Carbohydrate dienes, Diels-Alder reactions

Lopez J. C., Lukacs G. Pyranose-Derived Dienes and Conjugated Enals. Preparation and Diels-Alder Cycloaddition Reactions ACS Symp. Ser. 1992 494 33-49 Keywords carbohydrate, befera-Diels-Alder reactions, stereoselectivity... 

Carbohydrates have found widespread use as chiral auxiliaries in asymmetric Diels-Al-der reactions156. A recent example is a study conducted by Ferreira and colleagues157 who used carbohydrate based chiral auxiliaries in the Lewis acid catalyzed Diels-Alder reactions of their acrylate esters 235 with cyclopentadiene (equation 66). Some representative results of their findings, including the ratios of products 236 and 237, have been summarized in Table 9. The formation of 236 as the main product when diethylaluminum chloride was used in dichloromethane (entry 3) was considered to be the result of an equilibrium between a bidentate and monodentate catalyst-dienophile complex. The bidentate complex would, upon attack by the diene, lead to 236, whereas the monodentate complex would afford 236 and 237 in approximately equal amounts. The reversal of selectivity on changing the solvent from dichloromethane to toluene (entry 2 vs 3) remained unexplained by the authors. 

A review of Diels-Alder reactions of fullerenes with acyclic and cyclic dienes has been presented. The addition of substituted pyrimidine o-quinodimethanes (75) to [60]fullerenes yields novel organofullerenes (76) bearing a pyrimidine nucleus covalently attached to the Ceo cage (Scheme 26). The Diels-Alder dimerization of cyclopenta[/]phenanthrene (77) with isobenzindene (78) yields the dimer (79) in 85% yield (Scheme 27). Further evidence has been supplied to support an early reorganization of the r-network in the dimerization of 2-methoxycarbonylbuta-1,3-diene. The Lewis acid-catalysed Diels-Alder reactions of acrylate derivatives of new carbohydrate-based chiral auxiliaries with cyclohexadiene show excellent endo. exo... 

Diels-Alder reactions can be applied to the synthesis of cyclohexane rings by use of carbohydrate-derived dienophiles or dienes, and intramolecular processes allow the controlled elaboration of bicyclic systems. 

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). 

The dihydropyrans resulting from an oxa Diels-Alder reaction represent valuable intermediates for the synthesis of numerous natural compounds. In particular, they exhibit many structural elements of carbohydrates. It is therefore not surprising that both the normal electron demand cycloaddition of dienes to carbonyl dienophiles as well as the reaction of 1-oxa-l,3-butadienes with electron-rich alkenes have extensively been used for the synthesis of sugar derivatives. Nevertheless, various approaches to other natural products have been worked out by means of these powerful tools. 

Hetero Diels-Alder reactions with imino dienophiles have been employed as key step in several syntheses of naturally occuring alkaloids. With regard to stereoselective transformations, the approach to (S)-anabasin worked out by Kunz et al. impressively illustrates the high utility of natural carbohydrates as source of chirality in asymmetric synthesis [505]. The N-galactosyl imine 7-28 underwent a Lewis acid catalysed aza Diels-Alder reaction with Danishefsky s diene which proceeded with excellent induced diastereoselectivity to yield the adduct 7-29. A short sequence then afforded the desired alkaloid 7-30. This work also deals with the suitability of several other dienes and imino dienophiles for such transformations (Fig. 7-7). 

The addition of a C-2 (equation 1 R = H > alkyl, aryl > OMe NR2), C-3, or C-4 electron-donating substituent to a 1 -oxa-1,3-butadiene electronically decreases its rate of 4ir participation in a LUMOdiene-controlled Diels-Alder reaction (c/. Table 5). Nonetheless, a useful set of C-3 substituted l-oxa-l,3-buta-dienes have proven to be effective dienes ° and have been employed in the preparation of carbohydrates (Table 6). The productive use of such dienes may be attributed to the relative increased stability of the cisoid versus transoid diene conformation that in turn may be responsible for the Diels-Alder reactivity of the dienes. Clear demonstrations of the anticipated [4 + 2] cycloaddition rate deceleration of 1-oxa-1,3-butadienes bearing a C-4 electron-donating substituent have been detailed (Table 6 entry 4). >> "3 In selected instances, the addition of a strong electron-donating substituent (OR, NR2) to the C-4 position provides sufficient nucleophilic character to the 1-oxa-1,3-butadiene to permit the observation of [4 + 2] cycloaddition reactions with reactive, electrophilic alkenes including ketenes and sul-fenes, often in competition with [2 + 2] cycloaddition reactions. ... 

The unique feature of the Diels-Alder reaction — generating up to four new stereogenic centers in one step — combined with the variety of useful reactants, has made this reaction a favorite methodology for constructing molecular diversity [54]. Therefore, asymmetric versions of this reaction represent an attractive tool for the diastereoselective synthesis of optically active compounds [55,56]. Various carbohydrate auxiliaries, either attached to the diene or to the dienophUe component, have been successfully used to produce stereochemically pure cycloadducts [57]. 

Oxa-Diels-Alder reactions between l-oxy-3-silyloxybuta-1,3-dienes and aromatic aldehydes (either component being attached to a carbohydrate auxiliary) have been investigated by Stoodley et al. [109,110], drawing on the pioneering work of the Danishefsky group [111,112]. For example, the reaction of the carbohydrate-linked diene 143 with p-nitrobenzaldehyde in the presence of Eu(III) catalysts gave dihydropyrans 144-147 [109] (Scheme 10.47). When the chiral Eu complexes (- -)-Eu(hfc)3 and (—)-Eu(hfc)3 were used, double stereodifferentiation was... 

Cycloadditions are widely used methods for carbocycle construction [352], In this context, the Diels-Alder reaction has been studied in carbohydrate chemistry. Using this approach, the sugar can be used as the dienophile or as the diene with a large preference for the former. 

There are also special procedures which allow the preparation of sugars with only endo- or only exo-cyclic double bonds. The first group of compounds with endo-cyclic double bond may be prepared by total synthesis from non-carbohydrate precursors. The particularly useful hetero Diels-Alder reaction (O Fig. 3) allows one to obtain the dihydropyran skeleton either by reaction of a diene with a heterodienophile [3,17] or by reaction of a heterodiene with a normal dienophile [18]. 

The aqueous Diels-Alder reaction has been widely exploited at the preparative level since the first studies of Breslow. Two reviews [4, 6] were in part devoted to this aspect. In order to increase the water-solubility, dienes have been attached at the anomeric position of a carbohydrate. The sugar moiety, which induces chirality, can easily be removed after the cycloaddition either via acidic or enzymic hydrolysis [37]. 

An important development in the hetero Diels-Alder reaction came when Jurczak used high pressure to help improve the reactivity of dienes with aldehydes. 1-Methoxybutadiene, for example, was shown to react at 15-25 kbar (I bar = l(X) kPa) with a variety of unactivated aldehydes. - These reactions give predominantly endo adducts and allow for the use of simple alkyl and aromatic aldehydes as dienophiles. Jurczak also realized the importance of this reaction in the synthesis of carbohydrates and applied it to the construction of simple monosaccharide derivatives (see Section 2.5.2. ). " ... 

Alkoxy-1,3-butadienes containing a carbohydrate moiety are excellent dienes for the Diels-Alder reaction conducted in water as a solvent. It has been observed that the reaction is much faster in water and is highly eflrfo-selective, but unfortunately the diastereoselectivity of these reactions is rather low16,17 (see Table 7). 

The thermal hetero-Diels - Alder reaction of diene 1 a to butyl glyoxylate (2 a) leads to a mixture of four possible diastereomers 3-6 in good yield with a predominance of enrfo-attack (jS-sugar) and a d.r. 69 31 in favor of the L-sugar. Dienes lb andc, in the same reaction, produce almost equal amounts of endo- and exo-products with a low selectivity in the formation of new stereogenic centers at C-5 (carbohydrate nomenclature)23-25. 

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