Diels-Alder reaction bicyclic compound synthesis

Intramolecular versions of the Diels-Alder reaction are well known, and this is a powerful method for the synthesis of mono- and polycyclic compounds.There are many examples and variations. One interesting internal Diels-Alder reaction links the diene and dienophile by a C—O—SiR2—or a C—O—SiR2—O—C linkage. Internal cyclization to give a bicyclic product is followed by cleavage of the O-Si unit to give a monocyclic alcohol. 

Subsequently, Posner published the completely regioselective and highly stereoselective cyclo additions of racemic 3-(p-tolylsulfinyl)-2-pyrone (141) (Scheme 70) with 1,1-dimethoxyethylene [133],vinylether,and vinylthioethers [134]. With the first dienophile, the best diastereoselectivity (an 88 12 ratio of the two endo-adducts) was achieved at room temperature in toluene or hexane as the solvent (48 h). A 10 1 endo/exo mixture of cycloadducts was obtained with vinyl-ether in the presence of ZnBr2 as the catalyst, whereas a total endo selectivity was observed in reactions of 141 with vinylthioethers [134] conducted under high pressures. The bridged bicyclic lactone cycloadducts 142 have been used as versatile synthons in the synthesis of shikimic acid derivatives. Although enantio-merically pure samples of compound 141 could be obtained [134] it was not used as a starting material for asymmetric Diels-Alder reactions (the low yield of (S)-141 precluded this). 

Dienones of this class are useful starting materials for the preparation of bicyclic compounds via Diels-Alder reactions and for the synthesis of small ring compounds. The 2,4-dienone can be converted quantitatively to the 2,5-isomer by treatment with fuming sulfuric acid and subsequent hydrolysis. The oxidation procedure is also applicable to the conversion of mesity-lene to mesitol or of isodurene to isodurenol, and can be used to convert tetramethylethylene quantitatively and directly to pinacolone. ... 

Compound 117 is also a key intermediate in the synthesis of diplodiatoxin, a toxin produced by Diplodia maydis on maize and responsible for cattle disease [99]. The two chiral centers present in 117 are transferred in the target compound and induce all other chiralities of this bicyclic strucmre constructed via an intramolecular Diels-Alder reaction (Scheme 11.29). 

An example of an oxaallylic carbanion has been described by Oppolzer et alP In the alkylation of 3-triethylsilyloxypentadienyllithium (5 X = H) the y-alkylated product predominated. With the anion (5 X = SMe) alkylation occurs exclusively at the y-carbon atom. The synthetic potential of the anions (5) was demonstrated by the synthesis of bicyclic compounds via intramolecular Diels-Alder reactions of the alkylation products (Scheme 5). 

In a continuation of his work on dendrobine synthesis, Roush132 has found that the intramolecular Diels-Alder reaction of the diene-ester (265) gives predominantly the bicyclic compound (266). This was an unexpected result because... 

A dramatic application was the asymmetric synthesis of epibatidine 70 by Simpkins.18 Diels-Alder reaction of the deactivated pyrrole 63 with the alkynyl sulfone 64 gave the bicyclic core 65 of epibatidine. Selective reduction gave the compound 66 needed for epibatidine, but in racemic form. A directed lithiation (chapter 7) and sulfonation led to achiral bis sulfone 67. 

The Diels-Alder reaction between furan and maleic anhydride is reversible and gives the more stable exo-adduct 100 (also commercially available). This compound contains the bicyclic ring system of ifetroban but is achiral and the key problem is to disrupt symmetry of the adduct 100 in a controlled way. The original synthesis used to make the drug17 converted the adduct 100 into the menthyl acetal 101 as a single enantiomer in four steps and then into the carboxylic acid 102 in another six steps. This strategy amounts to a resolution as each menthol adduct could be isolated by crystallisation of a diastereoisomeric mixture in only about 30% yield. 

Bicyclo[2.2.1]heptanes are widely distributed in namre among the bicyclic ter-penes, and the Diels-Alder reaction provides a convenient method for their synthesis. Thus, cyclopentadiene and vinyl acetate react smoothly on warming to form the adduct 49, which is easily transformed into norcamphor 50 and related compounds (3.44). 

In the clay-catalysed reaction even oleate will furnish a cyclic dimer along with monomer which is a mixture of saturated and unsaturated (mainly tram), straight-chain and branched-chain Cis compounds formed by hydrogen transfer and rearrangement. Dimers are formed by diene synthesis (Diels Alder reaction) between a monoene and a conjugated diene produced from monoene by hydrogen transfer. The cyclohexene derivatives are converted by hydrogen transfer to cyclohexane and benzene derivatives. These monocyclic dimers are accompanied by acyclic and bicyclic dimers such as those formulated below. Linoleate reacts in a similar manner. 

A domino sequence comprising a cycloaddition and subsequent cycloreversion step can often find a more general application in organic synthesis, especially in the formation of aromatic compounds such as furans or pyrroles. Oxazole moieties as electron-deficient dienes often serve as the crucial reactive centers which cycloadd to a triple bond and eliminate a nitrile upon cycloreversion. If the first step is intramolecular, the impelling enthalpy preserved in the stability of the formed CN function is additionally accompanied by a positive entropy when the nitrile, sometimes volatile, leaves the substrate. In an older example from 1984 [10], Jacobi and coworkers devised a scheme for the preparation of a highly substituted furan on their synthetic way to paniculide A. An intramolecular Diels-Alder reaction was followed by the critical extrusion of volatile acetonitrile, furnishing the bicycle 8 in 94% yield (Scheme 6.2). 

---