Hetero-Diels-Alder Reaction HDA

A keteneacetal, the Brassard diene, has also been bound to polystyrene-based resin (308). This has been achieved by the reaction of diketene with alcohol functions on polystyrene resin. The ketone function of the resulting acet-oacetate could readily be enolized by TMOF (trimethyl orthoformate) and a catalytic amount of H, giving the methyl enolate. The remaining ester function was then deprotonated with LDA and subsequently silylated with TBDMSCl. The resulting diene (311) was used in many hetero-Diels-Alder reactions (HDA) with aldehydes and ketones as dienophiles, giving a library... 

In the field of sustainability, atom economy is an important asset and cycloaddition is an interesting way to build functionalised cycles with simultaneous creation of new stereocentres without production of waste/ The use of immobilised Lewis-acids to catalyse this pericyclic rearrangement renders it much more attractive for environmental considerations and such effort has been made in the titanium-catalysed Diels-Alder reaction (DA), hetero-Diels-Alder reaction (HDA) ° and 1,3-dipolar cycloaddition. 

The hetero-Diels-Alder reaction (HDA) has been used extensively for the construction of spiroacetals [4], notably in the synthesis of the reveromycins [150-153]. In particular, the recent development of mild methods for the generation of ort/to-quinone methides (o-QM) in the presence of sensitive five-membered exocyclic enol ethers has revealed an alternative route to benzannulated... 

The enantioselechve hetero-Diels-Alder reaction of carbonyl compounds with 1,3-dienes represents an elegant access to optically active six-membered oxo-heterocy-cles. Since the pioneering work of Rawal et al. in 2003 [40], the enantioselective HDA reaction catalyzed by diols (such as TADDOLs) has become a flourishing field of research [41]. 

Several diastereoselective HDA (hetero-Diels-Alder) reactions of a,/3-unsaturated carbonyl compounds and electron-rich alkenes have been exploited to gain carbohydrate derivatives with good diastereomeric excess. In HDA reaction, up to three chiral centers are formed with high stereoselectivity at each chiral carbon [78]. 

Asymmetric Hetero-Diels-Alder Reactions. By using stoichiometric amounts of the bis(oxazoline)-copper(II) triflate system as catalyst, asymmetric hetero-Diels-Alder (HDA) cycloaddition reactions were performed with cyclic and acyclic 1,3-dienes. The reported enantioselectivity (70-98% ee) and... 

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). 

Besides nucleophile-induced transformations the Hetero Diels-Alder (HDA) cycloaddition reactions are also very suitable ways to perform the pyrimidine-to-pyridine ring transformations. They can occur either by a reaction of an electron-poor pyrimidine system with an electron-rich dienophile (inverse HDA reactions) or by reacting an electron-enriched pyrimidine with an electron-poor dienophile (normal HDA reactions) (see Section II.B). 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

Diels-Alder Reactions The organocatalytic Diels-Alder reaction of a,P-unsaturated carbonyl compounds can be performed either via iminium (see Section 11.3) or enamine catalysis. The first highly selective enamine-promoted cycloaddition reaction was reported by Jprgensen and coworkers, who developed an amine-catalyzed inverse-electron-demand hetero-Diels-Alder (HDA) reaction (Scheme ll.lOa). ... 

Scheme 9 Enantioselective hetero-Diels-Alder (HDA) reaction of Danishefsky s diene with benzaldehyde...

The (2pyrrolidine derivative 843 can catalyze a hetero Diels-Alder (hDA) reaction between aldehydes and enones 844 to form dihydropyranols 845, PCC oxidation of which affords tf //-3,4-dihydropyran-2-ones 846 in good yield and enantioselectivity (Scheme 238) <2003AGE1498>. 

New additions to the hetero Diels-Alder (hDA) approach to dihydropyrans include the reaction between enol ethers and 3-aryl-2-cyanoprop-2-enoates that under high pressure yields substituted 3,4-dihydro-2W-pyrans with high endo- and complete regio- selectivity. The products can be transformed into a wide variety of other compounds <02EJO3126>. 

An interesting example of the synthesis of dihydropyrans using hetero Diels-Alder (HD A) methodology is the formation of the polycyclic cage compounds 3 from fulvenes and the tetracyclic enone 2 <06SL3479>. A HDA reaction also features in the synthesis of (+)-8-methoxygoniodiol <06TL4545>. 

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