxi)etila com lipase de P. fluorensces imobilizada em nanossÃlica modificada levou ao acetato de (1R)-(clorometil)-2-(1H-indol-4-iloxi)etila com c = 47%; ee = 97% e E = 150, em 12h de reaÃÃo. O estudo do reuso da lipase de P. fluorensces imobilizada em nanossÃlica modificada permitiu verificar que o referido biocatalisador manteve a atividade e enantiosseletividade inalteradas em atà 10 ciclos reacionais. Cabe ressaltar que a hidrÃlise do (R)-acetato de 1-(clorometil)-2-(1H-indol-4-iloxi)etila na presenÃa de C. rugosa imobilizada em nanossÃlica modificada resultou no correspondente (2R)-1-cloro-3-(1H-indol-4-iloxi)-2-propanol em rendimento quantitativo em 12h de reaÃÃo, mantendo inalterada a atividade enzimÃtica em atà 10 ciclos de reuso. A reaÃÃo entre o (R)-1-cloro-3-(1H-indol-4-iloxi)-2-propanol e isopropilamina, em excesso, na presenÃa de etanol levou a obtenÃÃo de um sÃlido branco, caracterizado como (S)-Pindolol, com rendimento de 66%.

Neste trabalho, avaliou-se o potencial do uso de oxidantes quirais em oxidações enantiosseletivas de compostos orgânicos de boro. É de conhecimento geral que compostos orgânicos de boro, especialmente ésteres e ácidos borônicos são facilmente oxidados por hidroperóxidos em meio básico. No entanto, são escassos na literatura exemplos destas reações de modo enantiosseletivo. A fim de realizar as reações mencionadas, sintetizou-se os hidroperóxidos quirais TADOOH ({(4R,5R)-5-[(hidroperoxidifenil)metil]-2,2-dimetil-1,3-dioxolan-4il}difenilmetanol) e o hidroperóxido quiral derivado de carboidrato, 2,3-dideoxi1-O-oxidanil-4,6-di-O-pivaloil-α-D-eritro-hex-2-enopiranose (di-O-PivOOH). Estes compostos apresentaram resultados interessantes na literatura em oxidações enantiosseletiva de sulfetos orgânicos, em epoxidações de alcenos e em oxidações de Baeyer-Villiger. Inicialmente o potencial oxidativo de ambos hidroperóxidos, bem como a seletividade destes, foi avaliado frente a diversos ésteres borônicos, sendo que somente o TADOOH apresentou resultados promissores. (Ver esquema no PDF) Observou-se uma melhor seletividade do TADOOH frente a ésteres borônicos que possuíam grupos carbonílicos em sua estrutura. Ao submeter o β-boronil-éster, 3-fenil-3-(4,4,5,5-tetrametil-1,3,2-dioxaborolan-2-il)propanoato de etila, à oxidação com o TADOOH em THF utilizando NaOH como base, a -30°C por 1 hora, obteve-se o respectivo álcool com 40% de e.e. Cálculos de DFT para o estado de transição na oxidação dos ésteres borônicos com o TADOOH foram realizados em colaboração com o grupo do Prof. Dr. Ataualpa Albert Carmo Braga. Estes cálculos demonstraram que o estado de transição é estabilizado por uma ligação de hidrogênio não clássica entre o oxigênio da carbonila e umas das ligações C-H dos grupos fenila do TADOOH. Além dos estudos relatados, a reconhecida metodologia de Sharpless na epoxidação assimétrica de alcoóis alílicos foi adaptada para a oxidação enantiosseletiva de ésteres borônicos. Ao trocar o ligante derivado de éster tártarico, normalmente utilizado nas epoxidações de Sharpless, por (-)-efedrina observou-se uma moderada seletividade deste sistema frente ao pinacol l-fenietilboronato. Investigações mais detalhadas demonstraram que a presença do Ti(IV) não era necessária, sendo que a (-)efedrina era a responsável pela ativação e indução quiral nesta reação. / In this work, it was investigated the potential use of chiral oxidants in organic boron compound oxidation. It is known in the literature, that organic boron compounds can be easily oxidized by hydroperoxides. However, an enantioselective approach in literature is scarce. In order to perform these reactions, hydroperoxide TADOOH ({(4R,5R)-5[(hydroperoxydiphenyl)methyl]-2,2-dimethyl-l,3-dioxolan-4-yl}diphenylmethanol) and carbohydrate derived hydroperoxide, 2,3-dideoxy-1-O-oxidanyl-4,6-di-O-pivaloyl-α-D-erythro-hex-2-enopyranose (di-O-PivOOH), have been synthesized. These compounds showed interesting results in several enantioselective oxidations, as like, organic sulfides oxidation, alkenes epoxidation and Baeyer-Villiger oxidations. The oxidative potential of both hydroperoxides, as well as their selectivity, were evaluated against several boronic esters. Only TADOOH has shown promissing results for further studies. (See Scheme on PDF). Boronic esters containing a carbonyl moiety showed better selectivities with TADOOH, for example, the reaction of β-boronyl-ester, ethyl 3-phenyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)propanoate, gave the correponding alcohol with 40% e.e. DFT calculations for the transition state in the oxidation of the boronic esters with TADOOH were carried out in collaboration with the group of Prof. Dr. Ataualpa Albert Carmo Braga. These calculations have shown that the transition state is stabilized by a non-classical hydrogen bond between the carbonyl oxygen and one of the C-H bonds of the TADOOH phenyl groups. In addition to the studies, the well-known Sharpless protocol for asymmetric epoxidation of allylic alcohols was adapted in the enantioselective oxidation of boronic esters. By replacing the tartaric ester-derived, commonly used in the Sharpless experiments, for (-)-ephedrine moderate selectivity was observed with pinacol 1-phenylethyl boronate. Further investigations showed that the presence of Ti (IV) was not necessary, and (-)-ephedrine was responsible for the activation and chiral induction in this reaction.

This thesis describes, in detail, the synthesis of novel heterobidentate ligands. These ligands were subsequently used in palladium catalysed allylic substitution reactions to synthesise enantiomerically enriched alkylated products. The thesis also describes novel approaches to asymmetric catalysis, in particular asymmetric epoxidation derived from Katsuki-Sharpless methodology. Chapter 1 - This chapter reviews the literature, discussing the significant synthetic advancements in asymmetric catalysis in the past 10-15 years. Chapter 2 - This chapter describes in detail the synthesis of new heterobidentate ligands containing nitrogen and phosphorus ligating atoms. These ligands are based on imines containing enantiomerically pure asymmetric centres in an alpha position to the nitrogen moiety. Other ligands that were synthesised were derived from C2- symmetric diamines, also containing an asymmetric centre alpha position to the nitrogen, that produce ligands with the nitrogen functionality contained in a ring. Chapter 3 - This chapter describes the use of the novel ligands synthesised in Chapter 2 in palladium catalysed allylic substitution reactions. The racemic substrate, 1 ,3-diphenyl-3-acetoxy-1-propene, was alkylated to produce an enantiomeric enriched alkylated product. The alkylated product was obtained with up to 77 % enantiomeric excess. The reaction was conducted with a palladium catalyst in the presence of a novel ligand using dimethyl malonate as a nucleophile. The development and optimisation of these ligands within this reaction is discussed. Chapter 4 - This chapter discusses some novel approaches to asymmetric epoxidation. The epoxidation is based on methodology developed by Katsuki and Sharpless. This epoxidation relies on the substrate containing an up-unsaturated alcohol. The chapter discusses the use of a reversible nucleophile in the form of cyanide. The nucleophile is designed to react with a substrate to provide an upunsaturated cyanohydrin, suitable to undergo a Katsuki-Sharpless epoxidation. Once the asymmetric epoxidation is complete, the nucleophile would be removed. This chapter describes the attempts to develop the principle further. An improvement to the system would be to provide an environment capable of sustaining a dynamic kinetic resolution. Chapter 5 - This chapter contains the experimental which provides the exact details of the reactions reported in the thesis.

Part 1: Transition-metal-catalyzed direct transformations of aromatic C-H bonds are emerging as valuable tools in organic synthesis. These reactions are attractive because of they allow for inherently efficient construction of organic building blocks by minimizing the pre-activation of substrates. Of these processes, direct arylation has recently received much attention due to the importance of the biaryl core in medicinal and materials chemistry. Also, alkyne hydroarylation has garnered interest because it allows for the atom-economical synthesis of functionalized alkenes directly from simple arenes and alkynes. Described in this thesis are number of advancements in these areas. First, palladium catalyzed direct arylation of azine N-oxides using synthetically important aryl triflates is described. Interesting reactivity of aryl triflates compared to aryl bromides was uncovered and exploited in the synthesis of a compound that exhibits antimalarial and antimicrobial activity. Also reported is the efficient, direct arylation enabled (formal) synthesis of six thiophene based organic electronic materials in high yields using simple starting materials. Additionally, the site-selective direct arylation of both sp2 and sp3 sites on azine N-oxide substrates is described. The arylation reactions are carried out in either a divergent manner or a sequential manner and is applied to the synthesis of the natural products, Papaverine and Crykonisine. Mechanistic investigations point towards the intimate involvement of the base in the mechanism of these reactions. Next, the rhodium(III)-catalyzed hydroarylation of internal alkynes is described. Good yields are obtained for a variety of alkynes and arenes with excellent regioselectivity for unsymmetrically substituted alkynes. Mechanistic investigations suggest that this reaction proceeds through arene metalation with the cationic rhodium catalyst, which enables challenging intermolecular reactivity. Part 2: Access to single enantiomer compounds is a fundamental goal in organic chemistry and despite remarkable advances in enantioselective synthesis, their preparation remains a challenge. Kinetic resolution of racemic products is an important method to access enantioenriched compounds, especially when alternative methods are scarce. Described in this thesis is the resolution of tertiary and secondary alcohols, which arise from ketone and aldehyde aldol additions. The method is technically simple, easily scalable, and provides tertiary and secondary alcohols in high enantiomeric ratios. A rationale for the unique reactivity/selectivity associated with (1S,2R)-N-methylephedrine in the resolution is proposed. Organocatalysis is a rapidly developing, powerful field for the construction of enantioenriched organic molecules. Described here is a complimentary class of organocatalysis using simple aldehydes as temporary tethers to perform challenging formally intermolecular reactions at room temperature. This strategy allows for the enantioselective, intermolecular cope-type hydroamination of allylic amines with hydroxyl amines. Also, interesting catalytic reactivity for dichloromethane is revealed.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第19513号 / 理博第4173号 / 新制||理||1599(附属図書館) / 32549 / 京都大学大学院理学研究科化学専攻 / (主査)教授 丸岡 啓二, 教授 大須賀 篤弘, 教授 依光 英樹 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第21779号 / 工博第4596号 / 新制||工||1716(附属図書館) / 京都大学大学院工学研究科材料化学専攻 / (主査)教授 松原 誠二郎, 教授 中尾 佳亮, 教授 杉野目 道紀 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

The major part of this thesis describes the asymmetric synthesis of β- and γ-amino alcohols through the combination of ruthenium catalyzed racemization and enzymatic kinetic resolution. The dynamic kinetic resolution, DKR, protocol for chlorohydrins was improved by employing Bäckvall’s catalyst, which is a base activated racemization catalyst, in combination with Burkholderia cepacia lipase. These optimized conditions broadened the substrate scope and improved the yields and ee’s of the obtained chlorohydrin acetates. The utility of the method was demonstrated in the synthesis of (S)-salbutamol. In the second part of the thesis, DKR was utilized in the enantio-determining step of the total synthesis of (R)-duloxetine. Optimized DKR conditions, combining Bäckvall’s catalyst together with Candida antarctica lipase B, afforded a β-cyano acetate in high yield and ee. (R)-Duloxetine was accessible through synthetic alterations of the enantioenriched β-cyano acetate in high overall yield. A dynamic kinetic asymmetric transformation, DYKAT, protocol to obtain enantio- and diastereomerically pure γ-amino alcohols was developed. In a first step N-Boc-aminoketones were obtained in high enantiomeric purity through a proline-catalyzed Mannich reaction. Subsequent in situ reduction coupled with a highly efficient DYKAT yielded γ-amino acetates in high dr and ee. The γ-amino alcohols were available through simple hydrolysis/deprotection with retained stereochemistry. In the final part of the thesis a heterogeneous bifunctional catalytic system is reported, which combines the catalytic properties of transition metal-catalyzed racemization with enzymatic acylation. A novel ruthenium-phosphonate complex was synthesized and then covalently anchored to the active site of solid supported Candida antarctica lipase B. The partially inhibited beads proved to be catalytically active both in racemization as well as enzymatic acylation. / At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: In press. Paper 3: Epub ahead of print.