Glycine Imino Ester Research Articles

Silver/Segphos‐Catalyzed Asymmetric 1,3‐Dipolar Cycloaddition for the Enantioselective Synthesis of Pyrrolidine Spirooxindoles

Enantioselective synthesis of chiral heterocyclic derivatives is an important and challenging topic in the field of synthetic chemistry. In this work, a silver‐catalyzed asymmetric 1,3‐dipolar cycloaddition of glycine iminoesters with 3‐isopropylidene‐2‐oxindoles was developed. The DTBM‐Segphos‐induced spirooxindole cycloaddition reaction was used to synthesize a range of stereodivergent alkyl‐substituted 3‐methylene‐2‐oxindoles, achieving excellent enantioselectivities (up to 99% ee), good diastereoselectivities (up to 20:1 dr), and high yields under mild reaction conditions. Computational insights from DFT calculations indicate that the Michael addition step is crucial in determining the reaction rate and enantioselectivity.

Modular Access to Tetrasubstituted N−H Pyrroles by Catalytic 1,3‐Dipolar Cycloaddition of Azomethine Ylides and α,β‐Ynones

AbstractThe development of efficient synthetic strategies for the preparation of tetrasubstituted N−H pyrrole derivatives, especially in an environmentally benign fashion is important yet challenging. Herein, we report a copper(II)‐catalyzed tandem reaction involving 1,3‐dipolar cycloaddition of α,β‐ynones and glycine iminoesters, followed by copper(II)‐promoted oxidative (air) dehydrogenative aromatization, allowing de novo access to tetrasubstituted N−H pyrroles in up to 81 % yield under green reaction conditions. A possible reaction pathway is tentatively proposed. Finally, fully substituted pyrroles are available by N‐alkylation, and a preliminary phase‐transfer catalytic asymmetric N‐alkylation was also studied to give an axially chiral pyrrole.

Synthesis of Spirocyclic Pyrrolidine Compounds via Silver-Catalyzed Asymmetric [3 + 2] Cycloaddition Reaction of Imino Esters with α-Alkylidene Succinimides.

In this study, the AgOAc/ThioClickFerrophos (TCF) complex was used to successfully catalyze asymmetric [3 + 2] cycloaddition between glycine imino esters and CO2Me-appended α-alkylidene succinimides to afford spiropyrrolidines in good yields with high diastereo- and enantioselectivities (up to 95% ee). The silver/TCF afforded endo-(2,5-cis) cycloadducts in contrast to the previous exo'-(2,5-trans) selective reaction with ylidene-2,3-dioxopyrrolidine. A wide variety of imino esters bearing electron-donating and electron-withdrawing groups on the phenyl groups and heteroaryl substrates were utilized in this reaction. The scope of α-alkylidene succinimides was investigated, which revealed that substituents on α-benzylidene derivatives had negligible effect on the product yield and stereoselectivity, and α-alkylidene derivatives could be efficiently used as dipolarophiles.

Regioselective Construction of Coumarin-1,2,4-triazines via a Cs2CO3-Catalyzed [3+3] Cycloaddition Reaction

AbstractA cesium carbonate (Cs2CO3)-catalyzed [3+3] cycloaddition reaction of coumarin-diazo reagents with glycine imino esters is established to produce tetrahydro-1,2,4-triazines in good yields with excellent regioselectivity. One-pot cycloaddition/oxidation protocol could further provide practical access to a series of new coumarin-decorated 1,2,4-triazines.

Simple Rules for Complex Near-Glass-Transition Phenomena in Medium-Sized Schiff Bases.

Glass-forming ability is one of the most desired properties of organic compounds dedicated to optoelectronic applications. Therefore, finding general structure–property relationships and other rules governing vitrification and related near-glass-transition phenomena is a burning issue for numerous compound families, such as Schiff bases. Hence, we employ differential scanning calorimetry, broadband dielectric spectroscopy, X-ray diffraction and quantum density functional theory calculations to investigate near-glass-transition phenomena, as well as ambient- and high-pressure molecular dynamics for two structurally related Schiff bases belonging to the family of glycine imino esters. Firstly, the surprising great stability of the supercooled liquid phase is shown for these compounds, also under high-pressure conditions. Secondly, atypical self-organization via bifurcated hydrogen bonds into lasting centrosymmetric dimers is proven. Finally, by comparing the obtained results with the previous report, some general rules that govern ambient- and high-pressure molecular dynamics and near-glass transition phenomena are derived for the family of glycine imino esters. Particularly, we derive a mathematical formula to predict and tune their glass transition temperature (Tg) and its pressure coefficient (dTg/dp). We also show that, surprisingly, despite the presence of intra- and intermolecular hydrogen bonds, van der Waals and dipole–dipole interactions are the main forces governing molecular dynamics and dielectric properties of glycine imino esters.

Silver/ThioClickFerrophos-Catalyzed 1,3-Dipolar Cycloaddition and Tandem Addition-Elimination Reaction of Morita-Baylis-Hillman Adducts.

The asymmetric 1,3-dipolar cycloaddition of glycine imino esters to Morita-Baylis-Hillman (MBH) adducts or acetylated MBH adducts is described. The reaction was efficiently catalyzed by AgOAc/(R,Sp)-ThioClickFerrophos at room temperature to afford pyrrolidine derivatives bearing a quaternary carbon as a single diastereomer with excellent enantioselectivity. When a cyclic pyrroline ester was used as the nucleophile instead of a glycine imino ester, the enantioselective tandem addition-elimination reaction with an acetylated MBH adduct proceeded with an excellent yield and enantioselectivity, resulting in the formation of an exo-olefin. The wide substrate scope of these reactions and the transformability of the products enable expeditious access to divergent multifunctionalized pyrrolidines in an optically pure fashion.

Synergistic Pd/Cu catalysis for stereoselective allylation of vinylethylene carbonates with glycine iminoesters: Enantioselective access to diverse trisubstituted allylic amino acid derivatives

We reported a synergistic Pd/Cu catalyzed enantioselective decarboxylative allylation of vinylethylene carbonates with glycine iminoesters, which provides facile access to non-proteinogenic diverse trisubstituted allylic amino acid derivatives in high yields, exclusive regioselectivities and excellent stereoselectivities. This reaction tolerates a wide range of γ and β-aryl substituted vinylethylene carbonates with either electron-donating or electron-withdrawing groups. Significantly, this method was proven to be sufficient in the gram scale synthesis of chiral trisubstituted allylic amino acid while retaining the enantioselectivity and geometric control.

Copper-Catalyzed Asymmetric 1,3-Dipolar Cycloaddition of Imino Esters to Unsaturated Sultones.

The asymmetric 1,3-dipolar cycloaddition of glycine imino esters to 1-propene-1,3-sultone or sulfocoumarins is described. The reaction was efficiently catalyzed by Cu(MeCN)4BF4/DTBM-Segphos or Cu(MeCN)4BF4/tBu-FcPhox at room temperature to afford fused pyrrolidines as single regioisomers with excellent diastereoselectivity and enantioselectivity. The broad substrate scope of this reaction provides convenient access to structurally diverse multisubstituted pyrrolidines in an optically pure fashion.

Silver-Catalyzed [3+3] Annulation of Glycine Imino Esters with Seyferth–Gilbert Reagent To Access Tetrahydro-1,2,4-triazinecarboxylate Esters

A silver-catalyzed protocol for [3+3] annulation of glycine imino esters with Seyferth–Gilbert reagent was developed. A variety of phosphorylated tetrahydro-1,2,4-triazinecarboxylate esters were synthesized in moderate to good yields and with excellent diastereoselectivities. The dehydrogenation of a tetrahydro-1,2,4-triazine product to the corresponding triazine counterpart was also demonstrated.

Copper(i)/Ganphos catalysis: enantioselective synthesis of diverse spirooxindoles using iminoesters and alkyl substituted methyleneindolinones.

A copper-catalyzed asymmetric 1,3-dipolar cycloaddition of glycine iminoesters with alkyl substituted 3-methylene-2-oxindoles is described. By using de novo design of P-stereogenic phosphines as ligands, spiro[pyrrolidin-3,3'-oxindole]s are generated in good to excellent yields with high asymmetric induction. A further reduced catalyst loading of 0.1 mol% is sufficient to achieve a satisfactory enantioselectivity of 90% ee. The DFT calculations suggest the second Michael addition of the 1,3-dipole to be the rate- and enantio-determining step. A key feature of this 1,3-dipolar cycloaddition is the wide substrate applicability, even with alkyl aldehyde-derived azomethine ylide; thus it has streamlined a highly enantioselective access to a new class of antiproliferative agents, MDM2-p53.

Enantioselective Mannich Reaction of Glycine Iminoesters with N-Phosphinoyl Imines: A Bifunctional Approach.

A bifunctional catalytic approach for the asymmetric Mannich reaction of glycine iminoesters with N-phosphinoyl imines has been developed. By the combination of metal catalysis and organocatalysis, the vicinal two stereogenic centers were efficiently constructed, affording a wide range of syn-diamino esters in high yields with excellent enantio- and diastereoselectivities (up to >99:1 dr, 99% ee).

Copper‐Catalyzed Regio‐ and Diastereoselective 1,3‐Dipolar Cycloaddition Reactions of Glycine Imino Esters with 1‐Propene‐1,3‐sultone

The 1,3‐dipolar cycloaddition of glycine imino esters (azomethine ylide precursors) with 1‐propene‐1,3‐sultone proceeded smoothly by using copper phosphine complexes at room temperature to give the bicyclic sultone‐fused pyrrolidines as single regio‐ and stereoisomers in good yields. A preliminary asymmetric reaction with a chiral copper complex gave the fused sultone‐pyrrolidine with excellent enantioselectivity.

Silver-Catalyzed Diastereo- and Enantioselective Michael Addition and 1,3-Dipolar Cycloaddition Reactions of Imino Esters to 3-Methyl-4-nitro-5-styrylisoxazoles.

The AgOAc/ThioClickFerrophos complex catalyzed conjugate additions and 1,3-dipolar cycloadditions of 3-methyl-4-nitro-5-styrylisoxazoles with 1-pyrroline-5-carboxylates and glycine imino esters to give the corresponding Michael adducts and cycloadducts, respectively, in good yields with excellent diastereo- and enantioselectivities. These reactions can provide pyrroline- or pyrrolidine-containing isoxazole hybrid molecules that have potential biological and pharmaceutical activities.

ChemInform Abstract: Bifunctional AgOAc/ThioClickFerrophos Catalyzed Asymmetric 1,3‐Dipolar Cycloaddition Reaction of Azomethine Ylides to Nitroalkenes

Abstract18 examples

Bifunctional AgOAc/ThioClickFerrophos catalyzed asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides to nitroalkenes

AgOAc/ThioClickFerrophos (TCF) complex catalyzed the 1,3-dipolar cycloaddition of azomethine ylides (glycine imino ester) to nitroalkenes. The corresponding endo-cycloadducts (88:12–98:2 endo/exo) were afforded in good yields with high enantioselectivities, up to 98% ee, without addition of external amine. AgOAc/TCF works as a bifunctional (Lewis acid and base) catalyst.

ChemInform Abstract: Remote Substituent Effects on the Stereoselectivity and Organocatalytic Activity of Densely Substituted Unnatural Proline Esters in Aldol Reactions.

AbstractDensely substituted proline esters are prepared by asymmetric [3+2] cycloadditions of azomethine ylides derived from glycine iminoesters.

Remote Substituent Effects on the Stereoselectivity and Organocatalytic Activity of Densely Substituted Unnatural Proline Esters in Aldol Reactions

AbstractThe organocatalytic activities of highly substituted proline esters obtained through asymmetric [3+2] cycloadditions of azomethine ylides derived from glycine iminoesters have been analyzed by 19F NMR and through kinetic isotope effects. Kinetic rate constants have been determined for unnatural proline esters incorporating different substituents. It has been found that exo‐L and endo‐L unnatural proline methyl esters yield opposite enantiomers in aldol reactions between cyclic ketones and aromatic aldehydes. The combined results reported in this study show subtle and remote effects that determine the organocatalytic behavior of these synthetic but readily available amino acid derivatives. These data can be used as design criteria for the development of new pyrrolidine‐based organocatalysts.

Synthesis of α,β-diamino acid derivatives via asymmetric Mannich reactions of glycine imino esters catalyzed by a chiral phosphoramidite·silver complex

AgOTf·phosphoramidite complexes efficiently catalyze the enantioselective Mannich-type reaction between benzophenone-imine glycine methyl ester and N-tosyl aldimines in the absence of a base. The corresponding syn-adducts, which are the direct precursors of α,β-diamino acids, are obtained with moderate to good syn-diastereoselectivities (up to 9:1) and high enantioselectivities (up to 99% ee).

ChemInform Abstract: Asymmetric Organocatalysis Combined with Metal Catalysis: Concept, Proof of Concept, and Beyond

AbstractReview: 74 refs.

ChemInform Abstract: Bifunctional AgOAc/ThioClickFerrophos Complex‐Catalyzed Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Ylides with Aryl‐ and Alkylidene Malonates.

Abstract AgOAc/ThioClickFerrophos complex-catalyzed 1,3-dipolar cycloaddition of glycine imino ester, the precursor of azomethine ylide, with aryl- and alkylidene malonates afforded the corresponding exo-cycloadducts, that is, proline ester derivatives in high yields with high enantiomeric excess (up to 99% ee). The reactions proceeded smoothly under base-free conditions demonstrating the bifunctional catalysis of the silver complex.