Regioselectivity of Cycloaddition Reactions

Regioselectivity of Cycloaddition Reactions. It is apparent from several of the preceding examples that with certain substituent patterns on the diene and/or alkene, more than one regioisomerie cyclo-adduet is possible. When the 2-substituted diene 55 reaets with alkene 56, two orientations for the X group are possible relative to R the meta orientation in 57 and the para orientation in 58. Dienes with substituents at Cl, 

The propensity for ortho, meta, or para selectivity will vary with the diene (electron-releasing or -withdrawing substituents) and the alkene (electron-releasing or -withdrawing substituents). Fleming 

Selectivity is predicted by examination of the orbital coefficients of the HOMO and LUMO for both diene and alkene. The transition state for a typical reaction is shown for the reaction of methyl acrylate and 2-phenyl-1,3-butadiene (see 67), where the orbitals with largest coefficients (HOMOdiene-LUMOalkene) combine (the absolute value of the orbital coefficient is used, -0.625 0.69l and -0.475 1-0.471)) to predict the cycloadduct produced in the greatest amount (the para product, 68). Just as the HOMOgy-LUMOaikene is [0 - (-8.77) = 8.77], and it predicts the relative reactivity of these reactants. The magnitude of the orbital coefficients in each partner is important for predicting selectivity. In this case, the orbital coefficients are 0.065 and 0.004, respectively, and there is selectivity for the para product. Similarly, the orbital coefficients for 1-methoxy-1,3-butadiene and acrolein correctly predict the major product is the ortho adduct. For simple cases, the orbital coefficients can be estimated by a simple Hiickel molecular orbital calculation (a very low level calculation but one that gives a first approximation that is useful for estimating relative differences). 

The ability to predict the regioselectivity of Diels-Alder reactions is a cornerstone of their use in synthesis. Methyl vinyl ketone, for example, reacted with 2-methyl-1,3-butadiene to give a 3 1 mixture of 69 and 70. Gutsche et al. used the para product (69) to synthesize a-bisabalol. They also reported that using stannic chloride as a catalyst (sec. 11.6.A) increased the ratio of 69/70 to 93 7.  

The diene and/or the alkene components can be part of a very complex structure. An example is the reaction of ( )-butenal with 71 to give an 83% yield of 72 in Shirai s synthesis of dysidiolide. Note the regioselectivity and stereoselectivity of the reaction. Note also that it is catalyzed by a Lewis acid which, as mentioned, will be discussed in Section 11.6.A. 

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