Azadienes, Diels-Alder

Heterocyclic and acyclic azadiene Diels-Alder reaction in total synthesis of nothapodyine B, alkaloid with antiviral activity 98JHC1003. 

Boger D. L. Heterocyclic and Acyclic Azadiene Diels-Alder Reactions Total Synthesis of Nothapodytine B. J. Heterocycl. Chem. 1998 35 1003-1011 Keywords inverse electron-demand Diels-Alder reactions, acyclic azadienes, synthesis of natural products... 

Scheme6.241 Azadiene Diels—Alder cycloaddition of fulvenes.

The Boger pyrrole synthesis based on a heterocyclic azadiene Diels-Alder strategy (1,2,4,5-tetrazine to 2,2-diazine to pyrrole) was employed by the author for the total synthesis of ningalin B . Thus a Diels-Alder reaction of the electron-rich acetylene 52 with the electron deficient 1,2,4,5-tetrazine 53 proceeded to give the desired diazine 54 which underwent subsequent ring contraction to afford the core pyrrole structure 55. 

In a related transformation, Bode and co-workers have demonstrated the utility of homoenolate protonation in an azadiene Diels-Alder reaction catalyzed by aminoin-danol derived A-mesityl pre-catalyst 214 [118,119], The cyclization products 213 are obtained as a single diastereomer in excellent enantiomeric excess (Table 16). Electron-deficient enals are used in order to increase the electrophihcity and reactivity of the compounds. After protonation of the homoeneolate moiety, an inverse electron demand Diels-Alder is proposed to provide the desired cychzed product. 

Boger et al. reported the first total synthesis of ningaline D (282) starting from the diphenylacetylene 1092 and dimethyl l,2,3,4-tetrazine-3,6-dicarboxylate (1093) (687). In this synthesis, the key step is the formation of the fully substituted pyrrole core using an inverse electron demand heterocyclic azadiene Diels-Alder reaction followed by a reductive ring contraction of the resultant 1,2-diazine. 

He M, Bode JW (2005) Catalytic synthesis of y-lactams via direct annulations of enals and N-sulfonylimines. Qrg Lett 7 3131-3134 He M, Struble JR, Bode JW (2006) Highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral N-heterocyclic carbenes. J Am Chem Soc 128 8418-8420... 

The electron-rich alkyne 14 reacts with the electron-deficient 1,2,4,5-tetrazine 15 in a thermal inverse electron-demand azadiene Diels-Alder cycloaddition reaction (see Key Chemistry). 

Among the few examples of simple 1-azadiene Diels-Alder reactions is a dihydropyridine synthesis using the stable azadiene 39 (prepared from cinnamaldehyde and aniline) with the dienophile 38 prepared from the isoxazole 35 by elimination. This is a reverse-electron-demand cycloaddition, the HOMO of the dienophile 38 combining with the LUMO of the azadiene 39 to give the cycloadduct 40 and hence the dihydropyridine 41 with complete regioselectivity and in very high yield.3... 

In many instances, the entropic assistance provided in the intramolecular Diels-Alder reaction is sufficient to promote azadiene participation in Diels-Alder reactions.12 The incorporation of the azadiene system, or dienophile, into a reactive or sensitive system, e.g., heterocumulene or strained olefin, allows a number of specialized azadiene Diels-Alder reactions. Many such examples may represent stepwise, polar [4 + 2] cycloaddition reactions. 

The synthetic utility of azadienes Diels-Alder reactions lies in the synthesis of heterocycles and alkaloids. Three disconnections related to this section are... 

Boger DL (1996) Azadiene Diels-Alder reactions scope and applications. Total synthesis of natural and ent-fredericamycin A. J Heterocycl Chem 33 1519-1531... 

The catalytic asymmetric azadiene-Diels-Alder reaction has also received some recent attention. Initial work in this area used hydroxyaniline-derived imine... 

Scheme 6. Initial double azadiene Diels-Alder reaction/retro-Diels-Alder process leading to key biaryl intermediate 27.

Bode, et al. developed a highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral A-heterocyclic carbenes. Scheme 3.28 [43]. Reactions of alkyl fra -4-oxo-2-butenoate 80 with A-sulfonyl imines 81 and catalyst 82 (10-15 mol%), DIPEA (10 mol%) in toluene-THF (10 1) at room temperature afforded the dihydopyridinones 83 in excellent diastereo- and enantioselectivity (>50 1 cw-diastereoselectivity, 99% ee). The LUMO -controUed inverse electron demand Diels-Alder cycloaddition was facilitated by NHC-carbene catalyst 82. Similar reactions without the catalyst would require high pressure (12 bar) or high temperature. The high cw-diastereoselectivity which would arise from (Z)-enolate reacting with the dienophile is rationalized as depicted in Scheme 3.28. 

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