Hetero-Diels-Alder HDA Cycloaddition

2-diaza butadienes 1,3-diaza butadienes 1,4-diaza butadienes 

Mechanistically the all-carbon Diels-Alder reaction is generally considered a concerted, pericyclic reaction with an aromatic transition state, but there is also evidence for a stepwise (diradical or diion) process. For HDA reactions, theoretical studies revealed that the transition states are usually concerted, but less symmetrical. Depending on the reaction conditions and the number and type of substituents on the reactants, the HDA reaction can become stepwise, exhibiting a polar transition state. 

The enantioselective total synthesis of the epidermal growth factor inhibitor (-)-reveromycin B was completed by M.A. Rizzacasa and co-workers/° The key step to assemble the 6,6-spiroketal moiety was the HDA reaction between an a,P-unsaturated aldehyde (butylacrolein) and an enantiopure methylene pyran. The desired 6,6-spiroketal was obtained as a single enantiomer after heating the neat reactants in the absence of solvents at 110 °C for 2 days. 

In the laboratory of S.F. Martin, a biomimetic approach toward the total synthesis of ( )-strychnine was developed by using tandem vinylogous Mannich addition and HDA reaction to construct the pentacyclic heteroyohimboid core of the natural product.The commercially available 4,9-dihydro-3/-/-P-carboline was first converted to the corresponding A/-acylium ion and then reacted with 1-trimethylsilyloxybutadiene in a vinyiogous Mannich reaction. The resulting cycloaddition precursor readily underwent the expected HDA reaction in 85% yield. 

Swindell and co-workers enantioselectively prepared the Taxol A-ring side chain by using a thermai inverse eiectron-demand HDA reaction as the key step. The (Z)-ketene acetal was attached to a chiral auxiliary and reacted with the A/-benzoylaldimine to give the desired dihydrooxazine in 75% yield with good diastereoselectivity. 

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Cu A AC) (Johnson et at, 2008), historically the first one that has been given this name, is up to now the most apphed method. However, despite the popularity of this reaction on a lab scale, its widespread use is limited by the presence of a cytotoxic transition metal and the need for potentially explosive azides. For that reason, a range of copper-ftee click approaches are now intensively studied, including thiol-ene/yne addition reactions and (ultrafast) hetero-Diels— Alder cycloaddition (HDA) reactions, which are believed to have great potential to become as popular as the CuAAC in the click chemistry toolbox (Lutz, 2008 Becer et ai, 2009). 

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