The development of novel methodologies for the preparation of enantiomerically pure compounds is a topic of great interest for several fields. In particular, it must be mentioned that chiral amines are finding applications in an ever-increasing number of fields, so the possibility of developing an organocatalytic approach has gained much attention. During my work, the enantioselective organocatalytic reduction of fluorinated ketimines was successfully realized by using trichlorosilane as reducing agent in the presence of catalytic amounts of an inexpensive and readily available picolinamide derived from ephedrine. The methodology allowed to reduce imines derived both from aryl and alkyl trifluoromethyl ketones in very good yields and high enantioselectivities, typically of 90% e.e. and up to 98% e.e.. With a ACE (Asymmetric Catalyst Efficiency) value of about 44, the ephedrine-derived picolinamidic catalyst established itself as one of the most efficient and versatile catalyst for the reduction of a wide range of fluorinated imines, favourably comparing both with chiral phosphoric acids and even with organometallic catalysts. The well documented possibility to easily remove the N-PMP residue or the benzyl group makes the present method a viable and attractive synthesis also for highly enantiomerically enriched fluorinated primary amines. Moreover, the straight forward synthesis of a novel class of cinchona-based chiral Lewis bases was developed. A series of enantiomerically pure Lewis bases were obtained by performing a Mitsunobu reaction on the commercially available alkaloids followed by simple condensation with picolinic acid. Under the optimized reaction conditions, such compounds were shown to promote the enantioselective reduction of ketimines with trichlorosilane with nearly quantitative chemical yield and high enantioselectivity. Even more interestingly, these high levels of yields and enantioselectivity remained constant when the reaction was carried out with only a 1 mol % catalyst loading. Further modification of these compounds allowed to raise the enantioselectivity of the process, leading to the quantitative formation of the corresponding amine with up to 88% e.e.. These catalyst were successfully employed also in the organocatalytic reduction of alpha-imino and beta-enamino esters with trichlorosilane, obtaining the corresponding products with high chemical yield and good enantiomeric excess. Moreover, the combination of this low cost, easy to make metal-free catalyst and an inexpensive chiral auxiliary allowed to obtain chiral beta-amino esters with nearly total control of the stereoselectivity. In the field of catalytic methods for carbon nitrogen double bond reduction, I’ve also studied a very novel catalytic approach to realize the activation and utilization of H2: the concept of frustrated Lewis pair (FLP) recently introduced by the Stephan’s research group. Once performed a screening of several additives to find an efficient catalytic pair, the FLP catalyzed diastereoselective hydrogenation of a chiral ketimine was accomplished with 67% yield and 82:18 d.r. without the necessity to perform the reaction in glovebox. Finally, taking into account the excellent enantioselectivities obtained in the reduction of C-N double-bonds with phosphoric acid catalysis, we decided to explore the performance of these systems employing HSiCl3 as reducing agent. After an optimization of the stoichiometry of the reaction, we were able to achieve up to 29% e.e. using 10 mol % unsubstituted BINOL-derived phosphoric acid, which could be raised up to 60% e.e. using a stoichiometric amount of the acid.

EXPLORING NOVEL ORGANOCATALYTIC METHODOLOGIES FOR CARBON-NITROGEN DOUBLE BOND REDUCTION / A. Genoni ; tutor: M. Benaglia ; coordinatore: D. M. Roberto. - : . DIPARTIMENTO DI CHIMICA, 2014 Jan 10. ((26. ciclo, Anno Accademico 2013. [10.13130/genoni-andrea_phd2014-01-10].

EXPLORING NOVEL ORGANOCATALYTIC METHODOLOGIES FOR CARBON-NITROGEN DOUBLE BOND REDUCTION

A. Genoni
2014-01-10

Abstract

The development of novel methodologies for the preparation of enantiomerically pure compounds is a topic of great interest for several fields. In particular, it must be mentioned that chiral amines are finding applications in an ever-increasing number of fields, so the possibility of developing an organocatalytic approach has gained much attention. During my work, the enantioselective organocatalytic reduction of fluorinated ketimines was successfully realized by using trichlorosilane as reducing agent in the presence of catalytic amounts of an inexpensive and readily available picolinamide derived from ephedrine. The methodology allowed to reduce imines derived both from aryl and alkyl trifluoromethyl ketones in very good yields and high enantioselectivities, typically of 90% e.e. and up to 98% e.e.. With a ACE (Asymmetric Catalyst Efficiency) value of about 44, the ephedrine-derived picolinamidic catalyst established itself as one of the most efficient and versatile catalyst for the reduction of a wide range of fluorinated imines, favourably comparing both with chiral phosphoric acids and even with organometallic catalysts. The well documented possibility to easily remove the N-PMP residue or the benzyl group makes the present method a viable and attractive synthesis also for highly enantiomerically enriched fluorinated primary amines. Moreover, the straight forward synthesis of a novel class of cinchona-based chiral Lewis bases was developed. A series of enantiomerically pure Lewis bases were obtained by performing a Mitsunobu reaction on the commercially available alkaloids followed by simple condensation with picolinic acid. Under the optimized reaction conditions, such compounds were shown to promote the enantioselective reduction of ketimines with trichlorosilane with nearly quantitative chemical yield and high enantioselectivity. Even more interestingly, these high levels of yields and enantioselectivity remained constant when the reaction was carried out with only a 1 mol % catalyst loading. Further modification of these compounds allowed to raise the enantioselectivity of the process, leading to the quantitative formation of the corresponding amine with up to 88% e.e.. These catalyst were successfully employed also in the organocatalytic reduction of alpha-imino and beta-enamino esters with trichlorosilane, obtaining the corresponding products with high chemical yield and good enantiomeric excess. Moreover, the combination of this low cost, easy to make metal-free catalyst and an inexpensive chiral auxiliary allowed to obtain chiral beta-amino esters with nearly total control of the stereoselectivity. In the field of catalytic methods for carbon nitrogen double bond reduction, I’ve also studied a very novel catalytic approach to realize the activation and utilization of H2: the concept of frustrated Lewis pair (FLP) recently introduced by the Stephan’s research group. Once performed a screening of several additives to find an efficient catalytic pair, the FLP catalyzed diastereoselective hydrogenation of a chiral ketimine was accomplished with 67% yield and 82:18 d.r. without the necessity to perform the reaction in glovebox. Finally, taking into account the excellent enantioselectivities obtained in the reduction of C-N double-bonds with phosphoric acid catalysis, we decided to explore the performance of these systems employing HSiCl3 as reducing agent. After an optimization of the stoichiometry of the reaction, we were able to achieve up to 29% e.e. using 10 mol % unsubstituted BINOL-derived phosphoric acid, which could be raised up to 60% e.e. using a stoichiometric amount of the acid.
BENAGLIA, MAURIZIO
ROBERTO, DOMINIQUE MARIE
organocatalysis ; trichlorosilane ; imine ; amine ; ketoester ; reduction ; hydrogenation ; phosphoric acid ; cinchona ; picolinamide ; flp ; fluorine
Settore CHIM/06 - Chimica Organica
EXPLORING NOVEL ORGANOCATALYTIC METHODOLOGIES FOR CARBON-NITROGEN DOUBLE BOND REDUCTION / A. Genoni ; tutor: M. Benaglia ; coordinatore: D. M. Roberto. - : . DIPARTIMENTO DI CHIMICA, 2014 Jan 10. ((26. ciclo, Anno Accademico 2013. [10.13130/genoni-andrea_phd2014-01-10].
Doctoral Thesis
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/229551
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