A convenient procedure for the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides and alkenes

[reaction: see text] Silver fluoride and cinchona alkaloids catalyze the diastereo- and enantioselective 1,3-dipolar cycloaddition between azomethine ylides, generated from N-alkylideneglycine esters, and acrylates to give the corresponding endo-adducts. Azomethine ylides derived from aromatic and aliphatic aldehydes react in a highly diastereoselective reaction with good yields and enantioselectivities of the substituted pyrrolidines.     

A diastereoselective three-component coupling approach to highly substituted pyrrolidines

Building on the observation that metal complexation facilitates azomethine ylide formation, we report that chelating aldehydes participate in metal-templated, one-pot reactions with unprotected amino acid esters and activated olefins to provide highly substituted pyrrolidines. The high yields, broad substrate scope, excellent diastereoselectivities, functional group tolerance, and incorporation of commercially available materials in this reaction simplifies access to medicinally relevant proline derivatives.     

An amine-catalyzed enantioselective [3+2] cycloaddition of azomethine ylides and α,β-unsaturated aldehydes: applications and mechanistic implications

The catalytic enantioselective [3+2] cycloaddition between azomethine ylides and α,β-unsaturated aldehydes catalyzed by α,α-diphenylprolinol has been studied in detail. In particular, the reaction has been extended to the use of 2-alkenylidene aminomalonates generated in situ as azomethine ylide precursors. These reactions lead to the formation of pyrrolidines containing a 5-alkenyl side chain with potential for chemical manipulation. Moreover, a detailed and concise computational study has been carried out to understand the exact nature of the mechanism of this reaction and especially the consequences derived from the incorporation of the chiral secondary amine catalyst on the reaction pathway.     

An Amine‐Catalyzed Enantioselective [3+2] Cycloaddition of Azomethine Ylides and α,β‐Unsaturated Aldehydes: Applications and Mechanistic Implications

The catalytic enantioselective [3+2] cycloaddition between azomethine ylides and α,β‐unsaturated aldehydes catalyzed by α,α‐diphenylprolinol has been studied in detail. In particular, the reaction has been extended to the use of 2‐alkenylidene aminomalonates generated in situ as azomethine ylide precursors. These reactions lead to the formation of pyrrolidines containing a 5‐alkenyl side chain with potential for chemical manipulation. Moreover, a detailed and concise computational study has been carried out to understand the exact nature of the mechanism of this reaction and especially the consequences derived from the incorporation of the chiral secondary amine catalyst on the reaction pathway.     

Regioselective Synthesis of Novel Spirooxindolo and Spiroindano Nitro Pyrrolidines Through 3+2 Cycloaddition Reaction

β‐Nitro styrene reacts with nonstabilized azomethine ylides generated from isatin/ninhydrin with sarcosine, resulting in the formation of a series of spiroxindolo nitro pyrrolidines, and spiroindano nitro pyrrolidines, respectively, in good yields. It was noted that in a one‐pot 3+2 cycloaddition reaction, the azomethine ylides generated from isatin and ninhydrin have reacted with the β‐nitro styrenes regiochemically in opposite ways.     

A new chiral phosphine oxide ligand for enantioselective 1,3-dipolar cycloaddition reactions of azomethine ylides

A new set of phosphorus-containing chiral ligands has been synthesized and used with silver(I) for the catalytic asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides. One of these ligands (POFAM6) was found to produce an effective catalyst for the asymmetric 1,3-dipolar cycloaddition reaction of azomethine ylides with electron deficient dipolarophiles to form pyrrolidines in up to 97% yield and 89% ee.     

Synthesis of chromeno[4,3-b]pyrrolidines from azomethine ylides and vinyl para-quinone methides via (3 + 2) cycloaddition/oxa-1,6-addition

An efficient synthesis of chromeno[4,3-b]pyrrolidines has been successfully developed. This strategy involves a base-catalyzed reaction of p-VQMs and o-hydroxy azomethine ylides via (3 + 2) cycloaddition/oxa-1,6-addition reaction sequence. The reaction condition is mild, and a series of chromeno[4,3-b]pyrrolidines were obtained in 49-95% yields with excellent diastereoselectivity (dr > 20:1).     

Generation and cycloaddition of polymer-supported azomethine ylide via a 1,2-silatropic shift of alpha-silylimines: traceless synthesis of pyrrolidine derivatives

The 1,3-dipolar cycloaddition of polymer-supported azomethine ylides to dipolarophiles gave pyrrolidine derivatives in good yields. The azomethine ylides were generated from resin-bound alpha-silylimines via a 1,2-silatropic shift. The features of this method are not only a traceless synthesis but also a unique solid-phase route to pyrrolidines with extensive diversity. [reaction: see text]     

Stereoselective synthesis of functionalized pyrrolidines by ruthenium porphyrin-catalyzed decomposition of alpha-diazo esters and cascade azomethine ylide formation/1,3-dipolar cycloaddition reactions

[reaction: see text] Ruthenium porphyrins catalyze three-component coupling reaction of alpha-diazo esters with a series of N-benzylidene imines and alkenes to form functionalized pyrrolidines in excellent diastereoselectivities. The reaction proceeds via a reactive ruthenium-carbene intermediate and its subsequent reaction with imine to generate azomethine ylide, which reacts with alkenes via 1,3-diploar cycloaddition.     

Diastereoselective synthesis of pyrrolidines via 1,3-dipolar cycloaddition of a chiral azomethine ylide

1,3-Dipolar cycloaddition of d-glucose-derived azomethine ylides for the synthesis of chiral pyrrolidines accompanied an unexpected 1,2-elimination in the furanose moiety of the products. The C3′ alkoxy/hydroxy group of the furanose moiety was invariably eliminated under the reaction conditions. Also, in contrast to the previous reports, moderate to good exo-diastereoselectivity was observed in the reaction products.     

Brønsted acid catalyzed regioselective aza-Ferrier reaction: a novel synthetic method for alpha-(N-Boc-2-pyrrolidinyl) aldehydes

The 1,4-elimination reaction of (Z)-N-Boc-2-(4-methoxy-2-alkenyloxy)pyrrolidines is shown to proceed with high (1E,3E)-stereoselectivity to afford N-Boc-2-(1,3-dienyloxy)pyrrolidines; the Br?nsted acid catalyzed aza-Ferrier reaction of the N-Boc-2-(1,3-dienyloxy)pyrrolidines (3) provides alpha-(N-Boc-2-pyrrolidinyl) aldehydes in excellent yields with high alpha-regioselectivities.     

One-pot synthesis of dihydroquinazolinethione-based polycyclic system

A one-pot and diastereoselective synthesis of quinazoline-2(1H)-thione-containing polycyclic compounds is introduced. The reaction process includes [3?+?2] cycloaddition of azomethine ylides for pyrrolidines, Staudinger-aza-Wittig reaction of azides for iminophosphoranes, formation of isothiocyanates, and finally cyclization of amines to isothiocyanates for dihydroquinazolinethiones.     

One-Pot,Three-Component Cycloaddition of Nonstabilized Azomethine Ylides to β-Nitrostyrene,a Highly Electron Deficient Dipolarophile

A facile route to tetra-substituted pyrrolidines has been accomplished by 1,3-dipolar cycloaddition reaction. Several pyrrolidine compounds have significant biological activity. A highly electron-deficient dipolarophile, β-nitrostyrene, was reacted with nonstabilized azomethine ylides derived from aryl aldehyde and L-phenylglycine in dry dimethyl formanide. The structures and stereochemistry of the cycloadducts were established by infrared, NMR spectroscopy, and single-crystal x-ray crystallographic analyses.     

Diastereofacial selectivity in azomethine ylide cycloaddition reactions derived from chiral α-cyanoaminosilanes

A series of α-cyanoaminosilanes has been found to act as azomethine ylide equivalents. Treatment of these compounds with silver fluoride in the presence of electron deficient olefins gives substituted pyrrolidines in high yield. The extent ofdiastereoselectivity associated with the 1,3-dipolar cycloaddition of chiral azomethine ylides with several dipolarophiles has been studied. Reasonable levels of such diastereoselectivity have been found when optically active α-cyanoaminosilanes are employed as azomethine ylide equivalents. These compounds can be prepared in multigram quantities by treating the appropriate chiral amine with chlorotrimethylsilane followed by reaction of the resulting secondary amine with formaldehyde in the presence of potassium cyanide. It was found that N-benzyl-N-cyanomethyl-N-trimethylsilylmethylamine undergoes stereospecific cycloaddition with dimethyl fumarate and maleate. The stereospecificity of the reaction is consistent with a concerted cycloaddition reaction.     

Synthesis of Highly Substituted Pyrrolidines Through 1,3-Dipolar Cycloaddition Reaction of N-Metalated Azomethine Ylides with Triarylideneacetylacetone as Dipolarophile Using Titanocene Dichloride

The 1,3-dipolar cycloaddition reaction of tryarylideneacetyacetone derivatives with N-metalated azomethine ylides in the presence of titanocene dichloride and triethylamine has been investigated. This two-step synthetic sequence is very efficient and yielded the highly substituted pyrrolidines in good yields. The structure and stereochemistry of one of the products has been established by single-crystal x-ray structure and spectroscopic techniques.     

Binaphthol-derived bisphosphoric acids serve as efficient organocatalysts for highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides to electron-deficient olefins

A variety of chiral bisphosphoric acids derived from binaphthols have been evaluated for enantioselective 1,3-dipolar cycloaddition reactions, revealing that the feature of the linker in the catalysts exerted great impact on the stereoselectivity. Among them, the oxygen-linked bisphosphoric acid 1a provided the highest level of stereoselectivity for the 1,3-dipolar cycloaddition reaction tolerating a wide range of substrates including azomethine ylides, generated in situ from a broad scope of aldehydes and α-amino esters, and various electron-deficient dipolarophiles such as maleates, fumarates, vinyl ketones, and esters. This reaction actually represents one of the most enantioselective catalytic approaches to access structurally diverse pyrrolidines with excellent optical purity. Theoretical calculations with DFT method on the formation of azomethine ylides and on the transition states of the 1,3-dipolar cycloaddition step showed that the dipole and dipolarophile were simultaneously activated by the bifunctional chiral bisphosphoric acids through the formation of hydrogen bonds. The effect of the bisphosphoric acids on reactivity and stereochemistry of the three-component 1,3-dipolar cycloaddition reaction was also theoretically rationalized. The bisphosphoric acid catalyst 1a may take on a half-moon shape with the two phosphoric acid groups forming two intramolecular hydrogen bonds. In the case of maleates, one phosphate acts as a base to activate the 1,3-dipole, and simultaneously, the two hydroxyl groups in the catalyst 1a may respectively form two hydrogen bonds with the two ester groups of maleate to make it more electronically deficient as a much stronger dipolarophile to participate in a concerted 1,3-dipolar cycloaddition with azomethine ylide. However, in the cases involving acrylate and fumarate dipolarophiles, only one hydroxyl group forms a hydrogen bond with the ester functional group to lower the LUMO of the C-C double bond and another one is remained to adjust the acidity and basicity of two phosphoric acids to activate the dipole and dipolarophile more effectively.     

Catalytic,three-component assembly reaction for the synthesis of pyrrolidines

[reaction: see text] Copper(I) salts catalyze the three-component assembly reaction between an alpha-diazo ester, an imine, and various alkenes and alkynes to form substituted pyrrolidines with excellent to good diastereoselectivities in high yields. The transition metal-catalyzed decomposition of the alpha-diazo compound in the presence of the imine likely generates a transient azomethine ylid that undergoes addition with various dipolarophiles in a highly convergent manner.     

Chemoselective 1,3-dipolar cycloadditions of azomethine ylide with conjugated dienes

Methods are described of synthesizing various 3-carboxy-4-vinyl pyrrolidines, versatile building blocks for our drug discovery efforts. The 1,3-dipolar cycloaddition between activated olefins and nonstabilized azomethine ylide is a known method for synthesizing pyrrolidines in a stereospecific manner. Steric and electronic effects on the chemoselectivity of the 1,3-dipolar cycloaddition between azomethine ylide and α,β,γ,δ-unsaturated carboxylates have been explored.     

Asymmetric synthesis of cis- and trans-2,5-disubstituted pyrrolidines from 3-oxo pyrrolidine 2-phosphonates: synthesis of (+)-preussin and analogs

Pyrrolidine enones, derived from 3-oxo pyrrolidine 2-phosphonates and a HWE reaction with aldehydes, on Luche reduction give pyrrolidine allylic alcohols. The alcohols on hydrogenation (Pd/H2) give cis-2,5-disubstituted pyrrolidines and on treatment with TFA-NaBH3CN undergo a hydroxy directed reduction to trans-2,5-disubstituted pyrrolidines.     

Microwave-assisted [3 + 2] cycloadditions of azomethine ylides

The microwave-assisted intramolecular [3 + 2] cycloaddition reaction of azomethine ylides to activated and nonactivated alkenes and alkynes is described. The procedure allows the synthesis of pyrrolidines and pyrrole products in good to excellent overall yields in short reaction times. It appears from parallel comparative studies that the microwave procedure favors the reaction times and overall purity of the crude reaction mixture. The reactions can also be performed in the absence of solvent. [reaction: see text]