Dienophile, Sugar-derived

Nitroalkenes are relatively good dienophiles in Diels-Alder cycloadditions. Thus, the easily available sugar-derived chiral nitroalkenes o-manno and... 

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. 

SCHEME 10.33 Acyclic sugar-derived dienophiles can undergo highly stereoselective cycloadditions with cyclopentadiene. 

AlCb-promoted Diels-Alder addition of butadiene to another sugar-derived dienophile (2SH)) proceeded, as expected, only from the face offsite to the allylic ethoxy substituent, giving cycloadduct (291) (Scheme 70). ... 

A number of examples have been reported of the asymmetric hetero Diels-Alder reaction of heterodienes or heterodienophiles such as imines, nitroso or carbonyl compounds.The chiral auxiliary is commonly attached to the nitrogen atom of the imine or nitroso compound, or a chiral ester or amide substituent may provide the necessary asymmetric induction. As an example, the a-cWoronitroso dienophile 132, bearing a sugar-derived auxiliary, has been found to be effective for the formation of cyclic hydroxylamines with high optical purity (3.95). The initial cycloadduct breaks down readily (see Scheme 3.32), via an iminium ion with subsequent methanolysis to release the chiral auxiliary and the product 133. 

It should be noted that the first instance of the use of a sugar-derived dienophile in a Diels-Alder reaction was reported by Baer in 1968.(76 ) Base treatment of nitrpglucose derivative 34 produced the nitropyran 35 which functioned both as a diene and a dienophile to afford a major product the connectivity of which was tentatively assigned as shown in 36, but the relative configuration of the product has not been assigned and the structure shown is simply a guess on the part of the present author. Interestingly, the product is racemic, presumably because the intermediate pyran 35 becomes racemic prior to cycloaddtion. 

Direct Wittig reaction of Ph PCHCOn,Me with the four unsubstituted D-aldopentoses followed by acetylation provides convenient preparative access to acyclic seven-carbon trans-2.3-unsaturated sugar derivatives. These products served as dienophiles for a detailed comparative study in Diels—Alder cycloaddition with cyclopentadiene. Related syntheses afforded analogous cis-dienophiles. Cycloaddition under uncatalyzed thermal conditions gave mixtures of the four possible stereoisomeric norbornene adducts. The endo, exo ratios, and diastereofacial selectivities of the adducts were determined by NMR spectroscopy and by chemical transformations, supplemented by selected X-ray crystallographic analyses. Different distributions of isomers were encountered when a Lewis acid was used to catalyze the cycloaddition. The reaction can be controlled to provide preparative access to selected isomers and thus constitutes a versatile method for chirality transfer from the precursor sugar to four new asymmetric centers in a carbocyclic framework. 

As part of a general program (1—4) on synthetic transformations of sugars having potential value for access to enantiomerically pure, polysubstituted carbocycles, we have made a systematic study of the reactions of various dienes with sugar-derived alkenes serving as dienophiles. Here we present the results of reactions between cyclopentadiene and a complete stereoisomeric set of seven-carbon trans-2,3-unsaturated aldonic esters derived from the D-aldopentoses. 

The pentoses may be converted by the conventional sequence (5) of dithioacetal formation, acetylation, and demercaptalation into the respective aldehydo-oentose 2,3,4,5-tetraacetates, which afford by Wittig chain-extension (2) the desired dienophiles. Thus aldehydo-D-arabinose 2,3,4,5-tetraacetate reacted with Ph3PCHC02Me in boiling benzene to give 90% of the pure, crystalline E-unsaturated sugar derivative 6, and the corresponding enantiomer was likewise prepared from L-arabinose. 

Another approach to asymmetric cycloaddition reactions of furans relies on sugar-derived dienophiles. o-Mannose-derived 112, for example, reacted with fiiran at rt under 13kbarofpressureover3 days to give 113-115 as a 3.4 7.3 1 mixture (Scheme 13.30) [62]. Isomer 114 crystaUized from the mixture to provide 33% of pure material. Deprotection of 114 by the action of K2CO3 in MeOH and oxidative cleavage mediated by NaI04 produced aldehyde 116 in 68% yield from 114. 

Hultin P. G., Earle M. A. and Sudharshan M. Synthetic Studies with Carbohydrate-Derived Chiral Auxiliaries Tetrahedron 1997 53 14823-14870 Keywords sugar-linked dienes, sugar-linked dienophiles... 

Another combination of hetero-Diels-Alder reactions and a [3+2] cycloaddition of a nitroalkene was described by Avalos and coworkers [46]. Using the chiral substrate 4-134 derived from a sugar, the domino process can be performed as a three-component transformation using an electron-rich dienophile and an electron-poor... 

Diels-Alder reactions carbohydrates.2 This 3,y-unsaturated a-keto ester undergoes Diels-Alder reactions with electron-rich dienophiles to provide protected sugars. The thermal and pressure-promoted reaction of 1 with ethyl vinyl ketone provides the endo-adduct 2, which can be converted in two steps into the ethyl (3-mannopyranoside 3. The same reaction of 1 with (Z)-l-acetoxy-2-benzy-loxyethylene is even more endo-selective, and gives the endo-adduct 4, which can be converted into a derivative of benzyl DL-mannopyranoside. 

Horton, D, Koh, D, Stereocontrol in Diels-Alder cycloaddition to unsaturated sugars reactivities of acychc seven-carbon trans-dienophiles derived from aldopentoses, Carbohydr. Res., 250, 249-260, 1993. 

These first cycloadditions are only complete after 72 h at 60°C. When partners are more reactive and the cycloaddition can be catalysed by Lewis acids, it is possible to work at -78°C. Under these conditions, it may be possible to observe high asymmetric induction. Reaction (8.4) of cyclopentadiene with an acrylate derivative of 5-0-trimethylsilyl-a-D-xylofuranose carried out at -78°C in dichloromethane in the presence of TiCl4 gives exclusively the endo adduct ( / , 2 R). This is explained by the formation of an intermediate complex which contains both the dienophile and Lewis acid attached to the chiral sugar inductor (Kunz etal. 1987). 

Dienophiles derived from sugars are ideal chiral auxiliaries. The diethylaluminum chloride (2.2 equiv) catalyzed double addition of cyclopen tadiene (2) to the D-mannitol derivative 1 was performed, affording a 2 1 mixture of 3 and 4 in 96% yield. Although degradation of 4 leads to a racemic compound, the adduct 3 (crystalline 60 %) was further transformed to an optically pure precursor of loganin (5)1. 

Besides the loss of the inductive stereogenic centers, the need to resolve the starting material is undoubtedly a drawback to this method. In this regard, the dienophiles derived from sugars are certainly more advantageous. 

Cycloadditions of conjugated dienes to alkenes (dienophiles) provide rapid access to substituted cyclohexenes. In view of the widespread occurrence of carbocyclic compounds in nature, and the recent demands for the synthesis of enantiomerically pure compounds, it is not surprising that carbohydrates were examined as substrates for Diels-Alder reactions. Both carbohydrate-derived dienophiles and dienes have been described in the literature. The products of reactions involving these types of compounds, referred to as annulated sugars, are most often formed stereoselectively. The hi levels of both diastereofacial selectivity and endo/exo selectivity sometimes result in the formation of a single cycloadduct from among several possibilities. 

The carbohydrate dienophiles in the above examples are all derived from cyclic structures. Acyclic sugar dienophiles have also been studied. These substrates arc accessible through the reaction of a carbohydrate with a stabilized Witdg reagent or by fragmentation reactions. Two examples of the use of acyclic carbohydrate dienophiles in Diels-Alder reactions are presented below. 

In their work on aureolic acid antibiotic, Franck and co-workers examined the Diels-Alder reaction of the quinone methide derived from 26 with sugar dienophile 27 (Scheme 4). Heating of 26 in a sealed tube for 3 days in chlorobenzene afforded cycloadducts 28 and 29 in a 4 1 ratio in 71% yield. The major product has the 5-configuration at C-3 and results from the addition of the diene to the si face of the dienophile, in the endo mode, as shown below (76). 

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