Enantioselective 1,3-dipolar cycloadditions of azlactones and electrophilic alkenes catalyzed by dimeric BinapAuTFA complexes

Glycine-derived azlactones react with maleimides using (S)- or (R)-dimeric BinapAuTFA complexes affording the corresponding cycloadducts in good yields and high enantioselections (up to 99% ee). The intermediate carboxylic acids are treated with trimethylsilyldiazomethane and isolated as Δ¹-pyrroline methyl esters. These cycloadducts are transformed into exo-proline derivatives by reduction with NaBH3CN in acidic media. On the other hand, N-benzoylalanine-derived oxazolone reacts with tert-butyl acrylate providing the cycloadduct with the ester group at the 3-position with a trans-relative configuration with respect to the methyl ester group.

Asymmetric 1,3-Dipolar Cycloadditons of Stabilized Azomethine Ylides with Nitroalkenes

This review highlights the biological importance of many polysubstituted nitro-prolines and -pyrrolidines. Their preparation using asymmetric 1,3-dipolar cycloadditions of azomethine ylides with nitroalkenes using diastereoselective and enantioselective strategies is described remarking the scope and main features of each one.

1,3-Dipolar cycloadditions of azomethine imines

Azomethine imines are considered 1,3-dipoles of the aza-allyl type which are transient intermediates and should be generated in situ but can also be stable and isolable compounds. They react with electron-rich and electron-poor olefins as well as with acetylenic compounds and allenoates mainly by a [3 + 2] cycloaddition but they can also take part in [3 + 3], [4 + 3], [3 + 2 + 2] and [5 + 3] with different dipolarophiles. These 1,3-dipolar cycloadditions (1,3-DC) can be performed not only under thermal or microwave conditions but also using metallo- and organocatalytic systems. In recent years enantiocatalyzed 1,3-dipolar cycloadditions have been extensively considered and applied to the synthesis of a great variety of dinitrogenated heterocycles with biological activity. Acyclic azomethine imines derived from mono and disubstituted hydrazones could be generated by prototropy under heating or by using Lewis or Brønsted acids to give, after [3 + 2] cycloadditions, pyrazolidines and pyrazolines. Cyclic azomethine imines, incorporating a C–N bond in a ring, such as isoquinolinium imides are the most widely used dipoles in normal and inverse-electron demand 1,3-DC allowing the synthesis of tetrahydro-, dihydro- and unsaturated pyrazolo[1,5-a]isoquinolines in racemic and enantioenriched forms with interesting biological activity. Pyridinium and quinolinium imides give the corresponding pyrazolopyridines and indazolo[3,2-a]isoquinolines, respectively. In the case of cyclic azomethine imines with an N–N bond incorporated into a ring, N-alkylidene-3-oxo-pyrazolidinium ylides are the most popular stable and isolated dipoles able to form dinitrogen-fused saturated and unsaturated pyrazolopyrazolones as racemic or enantiomerically enriched compounds present in many pharmaceuticals, agrochemicals and other useful chemicals.

Coinage Metal Complexes as Chiral Catalysts for 1,3-Dipolar Cycloadditions

In this account, we describe the experience of our research group in the implementation of chiral coinage metal complexes into the efficient enantioselective 1,3-DC of azomethine ylides derived from α-amino acids and azlactones with different dipolarophiles. The corresponding chiral metallodipoles were generated in situ and next focused on the synthesis of highly substituted prolines. For this purpose, privileged ligands such as phosphoramidites and binap with silver(I), gold(I) and copper(II) salts are described. Depending from the ligand and mainly from the metal salt it can be possible to control the facial endo/exo-diasteroselectivity and the enantioselectivity of these types of processes. The synthetic processes are also supported by DFT calculations in order to elucidate the most plausible mechanism and the stereochemical results.

Nuevos precursores de iluros de azometino para cicloadiciones 1,3-dipolares

En la presente memoria se describe la síntesis de derivados de pirrolidina, pirrolizidina e indolizidina mediante diferentes metodologías que involicruan una cicloadición 1,3-dipolar multicomponente a través de iluros de azometino generados in situ, así como el estudio cinético de esta reacción vía dos componentes. En el Capítulo I, se describen diferentes métodos de estudio cinético para la interpretación y obtención de parámetros mecanísticos de dicha reacción a partir de la información obtenida mediante Análisis Térmico y más concretamente calorimetría diferencial de barrido. En el Capítulo II, dividido en tres partes, se describe la síntesis de pirrolidinas mediante cicloadición 1,3-dipolar multicomponente (a partir de iluros de azometino) térmica y por irradiación por microondas (Parte 1), catalizada por plata(I) (Parte II) y asimétrica mediante catálisis por plata(I) y un ligando quiral (Parte III); así como la posible aplicabilidad en la síntesis de productos naturales o que presenten actividad biológica. En el Capítulo III, se describe la síntesis de pirrolizidinas mediante la cicloadición 1,3-dipolar multicomponente con iluros de azometino con y sin uso de sales de plata(I), así como un ejemplo en la construcción de un esqueleto de indolizidina siguiendo la misma metodología. Finalmente se incluyen las conclusiones junto con otro tipo de anexos como son las referencias, abreviaciones y la biografía.

Chiral gold(I) vs chiral silver complexes as catalysts for the enantioselective synthesis of the second generation GSK-hepatitis C virus inhibitor

The synthesis of a GSK 2nd generation inhibitor of the hepatitis C virus, by enantioselective 1,3-dipolar cycloaddition between a leucine derived iminoester and tert-butyl acrylate, was studied. The comparison between silver(I) and gold(I) catalysts in this reaction was established by working with chiral phosphoramidites or with chiral BINAP. The best reaction conditions were used for the total synthesis of the hepatitis C virus inhibitor by a four step procedure affording this product in 99% ee and in 63% overall yield. The origin of the enantioselectivity of the chiral gold(I) catalyst was justified according to DFT calculations, the stabilizing coulombic interaction between the nitrogen atom of the thiazole moiety and one of the gold atoms being crucial.

Enantioselective Synthesis of exo-4-Nitroprolinates from Nitro­alkenes and Azomethine Ylides Catalyzed by Chiral Phosphor­amidite·Silver(I) or Copper(II) Complexes

Chiral complexes formed by privileged phosphoramidites derived from chiral binol and optically pure Davies’ amines, and copper(II) triflate, silver(I) triflate or silver(I) benzoate are excellent catalysts for the general 1,3-dipolar cycloaddition between nitroalkenes and azomethine ylides generated from α-amino acid derived imino esters. These three methods can be conducted at room temperature to afford the exo-cycloadducts (4,5-trans-2,5-cis-4-nitroprolinates) with high diastereoselectivity and high enantioselectivity. In general, the three procedures are complementary but silver catalysts are more versatile and less sensitive to sterically congested starting materials.