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Chiral amines are ubiquitous in natural products and are found in many drugs and drug candidates. Enantiopure sulfinimines [RS(O)N=CHR1] are useful chiral building blocks for the stereoselective synthesis of amines and amine derivatives. The aim of this thesis research is to develop new methods to access chiral amine building blocks for applications in the synthesis of nitrogen-heterocycles including ring-substituted tropinones, tropanes, cyclic cis-beta-amino acid derivatives, and amino-cyclopentitols. / Chemistry

Orientador: Luiz Carlos Dias / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Quimica / Made available in DSpace on 2018-08-12T23:49:44Z (GMT). No. of bitstreams: 1 Marchi_AndersonAparecidode_M.pdf: 3517303 bytes, checksum: 4fbe84bf0a557b032571d7cac8591000 (MD5) Previous issue date: 2008 / Resumo: Reações aldólicas entre enolatos de boro de metil-cetonas e aldeídos mostram-se como uma ferramenta bastante útil na formação de ligações carbono-carbono e tem sido empregada na síntese de fragmentos complexos de produtos naturais com potencial atividade biológica. O emprego de enolatos oriundos de b-alcoxi metil-cetonas leva a adutos com altas diastereosseletividades 1,5-anti dependendo da natureza estéreo-eletrônica do grupo b-alcóxi. Visando avaliar a influência de grupos fortemente retiradores de elétrons em reações aldólicas, esse trabalho vem ilustrar os resultados obtidos quando enolatos de boro de b-trialometil b-alcóxi metil-cetonas são colocados para reagir com aldeídos aquirais. Os adutos trialogenados são obtidos em diferentes graus de seletividade, no entanto, 1,5-syn sempre foi a estereoquímica relativa dos produtos principais, a qual foi determinada através de preparação de derivados bicíclicos. A reação aldólica de substratos trialogenados pode ser um recurso adicional na obtenção diastereosseletiva de moléculas com potenciais atividades biológicas ou mesmo como intermediários sintéticos visto que grupos trialometil são precursores de uma série de funções orgânicas / Abstract: The aldol reaction between boron enolates generated from methyl-ketones and aldehydes provides a very attractive method for carbon-carbon bond formation and has been applied for the syntheses of a wide variety of natural products with biological and pharmacological significance. The presence of a b-heteroatom substituent in the boron enolates of methylketones influences the stereochemical outcome of the corresponding aldol reactions and controls the overall diastereoselectivity of the process leading to moderate to high levels of 1,5-anti stereoinduction. In order to investigate the stereochemical impact groups we have prepared the b-trihalomethyl b-alkoxy methyl-ketones, which corresponding kinetic enol borinate were used in the aldol reactions with achiral aldehydes. Moderate to good levels of substrate-controlled, 1,5-syn-stereoinduction were obtained in these aldol reactions independent of the nature of the b-alkoxy protecting group. The relative stereochemistries of the major aldol trihalogenated adducts were determined by H-NMR and NOESY analysis of bicyclic derivatives / Mestrado / Quimica Organica / Mestre em Química

Zusammenfassung: Im Hinblick auf eine medikamentöse Behandlung der Harninkontinenz ist die Entwicklung neuartiger, selektiv und damit nebenwirkungsreduzierter, am Muscarin-M3-Rezeptor wirkender Therapeutika ein wichtiges Ziel der Pharmaforschung. An verschiedenen stickstoffhaltigen und stickstofffreien Esterderivaten der 2,2-Diphenylessigsäure (Alkyl-, Cycloalkyl, Aminoalkyl- und Piperidinylester) wurden über die Generierung von Enolatstrukturen mit Hilfe metallorganischer Verbindungen systematisch elektrophile Additionsreaktionen mit einer breiten Palette von Alkyl- und Acylhalogeniden, Acylcyaniden sowie Carbonylverbindungen durchgeführt. Durch Variation von Lösungsmittel, verwendeter Base sowie Änderungen in der Struktur von Elektrophil und Substrat konnten neue Erkenntnisse bezüglich der Reaktivität und Regioselektivität dieser sterisch gehinderten Esterenolate gewonnen werden. Die experimentellen Ergebnisse konnten durch Röntgenkristallstrukturanalysen sowie semiempirische Berechnungen bestätigt werden. / abstract: The development of new M3-selective muscarinic antagonists for use in therapy of urinary incontinence is an important goal of drug research. This thesis describes investigations of synthesis and reactivity of ester enolates of diphenylacetic acid derivatives, which are intermediates in the synthesis of anticholinergic agents. A series of aliphatic, cycloaliphatic , aminoalkyl and piperidinyl esters were prepared using lithium alkyles and / or grignard compounds followed by addition of various electrophiles such as acid chlorides, aldehydes, ketones or alkylating reagents. Studies involving variations of solvents and bases and modifications of substrate and electrophile structure have lead to new information about reactivity of these sterically hindered ester enolates. The experimental results were confirmed by x-ray analysis and semiempirical calculations.

Les acides α-aminés quaternaires permettent l’accès à des structures et dérivés peptidiques présentant des propriétés biologiques intéressantes. De nombreuses voies de synthèses asymétriques sont décrites dans la littérature. La voie de synthèse la plus utilisée est l’alkylation d’acides α-aminés tertiaires. Dans les versions énantioselectives décrites, peu utilisent la chiralité initiale des acides α-aminés tertiaires comme inducteurs de chiralité. La mémoire de chiralité est un des principes permettant l’accès à des acides α-aminés quaternaires énantioenrichis avec, comme unique source de chiralité, la chiralité initiale centrale des acides α-aminés tertiaires. Les objectifs de cette thèse sont de développer de nouveaux procédés pour la synthèse d’acides α-aminés quaternaires par mémoire de chiralité. Deux axes principaux ont été étudiés : 1) Le couplage oxydant d’énolates par mémoire de chiralité permettant l’accès à de nouveaux acides α-aminés quaternaires. 2) L’alkylation par mémoire de chiralité dans des microréacteurs basés sur l’adaptation en flux continu des travaux antérieurs du laboratoire ce qui permet la synthèse reproductible d’une quantité plus importante d’acides α-aminés quaternaires. Ces deux axes ont été étudiés afin d’améliorer la stratégie de synthèse d’acides α-aminés par mémoire de chiralité précédemment développée au laboratoire. / Quaternary α-amino acids allow access to molecular structures and peptides derivatives with interesting biological activites. Many asymmetric synthesis are described in the literature. The most common one is the alkylation of tertiary α-amino acids. Only few methods use the chirality of the starting material as a chiral inductor. Among them, Memory of Chirality is one strategy allowing the access to enantioenriched quaternary α-amino acids using, as a unique source of chirality, the central initial chirality of tertiary α-amino acids. The objective of this PhD is the investigation of new methods for the quaternary α-amino acid synthesis by Memory of Chirality. Two main axes have been studied: 1) Oxidative heterocoupling of enolates by Memory of Chirality that allow access to new enantioenriched quaternary α-amino acids. 2) Alkylation by Memory of Chirality using a microflow system with the objective to adapt in continuous flow the previous works performed in our laboratory. That would allow the reproductible and scalable synthesis of enantioenriched quaternary α-amino acids. This two axes enable the improvement of the synthesis of quaternary α-amino acid synthesis by Memory of Chirality strategy previously developed in our laboratory.

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