Carbonyl compounds, 1,3-dienes hetero-Diels-Alder

The mechanism for the hetero-Diels-Alder reaction of benzaldehyde 9 with the very reactive diene, Danishefsky s diene 10, catalyzed by aluminum complexes has been investigated from a theoretical point of view using semi-empirical calculations [27]. The focus in this investigation was to address the question if the reaction proceeds directly to the hetero-Diels-Alder adduct 11, or if 11 is formed via a Mukaiyama aldol intermediate (Scheme 8.4) (see the chapter dealing with hetero-Diels-Alder reactions of carbonyl compounds). 

The use of chiral bis(oxazoline) copper catalysts has also been often reported as an efficient and economic way to perform asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines with conjugated dienes [81], with the main focus on the application of this methodology towards the preparation of biologically valuable synthons [82]. Only some representative examples are listed below. For example, the copper complex 54 (Scheme 26) has been successfully involved in the catalytic hetero Diels-Alder reaction of a substituted cyclohexadiene with ethyl glyoxylate [83], a key step in the total synthesis of (i )-dihydroactinidiolide (Scheme 30). 

An extensive review of the hetero-Diels-Alder reactions of 1-oxabuta-1,3-dienes has been published. Ab initio calculations of the Diels-Alder reactions of prop-2-enethial with a number of dienophiles show that the transition states of all the reactions are similar and synchronous.Thio- and seleno-carbonyl compounds behave as superdienophiles in Diels-Alder reactions with cyclic and aryl-, methyl-, or methoxy-substituted open-chain buta-1,3-dienes.The intramolecular hetero-Diels-Alder reactions of 4-benzylidine-3-oxo[l,3]oxathiolan-5-ones (100) produce cycloadducts (101) and (102) in high yield and excellent endo/exo-selectivity (Scheme 39). A density functional theoretical study of the hetero-Diels-Alder reaction between butadiene and acrolein indicates that the endo s-cis is the most stable transition structure in both catalysed and uncatalysed reactions.The formation and use of amino acid-derived chiral acylnitroso hetero-Diels-Alder reactions in organic synthesis has been reviewed. The 4 + 2-cycloadditions of A-acylthioformamides as dienophiles have been reviewed. ... 

The enantioselective hetero-Diels-Alder (HDA) reaction of carbonyl compounds with 1,3-dienes represents an elegant access to optically active six-membered oxo-heterocycles. Since the pioneering work of Rawal et al. in 2003 [55], the enantioselective HDA reaction catalyzed by diols (such as TADDOLs) has become a flourishing field of research [56]. 

Aiming at the pyranose form of sugars, normal type hetero-Diels-Alder reactions were extensively used for the synthesis of functionally substituted dihydropyran and tetrahydropyran systems (5-10) (see routes A - D in the general Scheme 1) which are also important targets in the "Chiron approach" to natural product syntheses (2.) Hetero-Diels-Alder reactions with inverse electron demand such as a, p-unsaturated carbonyl compounds (l-oxa-1,3-dienes) as heterodienes and enol ethers as hetero-dienophiles, are an attractive route for the synthesis of 3,4-dihydro-2H-pyrans (11). 

The hetero-Diels-Alder reaction of activated butadienes with carbonyl compounds is a convenient method for the preparation of precursors of sugars. Up to three chiral centers are created simultaneously. The high-pressure [4 + 2]cycloaddition of l-methoxybuta-1,3-diene 32 to N-mono- and N,N-diprotected alaninals was investigated [42-45]. The Eu(fod)3-mediated reaction of 32 with alaninal 25 gave a mixture of four diastereoisomers, which was then subjected to acidic isomerization, leading to the thermodynamically more stable pair of adducts syn-33 and anti-34, with predominance of the latter isomer (Scheme 12). The N-monoprotected alaninals reacted with a moderate ryn-diastereoselectivity. This method was used in the synthesis of purpurosamines (see Sec. DI.C). 

An attractive entry to the carbohydrate synthesis is provided by the cycloaddition reaction. Hetero-Diels-Alder reaction, either between an oxa-diene (a,[3-unsaturated aldehyde) and an nucleophilic dienophile, or between activated diene and carbonyl compound (usually an aldehyde), leads to dihydropyrans, which can be subsequently functionalized to sugars in the desired manner (Scheme 3). 

Although the reactions of carbonyl compounds with dienes follow a stepwise addition, the overall stereochemical outcome mimics that of the Diels-Alder reaction.1 2 5 242-244 The products of the hetero Diels-Alder reaction have been used as substrates for a wide variety of transformations and natural products syntheses.242,245-258 Many hetero Diels-Alder reactions use chiral auxiliaries or catalysts that have been successful for the Diels-Alder reaction. 

All investigations on the use of Lewis acids in the hetero Diels-Alder reaction of carbonyl compounds clearly show that a careful adjustment of the Lewis acidity for a given system is neccessary. Especially with trimethylsilyloxybuta-dienes a Mukayama type aldol reaction can easily take place instead of the desired hetero Diels-Alder reaction. 

A major problem in the reaction of a,/3-unsaturated carbonyl compounds and alkenes proves to be the competition between hetero Diels-Alder and ene reactions. Intramolecular cycloadditions of 1,6- and 1,7-dienes with ester and cyano groups at the double bond yield the ene product nearly exclusively, but with alkylidene- and benzylidene-ketoesters and 1,3-diketones the Diels-Alder reaction is preferred under thermal conditions, however under Lewis acid catalysis also ene reactions occur [12]. 

Where, as illustrated in the above described example, the Diels-Alder reaction provides avenues into the formation of C-glycosides from furan-derived dienes, the hetero Diels-Alder reaction allows for the direct formation of sugar rings from carbonyl groups. As shown in Scheme 7.5.2, Schmidt, et al.,25 effected reactions between conjugated carbonyl compounds and olefins. The illustrated reaction proceeded in 81% yield giving an adduct which, after further manipulations, was converted to a C-aryl glycoside. 

The catalytic hetero-Diels—Alder reaction is also of particular interest, since it allows a convenient access to prepare six-membered heterocycles. The hetero-Diels—Alder reaction is classified into two groups, as shown in Scheme 136 (a) [4 + 2]-cycloaddition of 1,3-dienes with a carbon-heteroatom or heteroatom-heteroatom double bond198 and (b) [4 + 2]-cycloaddition of a,/Tunsaturated carbonyl compounds with olefins.199... 

Copper complexes of the bisoxazoline ligands have been shown to be excellent asymmetric catalysts not only for the formation of carbocyclic systems, but also for the hetero-Diels-Alder reaction. Chelation of the two carbonyl groups of a 1,2-dicarbonyl compound to the metal atom of the catalyst sets up the substrate for cycloaddition with a diene. Thus, the activated diene 20 reacts with methyl pyruvate in the presence of only 0.05 mol% of the catalyst 66 to give the adduct 138 with very high enantiomeric excess (3.99). 

The hetero-Diels-Alder reaction between 1-oxygenated or 1,3-dioxygenated buta-1,3-diene derivatives and carbonyl compounds is a convenient method for the preparation of sugars [38-41]. There are only few works connected with the application of this methodology to the lincosamine chemistry. 

A full study on the hetero-Diels-Alder reaction using a,0-unsaturated carbonyl compounds as the diene component has been... 

Compared to the hetero-Diels-Alder reaction of carbonyl compounds and derivatives with dienes, where only a limited number of catalytic and enan-tioselective reactions have been reported, the number of asymmetric hetero-Diels-Alder reactions in which the ketone or imine functionality is part of a heterodiene is much higher. In contrast, there are only a few examples of using a,p-unsaturated aldehydes in inverse hetero-Diels-Alder reactions. In the case of the inverse electron demand hetero-Diels-Alder reaction, the ketone or imine functionality is part of an a,(I-unsaturated system, which reacts in a cycloaddition reaction with an electron-rich alkene. The inverse electron demand hetero-Diels-Alder reaction is primarily controlled by a LUMOdiene-HOMOdienophiie interaction, which can be found, for example, in the reactions... 

Of course, the carbonyl group is involved in the reactivity of unsaturated ketones or aldehydes toward dienes in cycloaddition pathways. Aqueous hetero Diels-Alder reactions of activated carbonyl compounds have also been reported, and are extensively described elsewhere in this book. 

Compounds with certain [3]heterodendralene structures including more complex substructures and substituents such as carbonyls, imines, and ylides are very popular, and hence many reports on their synthesis/generation, application and/or characterization, and so on, were found. However, only a few examples of their diene-transmissive hetero-Diels-Alder (DTHDA) reactions have been reported so far. For instance, although divinyl ketones ([3]-3-oxadendralenes, Scheme 2.1) are well recognized, for example, for their Nazarov cychzation [1] (see Chapter 3), only two reports are known on DTHDA reactions of p,p -diphenyl- and di-2-thienyl-substituted divinyl ketones vide infra) [8]. 

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