N-metalated Azomethine Ylides Research Articles

Catalytic Enantioselective [3+2] Cycloaddition of N-Metalated Azomethine Ylides.

Asymmetric [3+2] cycloaddition reactions are fascinating and powerful methods for the synthesis of enantioenriched pyrrolidines up to four stereocentres. Pyrrolidines are important compounds for both biology and organocatalytic applications. This review summarizes the most recent advances in the enantioselective synthesis of pyrrolidines by [3+2] cycloadditions of azomethine ylides using metal catalysis. It has been organized by the type of metal catalysis used and further arranged by the complexity nature of dipolarophile. The presentation of each reaction type highlights their advantages and limitations.

Stereoselective Allylic Alkylation of 1-Pyrroline-5-carboxylic Esters via a Pd/Cu Dual Catalysis.

The asymmetric allylation of 1-pyrroline-5-carboxylic esters has been accomplished through a synergistic Pd/Cu catalyst system under mild reaction conditions. The mechanistic studies suggested that (1) nucleophilic attack is the enantiodiscriminating step; (2) the cooperative action of two chiral reactive species, N-metalated azomethine ylides and π-allylpalladium, is most likely responsible for its high reactivity and excellent enantioselectivity (up to >99% ee); and (3) the steric hindrance and electronic factors of the allylic electrophiles and imino ester substrates are crucial for the formation of the linear products. A series of 3,4-2 H-pyrrole derivatives bearing a quaternary stereogenic center were easily synthesized in high yields and with high to excellent regioselectivity and enantioselectivity.

Catalytic Stereodivergent Synthesis of Steroid-Fulleropyrrolidine Hybrids.

The diastereoselective synthesis of cis and trans steroid-fulleropyrrolidines hybrids by reaction of N-metalated azomethine ylides [Cu(II) or Ag(I)] with the appropriate chiral ligand and C60 is described. The experimental findings reveal that the azomethine ylide stabilized by an allylic group cycloadds to [60]fullerene in an efficient manner and with a good diastereomeric excess. Furthermore, the new generated stereocenters are fully controlled by the catalytic systems used without being influenced by the chirality of the steroid. Interestingly, by this synthetic methodology the each one of the four possible stereoisomers have efficiently been obtained and characterized by CD spectra.

Enantiodivergent Synthesis of Bis-Spiropyrrolidines via Sequential Interrupted and Completed (3 + 2) Cycloadditions.

Both (5R)- and (5S)-1,7-diazaspiro[4.4]nonan-6-ones are obtained via a sequence of interrupted and completed stepwise (3 + 2) cycloadditions between azomethine ylides and π-deficient alkenes. The only source of chirality along the whole process is an enantiopure ferrocenyl pyrrolidine catalytic ligand. When the starting imine incorporates two aryl groups or one aryl group with one electron-releasing substituent, the reaction between the azomethine ylide and the alkene stops at the first step, leading to the corresponding Michael adduct. When imines derived from p-methoxybenzaldehyde are used, the corresponding syn-α-amino-γ-nitro ester is obtained with almost complete enantiocontrol. In contrast, imines derived from benzophenone lead to the corresponding anti analogue. From this interrupted (3 + 2) cycloaddition, cis- and trans-α-amino-γ-lactams can be obtained via hydrogenation of the nitro group followed by in situ cyclization. Imines derived from these latter compounds are the precursors of N-metalated azomethine ylides from which up to four new chiral centers can be generated via completed (3 + 2) cycloaddition reactions with full regio- and diastereocontrol. Cis- and trans-γ-lactams lead to opposite bis-spiropyrrolidine enantiomers. Therefore, both enantiomeric series of spiro compounds can be obtained by means of the same catalytic system. The potential of these rigid, densely substituted homochiral compounds in medicinal chemistry is briefly described.

Synthesis of highly substituted spiropyrrolidines via 1, 3-dipolar cycloaddition reaction of N-metalated azomethine ylides. A new access to spiropyrrolines derivatives

Synthesis of highly substituted spiropyrrolidines via 1, 3-dipolar cycloaddition reaction of N-metalated azomethine ylides. A new access to spiropyrrolines derivatives

ChemInform Abstract: Stereodivergent Synthesis of Chiral Fullerenes by [3 + 2] Cycloadditions to C60.

A wide range of new dipoles and catalysts have been used in 1,3-dipolar cycloadditions of N-metalated azomethine ylides onto C60 yielding a full stereodivergent synthesis of pyrrolidino[60]fullerenes with complete diastereoselectivities and very high enantioselectivities. The use of less-explored chiral α-iminoamides as starting 1,3-dipoles leads to an interesting double asymmetric induction resulting in a matching/mismatching effect depending upon the absolute configuration of the stereocenter in the starting α-iminoamide. An enantioselective process was also found in the retrocycloaddition reaction as revealed by mass spectrometry analysis on quasi-enantiomeric pyrrolidino[60]fullerenes. Theoretical DFT calculations are in very good agreement with the experimental data. On the basis of this agreement, a plausible reaction mechanism is proposed.

Stereodivergent synthesis of chiral fullerenes by [3 + 2] cycloadditions to C₆₀.

A wide range of new dipoles and catalysts have been used in 1,3-dipolar cycloadditions of N-metalated azomethine ylides onto C60 yielding a full stereodivergent synthesis of pyrrolidino[60]fullerenes with complete diastereoselectivities and very high enantioselectivities. The use of less-explored chiral α-iminoamides as starting 1,3-dipoles leads to an interesting double asymmetric induction resulting in a matching/mismatching effect depending upon the absolute configuration of the stereocenter in the starting α-iminoamide. An enantioselective process was also found in the retrocycloaddition reaction as revealed by mass spectrometry analysis on quasi-enantiomeric pyrrolidino[60]fullerenes. Theoretical DFT calculations are in very good agreement with the experimental data. On the basis of this agreement, a plausible reaction mechanism is proposed.

Catalytic stereodivergent functionalization of H2@C60

A complete stereocontrol of 1,3-dipolar cycloaddition of N-metalated azomethine ylides onto endohedral fullerene H2@C60 is reported for the first time. The stereodivergent synthesis of either the cis or the trans endohedral cycloadduct is achieved with excellent diastereo- and enantioselectivities.

Enantioselective Cycloaddition of N-metalated Azomethine Ylides onto Fullerenes

not Available.

Stereodivergency in Catalytic Asymmetric Conjugate Addition Reactions of Glycine (Ket)imines

Stereodivergent catalytic asymmetric conjugate reactions of glycine (ket)imines with nitroalkenes have been achieved using various chiral catalyst systems derived from a multidentate amino alcohol (1). The stepwise nature of the [3 + 2] cycloaddition reactions of N-metalated azomethine ylides has also been demonstrated by highly enantio- and diastereoselective syntheses of exo-5 and endo-8 from the respective syn-4 and anti-7 conjugate addition products in a one-pot tandem fashion.

ChemInform Abstract: Cornerstone Works for Catalytic 1,3‐Dipolar Cycloaddition Reactions

AbstractReview: 42 refs.

Cornerstone Works for Catalytic 1,3-Dipolar Cycloaddition Reactions

This review covers the following subjects: (1) The chemistry of N-metalated azomethine ylide as a new 1,3-dipole containing a metal atom is studied. This 1,3-dipole, generated from (N-alkylideneamino)alkanoates upon treatment with a Lewis acid and amine base, undergoes rapid 1,3-dipolar cycloadditions toward electron-deficient alkenes. Especially, α,β-unsaturated carbonyl substrates show high rate acceleration to give pyrrolidine-2,4-dicarboxylates in a highly regio- and endo-selective manner. (2) This 1,3-dipolar cycloaddition reaction of (N-alkylideneamino)acetate can be switched into anti-selective Michael addition reaction by modification of substrate structures as well as reaction conditions. (3) Two types of heterocyclic chiral auxiliaries are demonstrated for the asymmetric 1,3-dipolar cycloadditions. One types are attached at the β-position of α,β-unsaturated esters. The resulting chiral α,β-unsaturated esters are successfully applied to the stereoselective asymmetric cycloadditions of N-metalated azomethine ylides. The other types include 4-benzyl-2,2,5,5-tetramethyloxazolidine-3-acrylamides which are based on the conformational control of the acrylamide reaction site and that of steric shielding of 4-benzyl amoiety. These are applied to the absolutely asymmetric nitrile oxide cycloadditions. (4) The nitrone cycloadditions to electron-deficient alkenes is attained in the presence of a Lewis acid catalyst. This provides the first catalytic stereo control of 1,3-dipolar cycloadditions. (5) The extremly effective rate enhancement of nitrile oxide 1,3-dipolar cycloadditions to the magnesium alkoxides of allylic alcohols. Maximum rate enhancement observed is 16,000 fold rate acceleration of the uncatalyzed reaction. This method offers the first successful rate acceleration in nitrile oxide 1,3-dipolar cycloadditions. (6) Use of magnesium alkoxide of allylic alcohols is also highly effectve in nitrone 1,3-dipolar cycloadditons, resulting in high stereo- and regioselectivities. (7) Catalytic enantioselective 1,3-dipolar cycloadditions are achieved by use of nitrones, nitronates, diazomethane, and nitrile oxides in the presence of tolerant chiral catalysts based on our R,R-DBFOX/Ph ligand.

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.

Stereoselective 1,3-Dipolar Cycloaddition of a Maleate Derivative with Azomethine Ylides Derived from α-Amino Esters: Synthesis of 3-Pyrrolines

A new preparation of 3-pyrrolines is described by [3+2] cycloadditions of N-metalated azomethine ylides derived from α-amino esters with a dimethyl 7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate derivative, followed by retro-Diels-Alder reactions. This two-step sequence appears superior to the direct reaction of ylides with dimethyl acetylenedicarboxylate and should be applicable to solid-phase synthesis.

Stereocontrolled formation of substituted imidazolidines in the reaction between N-metalated azomethine ylides and isocyanates

Stereocontrolled formation of substituted imidazolidines in the reaction between N-metalated azomethine ylides and isocyanates

Hetero [6+3] cycloaddition of fulvenes with N-alkylidene glycine esters: a facile synthesis of the delavayine and incarvillateine framework.

[reaction: see text] In contrast to the [3+2] or [4+3] cycloaddition of N-metalated azomethine ylides and various alkenes, N-benzylidene glycine ethyl ester reacts with fulvenes to give the hetero [6+3] cycloaddition adducts with high stereoselectivity, constituting an efficient and novel route to [2]pyrindines.

Stereoselective synthesis of 5-(4 1-azetidinyl)-proline esters via 1,3-dipolar cycloaddition reaction of N-metalated azomethine ylides

The conformationally locked s- trans enone functionality present in the ( E)-3-arylidene-4-chromanones undergo regioselective 1,3-dipolar cycloaddition reaction with N-metalated azomethine ylides derived from β-lactam imines of glycine methyl ester in the presence of silver acetate to give spiropyrrolidines in moderate to good yield. The regio and stereochemistry of the cycloadducts have been established by single crystal X-ray structure and spectroscopic techniques.

Metal‐Assisted Stereocontrol of 1,3‐Dipolar Cycloaddition Reactions.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Asymmetric 1,3-dipolar cycloaddition of N-metalated azomethine ylides to methyl (S)-2-(p-tolylsulfinyl)acrylate. Synthesis of optically pure 2,4,5-trisubstituted 2,5-dihydro-1H-pyrroles.

The first 1,3-dipolar reaction of azomethine ylides with optically pure vinyl sulfoxide are reported. The presence of the sulfinyl group increase the reactivity of the acrylate moiety as a dipolarophile, and the reactions evolve with complete regio- and endo-selectivities. Nevertheless, mixtures of the two diastereoisomers 4 and 5 (75-88% de) resulting from the anti dipole/s-cis dipolarophile and syn dipole/s-trans dipolarophile approaches, respectively, are obtained. The stereoselectivity can be controlled by using THF or MeCN as solvents or by changing the reaction temperature in MeCN. After separation of the cycloadducts, optically pure 2,5-dihydro-1H-pyrroles are easily obtained by pyrolytic desulfinylation.

Metal-Assisted Stereocontrol of 1,3-Dipolar Cycloaddition Reactions

A study on the metal ion-mediated stereo- and regiocontrol of 1,3-dipolar cycloaddition reactions, which have been developed and established in Kyushu University in Kasuga, is reviewed in this account. The first success involves the generation of metal-containing 1,3-dipoles. N-Metalated azomethine ylides are generated under reversible and irreversible conditions and undergo exclusively endo-selective 1,3-dipolar cycloadditions with carbonyl-activated alkenes through the chelated transition structure. The closely related intermediates derived from bulky imine esters can be utilized for the anti-selective Michael additions. The second topic is the regio- and syn-sclective nitrone and nitrile oxide cycloadditions to allylic alcohols in the presence of magnesium ions. These reactions are magnesium ion specific. Lewis acid-mediated nitrone cycloadditions to electron-deficient alkenes have been also been discovered in Kasuga and this discovery was a starting point for the chiral Lewis acid catalyzed enantioselective nitrone cycloadditions. With powerful Lewis acid catalysts in hand, the author's group has developed highly efficient enantioselective nitrone cycloadditions and diazo cycloadditions catalyzed by the transition metal aqua complexes derived from the DBFOX/Ph ligand.