Regiochemistry of the Diels-Alder

Dienes Undergo Disrotatory Motion in Thermal Diels-Alder 

When the substituent on the diene is instead on one of the internal carbons of the diene (C2 or C3), then the two possible Diels-Alder products are the 

4- disubstituted or 1,3-disubstituted cyclohexenes. Once again, the 1,3-product is disfavored, and the 1,4-product is the major product. As demonstrated above, resonance and/or diradical methods can be used to explain the formation of the observed major product. 

The Diels-Alder-based retrosynthesis of a cyclohexene begins with the identification within the six-membered ring of the four carbons contributed by the diene and the two carbons from the dienophile.The double bond in the cyclohexene target molecule marks the nuddle two carbons (C2 and Cj) of the four-carbon diene. Two disconnections are made in the ring to separate the four-carbon and two-carbon units. It is helpful to show the mechanism for the retro Diels-Alder, since that will not only achieve the required disconnection, but it will also properly locate all of the necessary pi bonds in the starting diene and dienophile. 

For bicyclic target molecules, identify the cyclohexene ring and note the size of the carbon bridge to properly guide the retrosynthesis. The stereochemistry of the target molecule determines where the substituents must be positioned on the starting materials. 

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As an approach to biomimetic catalysis, Sanders and colleagues [67] synthesized a series of 1,1,2-linked cyclic porphyrin trimers that allow the stereo- and regiochemistry of the Diels-Alder reaction of 84 and 85 within the molecular cavity to be controlled, thereby producing prevalently or exclusively the endo 86 or the exo 87 adduct. Two examples are illustrated in Scheme 4.18. At 30 °C and in the absence of 88, the reaction furnishes a mixture of diastereoisomers, while the addition of one equivalent of trimer 88 accelerates the reaction 1000-fold and the thermodynamically more stable exo adduct 87 is the sole detectable product. 

Complexes 17-19 can be written in one valence structure as a, /3-unsaturated carbonyl compounds in which the carbonyl oxygen atom is coordinated to a BF2(OR) Lewis acid. The C=C double bonds of such organic systems are activated toward certain reactions, like Diels-Alder additions, and complexes 17-19 show similar chemistry. Complexes 17 and 18 undergo Diels-Alder additions with isoprene, 2,3-dimethyl-1,3-butadiene, tram-2-methyl-l,3-pentadiene, and cyclopentadiene to give Diels-Alder products 20-23 as shown in Scheme 1 for complex 17 (32). Compounds 20-23 are prepared in crude product yields of 75-98% and are isolated as analytically pure solids in yields of 16-66%. The X-ray structure of the isoprene product 20 has been determined and the ORTEP diagram (shown in Fig. 3) reveals the regiochemistry of the Diels-Alder addition. The C-14=C-15 double bond distance is 1.327(4) A, and the... 

The regiochemistry of the Diels-Alder reaction of l-alkoxy-3-(rm-butyldimethylsilyl)oxy-2-azadienes and naphthoquinones, as a route to 2-azaanthraquinon-3-ones, has been investigated (91H915). 

The regiochemistry of the Diels-Alder reaction of a thioaldehyde depends on the nature of the substituent directly linked to the sp2-carbon atom [175]. 

The strong directive effect of an allylic silicon in a diene on the regiochemistry of the Diels-Alder reaction proved to be a blessing in synthesis of 11-deoxycarminomycinone [383],... 

At this point it is instructive to examine the regiochemistry of the Diels-Alder reactions of the substituted naphthoquinones 47, 87, and 89 with the dienes 81 and 83 (Scheme 25) [74]. 

Dienophiles substituted with appropriate heteroatoms may offer a number of advantages such as (1) provide dienophilic equivalents of C-—C and moieties which do not undergo [4 + 2] cycloadditions to 1,3-dienes because of low (e.g. isolated alkenes, alkynes, allenes) or different reactivities (e.g. ketenes) (2) enhance or invert the regiochemistry of the Diels-Alder process (3) permit facile removal of the activating and/or regiocontrolling group after cycloaddition with or without introduction of further functionalities. The use of nitroalkenes as dienophiles demonstrates these issues most strikingly. 

Dienes substituted with heteroatoms, X or Y in 145, give allyl (Y in 146) or vinyl (X in 146) derivatives by the Diels-Alder reaction. The heteroatom(s) not only provide latent functionality in the product but also control the regiochemistry of the Diels-Alder reaction itself86. In Danishefsky s vemolepin synthesis87, a compound of type 146 was converted into an enone 147 by hydrolysis since 146 is a 1,3-disub-stituted allyl compounds like the enone precursors in the last section. 

Predict the regiochemistry of the Diels-Alder addition of these two reactants. 

The regiochemistry of the Diels—Alder reaction can then easily be predicted by a careful match of the charges. If an EDG is located at C-1 of a diene, then the dienophile will approach with the EWG group next to the EDG group. This is called a 1-2 or ortho arrangement of the substituents (Scheme 4.15). 

The regiochemistry of the Diels-Alder reaction is also sensitive to the nature of substituents on the diene and dienophile. The combination of an electron donor in the diene and an electron acceptor in the dienophile gives rise to caseA 4 atid B. The preferred orientations are shown in Scheme 11.3. There are also examples where the substituents are reversed so that the electron donor substituent is on the diefiopTiHe and the elecTfon-accepting su is on the diene. These are called... 

When multiple substituents are involved, a new issue arises, that of the regiochemistry of the Diels-Alder reaction. When both the diene and dienophile have a substituent, we can speak in terms of pseudo-ortho, meta, and para patterns for the product, as shown in Figure 15.11. The nomenclature is imperfect, as two different pseudo-meta forms are shown, but usually it is clear in context which isomers are being discussed. Houk and co-workers have... 

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