Retro aza-Diels-Alder reactions

Immonium ion based synthetic methodology a novel method for the N-methylation of dipeptides and amino acid derivatives via retro aza-Diels-Alder reactions [93]... 

Retro aza-Diels-Alder reactions also readily occurred in water. 

Theoretical and synthetical studies carried out by van der Plas et al. deal with intramolecular aza Diels-Alder reactions of co-alkynylpyrimidines [311, 312]. The substrate 3-71 initially formed a bridged adduct 3-72 upon heating with subsequent release of the fused pyridine derivative 3-73 by retro-Diels-Alder reaction (Fig. 3-22). 

Nitrogen-containing heterocycles are also available via intramolecular hetero Diels-Alder reactions. Williams employed an aza diene to prepare a complex polycyclic synthetic intermediate in his synthesis of versicolamide B. Boger reported a tandem intramolecular hetero Diels-Alder/l,3-dipolar cycloaddition sequence for the synthesis of vindorosine. Cycloaddition precursor 137 undergoes an inverse electron demand Diels-Alder reaction to yield 138. This compound decomposes via a retro dipolar cycloaddition to generate nitrogen gas and a 1,3-dipole that completes the cascade by reacting with the indole alkene to afford 139. Seven more steps enable the completion of vindorosine. ... 

The synthesis commences with alkylation of oxindole 120 with spiroaziri-dinium triflate 109, providing the 3,3-disubstituted 121 in 53% yield (cf. Scheme 2.17). Treatment of 121 with boron trifluoride etherate at 100°C in toluene initiates the tandem retro Diels-Alder/intramolecular aza Diels-Alder process, leading to spiro-tetracyclic oxindoles 122 and 123 (1.5/1) in 61% yield. Addition of 2-lithio-l,l-diethoxy-2-propene to oxindole 122 provides carbinolamine 124 (95%). Exposure of 124 to p-toluenesulfonic acid in acetone-water followed by treatment with excess triethylamine in acetonitrile at 80°C effects the biomimetic transformation to adduct 126, which possesses the pentacyclic carbon framework of pseudotabersonine. This unique two-step one-pot transformation generates the inherently unstable dihydropyridine portion of dehydrosecodine 125, which participates in an intramolecular reverse electron-demand Diels-Alder reaction, providing 126 in 50% yield. The total synthesis is completed by transformation of the formyl group into the requisite carbomethoxy unit followed by N-benzyl deprotection (Scheme 2.19). 

Malononitrile reacts with acetone in water in the presence of KF-alumina to give 2-aza[2.2.2]octane in high yield via Knoevenagel condensation followed by double cyclization [15]. The bicyclo adduct heated directly or refluxed in tetralin releases 2-methylpropene (retro Diels-Alder reaction), giving the corresponding pyridine derivative. 

The antitumor antibiotic phloeodictine A1 (171) has been synthesized by Snider s group (Scheme 15.37). The unstable azide derived from 167 was subjected to a polymer supported tandem Staudinger-aza-Wittig followed by a retro Diels-Alder reaction to afford intermediate 170. Addition of 11-dodecenyl magnesium bromide followed by alkylation reaction and deprotection completes an efficient synthesis of phloeodictine A1 (171). 

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