Une nouvelle voie d’accès à des structures tri-cycliques originaux les « oxazino-indole di-iodés» a été mise au point à partir des acides 1H-indole-2-carboxyliques commerciaux ou des acides 1H-indole-2-carboxyliques fonctionnalisés obtenus par la réaction d’Hemetsberger-Knittel. La dernière étape de cette séquence est une réaction d’iodocyclisation qui s’est avérée totalement régio- et stéréosélective selon un processus de type 6-exo-dig. Cette méthodologie a ensuite été étendue en série isoindolique permettant un accès à des motifs « oxazino-isoindolique di-iodés » originaux. Afin d'étendre davantage cette méthodologie, de nouveaux « oxazepino-indole di-iodés » ont été préparés en utilisant la même approche synthétique à partir de l'acide 1H-indole-7-carboxylique. La réactivité des structures tri-cycliques di-iodés a été étudiée via des réactions de Cross-Coupling (Stille, Sonogashira, Suzuki) par l’utilisation de sels de palladium permettant une fonctionnalisation régiosélective de l’iode exocyclique. / A new access pathway to the original tricyclic structures "di-iodinated oxazino-indole" was developed from the commercial 1H-indole-2-carboxylic acids or functionalized 1H-indole-2-carboxylic acid obtained by Hemetsberger-Knittel reaction. The last step in this sequence is an iodocyclisation reaction that is proved to be completely regio- and stereoselective via 6-exo-dig process. This methodology was then extended to isoindolic series allowing access to original "di-iodinated oxazino-isoindole" motifs. To further extend this methodology, new"di-iodinated oxazepino-indoles" were prepared using the same synthetic approach from the 1H-indole-7-carboxylic acid. The reactivity of the di-iodinated tri-cyclic structures has been studied via Cross-Coupling reactions (Stille, Sonogashira and Suzuki) by the use of palladium salts allowing a regioselective functionalization of the exocyclic iodine.

Nesta tese foi empregada a iodociclofuncionalização de β-enamino ésteres para obtenção de análogos conformacionalmente restritos do ácido γ-aminobutírico (GABA) e de 4-aril-1,4-di-hidropiridinas (DHP\'s). Foram preparados ciclopentanos trissubstituídos a partir de b-enamino ésteres cíclicos, com o objetivo de investigar o mecanismo desta reação. Utilizando ESI(+)-MS/MS, foi possível identificar e caracterizar os intermediários bicíclicos catiônicos, confirmando que a reação se processa através de uma SN2 intramolecular. A biorredução do grupo acetila existente nos ciclopentanos, utilizando raízes de Daucus carota e células íntegras de Aspergillus terreus CCT 3320 e Rhizopus oryzae CCT 4964, forneceu novos análogos oticamente ativos do GABA, com excelente enantiosseletividade. Também foram preparados iodo-β-enamino ésteres cíclicos de seis membros, contendo um grupo arila na posição 4 do anel tetra-hidropiridínico, cuja desidroiodação forneceu os respectivos derivados 1,4-di-hidropiridínicos. / This thesis presents a study of iodo-cyclization of β-enamino esters in order to obtain conformationally restricted analogues of γ-amino butiric acid (GABA) and of 1,4-dihydropyridines (DHP\'s). Trisubstituted cyclopentanes were obtained from iodo-β-enamino esters and the mechanism of their formation was proposed and corroborated by (+)-ESI-MS/MS through the interception and structural characterization of the key bicyclic iminium ion intermediates. Optically active GABA analogues have been prepared in high enantiomeric excesses (up to >99%) by bioreduction of the keto group in cyclopentane derivatives using whole fungal cells of Aspergillus terreus CCT 3320, Rhizopus oryzae CCT 4964 and Daucus carota root. 4-aryl-1,4,5,6-tetrahydropyridine derivatives were synthesized by iodo-cyclization of a-alkenyl-b-enamino esters and 4-phenyl-1,4-dihydropyridine derivatives were obtained after base-promoted dehydroiodination of the corresponding cyclic iodo-b-enamino esters.

Nesta tese foi empregada a iodociclofuncionalização de β-enamino ésteres para obtenção de análogos conformacionalmente restritos do ácido γ-aminobutírico (GABA) e de 4-aril-1,4-di-hidropiridinas (DHP\'s). Foram preparados ciclopentanos trissubstituídos a partir de b-enamino ésteres cíclicos, com o objetivo de investigar o mecanismo desta reação. Utilizando ESI(+)-MS/MS, foi possível identificar e caracterizar os intermediários bicíclicos catiônicos, confirmando que a reação se processa através de uma SN2 intramolecular. A biorredução do grupo acetila existente nos ciclopentanos, utilizando raízes de Daucus carota e células íntegras de Aspergillus terreus CCT 3320 e Rhizopus oryzae CCT 4964, forneceu novos análogos oticamente ativos do GABA, com excelente enantiosseletividade. Também foram preparados iodo-β-enamino ésteres cíclicos de seis membros, contendo um grupo arila na posição 4 do anel tetra-hidropiridínico, cuja desidroiodação forneceu os respectivos derivados 1,4-di-hidropiridínicos. / This thesis presents a study of iodo-cyclization of β-enamino esters in order to obtain conformationally restricted analogues of γ-amino butiric acid (GABA) and of 1,4-dihydropyridines (DHP\'s). Trisubstituted cyclopentanes were obtained from iodo-β-enamino esters and the mechanism of their formation was proposed and corroborated by (+)-ESI-MS/MS through the interception and structural characterization of the key bicyclic iminium ion intermediates. Optically active GABA analogues have been prepared in high enantiomeric excesses (up to >99%) by bioreduction of the keto group in cyclopentane derivatives using whole fungal cells of Aspergillus terreus CCT 3320, Rhizopus oryzae CCT 4964 and Daucus carota root. 4-aryl-1,4,5,6-tetrahydropyridine derivatives were synthesized by iodo-cyclization of a-alkenyl-b-enamino esters and 4-phenyl-1,4-dihydropyridine derivatives were obtained after base-promoted dehydroiodination of the corresponding cyclic iodo-b-enamino esters.