As populações axial/equatorial em oximas e O-metiI oximas de 2-X-cicloexanonas (X= F, CI, Br, OCH3, SCH3 e N(CH3)2) foram efetivamente determinadas pela análise dos deslocamentos químicos dos prótons 6, utilizando-se os derivados da 4-tércio-butil-cicloexanona como modelos das conformações equatorial e axial. As populações dos confôrmeros axiais também foram determinadas pela análise dos deslocamentos químicos do carbono 4. Este carbono está em uma posição gama gauche em relação ao heteroátomo e sofre assim uma blindagem quando a conformação é axial. Usando-se os deslocamentos químicos observados do carbono 4 do isômero Z, foi possível calcular estas populações no isômero E. Os isômeros Z não apresentam este equilíbrio axial I equatorial porque existe uma compressão estérica grande entre o heteroátomo e o oxigênio na hipotética conformação equatorial. As populações axiais nestes compostos variam de 86% a 96% e apresentam uma dispersão muito pequena com os diferentes métodos utilizados. Ao se comparar oximas com éteres nota-se que para os substituintes mais polarizáveis, como metiltio, cloro e bromo há um aumento da população axial nos éteres comparado às oximas. As frequências de estiramento vCN se correlacionaram com os parâmetros indutivos de Taft (σl) e com a polarizabilidade média da ligação carbono-heteroátomo, o que apoia a idéia de uma interação πCN/σ*cx. Além disso, as frequências de estiramento vOH também se correlacionaram com estes parâmetros e neste caso o efeito indutivo e a polarizabilidade levam a um aumento de acidez destas oximas. / The axial/equatorial populations of oximes and O-methyl oximes of 2-X-cyclohexanones ((X= F, CI, Sr, OCH3, SCH3 e N(CH3)2) were determined by the chemical shifts of the protons bonded to carbon 6, making use of the 4-tert-butyl- cyclohexanone derivatives as models for the equatorial and axial conformations. The axial conformer populations were also determined by the C-4 chemical shift analysis. This carbon lies in a gamma gauche position to the heteroatom and suffers shielding when the conformation is axial. It has been possible to calculate those populations in the E isomer, using the C-4 chemical shift of the Z isomer. The latter do not present an axial/equatorial equilibrium because there is a too high steric compression between the nitrogen and the heteroatom in the hypothethical equatorial conformation. The axial populations of these compounds vary from 86 to 96% and present a small deviation along the different methods used. All substituents are preferentially in the axial conformation, even fluorine and methoxyl, which are predominantly equatorial in the corresponding ketones. It is noted that there is a increase in the axial population for more polarizable substituents like methylthio, chloro and bromo, on going from the oximes to the oximes O-methyl ethers. The vCN stretching frequencies are correlated with Taft\'s inductive parameters (σl) and the mean polarizability of the carbon-heteroatom bond, which supports the view of a πCN/σ*cx interaction. Sesides, the vOH stretching frequencies are also correlated with those parameters and in this case, both the inductive effect and polarizability lead to a increase of the oximes acidity.

As populações axial/equatorial em oximas e O-metiI oximas de 2-X-cicloexanonas (X= F, CI, Br, OCH3, SCH3 e N(CH3)2) foram efetivamente determinadas pela análise dos deslocamentos químicos dos prótons 6, utilizando-se os derivados da 4-tércio-butil-cicloexanona como modelos das conformações equatorial e axial. As populações dos confôrmeros axiais também foram determinadas pela análise dos deslocamentos químicos do carbono 4. Este carbono está em uma posição gama gauche em relação ao heteroátomo e sofre assim uma blindagem quando a conformação é axial. Usando-se os deslocamentos químicos observados do carbono 4 do isômero Z, foi possível calcular estas populações no isômero E. Os isômeros Z não apresentam este equilíbrio axial I equatorial porque existe uma compressão estérica grande entre o heteroátomo e o oxigênio na hipotética conformação equatorial. As populações axiais nestes compostos variam de 86% a 96% e apresentam uma dispersão muito pequena com os diferentes métodos utilizados. Ao se comparar oximas com éteres nota-se que para os substituintes mais polarizáveis, como metiltio, cloro e bromo há um aumento da população axial nos éteres comparado às oximas. As frequências de estiramento vCN se correlacionaram com os parâmetros indutivos de Taft (σl) e com a polarizabilidade média da ligação carbono-heteroátomo, o que apoia a idéia de uma interação πCN/σ*cx. Além disso, as frequências de estiramento vOH também se correlacionaram com estes parâmetros e neste caso o efeito indutivo e a polarizabilidade levam a um aumento de acidez destas oximas. / The axial/equatorial populations of oximes and O-methyl oximes of 2-X-cyclohexanones ((X= F, CI, Sr, OCH3, SCH3 e N(CH3)2) were determined by the chemical shifts of the protons bonded to carbon 6, making use of the 4-tert-butyl- cyclohexanone derivatives as models for the equatorial and axial conformations. The axial conformer populations were also determined by the C-4 chemical shift analysis. This carbon lies in a gamma gauche position to the heteroatom and suffers shielding when the conformation is axial. It has been possible to calculate those populations in the E isomer, using the C-4 chemical shift of the Z isomer. The latter do not present an axial/equatorial equilibrium because there is a too high steric compression between the nitrogen and the heteroatom in the hypothethical equatorial conformation. The axial populations of these compounds vary from 86 to 96% and present a small deviation along the different methods used. All substituents are preferentially in the axial conformation, even fluorine and methoxyl, which are predominantly equatorial in the corresponding ketones. It is noted that there is a increase in the axial population for more polarizable substituents like methylthio, chloro and bromo, on going from the oximes to the oximes O-methyl ethers. The vCN stretching frequencies are correlated with Taft\'s inductive parameters (σl) and the mean polarizability of the carbon-heteroatom bond, which supports the view of a πCN/σ*cx interaction. Sesides, the vOH stretching frequencies are also correlated with those parameters and in this case, both the inductive effect and polarizability lead to a increase of the oximes acidity.

Plusieurs analogues de nucléosides thérapeutiques (Ara-C, Clofarabine), utilisés pour le traitement de leucémies, présentent un arrangement 1’,2’-cis entre la nucléobase reliée au centre anomère et le substituant (électroattracteur) en C-2’. Récemment, notre laboratoire a développé une approche synthétique pour former sélectivement des analogues de nucléosides et de thionucléosides 1’,2’-trans et 1’,2’-cis à partir de précurseurs acycliques. Ce mémoire présente une nouvelle méthodologie pour accéder efficacement aux analogues de nucléosides 1’,2’-cis à partir de furanosides. Différents groupements en position anomérique ont été examinés, sous conditions cinétiques en utilisant le bromure de diméthylbore pour générer sélectivement des produits acycliques ou cycliques. Les intermédiaires cinétiques de différents furanosides de méthyle formés en présence de Me2BBr ont été piégés in situ par un thiol pour générer des thioacétals acycliques avec de bonnes voire d’excellentes diastéréosélectivités. Les produits générés sont en accord avec une rétention globale de l’information stéréochimique du centre acétal et deux déplacements SN2 consécutifs ont été suggérés pour rationaliser ces résultats. Toutefois, l’objectif de synthétiser des analogues de nucléosides à partir de furanosides de méthyle a échoué. Tel que démontré par le Dr Michel Prévost, l’activation par Me2BBr des lactols des quatres différents furanosides suivie d’une addition in situ d’une base silylée a permis de former diastéréosélectivement les analogues de nucléosides 1’,2’-cis correspondants avec d’excellents rendements. Nous avons démontré que d’autres substrats peuvent être employés et que l’induction stéréochimique est sous contrôle du substituant électroattracteur en C-2. D’autres acides de Lewis, tel que TMSBr, peuvent également être utilisés. Cette méthodologie a également été étendue à d’autres nucléophiles tels que des Grignards ou des éthers d’énols silylés, conduisant à de bonnes sélectivités. / Many therapeutically relevant nucleoside analogs (Ara-C, Clofarabine) for the treatment of leukemia have a 1’,2’-cis arrangement between the nucleobase attached at the anomeric center and the non-hydrogen substituent at C-2’. Recently, our laboratory has developed a versatile approach to the synthesis of 1’,2’-trans and 1’,2’-cis nucleoside and thionucleoside analogues from acyclic scaffolds. This work will present a new methodology to access efficiently 1’,2’-cis nucleoside analogues from cyclic furanoside. Activation of various anomeric groups by Me2BBr was investigated, and under kinetic control acyclic substrates or cyclic ones could be generated selectively. Trapping the kinetic product of methyl furanoside formed in presence of Me2BBr by thiol in the presence of base led to the formation of acyclic thioacetal in good to excellent diastereoselectivity. The results obtained are in accordance with total retention of the stereochemical information of the acetal moiety and thus suggested that the mechanism of these two reactions is two successive SN2 displacements. The objective of synthesizing nucleoside analogs from methyl furanoside was unsuccessful. As shown recently by Dr Michel Prévost, activation of all four furanoside lactol scaffolds by Me2BBr with an in situ addition of silylated nucleobase afforded 1’,2’-cis pyrimidine nucleoside analogues in very good yields and with diastereoselectivities greater or equal to 20:1. Expending this methodology to other scaffolds provided evidence of stereoelectronic control of the C-2 electron-withdrawing substituent. Other Lewis acids such as TMSBr can be used. This methodology was also applied to other nucleophiles such as allyl Grignard and silylated enols ethers, which were successfully alkylated in good yield and 1,2-cis diastereoselectivity.

Plusieurs analogues de nucléosides thérapeutiques (Ara-C, Clofarabine), utilisés pour le traitement de leucémies, présentent un arrangement 1’,2’-cis entre la nucléobase reliée au centre anomère et le substituant (électroattracteur) en C-2’. Récemment, notre laboratoire a développé une approche synthétique pour former sélectivement des analogues de nucléosides et de thionucléosides 1’,2’-trans et 1’,2’-cis à partir de précurseurs acycliques. Ce mémoire présente une nouvelle méthodologie pour accéder efficacement aux analogues de nucléosides 1’,2’-cis à partir de furanosides. Différents groupements en position anomérique ont été examinés, sous conditions cinétiques en utilisant le bromure de diméthylbore pour générer sélectivement des produits acycliques ou cycliques. Les intermédiaires cinétiques de différents furanosides de méthyle formés en présence de Me2BBr ont été piégés in situ par un thiol pour générer des thioacétals acycliques avec de bonnes voire d’excellentes diastéréosélectivités. Les produits générés sont en accord avec une rétention globale de l’information stéréochimique du centre acétal et deux déplacements SN2 consécutifs ont été suggérés pour rationaliser ces résultats. Toutefois, l’objectif de synthétiser des analogues de nucléosides à partir de furanosides de méthyle a échoué. Tel que démontré par le Dr Michel Prévost, l’activation par Me2BBr des lactols des quatres différents furanosides suivie d’une addition in situ d’une base silylée a permis de former diastéréosélectivement les analogues de nucléosides 1’,2’-cis correspondants avec d’excellents rendements. Nous avons démontré que d’autres substrats peuvent être employés et que l’induction stéréochimique est sous contrôle du substituant électroattracteur en C-2. D’autres acides de Lewis, tel que TMSBr, peuvent également être utilisés. Cette méthodologie a également été étendue à d’autres nucléophiles tels que des Grignards ou des éthers d’énols silylés, conduisant à de bonnes sélectivités. / Many therapeutically relevant nucleoside analogs (Ara-C, Clofarabine) for the treatment of leukemia have a 1’,2’-cis arrangement between the nucleobase attached at the anomeric center and the non-hydrogen substituent at C-2’. Recently, our laboratory has developed a versatile approach to the synthesis of 1’,2’-trans and 1’,2’-cis nucleoside and thionucleoside analogues from acyclic scaffolds. This work will present a new methodology to access efficiently 1’,2’-cis nucleoside analogues from cyclic furanoside. Activation of various anomeric groups by Me2BBr was investigated, and under kinetic control acyclic substrates or cyclic ones could be generated selectively. Trapping the kinetic product of methyl furanoside formed in presence of Me2BBr by thiol in the presence of base led to the formation of acyclic thioacetal in good to excellent diastereoselectivity. The results obtained are in accordance with total retention of the stereochemical information of the acetal moiety and thus suggested that the mechanism of these two reactions is two successive SN2 displacements. The objective of synthesizing nucleoside analogs from methyl furanoside was unsuccessful. As shown recently by Dr Michel Prévost, activation of all four furanoside lactol scaffolds by Me2BBr with an in situ addition of silylated nucleobase afforded 1’,2’-cis pyrimidine nucleoside analogues in very good yields and with diastereoselectivities greater or equal to 20:1. Expending this methodology to other scaffolds provided evidence of stereoelectronic control of the C-2 electron-withdrawing substituent. Other Lewis acids such as TMSBr can be used. This methodology was also applied to other nucleophiles such as allyl Grignard and silylated enols ethers, which were successfully alkylated in good yield and 1,2-cis diastereoselectivity.

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