Asymmetric Diels-Alder reactions inverse-electron-demand

Scheeren et al. reported the first enantioselective metal-catalyzed 1,3-dipolar cycloaddition reaction of nitrones with alkenes in 1994 [26]. Their approach involved C,N-diphenylnitrone la and ketene acetals 2, in the presence of the amino acid-derived oxazaborolidinones 3 as the catalyst (Scheme 6.8). This type of boron catalyst has been used successfully for asymmetric Diels-Alder reactions [27, 28]. In this reaction the nitrone is activated, according to the inverse electron-demand, for a 1,3-dipolar cycloaddition with the electron-rich alkene. The reaction is thus controlled by the LUMO inone-HOMOaikene interaction. They found that coordination of the nitrone to the boron Lewis acid strongly accelerated the 1,3-dipolar cycloaddition reaction with ketene acetals. The reactions of la with 2a,b, catalyzed by 20 mol% of oxazaborolidinones such as 3a,b were carried out at -78 °C. In some reactions fair enantioselectivities were induced by the catalysts, thus, 4a was obtained with an optical purity of 74% ee, however, in a low yield. The reaction involving 2b gave the C-3, C-4-cis isomer 4b as the only diastereomer of the product with 62% ee. 

Inverse electron-demand asymmetric Diels-Alder reactions of 2-pyrone derivatives were reported (a) Posner GH, Carry J-C, Lee JK, Bull DS, Dai H (1994) Tetrahedron Lett 35 1321 (b) Markd IE, Evans GR (1994) Tetrahedron Lett 35 2771... 

Metal bis(oxazoline) catalysts are also highly efficient at promoting asymmetric Diels-Alder reactions. Ishira developed a highly selective copper bis(oxazoline) catalyst for use in standard intermolecular Diels-Alder reactions. Arrayas and Carretero used a nickel bis(oxazoline) catalyst in inverse electron demand hetero Diels-Alder reactions of 1-azadienes for the production of functionalized piperidines. bis(oxazoline) catalysts in reactions pyrazolidinone dienophiles and determined that copper and palladium catalysts were most efficient. Sibi applied a copper bis(oxazoline) catalyst in a kinetic resolution experiment in which one enantiomer of dienophile 46 reacts selectively with cyclopentadiene to yield cycloadduct 48 and 98% ee... 

In addition to metal-based catalysts, organocatalysts are also selective promoters of asymmetric Diels-Alder reactions. Several groups reported the use of cinchona alkaloid catalysts in standard Diels-Alder reactions. Deng combined 2-pyrones with a,P unsaturated ketones, while Bernard and Ricci focused on the reactions of vinylindoles with quinones and maleimides. Lectka reported enantioselective inverse electron demand hetero Diels-Alder reactions of ketene enolates and o-benzoquininone diimides catalyzed by a combination of benzoylquinidine and zinc triflate. For example, subjecting diimide 51 to the standard reaction conditions yields cycloadduct 52 as a single stereoisomer, which can be easily converted to... 

The intramolecular Diels-Alder reaction is most frequently used in natural product total synthesis, and numerous examples will be described in the synthetic utility section. As with the intermolecular variant, intramolecular reactions are highly regioselective and stereoselective and participate in hetero, inverse electron demand, and asymmetric Diels-Alder reactions. One report from 2008 describes the investigation of an intramolecular hetero Diels-Alder reaction in ionic liquids. ... 

Thus, we have developed catalytic asymmetric aza Diels-Alder reactions of imines with alkenes using a chiral lanthanide Lewis acid, to afford 8-hydroxyquinoline derivatives in high yields with high diastereo- and enan-tioselectivities. The characteristic points of this reaction are as follows, (i) Asymmetric aza Diels-Alder reactions between achiral azadienes and dienophiles have been achieved using a catalytic amount of a chiral source, (ii) The unique reaction pathway, in which the chiral Lewis acid activates not dienophiles but dienes, is revealed. In most asymmetric Diels-Alder reactions reported using chiral Lewis acids, the Lewis acids activate dienophiles [64, 65]. However, inverse electron-demand asymmetric Diels-Alder reactions of 2-pyrone derivatives have been reported [72]. (iii) A unique lanthanide complex including an azadiene and an additive, which is quite different from the conventional chiral Lewis acids, has been developed. 

Table 1.29 Asymmetric inverse electron demand Diels-Alder reactions catalyzed by 39 [58 ...

Keywords asymmetric synthesis, stereochemistry, inverse electron-demand Diels-Alder reaction, rare earth metals... 

Marko I. E., Evans G. R., Declercq J. P., Tinant B., Feneau-Dupont J. Asymmetric, Catalytic, Inverse Electron-Demand Diels-Alder Reactions of 3-Carboalk-oxy-2-Pyrone Derivatives Acros Org. Acta 1995 1 63 6... 

Aza-3-benzyl-l,5-diphenylpentane ligated Ti(lV) complex 17 is quite effective for the asymmetric inverse-electron-demand Diels-Alder reaction of... 

The aza-Diels-Alder reaction is an important and versatile tool for the preparation of nitrogen-containing heterocycles present in numerous natural products and drug candidates. It involves the [4 + 2] cycloaddition of either an imine with an electron-rich diene or an azabutadiene with an electron-rich alkene (inverse electron demand). Catalytic asymmetric variants employing not only metal complexes, but also organic molecules were disclosed over the last few years. 

Furthermore, Akiyama and coworkers applied phosphoric acid (/ )-3m (10 mol%, R = 9-anthryl) to the asymmetric inverse-electron-demand hetero-Diels-Alder reaction of A-2-hydroxyphenyl-protected aldimines 8 with vinyl ethers 99 (Scheme 38) [61], Tetrahydroquinolines 100 were obtained in good yields (59-95%), excellent yyn-diastereoselectivities (24 1-99 1), and high enantioselec-tivities (87-97% ee). 

As shown in Figure 41, Kobayashi s catalysis was also effective for asymmetric aza Diels-Alder reactions, and in this case 2.4 equiv. of DBU was used instead of 1,3,5-trimethylpiperidine. 2,6-Di-/m-butyl-4-methylpyridine appeared to be most effective additive 95 Mark6 et al. have reported that these catalysts are also effective for asymmetric inverse electron-demand Diels-Alder reactions of 2-pyrone... 

Akiyama T, Morita H, Itoh J, Fuchibe K (2005 a) Chiral Brpnsted acid catalyzed enantioselective hydrophosphonylation of imines asymmetric synthesis of alpha-amino phosphonates. Org Lett 7 2583-2585 Akiyama T, Morita H, Fuchibe K (2006b) Chiral Brpnsted acid-catalyzed inverse electron-demand aza Diels-Alder reaction. J Am Chem Soc 128 13070-13071... 

An interesting example of an asymmetric inverse-electron-demand Diels-Alder reaction is the smooth addition of chiral vinyl ether (436) (readily accessible from 435) to the electron-deficient 3-to-... 

Hetero- Diels-Alder reactions that proceed with good to excellent asymmetric induction are well known. " Chiral 1-aza-dienes have been developed as substrates, for example. " Chiral catalysts have been developed. " Conjugated aldehydes react with vinyl ethers, with a chiral chromium catalyst, in an inverse electron demand cycloaddition that give a dihydropyran with good... 

A representative of the hetero-Diels-Alder reaction of inverse electron demand is the cycloaddition of A-sulfonyl-l-azadienes with vinyl ethers. It is amenable to asymmetric catalysis, for example, by a nickel(II) complex of 101. ... 

The intramolecular 47t participation of an AAacylimine in a Diels-Alder reaction73 and the use of A/-acylimines bearing chiral auxiliaries in inverse electron demand Diels-Alder reactions with an observable high degree of asymmetric induction74 illustrate additional capabilities for the applica-... 

Diels-Alder reactions. The version with inverse electron demand involving a-pyrones and vinyl ethers is subjected to asymmetric induction by a BINOL-ytterbium complex. 

Swindell CS, Tao M (1993) Chiral Auxiliary-Mediated Asymmetric Induction in a Thermal Inverse Electron Demand Hetero-Diels-Alder Reaction - Enantioselective Synthesis of the Taxol A-Ring Side Chain. J Org Chem 58 5889... 

Example 3, Catalytic asymmetric inverse-electron-demand Diels—Alder reaction" ... 

Example 1, Catalytic asymmetric inverse electronic demand Diels-Alder reaction ... 

J0rgensen and Juhl reported the first organocatalytic enantioselective inverse-electron-demand hetero-Diels-Alder reaction of aldehydes (e.g., 71) and enones (e.g., 72) with excellent diastereo- and enantioselectivity. Scheme 3.26 [41], The reaction utilizes a chiral enamine intermediate as an alkene in catalytic asymmetric cycloaddition reactions. 

Scheme 3.31 Organocatalytic asymmetric inverse-electron-demand aza-Diels-Alder reaction of A-Sulfonyl-l-aza-1,3-butadienes and aldehydes...

X. Jiang, R. Wang, Recent developments in catalytic asymmetric inverse-electron-demand Diels—Alder reaction, Chem. Rev. 113 (7) (2013) 5515—5546. 

The nickel-iminophosphine-catalysed 4- -2-cycloaddition of enones with allenes formed highly substituted dihydropyrans. The enantioselective amine-catalysed 4-I-2-cycloaddition of allenoates with oxo-dienes produced polysubstituted dihydropyrans in high yields and with high enantioselectivities. Novel enam-ine/metal Lewis acid bifunctional catalysis has been used in the asymmetric inverse-electron-demand hetero-Diels—Alder reactions of cyclic ketones with Q ,j9-unsaturated a-ketoesters. The 4- -2-cycloaddition of acylketenes (80) with 2-unsubstituted and 2-monosubstituted 3-aryl-2//-azirines (81) produced 1 1 (82) or 2 1 (83) adducts, being derivatives of 5-oxa-l-azabicyclo[4.1.0]hept-3-ene or 5,7-dioxa-l-azabicyclo[4.4.1]undeca-3,8-diene. The formation of the monoadducts proceeds via a stepwise non-pericyclic mechanism (Scheme 25). A-heterocyclic carbene-catalysed 4- -2-cycloaddition of ketenes with 1-azadienes yielded optically active 3,4-dihydropyrimidin-2-ones (93% ee) ... 

Yamomoto reported an interesting carbocyclic inverse electron demand Diels-Alder reaction between tropone (25) and ketene diethyl acetal (26) catalyzed by tris(pentafluoro)phenylborane. Under these conditions, Diels-Alder product 27 is formed almost exclusively, while most other catalysts (including BF3 and BPhs) favor sole production of the [8 + 2] cycloadduct 28. Yamamoto also described the development of an asymmetric version of this Diels-Alder reaction. ... 

The application of bis- and monooxazoline ligands in the catalytic asymmetric inverse-electron demand Diels-Alder reactions has been reviewed (13CRV5515). 

---