Asymmetric aza Diels-Alder reactions with

Asymmetric aza Diels-Alder reactions with simpleprotonated iminium ions in aqueous media... 

Kaw cki used optically active sulfonamide 234 to perform an asymmetric aza-Diels-Alder reaction with Rawal diene 235. " The reaction was performed in the presence of a Lewis acid, trimethylsilyl trifluoromethanesulfonate (TMSOTf), to obtain dihydropyridinone 236 as the product with high enantiomeric excess (Scheme 40.51). 

To achieve catalytic enantioselective aza Diels-Alder reactions, choice of metal is very important. It has been shown that lanthanide triflates are excellent catalysts for achiral aza Diels-Alder reactions [5]. Although stoichiometric amounts of Lewis acids are often required, a small amount of the triflate effectively catalyzes the reactions. On the basis of these findings chiral lanthanides were used in catalytic asymmetric aza Diels-Alder reactions. The chiral lanthanide Lewis acids were first developed to realize highly enantioselective Diels-Alder reactions of 2-oxazolidin-l-one with dienes [6]. 

A chiral magnesium catalyst prepared from magnesium iodide and 1,2-diphenyl-ethylenediamine was also found to he effective in asymmetric aza Diels-Alder reaction of a-imino ester 21b with 7a (Scheme 5.12) [32]. The novel catalyst was discovered using parallel comhinatorial methods. 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

Asymmetric aza Diels-Alder reactions provide a useful route to optically active heterocyclics such as piperidines and tetrahydroquinolines.45 Although successful examples of diastereoselective approaches had been reported as early as 10 years ago,46 only recently have enantioselective reactions been accomplished.47 For example, the reaction of chiral amine-derived aromatic imine 115 with Brassard s diene 116 gives adduct 117 with up to 95% diaster-eoselectivity (Scheme 5-37).48... 

Kobayashi et al.51 have reported an asymmetric Mannich-type reaction using chiral zirconium catalysts of type 124 (see Section 3.7). This catalyst is also effective for asymmetric aza Diels-Alder reactions. Kobayashi s study showed that the ligand had a profound influence on the yields and enantiose-lectivities of the reaction, and NMI (1-methylimidazole) proved to be the best ligand.51 With an increase in the amount of catalyst, both the chemical yields and enantioselectivities of the product can be enhanced. Scheme 5-39 depicts such aza Diels-Alder reactions, and its table shows that good to excellent enantioselectivity can be obtained for most reactions. 

The chiral boron complex prepared in situ from chiral binaphthol and B(OPh)3 is utilized for the asymmetric aza-Diels-Alder reaction of Danishefsky s diene and imines [67] (Eq. 8A.43). Although the asymmetric reaction of prochiral imine affords products with up to 90% ee, the double asymmetric induction with chiral imine by using oc-benzylamine as a chiral auxiliary has achieved almost complete diastereoselectivity for both aliphatic and aromatic aldimines. This method has been successfully applied to the efficient asymmetric synthesis of anabasine and coniine of piperidine alkaloides. 

Hetero Diels-Alder reactions with imino dienophiles have been employed as key step in several syntheses of naturally occuring alkaloids. With regard to stereoselective transformations, the approach to (S)-anabasin worked out by Kunz et al. impressively illustrates the high utility of natural carbohydrates as source of chirality in asymmetric synthesis [505]. The N-galactosyl imine 7-28 underwent a Lewis acid catalysed aza Diels-Alder reaction with Danishefsky s diene which proceeded with excellent induced diastereoselectivity to yield the adduct 7-29. A short sequence then afforded the desired alkaloid 7-30. This work also deals with the suitability of several other dienes and imino dienophiles for such transformations (Fig. 7-7). 

A chiral Lewis acid prepared in situ from magnesium iodide and (/ ,f )-DPEN efficiently catalyzes asymmetric aza-Diels-Alder reaction of a methyl glyoxylate/p-anisidine derived imine with the Danishefsky diene to give the cyclic adduct in 97% ee (eq 11). ... 

For benzoic acid acceleration in Yb(OTf)3-catalyzed allylation of aldehydes in acetonitrile, (a) As-pinall, H.C. Greeves, N. Mclver, E. G. Tetrahedron Lett. 1998, 39, 9283. For acetic acid acceleration in Yb(fod)3-catalyzed ene reaction of aldehydes with alkyl vinyl ethers, ene reaction of aldehydes with alkyl vinyl ethers, (b) Deaton, M. V. Ciufolini, M.A. Tetrahedron Lett. 1993, 34, 2409. Yamamoto et al. reported Brpnsted acid-assisted chiral Lewis acids and Lewis acid-assisted Brpnsted acids which were used for catalytic asymmetric Diels-Alder reactions and protonations and stoichiometric asymmetric aza Diels-Alder reactions, aldol-type reactions of imines, and an aldol reaction, (c) Ishihara, K. Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561. (d) Ishihara, K. Kurihara, H. Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 3049. (e) Ishihara, K. Nakamura, S. Kaneeda, M. Yamamoto, H. J. Am. Chem. Soc. 1996, 118, 12854. (f) Ishihara, K. Miyata, M. Hattori, K. Tada, T. Yamamoto, H. J. Am. Chem. Sc c. 1994, 116, 10520. (g) Yamamoto, H. J. Am. Chem. Soc 1994, 116, 10520. (h) ishihara, K. Kurihara, H. Matsumoto, M. Yamamoto Ishihara, K. Kurihara, H. Matsumoto, M. Yamamoto, H. J. Am. Chem. Soc 1998, 120, 6920. 

A Yb(OTf)3-catalyzed three-component aza Diels-Alder reaction of a diene with aldehydes and benzhydrylamine to provide 2,5-disubstituted 2,3-dihydro-4-pyridones has been developed <05SL1018, 05T9594>. A catalytic asymmetric aza Diels-Alder reaction of acylhydrazones 183... 

Thus, catalytic asymmetric aza Diels-Alder reactions of imines with alkenes have been developed using a chiral lanthanide Lewis acid, to afford 8-hydroxy-quinoline derivatives in high yields with high diastereo- and enantioselectivi-ties. Characteristic points of this reaction are as follows. 

Asymmetric aza-Diels-Alder reactions.1 This reaction can be effected in 72-90% cc by catalysis with the chiral boron reagent 1, prepared by reaction of (R)-BINOL with triphenyl borate in CH2CI2 at 25°. Thus reaction of an aldiminc and the Danishefsky... 

In addition, silver-catalyzed asymmetric aza-Diels-Alder reactions provide a useful route to optically active nitrogen-heterocyclic compounds such as piperidines or pyrid-azines. Substituted dihydrobenzofurans can also be enantioselectively prepared through silver-promoted allylation of aldehydes. Other types of silver-mediated cyclizations can also be used in the synthesis of tetrahydrofnrans, tetrahydropyrans, 1,2-dioxetanes, 1,2-dioxolanes, medium-sized lactones, dihydroisoqninolines, and so on. Silver salts can also be used as cocatalysts with other transition metals. Unique activity was observed for these silver-based systems in several cases. Conseqnently, the use of silver can enrich several available heterocyclization methods, and fnrther developments in the application of chiral silver complexes will hopefnlly appear in the near future. 

Asymmetric aza-Diels-Alder reaction of chiral imines with Danishefsky s diene in chiral ionic liquids have been reported [89]. These reactions occur at room temperature under green chemistry conditions without using Lewis acid catalyst and organic solvent. For example, the reaction of Danishefsky s diene 76 with imine 104 in the presence of chiral ionic liquid (EL) 105, gives pyridone derivative in moderate diastereoselectivity [89]. In the TS, the chiral liquid 105 binds the diene... 

Synthetic applications of the asymmetric aqueous aza Diels-Alder reaction with simple protonated iminium ions... 

DPP) was used in the reaction of imine 23a with 23b. This could be explained by the slight difference in the asymmetric environment created by Yb(OTf)3, (i )-(+)-BINOL, DBU and the additive (see below). While use of butyl vinyl ether (24c) decreased the selectivities (entry 7), dihydrofuran (24d) reacted smoothly to achieve high levels of selectivity (entries 8 and 9). It was found that the imine (23c) prepared from cyclohexanecarboxaldehyde and 2-hydroxyaniline was unstable and difficult to purify. The asymmetric aza Diels-Alder reaction was successfully carried out using the three-component coupling procedure (successively adding the aldehyde, the amine and cyclopentadiene) in the presence of Sc(OTf)3 (instead of Yb(OTf)3), (7 )-(+)-BINOL, DBU and DTBMP. 

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. 

Encouraged by Jprgensen s inverse-electron-demand hetero-Diels-Alder reaction of aldehydes and a,P-unsaturated a-keto esters, Han, He, and others envisaged that an unprecedented asymmetric aza-Diels-Alder reaction of A-sulfonyl-l-aza-1,3-butadienes and aldehydes might be developed by employing a similar strategy. They found that the process proceeded with a chiral secondary amine, 34 (Scheme 1.26) [32]. Excellent enantioselectivities (up to 99% ee) were observed for a broad spectrum of substrates under mild conditions. 

A one-pot, three-component asymmetric aza-Diels-Alder reaction using S-proline as the organocatalyst was developed by Cordova et al. 2-cyclohexene-1-one 313, aqueous formaldehyde 314, and / -anisidine 315 were mixed with catalytic amount of proline to get the aza-Diels-Alder adduct 316 with excellent enantiomeric excess (Scheme 40.68). 

In the presence of a catalytic amount of chiral lanthanide triflate 63, the reaction of 3-acyl-l,3-oxazolidin-2-ones with cyclopentadiene produces Diels-Alder adducts in high yields and high ee. The chiral lanthanide triflate 63 can be prepared from ytterbium triflate, (R)-( I )-binaphthol, and a tertiary amine. Both enantiomers of the cycloaddition product can be prepared via this chiral lanthanide (III) complex-catalyzed reaction using the same chiral source [(R)-(+)-binaphthol] and an appropriately selected achiral ligand. This achiral ligand serves as an additive to stabilize the catalyst in the sense of preventing the catalyst from aging. Asymmetric catalytic aza Diels-Alder reactions can also be carried out successfully under these conditions (Scheme 5-21).19... 

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