Aza hetero-Diels-Alder

The groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

Liang G, Trauner D (2004) Enantioselective Nazarov reactions through catalytic asymmetric proton transfer. J Am Chem Soc 126 9544—9545 Liu B, Feng X, Chen F, Zhang G, Cui X, Jiang Y (2001) Synlett 2001 1551 Liu H, Cun LF, Mi AQ, Jiang YZ, Gong LZ (2006) Enantioselective direct aza hetero-Diels-Alder reaction catalyzed by chiral Brpnsted acids. Org Lett 8 6023-6026... 

SCHEME 6.16. Chiral pyirolidinol catalyzed aza-hetero-Diels-Alder reactions. 

SCHEME 6.18. Chiral Brpnsted acid/pyridinium salt catalyzed aza-hetero-Diels-Alder... 

In 2005, Cordova and coworkers described the first example of the enantioselective organocatalytic aza-hetero-Diels-Alder reaction [60]. The one-pot three-component direct aza-hetero-Diels-Alder reaction under the catalysis of prohne afforded the desired cycloadducts 135 with excellent chemo-, regjo-, and stereoselectivity (Scheme 38.39). This reaction was considered to proceed via a plausible Mannich-Michael reaction pathway. Recently, Wang and coworkers developed a chiral ionic liquid catalyst for this reaction to afford up to >99% ee [61]. 

Chen and coworkers presented a highly stereoselective inverse-electron-demand aza-hetero-Diels-Alder reaction of aldehydes 137 and a, 3-unsaturated imines 136 with the use of a chiral secondary amine 36 through enamine activation [62]. Excellent enantioselectivities can be achieved for a broad range of substrates (Scheme 38.40). Water is helpful in the hydrolysis of intermediate P to release... 

When using aliphatic aldehydes tethered to arene motifs as substrates, an enan-tioselective sequential aza-hetero-Diels-Alder and Friedel-Crafts reaction was successfully achieved by the same group [63]. Similarly, optically active lactone[3,3-b] piperidine skeletons 140 can be obtained by tandem aza-hetero-Diels-Alder reaction-hemiacetal formation-oxidation from a,P-unsaturated imines 136 and glutaraldehyde (139) (Scheme 38.41) [64]. Enamine catalysis of the inverse-electron-demand aza-hetero-Diels-Alder reaction was further extended to o-benzoquinone diimide 141 by Chen s group [65]. Various hydroquinoxalinones 142 can be obtained in high yields with excellent enantioselectivities (Scheme 38.42). 

Scheme 38.41 Aza-hetero-Diels-Alder reactions with glutaraldehyde.

By employing the dienamine-catalysis strategy, Chen and coworkers accomplished an unprecedented and highly regio- and stereoselective inverse-electron-demand aza-hetero-Diels-Alder reaction of a,P-unsaturated imines 136 with a,P-unsaturated aldehydes 143 [66]. Various multifunctional piperidine derivatives 144 and 145 can be obtained, with excellent levels of enantioselectivity, that are potentially useful in the synthesis of natural products and medicinal chemistry (Scheme 38.43). 

One of the potential problems associated with 148 lies in its strong acidity, in particular when applied to labile substrates. Akiyama and coworkers have found that its pyridinium salt 150 also exhibits efficient catalytic activity as a chiral Bron-sted acid catalyst that is compatible with labile substrates such as Brassard s diene 113 [68]. Accordingly, an efficient inverse-electron-demand aza-hetero-Diels-Alder reaction of aldimines 146 with Brassard s diene 113 catalyzed by 150 was accomplished to afford piperidinone derivatives 151 in high yields with excellent enan-tioselectivities (Scheme 38.45). 

Recently, Jacobsen described a novel strategy for inducing enantioselectivity in reactions of protio-iminium ions, wherein a chiral catalyst interacts with the highly active intermediate through a network of non-covalent interactions (as shown in transition state Q) [69]. Accordingly, a highly efficient and enantioselective aza-hetero-Diels-Alder reaction between N-aryl imines 152 and enamide 153 or ene-carbamate 154 has been achieved with the use of the combination of the bifunctional sulfinamido urea derivative 155 and ortho-nitrobenzensulfonic acid (156) (Scheme 38.46). The 2 1 ratio of 155 and 156 was essential to ensure the complete suppression of the racemic pathway catalyzed by 156 [69]. 

In 2006, Gong and coworkers reported the first chiral Br0nsted acidotalyzed asymmetric direct aza-hetero-Diels-Alder reaction [70]. Phosphoric acid catalyst 160 exhibited excellent catalytic activity and selectivity for the reaction of cyclohex-enone (31) with a broad range of aldimines 159 to produce N-containing heterocycles 162 with up to 87% ee (Scheme 38.47). More recently, Carter and coworker developed the modified proHne catalyst 161 for this reaction, and high levels of enantioselectivity and diastereoselectivity were obtained (Scheme 38.47) [71]. Interestingly, the aromatic imines favor exo products while the ahphatic imines favor endo products. 

With the use of chiral phosphoric acid catalyst 160, Zhu and coworkers have successfully developed the first three-component inverse-electron aza-hetero-Diels-Alder reaction (Povarov reaction) [72]. A broad range of aromatic and aliphatic aldehydes 110 as well as anihnes 163 were well tolerated to give... 

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