Diels-Alder additions, tandem

The two successive Diels-Alder additions (tandem cycloadditions) of the C2v-symmetrical tetraene 11 are not regioselective, i.e., mixtures of all the possible regioisomeric bis-adducts are obtained when utilizing non-symmetrical dienophiles. There is no control of the monoadduct on the regio-selectivity of the second cyclo addition. As we have seen with the synthesis of daunomycinone, control of the substitution pattern of the two remote rings A and D of the anthracyclinones can be achieved provided a number of adequate manipulations are carried out with the benzoquinone monoadduct of 11. A more efficient and more versatile way to control the regioselectivity of the tandem cycloadditions is through appropriate and stereoselective double substitutions of tetraene 11. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

A review of Claisen rearrangements in aqueous solution has appeared. The synthesis of natural products utilizing tandem Diels-Alder additions with sigmatropic rearrangement processes has been reviewed, and a brief review of the regioselective synthesis of coumarins, quinolones and thiocoumarins with 3,4-fused pyran or furan ring systems by the Claisen rearrangement has been presented. ... 

This regiocontrol permits a tandem alkylation-Diels-Alder addition (equation I). 

The Diels-Alder addition of 69 to methyl acrylate [76] gave the cycloadduct 70 in only 23% yield while addition to acryloyl chloride [77] followed by esterification afforded 71 in higher yield (57%) (Scheme 6). Removal of the bulky silyl group of 69 facilitated the DA reaction and allowed for the production of 71 by a tandem Michael addition/aldolization, which has proven useful in the construction of ISQs. Desilylation of 70 with BU4NF on silica gel, followed by... 

Oxazole cycloadditions have been reported with alkyne dienophiles (tandem Diels-Alder addition and retro Diels-Alder loss of a nitrile leads on to furans), benzyne (the primary adduct can be isolated), and with typical alkene dienophiles and the adducts can be transformed into pyridines (8.14.1.4). 

Preparation of enantiopure intermediates by the use of oxidation reactions was not limited to the synthesis of AB segment (J )-10. The synthesis of the modified daimomycinone, 9-deacetyl-ll-deoxy-9-hydroxymethyldauno-mycinone 44 by Naruta et al. provides an example of enantioselective epox-idation at the stage of a tetracycHc intermediate (Scheme 8) [56]. TetracycUc quinone 42, with the required stereochemistry of the C-4 and C-9 substituents and a protected phenolic hydroxyl group, was prepared in a tandem Michael-Diels-Alder addition of pentadienyltin with acryoylquinone 40 mediated by Lewis acid [57], followed by demethylation, acetylation, and selective hydrolysis. Sharpless enantioselective epoxidation [58] of 42 yielded epoxide 43 in 80% yield and 96% ee. Further transformations of 43 by known procedures, indicated in Scheme 8, furnished the target anthracyclinone 44 in 36% yield from 42. 

Regio-and Stereoselective Tandem Diels-Alder Additions. 198... 

Scheme 7 Regio- and stereoselective tandem Diels-Alder additions...

A domino Diels-Alder reaction (the term was chosen from the well-known game) is a one-pot process involving two or more Diels-Alder reactions carried out under the same reaction conditions without adding additional reagents or catalyst such that the second, third, etc., cycloaddition is the consequence of the functionality generated in the previous reaction. A historical example is illustrated in Equation 1.28 [60]. This type of transformation is sometimes named tandem or cascade, but these terms seem less appropriate for describing a time-resolved transformation. 

However, when 2,6-dimethylbenzoquinone with sodium ( >3,5-hexadienoate (generated in situ) was reacted in water in the presence of a catalytic amount of sodium hydroxide, pentacyclic adducts were formed via deprotonation of the Diels-Alder adduct followed by tandem Michael-addition reactions with another molecule of 2,6-dimethylbenzoquinone (Eq. 12.25).83 Similar results were obtained with sodium ( >4,6-heptadienoate. 

Hetero substituted 2-cyclopropylideneacetates are ring-strain activated acrylates, highly reactive dienophiles in Diels-Alder reactions, but also powerful Michael acceptors. The reactivity of these compounds is enhanced by the same strain release in the Diels-Alder cycloadditions as well as in the 1,4-additions, and indeed the borderline between tandem Michael-cyclization and Diels-Alder-type cycloaddition is not well defined in many cases. 

In order to demonstrate the potential of these resin-bound products for combinatorial applications, the readily prepared nitroalkenes were subsequently employed in Diels-Alder reactions with 2,3-dimethylbutadiene [56], In addition, the resin-bound nitroalkenes were also used in a one-pot , three-component tandem [4+2]/[3+2] reaction with ethyl vinyl ether and styrene. 

Over the past several years, Mascarenas and co-workers (150-153) utilized the oxidopyrylium ion with variously hetero-substituted olefin tethers. Mascarenas has used this methodology in tandem with a Diels-Alder reaction to prepare tricyclic cycloheptanoid substrates. Further, Mascarenas and co-workers (154—156) achieved the synthesis of optically active oxabicyclic[3.2.1]octane derivatives through the addition of a homochiral p-tolylsulfinyl group substituted at the olefin tether. The Mascarenas group has also used this methodology to prepare the THF portion of ( )-nemorensic acid via oxidative cleavage of the substituted a-hydroxyketone moiety (157) (Scheme 4.78). 

Usually, one would expect that an acrylate ester would be prepared by the acylation of an alcohol with acryloyl chloride. Jonathan M.J. Williams of the University of Bath reports (Tetrahedron Lett. 44 5523,2003) that this acylation can also be effected with the mild combination of Ph,P and maleic anhydride. The acrylate esters so prepared are interesting as polymerization precursors, and as Diels-Alder dienophiles. The allylic acrylates invite tandem conjugate addition / Ireland Claisen rearrangement. 

Nitrones can be generated by Michael reaction of oximes with appropriate conjugated substrates.25 If a generated nitrone has a built-in dipolarophile, cyclization can ensue (Scheme 15). There are three synthetic variations on this theme.25a,b First, the oxime may contain the dipolarophile as in (56). Reaction of (56) with phenyl vinyl sulfone provided a quantitative yield of the tandem product as one stereoisomer. Alternatively, die dipolarophile can reside in the Michael substrate as in (57). Reaction of (57) with cyclohexanone oxime produced two isoxazolidines from competitive cyclization of the intermediate nitrone through six- and seven-membered carbocyclic transition states. It is also possible to carry out an intramolecular Michael addition followed by an intramolecular nitrone cyclization as in thermolysis of (58) to produce a tricyclic isoxazolidine. Very recently several examples of a tandem Diels-Alder, Michael addition, nitrone cyclization sequence have been reported.250... 

Asymmetric synthesis of lignans may involve the use of several approaches like a tandem conjugate addition reaction, a Diels-Alder reaction or a radical carboxyarylation reaction, as mentioned above. 

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