Pericyclic reactions hetero-Diels-Alder reaction

The theoretical principles of cycloaddition reactions are well understood and there have been many computational studies (see Pericyclic Reactions The Diels-Alder Reaction). Often the hetero-cycloaddition reaction shows similar characteristics to the carbocyclic analog, but a number of special features have been noted. In heterocyclic chemistry the cycloaddition reactions are often dipolar computational studies show that a concerted mechanism is followed in the gas phase. However, a number of studies have noted that these dipolar cycloaddition reactions become stepwise when solvent effects are included (via the reaction field method), with a consequent loss of stereospecificity." Other characteristics of hetero-cycloaddition reactions which have been studied include the endo/exo selectivity" and the regiose-lectivity (for example, [2-1-2] vs. [2-1-4])." High levels of electron correlation are generally required in order to establish these selectivities. 

A hetero Diels-Alder reaction of a precursor 1-9 may be involved in the biosynthesis of the lignane carpanone 1-8 (Fig. 1-3), however, there is no proof for such an assumption [32]. On the other hand, it is well known that pericyclic reactions such as electrocyclic reactions and sigmatropic rearrangements occur in nature e.g. in the biosynthesis of vitamine D, vitamine B12 [33-35] and ecto-carpene [36]. 

One very fascinating domino reaction is the fivefold anionic/pericyclic sequence developed by Heathcock and coworkers for the total synthesis of alkaloids ofthe Daphniphyllum family [351], of which one example was presented in the Introduction. Another example is the synthesis of secodaphniphylline (2-692) [352]. As depicted in Scheme 2.154, a twofold condensation of methylamine with the dialdehyde 2-686 led to the formation of the dihydropyridinium ion 2-687 which underwent an intramolecular hetero-Diels-Alder reaction to give the unsaturated iminium ion 2-688. This cyclized, providing carbocation 2-689. Subsequent 1,5-hydride shift afforded the iminium ion 2-690 which, upon aqueous work-up, is hydrolyzed to give the final product 2-691 in a remarkable yield of about 75 %. In a similar way, dihydrosqualene dialdehyde was transformed into the corresponding polycyclic compound [353]. 

This chapter has been organized into sections based on the major reaction types. Hence, the hetero-Diels-Alder reaction has been included as a subsection of the Diels-Alder reaction. Although there are numerous reports of asymmetric pericyclic reactions, our discussion concentrates on reactions that are most likely to allow for scale up. 

Two-step highly diastercoselectivc pericyclic homodomino processes, involving hetero Diels-Alder reactions of ethyl vinyl ether on the nitroalkcne moiety of 4-nitroisoxazoles 34 and 13-DC of the same reagent on the nitronates 35, allowed the direct synthesis of spiro... 

The hetero Diels-Alder reaction has also been carried out efficiently in water. For instance, glyoxylic acid undergoes cycloadditions with various dienes [20] although the carbonyl function is almost exclusively present as its hydrate form. Other pericyclic reactions such as 1,3 dipolar [21] or [4+3] cycloadditions [Eq. (1), Table 1], and Claisen rearrangement [22] gave better results when conducted in aqueous media than in organic solvents. 

The nickel-iminophosphine-catalysed 4- -2-cycloaddition of enones with allenes formed highly substituted dihydropyrans. The enantioselective amine-catalysed 4-I-2-cycloaddition of allenoates with oxo-dienes produced polysubstituted dihydropyrans in high yields and with high enantioselectivities. Novel enam-ine/metal Lewis acid bifunctional catalysis has been used in the asymmetric inverse-electron-demand hetero-Diels—Alder reactions of cyclic ketones with Q ,j9-unsaturated a-ketoesters. The 4- -2-cycloaddition of acylketenes (80) with 2-unsubstituted and 2-monosubstituted 3-aryl-2//-azirines (81) produced 1 1 (82) or 2 1 (83) adducts, being derivatives of 5-oxa-l-azabicyclo[4.1.0]hept-3-ene or 5,7-dioxa-l-azabicyclo[4.4.1]undeca-3,8-diene. The formation of the monoadducts proceeds via a stepwise non-pericyclic mechanism (Scheme 25). A-heterocyclic carbene-catalysed 4- -2-cycloaddition of ketenes with 1-azadienes yielded optically active 3,4-dihydropyrimidin-2-ones (93% ee) ... 

Mesoxalates are highly reactive substrates because of their strongly polarized carbon-oxygen bond. They have been used in pericyclic processes (e.g. Diels-Alder reactions,8 ene reactions,9 [3+2]10 and [2+2]11 cycloadditions), in aldol12 and Wittig as well as Friedel-Crafts reactions.13 Further applications arise from the use of the corresponding imines in hetero Diels-Alder reactions14 and electrophilic cyclizations.15... 

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. 

Despite efforts made to improve enantioselectivities by supporting TADDOL-titanium catalyst, the homogeneous conditions remain the best ones. BINOL was also reported as an efficient ligand, however, to our knowledge supported-BINOL-titanium complexes were not studied in the asymmetric Diels-Alder reactions. In contrast, BINOL was extensively studied in the hetero-Diels-Alder reaction and in particular in the pericyclic rearrangement of several aldehydes and electron-rich and highly regioselective Danishefslqr s diene (84) that provide access to 2-substituted-2,3-dihydro-4/f-pyran-4-ones 85 (Scheme 7.50). 

The combination of pericyclic transformations as cycloadditions, sigmatropic rearrangements, electrocydic reactions and ene reactions with each other, and also with non-pericyclic transformations, allows a very rapid increase in the complexity of products. As most of the pericyclic reactions run quite well under neutral or mild Lewis acid acidic conditions, many different set-ups are possible. The majority of the published pericyclic domino reactions deals with two successive cycloadditions, mostly as [4+2]/[4+2] combinations, but there are also [2+2], [2+5], [4+3] (Nazarov), [5+2], and [6+2] cycloadditions. Although there are many examples of the combination of hetero-Diels-Alder reactions with 1,3-dipolar cycloadditions (see Section 4.1), no examples could be found of a domino all-carbon-[4+2]/[3+2] cycloaddition. Co-catalyzed [2+2+2] cycloadditions will be discussed in Chapter 6. 

There are two different modes of cyclizations in hetero [4+2] cycloadditions involving Danishefsky s diene 1) concerted (pericyclic) and 2) stepwise. When carbonyl compounds are reacted with Danishefsky s diene, the stepwise pathway is often referred to as the Mukaiyama aldol reaction pathway. The concerted process is called the Diels-Alder pathway. The mode of cyclization in the case of Lewis acid catalyzed reactions depends on the Lewis acid itself and whether it is present in stoichiometric or catalytic amounts. The Mukaiyama aldol pathway has been... 

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