Inverse electron demand asymmetric cycloadditions of cyclic carbonyl ylides catalyzed by chiral Lewis acids—Scope and limitations of diazo and olefinic substrates

High enantioselectivities (94-96% ee) were obtained for the inverse electron-demand 1,3-dipolar cycloadditions between cyclohexyl vinyl ether and 2-benzopyrylium-4-olate generated via Rh₂(OAc)₄-catalyzed decomposition of o-methoxycarbonyl-α-diazoacetophenone. The reactions were effectively catalyzed by Eu(OTf)₃, Ho(OTf)₃, or Gd(OTf)₃ complexes (10 mol %) of chiral 2,6-bis[(4S,5S)-4,5-diphenyl-2-oxazolinyl]pyridine. The reactions with the other electron-rich dipolarophiles such as allyl alcohol, 2,3-dihydrofuran, and butyl-tert-butyldimethylsilylketene acetal showed moderate enanantioselectivities (60-73% ee). Good to high enantioselectivities (73-97% ee) were also obtained for the cycloadditions between 3-acyl-2-benzopyrylium-4-olates, generated from methyl 2-(2-diazo-1,3-dioxoalkyl)benzoates and butyl or cyclohexyl vinyl ethers, in the presence of binaphthyldiimine (BINIM)-Ni(II) complexes (10 mol %). Under similar conditions, the reaction between methyl 2-(2-diazo-1,3-dioxohexyl)benzoate and 2,3-dihydrofuran was highly endo-selective, and moderately enantioselective (70% ee). For the BINIM-Ni(II)-catalyzed reactions of cyclohexyl vinyl ether, the use of an epoxyindanone as the 3-acyl-2-benzopyrylium-4-olate precursor revealed that the chiral Lewis acid can function as a catalyst for asymmetric induction. The scope of the cyclic carbonyl ylides was extended to those generated from 1-diazo-2,5-pentanedione derivatives, which were reacted with butyl or TBS vinyl ether and catalyzed using the (4S,5S)-Pybox-4,5-Ph₂-Lu(OTf)₃ complex to give good levels of asymmetric inductions (75-84% ee).     

Intramolecular cycloaddition of azomethine ylides, from imines of O-acylsalicylic aldehyde and ethyl diazoacetate, to ester carbonyl--experimental and DFT computational study

Intramolecular 1,3-dipolar cycloaddition of alkoxycarbonyl-substituted azomethine ylides to ester carbonyl was realized for the first time in the reaction of imines of O-acylsalicylic aldehyde with ethyl diazoacetate in the presence of Cu(tfacac)(2). The stereoselectivity of the cycloaddition is explained using DFT calculations.     

A convenient one-pot approach to Paclitaxel (Taxol) side chain via 1,3-dipolar cycloaddition of carbonyl ylides and N-benzoylbenzyl imines

An efficient cascade approach to α-hydroxy-β-amino acid derivatives is reported, which goes through a 1,3-dipolar cycloaddition of carbonyl ylides and N-benzoylbenzyl imines and followed by hydrolysis under acidic conditions. This is the first example of using N-benzoylbenzyl imine as dipolarophile for 1,3-dipolar cycloaddition with carbonyl ylide, which provides a direct and convenient access for the one-pot synthesis of paclitaxel side chain and its derivatives.     

Highly enantioselective copper(I)-fesulphos-catalyzed 1,3-dipolar cycloaddition of azomethine ylides

The catalyst system formed by Cu(CH3CN)4ClO4 and the planar chiral P,S-ligand Fesulphos behaves as a very efficient chiral Lewis acid in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. This catalyst shows a remarkable reactivity at low catalyst loading (0.5-3 mol %), affording in good yields the endo adducts with exceptional levels of enantioselectivity (up to >99% ee). This catalytic asymmetric procedure has a broad structural scope with regard to both azomethine and dipolarophile substitution. The first examples of catalytic asymmetric 1,3-dipolar cycloaddition with ketimine-derived azomethines are reported.     

Reactions of diazo esters with electron-deficient alkenes in the presence of Lewis acids

1,3-Dipolar cycloaddition reaction of diazo esters to electron-deficient dipolarophiles to yield the corresponding 1- or 2-pyrazolines was found to be significantly accelerated with Lewis acids (Yb(OTf)₃, Sc(OTf)₃, GaCl₃, EtAlCl₂). The use of GaCl₃ as the catalyst leads to the acceleration not only of the 1,3-dipolar cycloaddition reaction, but also subsequent insertion of the CHCO₂Me electrophilic fragment of methyl diazoacetate into the N-H bond of 2-pyrazolines formed. Such Lewis acids as SnCl₄, BF₃, TiCl₄, and In(OTf)₃ are not efficient in the described processes, since they rapidly decompose starting diazo compounds.     

Regioselective synthesis of mono- and bis-decahydrobenzocarbazoles via tandem reactions of α-diazo ketones

Regioselective intermolecular 1,3-dipolar cycloaddition reactions of rhodium generated carbonyl ylides with indoles are reported in this paper. Intermolecular 1,3-dipolar cycloaddition reactions of five-membered-ring cyclic carbonyl ylides with indole and substituted indoles afforded hexahydro-2H-carbazol-2-ones in a regioselective manner. Similarly, reactions of cyclic carbonyl ylides were carried out to afford decahydrobenzo[c]carbazoles or decahydrocyclopenta[c]carbazoles with high regioselectivity. Interestingly, the other possible regioisomer decahydrobenzo[a]carbazoles were also obtained by the reaction of cyclic carbonyl ylides and indoles having electron withdrawing substituents. The structure and stereochemistry of regioisomers 6,11c-epoxy-1,2,3,4,4a,5,6,6a,11b,11c-decahydro-4a-methyl-5-oxo-7H-benzo[c]carbazole and 11-benzenesulfonyl-6,11b-epoxy-2,3,4,4a,5,6,6a,11,11a,11b-decahydro-4a-methyl-5-oxo-1H-benzo[a]carbazole were unequivocally corroborated by single-crystal X-ray analyses. To advance this study, regioselective double 1,3-dipolar cycloaddition reaction of five-membered-ring cyclic carbonyl ylides has been demonstrated for the first time with biindoles having various aryl and alkyl spacers. This process constructed up to eight stereocenters, four carbon-carbon and two carbon-oxygen bonds in a single step with an excellent molecular complexity and stereoselectivity.     

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.     

Intermolecular silacarbonyl ylide cycloadditions: a direct pathway to oxasilacyclopentenes

Silacarbonyl ylides, generated by metal-catalyzed silylene transfer to carbonyls, participate in formal intermolecular 1,3-dipolar cycloaddition reactions with carbonyl compounds and alkynes to form dioxasilacyclopentane acetals and oxasilacyclopentenes in an efficient, one-step process.     

Reaction of chromone-3-carbaldehyde with α-amino acids—syntheses of 3- and 4-(2-hydroxybenzoyl)pyrroles

Azomethine ylides generated from the reaction of chromone-3-carbaldehyde with α-amino acids undergo 1,5-electrocyclization reactions to afford 3- and 4-(2-hydroxybenzoyl)pyrroles. These ylides can be trapped with dipolarophiles in 1,3-dipolar cycloaddition reactions to yield chromonyl pyrrolidines. The reaction of chromone-3-carbaldehyde with methyl glycinate gives a mixture of pyrrole, pyridine, and 3-aza-9-xanthenone derivatives.     

Catalytic Asymmetric [ 2,3 ] -Sigmatropic Rearrangement of Sulfur Ylides Generated from Carbenoids

The catalytic asymmetric reactions of oxygen or sulfur ylides generated from carbenoids have attracted consider able attention in recent years. High enantioselectivities have been achieved in the 1,3-dipolar cycloaddition reactions and [ 2,3 ]-sigmatropic rearrangement of oxygen ylides. In contrast to the oxygen ylide, the corresponding catalytic asymmetric reaction of sulfur ylide is less developed. Compared to oxygen ylides, the sulfur ylides are more stable and experimental evidence supports a free ylide rather than a metal-bound ylide as reaction intermediate. That means the enantio-control must be in the step of the ylide formation. If the subsequent reaction such as [ 2,3 ]-sigmatropic rearrangement or 1,3-dipolar cycloaddition is a concerted process and is faster than the racemization of the chiral ylide intermediate, then the catalytic asymmetric sulfur ylide reaction will be possible.     

Lewis acid catalyzed carbon-carbon bond cleavage of aryl oxiranyl diketones: synthesis of cis-2,5-disubstituted 1,3-dioxolanes

Carbonyl ylide is one of the most important intermediates which can undergo a series of 1,3-dipolar cycloaddition reactions. The C-C heterolysis of oxirane is believed to be the most atom-economic and straightforward way to generate carbonyl ylide. However, this chemistry was only achieved under photochemical and thermal conditions in past years. In this work, the one-step diastereoselective synthesis of cis-2,5-disubstituted 1,3-dioxolanes via [3 + 2] cycloadditions of aldehydes and carbonyl ylide, which is obtained from Lewis acid catalyzed C-C bond heterolysis of aryl oxiranyl diketones at ambient temperature, is described.     

Asymmetric Catalytic Synthesis of Hexahydropyrrolo-isoquinolines via Three-Component 1,3-Dipolar-Cycloaddition

An asymmetric three-component 1,3-dipolar cycloaddition of 3,4-dihydroisoquinolines, bromoacetates and α,β-unsaturated pyrazole amide is realized by using a chiral N,N’-dioxide-Y(OTf)₃ complex as the catalyst. The process includes a base-promoted formation of dihydroisoquinolium ylides in situ, and a chiral Lewis acid-catalyzed asymmetric [3+2] cycloaddition with α,β-unsaturated pyrazole amides. A series of hexahydropyrrolo-isoquinolines are obtained in moderate to good yields with excellent diastereo- and enantioselectivities.     

An expedient synthesis of pyrrolidinyl spirooxindole grafted 3-nitrochromanes through 1,3-dipolar cycloaddition reaction of azomethine ylides

A facile one-pot synthesis of pyrrolidinyl-spirooxindole grafted 3-nitrochromanes has been accomplished by 1,3-dipolar cycloaddition (1,3-DC) reaction of 3-nitrochromenes with azomethine ylides generated in situ from isatin and secondary amino acids. The regio- and stereochemical outcome of the cycloaddition reaction was ascertained by X-ray crystallographic analysis.     

Tandem cyclization-cycloaddition behavior of rhodium carbenoids with carbonyl compounds: stereoselective studies on the construction of novel epoxy-bridged tetrahydropyranone frameworks

Investigations and stereoselective studies on the tandem reactions of carbonyl ylides generated from alpha-diazo ketones in the presence of carbonyl compounds are presented in this paper. Intramolecular cyclization of rhodium carbenoids generated the transient five- or six-membered-ring carbonyl ylide dipoles, which efficiently underwent 1,3-dipolar cycloaddition reactions with various dipolarophiles such as aromatic aldehydes 15, alpha,beta-unsaturated aldehydes 18/24, alpha,beta-unsaturated ketones 27/28/31, and dienone 34. The transient carbonyl ylides underwent cycloadditions with various aromatic aldehydes to furnish diverse epoxy-bridged tetrahydropyranone ring systems in a diastereoselective manner. The cycloaddition of carbonyl ylides with alpha,beta-unsaturated aldehydes 18/24 or dienone 34 afforded C=O addition products in a chemoselective manner despite the presence of C=C bonds in the above dipolarophiles. Alternatively, the cycloaddition of carbonyl ylides with alpha,beta-unsaturated ketones 27/28 provided both the C=O and C=C cycloaddition products. The cycloaddition of carbonyl ylides with carbonyl compounds occurred in good yields and was found to be highly regio- and stereoselective. Single-crystal X-ray analyses were performed to unambiguously establish the structure and stereochemistry of the novel epoxy-bridged tetrahydropyranone ring systems 35a/38. Compound 35a exhibited both intermolecular C-H...O and intramolecular C-H...pi interaction motifs in the solid-state architecture. The regio-, chemo-, and stereoselectivity observed in these reactions have been investigated by semiempirical AM1 MO calculations. FMO analyses and transition state calculations have been performed for the cycloaddition of carbonyl ylides with alpha,beta-unsaturated carbonyl compounds such as tetracyclone (34) and cyclopentenone (27a). Both FMO and transition state calculations correctly predicted the regio- and stereochemistry of the cycloadducts. The calculations further revealed that a severe steric interaction caused by the phenyl rings present in dipolarophile 34 with dipole 14a increases the activation barrier of the transition state during the cycloaddition process.     

Cycloaddition chemistry of carbonyl ylides for alkaloid synthesis

As highlighted in this mini-review, a growing area of interest in organic synthesis involves the use of substituted carbonyl ylides as 1,3-dipoles for the preparation of alkaloidal natural products. Cascade reactions proceeding by an intramolecular 1,3-dipolar cycloaddition of carbonyl ylides are of particular interest to the synthetic organic community because of the increase in molecular complexity involved and the high isolated yields.     

Isomerization and 1,3-dipolar cycloaddition of gem-difluorinated NH-azomethine ylides in the reaction of difluorocarbene with diarylmethanimines

Reaction of difluorocarbene with diarylmethanimines leads to the formation of gem-difluorinated NH-azomethine ylides, two types of competing transformations of which are found to be characteristic: a formal 1,2-H shift into N-(difluoromethyl)imines and 1,3-dipolar cycloaddition to electron-deficient multiple bonds. α,α,α-Trifluoroaceto-phenones are efficient dipolar traps for difluoro NH-ylides, the addition of which to the dipole proceeds regioselectively with the formation of 4-fluoro-2,5-dihydrooxazoles. According to the quantum-chemical calculations by the DFT B3LYP/6-31G* method, 1,3-dipolar cycloaddition of difluorinated NH-azomethine ylides to a C=O bond with the formation of 4-fluoro derivatives of oxazole has lower barrier of activation than the reaction, leading to another regioisomer; the formal 1,2-H shift in the ylide occurs intermolecularly with participation of an imine, a precursor of the ylide.     

Highly enantioselective and diastereoselective 1,3-dipolar cycloaddition reactions between azomethine imines and 3-acryloyl-2-oxazolidinone catalyzed by binaphthyldiimine-Ni(II) complexes

[reaction: see text] We have found the first example of high levels of asymmetric induction (97-74% ee) along with high diastereoselectivity (>99:1-64:36) in dipole-HOMO-/dipolarophile-LUMO-controlled asymmetric 1,3-dipolar cycloaddition reactions between fused azomethine imines and 3-acryloyl-2-oxazolidinone using a chiral BINIM-Ni(II) complex as a chiral Lewis acid catalyst.     

Asymmetric synthesis of multifunctionalized pyrrolines by a ruthenium porphyrin-catalyzed three-component coupling reaction

[reaction: see text] Chiral multifunctionalized pyrrolines have been synthesized by a ruthenium porphyrin catalyzed three-component coupling reaction. In a one-pot reaction, ruthenium porphyrins catalyzed in situ generation of chiral azomethine ylides from chiral diazo esters and imines. Asymmetric 1,3-dipolar cycloaddition reactions of the chiral azomethine ylides with dipolarophiles afforded the corresponding pyrrolines in good yields and high diastereoselectivity (up to 92% de).     

Catalytic Asymmetric Hetero-Diels-Alder Reactions of Carbonyl Compounds and Imines

Asymmetric catalysis is a challenge for chemists: How can we design catalysts to achieve the goal of forming optically active compounds? This review provides the reader with an overview of the development of catalytic asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines. Since its discovery, the Diels-Alder reaction has undergone intensive development and is of fundamental importance for synthetic, physical, and theoretical chemists. The Diels-Alder reaction has been through different stages of development, and at the beginning of the 21st century catalytic Diels-Alder reactions are one of the main areas of focus. The preparation of numerous compounds of importance for our society is based on cycloaddition reactions to carbonyl compounds and imines. There are several parallels between the reactions of carbonyl compounds and those of imines, which, however, begin to vanish on entering the field of catalytic reactions. Why? From a mechanistic point of view some similarities can be drawn, but the synthetic development of catalytic enantioselective hetero-Diels-Alder reactions of imines are several years behind those of the carbonyl compounds. For hetero-Diels-Alder reactions of carbonyl compounds there a number of different chiral catalysts, and great progress has been achieved in developing enantioselective reactions for unactivated and activated carbonyl compounds. In contrast the development of catalytic enantioselective hetero-Diels-Alder reactions of imines is in its infancy and only few catalytic reactions have been published. This review will focus on the most important developments, and discuss the synthetic and mechanistic aspects of enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral Lewis acids. For the hetero-Diels-Alder reactions of imines, the diastereoselective reactions of optically substrates catalyzed by Lewis acids will be presented first, followed by the catalytic enantioselective reactions.     

The catalytic asymmetric 1,3-dipolar cycloaddition of ynones with azomethine ylides

The first catalytic asymmetric 1,3-dipolar cycloaddition of electron-deficient carbon-carbon triple bonds with azomethine ylides has been established. This reaction provides an unprecedented approach to access novel 2,5-dihydropyrrole derivatives with potential bioactivities in perfect enantioselectivities of up to >99% ee.