RESUMEN
P-Glycoprotein (Pgp)-mediated cellular efflux is recognized as a common challenge in CNS drug discovery. In this study, the influence of replacing a hydrogen atom with fluorine on the pKa and Pgp-mediated efflux is elucidated for a series of PDE9 inhibitors. The PDE9 inhibitors with and without fluorine were synthesized using a novel condensation-oxidation approach, providing access to several analogues, all from the same stereoenriched aldehyde building block. The incorporation of fluorine was found to influence two acid-base functionalities concomitantly, both of which were involved in Pgp-recognition. By methylating the acidic functionality, it was possible to isolate the effect responsible for lowering the Pgp-mediated efflux.
RESUMEN
A practical diastereodivergent access to ß-fluoropyrrolidines with two adjacent stereocenters has been demonstrated, by either enhancing or completely reversing the substrate control, in the diastereoselective fluorination of a series of diverse pyrrolidinyl carbaldehydes using organocatalysis. Furthermore, enamine catalysis has been successfully utilized for kinetic resolution, obtaining a fluorinated ß-prolinol analogue with two adjacent tetrasubstituted chiral centers in 95% ee from a racemic substrate.
RESUMEN
Catalysis with chiral secondary amines (asymmetric aminocatalysis) has become a well-established and powerful synthetic tool for the chemo- and enantioselective functionalization of carbonyl compounds. In the last eight years alone, this field has grown at such an extraordinary pace that it is now recognized as an independent area of synthetic chemistry, where the goal is the preparation of any chiral molecule in an efficient, rapid, and stereoselective manner. This has been made possible by the impressive level of scientific competition and high quality research generated in this area. This Review describes this "Asymmetric Aminocatalysis Gold Rush" and charts the milestones in its development. As in all areas of science, progress depends on human effort.
RESUMEN
Optically active 2,5-disubstituted-cyclohexen-2-one derivatives have been prepared in a one-pot process consisting of five reaction steps: an organocatalytic asymmetric conjugated addition of beta-ketoesters to alpha,beta-unsaturated aldehydes that proceeds in aqueous solutions or under solvent-free conditions has been implemented in a multi-step process.
Asunto(s)
Aldehídos/química , Ciclohexanonas/síntesis química , Ésteres/química , Cetonas/química , Catálisis , Ciclohexanonas/química , Estructura Molecular , Rotación Óptica , Estereoisomerismo , Agua/químicaRESUMEN
A new concept in organocatalysis is presented, the direct asymmetric gamma-functionalization of alpha,beta-unsaturated aldehydes. We disclose that secondary amines can invert the usual reactivity of alpha,beta-unsaturated aldehydes, enabling a direct gamma-amination of the carbonyl compound using azodicarboxylates as the electrophilic nitrogen-source. The scope of the reaction is demonstrated for the enantioselective gamma-amination of different alpha,beta-unsaturated aldehydes, giving the products in moderate to good yields and with high enantioselectivities up to 93% ee. Experimental investigations and DFT calculations indicate that the reaction might proceed as a hetero-Diels-Alder cycloaddition reaction. Such a mechanism can explain the "unexpected" stereochemical outcome of the reaction.
RESUMEN
The direct enantioselective introduction of a stereogenic carbon-heteroatom bond adjacent to a carbonyl functionality leads to optically active compounds of significant importance for e.g. the life-science industry. Organocatalytic enantioselective amination, oxygenation, fluorination, chlorination, bromination and sulfenylation of aldehydes and ketones, using chiral amines as the catalysts, are reviewed in this feature article. Furthermore, a few other transformations are also outlined. The scope, potential and application of these organocatalytic asymmetric reactions are presented and the mechanistic aspects discussed.
Asunto(s)
Aldehídos/química , Lactamas/síntesis química , Lactonas/síntesis química , Malonatos/química , Paroxetina/síntesis química , Antidepresivos/química , Catálisis , Cristalografía por Rayos X , Lactamas/química , Lactonas/química , Modelos Moleculares , Estructura Molecular , Paroxetina/química , Solventes , EstereoisomerismoRESUMEN
The development of the organocatalytic asymmetric one-pot Michael-Darzens condensation giving highly functionalized complex epoxycyclohexanone derivatives with up to four chiral centers is presented. Depending on the reaction conditions, either the polysubstituted 7-oxa-bicyclo[4.1.0]heptan-2-one ring system or 2-chloro-cyclohex-2-enone derivatives can be formed. For the former class of compounds a high diversity in substitution pattern is demonstrated, and the optically active products are obtained in excellent diastereo- and enantioselectivities. The potential synthetic applications of the products have been demonstrated by performing a series of highly diastereoselective transformations leading to optically active products useful for the life-science industry. Furthermore, mechanistic investigations on the formation of the chiral centers in the optically active epoxycyclohexanone are presented.
RESUMEN
The development of a general organocatalyst for the alpha-functionalization of aldehydes, via an enamine intermediate, is presented. Based on optically active alpha,alpha-diarylprolinol silyl ethers, the scope and applications of this catalyst for the stereogenic formation of C-C, C-N, C-F, C-Br, and C-S bonds are outlined. The reactions all proceed in good to high yields and with excellent enantioselectivities. Furthermore, we will present mechanistic insight into the reaction course applying nonlinear effect studies, kinetic resolution, and computational investigations leading to an understanding of the properties of the alpha,alpha-diarylprolinol silyl ether catalysts.
RESUMEN
An organocatalytic asymmetric multicomponent domino and a conjugated addition reaction to alpha,beta-unsaturated aldehydes are presented. The development is based, first, on an organocatalyzed highly enantioselective nucleophilic thiol addition to the beta-carbon atom in the iminium ion intermediate, followed by an electrophilic amination of the alpha-carbon atom to the enamine intermediate. The multicomponent reactions proceed to give enantiopure amino-thiols in moderate to good yields. Furthermore, the organocatalyzed thiol addition to alpha,beta-unsaturated aldehydes takes place in good yields and excellent enantioselectivities.
RESUMEN
The mechanism for the 2,5-diphenylpyrrolidine-catalyzed enantioselective alpha-chlorination of aldehydes with electrophilic halogenation reagents has been investigated by using experimental and computational methods. These studies have led us to propose a mechanism for the reaction that proceeds through an initial N-chlorination of the chiral catalyst-substrate complex, followed by a 1,3-sigmatropic shift of the chlorine atom to the enamine carbon atom. The suggested reaction course is different from previously proposed mechanisms for organocatalytic enamine reactions, in which the carbon-electrophile bond is formed directly. Furthermore, the rate-determining step in the overall reaction was determined and the presence of nonlinear effects was probed.
Asunto(s)
Aldehídos/química , Cloro/química , Pirrolidinas/química , Catálisis , Espectroscopía de Resonancia Magnética , Modelos Moleculares , EstereoisomerismoRESUMEN
The diastereo- and enantioselective organocatalytic epoxidation of alpha,beta-unsaturated aldehydes in aqueous solutions is presented. By the screening of the reaction conditions for the epoxidation of cinnamic aldehyde applying hydrogen peroxide as the oxidant and 2-[bis-(3,5-bis-trifluoromethyl-phenyl)-trimethylsilanyloxy-methyl]-pyrrolidine as the catalyst, a highly stereoselective reaction has been developed. The scope of the diastereo- and enantioselective organocatalytic epoxidation in aqueous solutions is documented by the asymmetric epoxidation of alpha,beta-unsaturated aldehydes with enantioselectivities up to 96% ee.
RESUMEN
The first organocatalytic enantioselective alpha-bromination of aldehydes and ketones is presented; a C2-symmetric diphenylpyrrolidine catalyst afforded the alpha-brominated aldehydes in good yields and up to 96% ee, while ketones were alpha-brominated by a C2-symmetric imidazolidine in up to 94% ee; furthermore, the organocatalytic enantioselective alpha-iodination of aldehydes is also demonstrated to proceed with up to 89% ee.
Asunto(s)
Aldehídos/química , Bromo/química , Imidazolidinas/química , Cetonas/química , Pirrolidinas/química , Catálisis , Estructura Molecular , EstereoisomerismoRESUMEN
The application of cinchona alkaloid derivatives as catalysts for enantioselective alpha-sulfenylation of activated C-H bonds in lactones, lactams, and beta-dicarbonyl compounds by different electrophilic sulfur reagents is presented. Optically active products are obtained in good to excellent yields and up to 91 % ee. Furthermore, the diastereoselective reduction of alpha-sulfenylated beta-keto esters to give optically active alpha-sulfenylated beta-hydroxy esters has been studied. A model for the intermediate is presented, in which the protonated cinchona alkaloid interacts with the substrate leading to face-shielding in accordance with the enantioselective alpha-sulfenylation step.
Asunto(s)
Carbono/química , Hidrógeno/química , Cetonas/química , Lactamas/química , Lactonas/química , Sulfamerazina/química , Catálisis , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos MolecularesRESUMEN
The first asymmetric organocatalytic epoxidation of alpha,beta-unsaturated aldehydes is presented. A chiral bisaryl-silyl-protected pyrrolidine acts as a very selective epoxidation organocatalyst using simple oxidation agents, such as hydrogen peroxide and tert-butyl hydroperoxide. The asymmetric epoxidation reactions proceed under environmental friendly reaction condition in, for example, water mixtures of alcohols, and the scope of the reaction is demonstrated by the formation of optically active alpha,beta-epoxy aldehydes in high yields and enantioselectivities >94% ee. Furthermore, the direct synthesis of the sex pheromone from an acaric mite by asymmetric epoxidation of citral is presented.