Asymmetric aza Diels-Alder

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]. 

Tab. 5.1 Effect of additives in the asymmetric aza Diels-Alder reaction...

Several examples of catalytic asymmetric aza Diels-Alder reactions are shown in Table 5.10 [30]. The reaction always proceeded smoothly to afford the correspond-... 

Thus, a novel chiral zirconium complex for asymmetric aza Diels-Alder reactions has been developed by efficient catalyst optimization using both solid-phase and liquid-phase approaches. High yields, high selectivity, and low loading of the catalyst have been achieved, and the effectiveness of chiral catalyst optimization using a combination of solid-phase and liquid-phase methods has been demonstrated. 

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. 

Tab. 5.13 Catalytic asymmetric aza Diels-Alder reactions of 2-azadienes...

Catalytic asymmetric aza-Diels-Alder reactions using a chiral lanthanide Lewis acid. Enantioselective synthesis of tetrahydroquinoline derivatives using a catalytic amount of a chiral source [98]... 

Waldmann H. Asymmetric Aza-Diels-Alder Reactions in Org. Synth. Highlights IF 1995 37, Ed. Waldmann, Pb. VCH Weinhein... 

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. 

Scheme 8 Model asymmetric aza Diels-Alder reaction in the presence of chiral ionic liquids...

An asymmetric aza-Diels-Alder reaction between functionalized 1,3-dienes and imines is mediated by a binaphthol-modified boronic ester (Scheme 108) (267). Unfortunately, at the present time the reaction requires a stoichiometric amount of the chiral promoter. 

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. 

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... 

Figure 41. Catalytic, asymmetric aza-Diels-Alder reaction reported by Kobayashi et al.

H. Waldmann, Asymmetric Aza-Diels-Alder Reactions, in Organic Synthesis Highlights II (H. Waldmann, Ed.), VCH, Weinheim, New York, 1995, 37-47. 

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). ... 

Catalytic Asymmetric Aza Diels-Alder Reactions Promoted by Chiral Ytterbium Catalysts... 

SCHEME 10.4S Asymmetric aza-Diels-Alder reactions can be achieved using sugar auxiliaries. 

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... 

Yamamoto also reported an asymmetric aza Diels-Alder reaction of an imine mediated by a stoichiometric amount of the chiral boron complex 19 which is conveniently prepared in situ simply by mixing a 1 1 molar ratio of optically active binaphthol and triphenyl borate in CH2CI2 at room temperature [22]... 

The polymer-supported Zr catalyst (12) is useful for asymmetric aza-Diels-Alder cycloaddition of benzaldehyde imine to Danishefsky diene [9]. The 6-substituted BINOL-Zr(IV) catalyst is useful for the enantioselective anft -preferred aldol reaction of benzaldehyde with ketene silyl thioacetal (15) (Scheme 5.5) [ 10]. The calculated charge densities on the oxygen atoms of the BINOL derivatives revealed that there is a good correlation between the charge density and the reactivity of 6-substituted BINOL [ 10]. 

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